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Sample records for progenitor cell-induced neovascularization

  1. Cathepsin L is required for endothelial progenitor cell-induced neovascularization

    SciTech Connect

    Urbich, Carmen; Heeschen, Christopher; Aicher, Alexandra; Sasaki, Ken-ichiro; Bruhl, Thomas; Hofmann, Wolf K.; Peters, Christoph; Reinheckel, Thomas; Pennacchio, Len A.; Abolmaali, Nasreddin D.; Chavakis, Emmanouil; Zeiher, Andreas M.; Dimmeler, Stefanie

    2004-01-15

    Infusion of endothelial progenitor cells (EPCs), but not of mature endothelial cells (ECs), promotes neovascularization after ischemia. We performed a gene expression profiling of EPCs and ECs to identify genes, which might be important for the neovascularization capacity of EPCs. Intriguingly, the protease cathepsin L (CathL) was highly expressed in EPCs as opposed to ECs and is essential for matrix degradation and invasion by EPCs in vitro. CathL deficient mice showed impaired functional recovery after hind limb ischemia supporting the concept for an important role of CathL in postnatal neovascularization. Infused CathL deficient progenitor cells failed to home to sites of ischemia and to augment neovascularization. In contrast, over expression of CathL in mature ECs significantly enhanced their invasive activity and induced their neovascularization capacity in vivo. Taken together, CathL plays a crucial role for the integration of circulating EPCs into the ischemic tissue and is required for neovascularization mediated by EPCs.

  2. Smooth muscle progenitor cells from peripheral blood promote the neovascularization of endothelial colony-forming cells

    SciTech Connect

    Joo, Hyung Joon; Seo, Ha-Rim; Jeong, Hyo Eun; Choi, Seung-Cheol; Park, Jae Hyung; Yu, Cheol Woong; Hong, Soon Jun; Chung, Seok; Lim, Do-Sun

    2014-07-11

    Highlights: • Two distinct vascular progenitor cells are induced from adult peripheral blood. • ECFCs induce vascular structures in vitro and in vivo. • SMPCs augment the in vitro and in vivo angiogenic potential of ECFCs. • Both cell types have synergistic therapeutic potential in ischemic hindlimb model. - Abstract: Proangiogenic cell therapy using autologous progenitors is a promising strategy for treating ischemic disease. Considering that neovascularization is a harmonized cellular process that involves both endothelial cells and vascular smooth muscle cells, peripheral blood-originating endothelial colony-forming cells (ECFCs) and smooth muscle progenitor cells (SMPCs), which are similar to mature endothelial cells and vascular smooth muscle cells, could be attractive cellular candidates to achieve therapeutic neovascularization. We successfully induced populations of two different vascular progenitor cells (ECFCs and SMPCs) from adult peripheral blood. Both progenitor cell types expressed endothelial-specific or smooth muscle-specific genes and markers, respectively. In a protein array focused on angiogenic cytokines, SMPCs demonstrated significantly higher expression of bFGF, EGF, TIMP2, ENA78, and TIMP1 compared to ECFCs. Conditioned medium from SMPCs and co-culture with SMPCs revealed that SMPCs promoted cell proliferation, migration, and the in vitro angiogenesis of ECFCs. Finally, co-transplantation of ECFCs and SMPCs induced robust in vivo neovascularization, as well as improved blood perfusion and tissue repair, in a mouse ischemic hindlimb model. Taken together, we have provided the first evidence of a cell therapy strategy for therapeutic neovascularization using two different types of autologous progenitors (ECFCs and SMPCs) derived from adult peripheral blood.

  3. Growth factor- and cytokine-stimulated endothelial progenitor cells in post-ischemic cerebral neovascularization

    PubMed Central

    Peplow, Philip V.

    2014-01-01

    Endothelial progenitor cells are resident in the bone marrow blood sinusoids and circulate in the peripheral circulation. They mobilize from the bone marrow after vascular injury and home to the site of injury where they differentiate into endothelial cells. Activation and mobilization of endothelial progenitor cells from the bone marrow is induced via the production and release of endothelial progenitor cell-activating factors and includes specific growth factors and cytokines in response to peripheral tissue hypoxia such as after acute ischemic stroke or trauma. Endothelial progenitor cells migrate and home to specific sites following ischemic stroke via growth factor/cytokine gradients. Some growth factors are less stable under acidic conditions of tissue ischemia, and synthetic analogues that are stable at low pH may provide a more effective therapeutic approach for inducing endothelial progenitor cell mobilization and promoting cerebral neovascularization following ischemic stroke. PMID:25317152

  4. Role of Pigment Epithelium-Derived Factor in Stem/Progenitor Cell-Associated Neovascularization

    PubMed Central

    Liu, Jung-Tung; Chen, Yuh-Lien; Chen, Wen-Chi; Chen, Huey-Yi; Lin, Yi-Wen; Wang, Shu-Huei; Man, Kee-Ming; Wan, Hui-Min; Yin, Wei-Hsian; Liu, Po-Len; Chen, Yung-Hsiang

    2012-01-01

    Pigment epithelium-derived factor (PEDF) was first identified in retinal pigment epithelium cells. It is an endogenously produced protein that is widely expressed throughout the human body such as in the eyes, liver, heart, and adipose tissue; it exhibits multiple and varied biological activities. PEDF is a multifunctional protein with antiangiogenic, antitumorigenic, antioxidant, anti-inflammatory, antithrombotic, neurotrophic, and neuroprotective properties. More recently, PEDF has been shown to be the most potent inhibitor of stem/progenitor cell-associated neovascularization. Neovascularization is a complex process regulated by a large, interacting network of molecules from stem/progenitor cells. PEDF is also involved in the pathogenesis of angiogenic eye disease, tumor growth, and cardiovascular disease. Novel antiangiogenic agents with tolerable side effects are desired for the treatment of patients with various diseases. Here, we review the value of PEDF as an important endogenous antiangiogenic molecule; we focus on the recently identified role of PEDF as a possible new target molecule to influence stem/progenitor cell-related neovascularization. PMID:22685380

  5. N-Acetylated Proline-Glycine-Proline Accelerates Cutaneous Wound Healing and Neovascularization by Human Endothelial Progenitor Cells

    PubMed Central

    Kwon, Yang Woo; Heo, Soon Chul; Lee, Tae Wook; Park, Gyu Tae; Yoon, Jung Won; Jang, Il Ho; Kim, Seung-Chul; Ko, Hyun-Chang; Ryu, Youngjae; Kang, Hyeona; Ha, Chang Man; Lee, Sang Chul; Kim, Jae Ho

    2017-01-01

    Human endothelial progenitor cells (hEPCs) are promising therapeutic resources for wound repair through stimulating neovascularization. However, the hEPCs-based cell therapy has been hampered by poor engraftment of transplanted cells. In this study, we explored the effects of N-acetylated Proline-Glycine-Proline (Ac-PGP), a degradation product of collagen, on hEPC-mediated cutaneous wound healing and neovascularization. Treatment of hEPCs with Ac-PGP increased migration, proliferation, and tube-forming activity of hEPCs in vitro. Knockdown of CXCR2 expression in hEPCs abrogated the stimulatory effects of Ac-PGP on migration and tube formation. In a cutaneous wound healing model of rats and mice, topical application of Ac-PGP accelerated cutaneous wound healing with promotion of neovascularization. The positive effects of Ac-PGP on wound healing and neovascularization were blocked in CXCR2 knockout mice. In nude mice, the individual application of Ac-PGP treatment or hEPC injection accelerated wound healing by increasing neovascularization. Moreover, the combination of Ac-PGP treatment and hEPC injection further stimulated wound healing and neovascularization. Topical administration of Ac-PGP onto wound bed stimulated migration and engraftment of transplanted hEPCs into cutaneous dermal wounds. Therefore, these results suggest novel applications of Ac-PGP in promoting wound healing and augmenting the therapeutic efficacy of hEPCs. PMID:28230162

  6. Critical Roles of Reactive Oxygen Species in Age-Related Impairment in Ischemia-Induced Neovascularization by Regulating Stem and Progenitor Cell Function

    PubMed Central

    Lam, Yuen Ting

    2016-01-01

    Reactive oxygen species (ROS) regulate bone marrow microenvironment for stem and progenitor cells functions including self-renewal, differentiation, and cell senescence. In response to ischemia, ROS also play a critical role in mediating the mobilization of endothelial progenitor cells (EPCs) from the bone marrow to the sites of ischemic injury, which contributes to postnatal neovascularization. Aging is an unavoidable biological deteriorative process with a progressive decline in physiological functions. It is associated with increased oxidative stress and impaired ischemia-induced neovascularization. This review discusses the roles of ROS in regulating stem and progenitor cell function, highlighting the impact of unbalanced ROS levels on EPC dysfunction and the association with age-related impairment in ischemia-induced neovascularization. Furthermore, it discusses strategies that modulate the oxidative levels of stem and progenitor cells to enhance the therapeutic potential for elderly patients with cardiovascular disease. PMID:26697140

  7. Dynamic compression promotes proliferation and neovascular networks of endothelial progenitor cells in demineralized bone matrix scaffold seed.

    PubMed

    Kong, Zhan; Li, Jianjun; Zhao, Qun; Zhou, Zhendong; Yuan, Xiangnan; Yang, Dongxiang; Chen, Xu

    2012-08-15

    Neovascularization is required for bone formation and successful fracture healing. In the process of neovascularization, endothelial progenitor cells (EPCs) play an important role and finish vascular repair through reendothelialization to promote successful fracture healing. In this study, we found that dynamic compression can promote the proliferation and capillary-like tube formation of EPCs in the demineralized bone matrix (DBM) scaffold seed. EPCs isolated from the bone marrow of rats have been cultured in DBM scaffolds before dynamic compression and then seeded in the DBM scaffolds under dynamic conditions. The cells/scaffold constructs were subjected to cyclic compression with 5% strain and at 1 Hz for 4 h/day for 7 consecutive days. By using MTT and real-time PCR, we found that dynamic compression can significantly induce the proliferation of EPCs in three-dimensional culture with an even distribution of cells onto DBM scaffolds. Both in vitro and in vivo, the tube formation assays in the scaffolds showed that the loaded EPCs formed significant tube-like structures. These findings suggest that dynamic compression promoted the vasculogenic activities of EPCs seeded in the scaffolds, which would benefit large bone defect tissue engineering.

  8. Sonic hedgehog improves ischemia-induced neovascularization by enhancing endothelial progenitor cell function in type 1 diabetes.

    PubMed

    Qin, Yuan; He, Yan-Huan; Hou, Ning; Zhang, Gen-Shui; Cai, Yi; Zhang, Gui-Ping; Xiao, Qing; He, Li-Shan; Li, Su-Juan; Yi, Quan; Luo, Jian-Dong

    2016-03-05

    The Sonic hedgehog (Shh) pathway is downregulated in type 1 diabetes, and it has been reported that augmentation of this pathway may alleviate diabetic complications. However, the cellular mechanisms underlying these protective effects are poorly understood. Recent studies indicate that impaired function of endothelial progenitor cells (EPCs) may contribute to cardiovascular problems in diabetes. We hypothesized that impaired Shh signaling contribute to endothelial progenitor cell dysfunction and that activating the Shh signaling pathway may rescue EPC function and promote diabetic neovascularization. Adult male C57/B6 mice and streptozotocin (STZ)-induced type 1 diabetic mice were used. Gli1 and Ptc1 protein levels were reduced in EPCs from diabetic mice, indicating inhibition of the Shh signaling pathway. EPC migration, tube formation ability, and mobilization were impaired in diabetic mice compared with non-diabetic controls (p < 0.05 vs control), and all were improved by in vivo administration of the Shh pathway receptor agonist SAG (p < 0.05 vs diabetes). SAG significantly increased capillary density and blood perfusion in the ischemic hindlimbs of diabetic mice (p < 0.05 vs diabetes). The AKT activity was lower in EPCs from diabetic mice than those from non-diabetic controls (p < 0.05 vs control). This decreased AKT activity led to an increased GSK-3β activity and degradation of the Shh pathway transcription factor Gli1/Gli2. SAG significantly increased the activity of AKT in EPCs. Our data clearly demonstrate that an impaired Shh pathway mediated by the AKT/GSK-3β pathway can contribute to EPC dysfunction in diabetes and thus activating the Shh signaling pathway can restore both the number and function of EPCs and increase neovascularization in type 1 diabetic mice.

  9. Adipose-Derived Stem Cell-Seeded Hydrogels Increase Endogenous Progenitor Cell Recruitment and Neovascularization in Wounds

    PubMed Central

    Kosaraju, Revanth; Rennert, Robert C.; Maan, Zeshaan N.; Duscher, Dominik; Barrera, Janos; Whittam, Alexander J.; Januszyk, Michael; Rajadas, Jayakumar; Rodrigues, Melanie

    2016-01-01

    Adipose-derived mesenchymal stem cells (ASCs) are appealing for cell-based wound therapies because of their accessibility and ease of harvest, but their utility is limited by poor cell survival within the harsh wound microenvironment. In prior work, our laboratory has demonstrated that seeding ASCs within a soft pullulan–collagen hydrogel enhances ASC survival and improves wound healing. To more fully understand the mechanism of this therapy, we examined whether ASC-seeded hydrogels were able to modulate the recruitment and/or functionality of endogenous progenitor cells. Employing a parabiosis model and fluorescence-activated cell sorting analysis, we demonstrate that application of ASC-seeded hydrogels to wounds, when compared with injected ASCs or a noncell control, increased the recruitment of provascular circulating bone marrow-derived mesenchymal progenitor cells (BM-MPCs). BM-MPCs comprised 23.0% of recruited circulating progenitor cells in wounds treated with ASC-seeded hydrogels versus 8.4% and 2.1% in those treated with controls, p < 0.05. Exploring the potential for functional modulation of BM-MPCs, we demonstrate a statistically significant increase in BM-MPC migration, proliferation, and tubulization when exposed to hydrogel-seeded ASC-conditioned medium versus control ASC-conditioned medium (73.8% vs. 51.4% scratch assay closure; 9.1% vs. 1.4% proliferation rate; 10.2 vs. 5.5 tubules/HPF; p < 0.05 for all assays). BM-MPC expression of genes related to cell stemness and angiogenesis was also significantly increased following exposure to hydrogel-seeded ASC-conditioned medium (p < 0.05). These data suggest that ASC-seeded hydrogels improve both progenitor cell recruitment and functionality to effect greater neovascularization. PMID:26871860

  10. Spatially Oriented, Temporally Sequential Smooth Muscle Cell-Endothelial Progenitor Cell Bi-Level Cell Sheet Neovascularizes Ischemic Myocardium

    PubMed Central

    Shudo, Yasuhiro; Cohen, Jeffrey E.; MacArthur, John W.; Atluri, Pavan; Hsiao, Philip F.; Yang, Elaine C.; Fairman, Alexander S.; Trubelja, Alen; Patel, Jay; Miyagawa, Shigeru; Sawa, Yoshiki; Woo, Y. Joseph

    2014-01-01

    Background Endothelial progenitor cells (EPCs) possess robust therapeutic angiogenic potential, yet may be limited in the capacity to develop into fully mature vasculature. This problem might be exacerbated by the absence of a neovascular foundation, namely pericytes, with simple EPC injection. We hypothesized that coculturing EPCs with smooth muscle cells (SMCs), components of the surrounding vascular wall, in a cell sheet will mimic the native spatial orientation and interaction between EPCs and SMCs to create a supratherapeutic angiogenic construct in a model of ischemic cardiomyopathy. Methods and Results Primary EPCs and SMCs were isolated from Wistar rats. Confluent SMCs topped with confluent EPCs were spontaneously detached from the Upcell dish to create an SMC-EPC bi-level cell sheet. A rodent ischemic cardiomyopathy model was created by ligating the left anterior descending coronary artery. Rats were then immediately divided into 3 groups: cell-sheet transplantation (n=14), cell injection (n=12), and no treatment (n=13). Cocultured EPCs and SMCs stimulated an abundant release of multiple cytokines in vitro. Increased capillary density and improved blood perfusion in the borderzone elucidated the significant in vivo angiogenic potential of this technology. Most interestingly, however, cell fate–tracking experiments demonstrated that the cell-sheet EPCs and SMCs directly migrated into the myocardium and differentiated into elements of newly formed functional vasculature. The robust angiogenic effect of this cell sheet translated to enhanced ventricular function as demonstrated by echocardiography. Conclusions Spatially arranged EPC-SMC bi-level cell-sheet technology facilitated the natural interaction between EPCs and SMCs, thereby creating structurally mature, functional microvasculature in a rodent ischemic cardiomyopathy model, leading to improved myocardial function. PMID:24030422

  11. Statins, HMG-CoA Reductase Inhibitors, Improve Neovascularization by Increasing the Expression Density of CXCR4 in Endothelial Progenitor Cells.

    PubMed

    Chiang, Kuang-Hsing; Cheng, Wan-Li; Shih, Chun-Ming; Lin, Yi-Wen; Tsao, Nai-Wen; Kao, Yung-Ta; Lin, Chih-Ting; Wu, Shinn-Chih; Huang, Chun-Yao; Lin, Feng-Yen

    2015-01-01

    Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, are used to reduce cholesterol biosynthesis in the liver. Accordingly, statins regulate nitric oxide (NO) and glutamate metabolism, inflammation, angiogenesis, immunity and endothelial progenitor cells (EPCs) functions. The function of EPCs are regulated by stromal cell-derived factor 1 (SDF-1), vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β), etc. Even though the pharmacologic mechanisms by which statins affect the neovasculogenesis of circulating EPCs, it is still unknown whether statins affect the EPCs function through the regulation of CXCR4, a SDF-1 receptor expression. Therefore, we desired to explore the effects of statins on CXCR4 expression in EPC-mediated neovascularization by in vitro and in vivo analyses. In animal studies, we analyzed the effects of atorvastatin or rosuvastatin treatments in recovery of capillary density and blood flow, the expression of vWF and CXCR4 at ischemia sites in hindlimb ischemia ICR mice. Additionally, we analyzed whether the atorvastatin or rosuvastatin treatments increased the mobilization, homing, and CXCR4 expression of EPCs in hindlimb ischemia ICR mice that underwent bone marrow transplantation. The results indicated that statins treatment led to significantly more CXCR4-positive endothelial progenitor cells incorporated into ischemic sites and in the blood compared with control mice. In vivo, we isolated human EPCs and analyzed the effect of statins treatment on the vasculogenic ability of EPCs and the expression of CXCR4. Compared with the control groups, the neovascularization ability of EPCs was significantly improved in the atorvastatin or rosuvastatin group; this improvement was dependent on CXCR4 up-regulation. The efficacy of statins on improving EPC neovascularization was related to the SDF-1α/CXCR4 axis and might be regulated by the NO. In conclusion, atorvastatin and rosuvastatin improved

  12. Statins, HMG-CoA Reductase Inhibitors, Improve Neovascularization by Increasing the Expression Density of CXCR4 in Endothelial Progenitor Cells

    PubMed Central

    Chiang, Kuang-Hsing; Cheng, Wan-Li; Shih, Chun-Ming; Lin, Yi-Wen; Tsao, Nai-Wen; Kao, Yung-Ta; Lin, Chih-Ting; Wu, Shinn-Chih; Huang, Chun-Yao; Lin, Feng-Yen

    2015-01-01

    Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, are used to reduce cholesterol biosynthesis in the liver. Accordingly, statins regulate nitric oxide (NO) and glutamate metabolism, inflammation, angiogenesis, immunity and endothelial progenitor cells (EPCs) functions. The function of EPCs are regulated by stromal cell-derived factor 1 (SDF-1), vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β), etc. Even though the pharmacologic mechanisms by which statins affect the neovasculogenesis of circulating EPCs, it is still unknown whether statins affect the EPCs function through the regulation of CXCR4, a SDF-1 receptor expression. Therefore, we desired to explore the effects of statins on CXCR4 expression in EPC-mediated neovascularization by in vitro and in vivo analyses. In animal studies, we analyzed the effects of atorvastatin or rosuvastatin treatments in recovery of capillary density and blood flow, the expression of vWF and CXCR4 at ischemia sites in hindlimb ischemia ICR mice. Additionally, we analyzed whether the atorvastatin or rosuvastatin treatments increased the mobilization, homing, and CXCR4 expression of EPCs in hindlimb ischemia ICR mice that underwent bone marrow transplantation. The results indicated that statins treatment led to significantly more CXCR4-positive endothelial progenitor cells incorporated into ischemic sites and in the blood compared with control mice. In vivo, we isolated human EPCs and analyzed the effect of statins treatment on the vasculogenic ability of EPCs and the expression of CXCR4. Compared with the control groups, the neovascularization ability of EPCs was significantly improved in the atorvastatin or rosuvastatin group; this improvement was dependent on CXCR4 up-regulation. The efficacy of statins on improving EPC neovascularization was related to the SDF-1α/CXCR4 axis and might be regulated by the NO. In conclusion, atorvastatin and rosuvastatin improved

  13. BMP signaling mediates stem/progenitor cell-induced retina regeneration.

    PubMed

    Haynes, Tracy; Gutierrez, Christian; Aycinena, Juan-Carlos; Tsonis, Panagiotis A; Del Rio-Tsonis, Katia

    2007-12-18

    We identified a mechanism whereby retina regeneration in the embryonic chick can be induced by the contribution of stem/progenitor cells. We show that bone morphogenetic protein (BMP) signaling is sufficient and necessary to induce retina regeneration and that its action can be divided into two phases. By 3 days after postretinectomy (d PR), the BMP pathway directs proliferation and regeneration through the activation of Smad (canonical BMP pathway) and the up-regulation of FGF signaling by the MAPK pathway. By 7d PR, it induces apoptosis by activating p38 (a noncanonical BMP pathway) and down-regulating FGF signaling (by both MAPK and AKT pathways). Apoptosis at this later stage can be prevented, and BMP-induced regeneration can be further induced by inhibition of p38. These results unravel a mechanism for stem/progenitor cell-mediated retina regeneration, where BMP activation establishes a cross-talk with the FGF pathway and selectively activates the canonical and noncanonical BMP pathways. Retina stem/progenitor cells exist in other species, including humans. Thus, our findings provide insights on how retinal stem cells can be activated for possible regenerative therapies.

  14. Microvesicles Derived from Indoxyl Sulfate Treated Endothelial Cells Induce Endothelial Progenitor Cells Dysfunction.

    PubMed

    Carmona, Andres; Guerrero, Fatima; Buendia, Paula; Obrero, Teresa; Aljama, Pedro; Carracedo, Julia

    2017-01-01

    Cardiovascular disease is a major cause of mortality in chronic kidney disease patients. Indoxyl sulfate (IS) is a typical protein-bound uremic toxin that cannot be effectively cleared by conventional dialysis. Increased IS is associated with the progression of chronic kidney disease and development of cardiovascular disease. After endothelial activation by IS, cells release endothelial microvesicles (EMV) that can induce endothelial dysfunction. We developed an in vitro model of endothelial damage mediated by IS to evaluate the functional effect of EMV on the endothelial repair process developed by endothelial progenitor cells (EPCs). EMV derived from IS-treated endothelial cells were isolated by ultracentrifugation and characterized for miRNAs content. The effects of EMV on healthy EPCs in culture were studied. We observed that IS activates endothelial cells and the generated microvesicles (IsEMV) can modulate the classic endothelial roles of progenitor cells as colony forming units and form new vessels in vitro. Moreover, 23 miRNAs were contained in IsEMV including four (miR-181a-5p, miR-4454, miR-150-5p, and hsa-let-7i-5p) that were upregulated in IsEMV compared with control endothelial microvesicles. Other authors have found that miR-181a-5p, miR-4454, and miR-150-5p are involved in promoting inflammation, apoptosis, and cellular senescence. Interestingly, we observed an increase in NFκB and p53, and a decrease in IκBα in EPCs treated with IsEMV. Our data suggest that IS is capable of inducing endothelial vesiculation with different membrane characteristics, miRNAs and other molecules, which makes maintaining of vascular homeostasis of EPCs not fully functional. These specific characteristics of EMV could be used as novel biomarkers for diagnosis and prognosis of vascular disease.

  15. Human CD133+ Renal Progenitor Cells Induce Erythropoietin Production and Limit Fibrosis After Acute Tubular Injury

    PubMed Central

    Aggarwal, Shikhar; Grange, Cristina; Iampietro, Corinne; Camussi, Giovanni; Bussolati, Benedetta

    2016-01-01

    Persistent alterations of the renal tissue due to maladaptive repair characterize the outcome of acute kidney injury (AKI), despite a clinical recovery. Acute damage may also limit the renal production of erythropoietin, with impairment of the hemopoietic response to ischemia and possible lack of its reno-protective action. We aimed to evaluate the effect of a cell therapy using human CD133+ renal progenitor cells on maladaptive repair and fibrosis following AKI in a model of glycerol-induced rhabdomyolysis. In parallel, we evaluated the effect of CD133+ cells on erythropoietin production. Administration of CD133+ cells promoted the restoration of the renal tissue, limiting the presence of markers of injury and pro-inflammatory molecules. In addition, it promoted angiogenesis and protected against fibrosis up to day 60. No effect of dermal fibroblasts was observed. Treatment with CD133+ cells, but not with PBS or fibroblasts, limited anemia and increased erythropoietin levels both in renal tissue and in circulation. Finally, CD133+ cells contributed to the local production of erythropoietin, as observed by detection of circulating human erythropoietin. CD133+ cells appear therefore an effective source for cell repair, able to restore renal functions, including erythropoietin release, and to limit long term maldifferentiation and fibrosis. PMID:27853265

  16. Diffusible Factors Secreted by Glioblastoma and Medulloblastoma Cells Induce Oxidative Stress in Bystander Neural Stem Progenitors

    PubMed Central

    Sharma, Neha; Colangelo, Nicholas W.; de Toledo, Sonia M.

    2016-01-01

    Harmful effects that alter the homeostasis of neural stem or progenitor cells (NSPs) can affect regenerative processes in the central nervous system. We investigated the effect of soluble factors secreted by control or 137Cs-γ-irradiated glioblastoma or medulloblastoma cells on redox-modulated endpoints in recipient human NSPs. Growth medium harvested from the nonirradiated brain tumor cells, following 24 h of growth, induced prominent oxidative stress in recipient NSPs as judged by overall increases in mitochondrial superoxide radical levels (p < .001), activation of c-jun N-terminal kinase, and decrease in the active form of FoxO3a. The induced oxidative stress was associated with phosphorylation of p53 on serine 15, a marker of DNA damage, induction of the cyclin-cyclin dependent kinase inhibitors p21Waf1 and p27Kip1, and perturbations in cell cycle progression (p < .001). These changes were also associated with increased apoptosis as determined by enhanced annexin V staining (p < .001) and caspase 8 activation (p < .05) and altered expression of critical regulators of self-renewal, proliferation, and differentiation. Exposure of the tumor cells to radiation only slightly altered the induced oxidative changes in the bystander NSPs, except for medium from irradiated medulloblastoma cells that was more potent at inducing apoptosis in the NSPs than medium from nonirradiated cells (p < .001). The elucidation of such stressful bystander effects provides avenues to understand the biochemical events underlying the development or exacerbation of degenerative outcomes associated with brain cancers. It is also relevant to tissue culture protocols whereby growth medium conditioned by tumor cells is often used to support the growth of stem cells. PMID:27511909

  17. High-mobility group box-1-Toll-Like receptor 4 axis mediates the recruitment of endothelial progenitor cells in alkali-induced corneal neovascularization.

    PubMed

    Yang, Shuai; Yang, Tian-Shu; Wang, Fang; Su, Shao-Bo

    2015-09-01

    Endothelial progenitor cells (EPCs) promote both physiological and pathological neovascularization. Recently we found high-mobility group box-1 (HMGB1)-Toll-like receptor 4 (TLR4) signaling pathway promotes corneal neovascularization (CNV) induced by alkali in a mouse model. However, it is still unclear whether HMGB1-TLR4 promotes the mobility of EPCs. In this study, we explored the role of HMGB1-TLR4 signaling in EPC recruitment by modulating the activity of HMGB1-TLR4 signaling in the corneas of alkali-induced CNV mouse model. The level of EPC recruitment in injured corneas, as detected by flow cytometry, is increased and reaches the peak level 4days after injury. Activating TLR4 with exogenous HMGB1 or LPS enhances the EPC recruitment, whereas inhibiting the activity of HMGB1 and TLR4 with A-box (selective HMGB1 antagonist) or LPS-RS (selective TLR4 antagonist), respectively, reverses this phenotype. Moreover, the TLR4 mediated EPC recruitment is associated with up-regulation of stromal cell-derived factor-1 (SDF-1), a pivotal cytokine in EPC mobilization. Activation of TLR4 or HMGB1 leads to increased SDF-1 expression, while blocking TLR4 or HMGB1 inhibits the expression of SDF-1. Topical administration of AMD-3100, an antagonist of SDF-1 receptor, suppresses the TLR4-mediated EPC recruitment and ameliorates CNV. Our results indicated that activation of HMGB1-TLR4 signaling pathway promotes EPC recruitment in CNV, at least in part through up-regulation of SDF-1.

  18. Impact of Indoxyl Sulfate on Progenitor Cell-Related Neovascularization of Peripheral Arterial Disease and Post-Angioplasty Thrombosis of Dialysis Vascular Access

    PubMed Central

    Wu, Chih-Cheng; Hung, Szu-Chun; Kuo, Ko-Lin; Tarng, Der-Cherng

    2017-01-01

    Patients with chronic kidney disease (CKD) have an increased risk of vascular disease, which is associated with considerable health care costs. Vascular disease in CKD differs clinically and pathobiologically from that in patients with normal renal function. Besides the traditional risk factors, retention of uremic toxins contributes to the pathogenesis of vascular disease in patients with CKD. Indoxyl sulfate is a protein-bound uremic toxin and is inefficiently removed by conventional dialysis. Accumulating evidence suggests that indoxyl sulfate is a vascular toxin involved in atherosclerosis, arteriosclerosis, vascular calcification and vascular repair. Clinically, indoxyl sulfate is associated with total and cardiovascular mortality in patients with CKD. Recent studies have indicated that in addition to coronary and cerebral arteries, indoxyl sulfate plays a role in peripheral artery disease (PAD) and dialysis graft thrombosis. Emerging evidence suggests that indoxyl sulfate is implicated via novel mechanisms, including progenitor cell-related neovascularization and tissue factor-related hypercoagulability. These findings raise the possibility that strategies targeting serum indoxyl sulfate may have the potential to improve the outcomes of PAD and dialysis vascular access in patients with CKD. PMID:28067862

  19. Impact of Indoxyl Sulfate on Progenitor Cell-Related Neovascularization of Peripheral Arterial Disease and Post-Angioplasty Thrombosis of Dialysis Vascular Access.

    PubMed

    Wu, Chih-Cheng; Hung, Szu-Chun; Kuo, Ko-Lin; Tarng, Der-Cherng

    2017-01-07

    Patients with chronic kidney disease (CKD) have an increased risk of vascular disease, which is associated with considerable health care costs. Vascular disease in CKD differs clinically and pathobiologically from that in patients with normal renal function. Besides the traditional risk factors, retention of uremic toxins contributes to the pathogenesis of vascular disease in patients with CKD. Indoxyl sulfate is a protein-bound uremic toxin and is inefficiently removed by conventional dialysis. Accumulating evidence suggests that indoxyl sulfate is a vascular toxin involved in atherosclerosis, arteriosclerosis, vascular calcification and vascular repair. Clinically, indoxyl sulfate is associated with total and cardiovascular mortality in patients with CKD. Recent studies have indicated that in addition to coronary and cerebral arteries, indoxyl sulfate plays a role in peripheral artery disease (PAD) and dialysis graft thrombosis. Emerging evidence suggests that indoxyl sulfate is implicated via novel mechanisms, including progenitor cell-related neovascularization and tissue factor-related hypercoagulability. These findings raise the possibility that strategies targeting serum indoxyl sulfate may have the potential to improve the outcomes of PAD and dialysis vascular access in patients with CKD.

  20. SCF promotes dental pulp progenitor migration, neovascularization, and collagen remodeling - potential applications as a homing factor in dental pulp regeneration.

    PubMed

    Pan, Shuang; Dangaria, Smit; Gopinathan, Gokul; Yan, Xiulin; Lu, Xuanyu; Kolokythas, Antonia; Niu, Yumei; Luan, Xianghong

    2013-10-01

    Stem cell factor (SCF) is a powerful chemokine that binds to the c-Kit receptor CD117 and has shown promise as a homing agent capable of progenitor cell recruitment. In the present study we have documented high levels of both SCF and its receptor c-Kit in differentiating dental pulp (DP) cells and in the sub-odontoblastic layer of Höhl. In vitro studies using human DP progenitors revealed a significant increase in cell proliferation after100 nM SCF application, explained by a 2-fold upregulation in cyclin D3 and FGF2 cell cycle regulators, and a 7-fold increase in CDK4 expression. DP cell migration in the presence of SCF was up-regulated 2.7-fold after a 24 h culture period, and this effect was accompanied by cytoskeletal rearrangement, a 1.5-fold increase in polymeric F-actin over G-actin, and a 1.8-fold increase in RhoA expression. Explaining the signaling effect of SCF on DP migration, PI3K/Akt and MEK/ERK pathway inhibitors were demonstrated to significantly reduce DP cell migration, while SCF alone doubled the number of migrated cells. ERK and AKT phosphorylation were dramatically upregulated already 3-5 min after SCF addition to the culture medium and declined thereafter, classifying SCF as a fast acting chemokine. When applied as an agent to promote tissue regeneration in subcutaneously implanted collagen sponges, SCF resulted in a 7-fold increase in the cell number in the implanted tissue construct, a more than 9-fold increase in capillaries, as well as collagen sponge remodeling and collagen fiber neogenesis. Together, these studies demonstrate the suitability of SCF as a potent aid in the regeneration of dental pulp and other mesenchymal tissues, capable of inducing cell homing, angiogenesis, and tissue remodeling.

  1. The mobilization, recruitment and contribution of bone marrow-derived endothelial progenitor cells to the tumor neovascularization occur at an early stage and throughout the entire process of hepatocellular carcinoma growth.

    PubMed

    Zhu, Haitao; Shao, Qianwen; Sun, Xitai; Deng, Zhengming; Yuan, Xianwen; Yu, Decai; Zhou, Xiang; Ding, Yitao

    2012-10-01

    Obvious neovascularization is a key feature of hepatocellular carcinoma (HCC) and the status of neovascularization in HCC is closely correlated with the tumor growth and patient prognosis. The actual effect of current antivascular treatment including embolization to HCC is not satisfactory. Compensatory angiogenesis is one of the primary causes responsible for failure of antiangiogenic therapy. Bone marrow-derived endothelial progenitor cells (BM-EPCs) are considered as important building blocks for adult neovascularization. However, the role of mobilized BM-EPCs in HCC remains unknown. In this study, GFP+-BM orthotropic HCC mice were established to investigate whether BM-EPCs are involved in HCC-induced neovascularization. We found that a large number of BM-EPCs were mobilized into the circulation with the development of HCC, recruited into the HCC region and incorporated into the vascular endothelium directly by differentiation into vascular endothelial cells, including sinus, capillary vessels and great vessels. Dynamic observation revealed that the mobilization and the incorporation of BM-EPCs into different types of vessels were present in early phases and throughout the whole process of HCC growth. The proportion of BM-EPCs in vessels increased gradually, from 17 to 21% with tumor growth. Moreover, injected GFP+-EPCs also specifically homed to tumor tissue and incorporated into tumor vessels directly. In this initial study, we demonstrated that BM-EPCs play a prominent role in HCC neovascularization. Blockade of BM-EPC-mediated vasculogenesis may improve the efficacy of current anti-vascularization therapy for patients with HCC.

  2. GroEL1, a Heat Shock protein 60 of Chlamydia pneumoniae, Impairs Neovascularization by Decreasing Endothelial Progenitor Cell Function

    PubMed Central

    Lin, Yi-Wen; Huang, Chun-Yao; Chen, Yung-Hsiang; Shih, Chun-Ming; Tsao, Nai-Wen; Lin, Cheng-Yen; Chang, Nen-Chung; Tsai, Chien-Sung; Tsai, Hsiao-Ya; Tsai, Jui-Chi; Huang, Po-Hsun; Li, Chi-Yuan; Lin, Feng-Yen

    2013-01-01

    The number and function of endothelial progenitor cells (EPCs) are sensitive to hyperglycemia, hypertension, and smoking in humans, which are also associated with the development of atherosclerosis. GroEL1 from Chlamydia pneumoniae has been found in atherosclerotic lesions and is related to atherosclerotic pathogenesis. However, the actual effects of GroEL1 on EPC function are unclear. In this study, we investigate the EPC function in GroEL1-administered hind limb-ischemic C57BL/B6 and C57BL/10ScNJ (a toll-like receptor 4 (TLR4) mutation) mice and human EPCs. In mice, laser Doppler imaging, flow cytometry, and immunohistochemistry were used to evaluate the degree of neo-vasculogenesis, circulating level of EPCs, and expression of CD34, vWF, and endothelial nitric oxide synthase (eNOS) in vessels. Blood flow in the ischemic limb was significantly impaired in C57BL/B6 but not C57BL/10ScNJ mice treated with GroEL1. Circulating EPCs were also decreased after GroEL1 administration in C57BL/B6 mice. Additionally, GroEL1 inhibited the expression of CD34 and eNOS in C57BL/B6 ischemic muscle. In vitro, GroEL1 impaired the capacity of differentiation, mobilization, tube formation, and migration of EPCs. GroEL1 increased senescence, which was mediated by caspases, p38 MAPK, and ERK1/2 signaling in EPCs. Furthermore, GroEL1 decreased integrin and E-selectin expression and induced inflammatory responses in EPCs. In conclusion, these findings suggest that TLR4 and impaired NO-related mechanisms could contribute to the reduced number and functional activity of EPCs in the presence of GroEL1 from C. pneumoniae. PMID:24376840

  3. Locally existing endothelial cells and pericytes in ovarian stroma, but not bone marrow-derived vascular progenitor cells, play a central role in neovascularization during follicular development in mice.

    PubMed

    Kizuka-Shibuya, Fumie; Tokuda, Nobuko; Takagi, Kiyoshi; Adachi, Yasuhiro; Lee, Lifa; Tamura, Isao; Maekawa, Ryo; Tamura, Hiroshi; Suzuki, Takashi; Owada, Yuji; Sugino, Norihiro

    2014-01-21

    Neovascularization is necessary for follicular growth. Vascularization is first observed in preantral follicles, and thereafter the vasculature markedly increases in follicles undergoing development. Neovascularization includes angiogenesis and vasculogenesis. Vasculogenesis is the formation of new blood vessels by bone marrow-derived endothelial progenitor cells. It is unclear whether vasculogenesis occurs during follicular growth. Blood vessels must be mature to be functional blood vessels. Mature blood vessels are characterized by the recruitment of pericytes. However, it is unclear where pericytes come from and whether they contribute to neovascularization in the follicle during follicular growth. In this study, we investigated whether bone marrow-derived progenitor cells that differentiate into vascular endothelial cells or pericytes contribute to neovascularization during follicular growth. A parabiosis model was used in this study. Six-week-old wild-type and transgenic female mice expressing green fluorescent protein (GFP) were conjoined between the lateral abdominal regions to create a shared circulatory system. After 6 weeks, the ovaries were obtained and immunostained for CD31/CD34 (a vascular endothelial cell marker), platelet-derived growth factor receptor-β (PDGFR-β) (a pericyte marker), and GFP (a bone marrow-derived cell marker). Cells that were positive for CD34 and PDGFR-β were observed in the stroma adjacent to the primary or early preantral follicles and in the theca cell layer of the follicles from the late preantral stage to the preovulatory stage. CD31/CD34 and GFP double-positive cells were observed in the theca cell layer of the follicle from the antral stage to the preovulatory stage while the number of double-positive cells in the preovulatory follicles did not increase. PDGFR-β and GFP double-positive cells were observed in the theca cell layer of the preovulatory follicle but not in the smaller follicle. Locally existing endothelial

  4. Smooth Muscle Progenitor Cells Derived From Human Pluripotent Stem Cells Induce Histologic Changes in Injured Urethral Sphincter.

    PubMed

    Li, Yanhui; Wen, Yan; Wang, Zhe; Wei, Yi; Wani, Prachi; Green, Morgaine; Swaminathan, Ganesh; Ramamurthi, Anand; Pera, Renee Reijo; Chen, Bertha

    2016-12-01

    : Data suggest that myoblasts from various sources, including bone marrow, skeletal muscle, and adipose tissue, can restore muscle function in patients with urinary incontinence. Animal data have indicated that these progenitor cells exert mostly a paracrine effect on the native tissues rather than cell regeneration. Limited knowledge is available on the in vivo effect of human stem cells or muscle progenitors on injured muscles. We examined in vivo integration of smooth muscle progenitor cells (pSMCs) derived from human pluripotent stem cells (hPSCs). pSMCs were derived from a human embryonic stem cell line (H9-ESCs) and two induced pluripotent stem cell (iPSC) lines. pSMCs were injected periurethrally into urethral injury rat models (2 × 10(6) cells per rat) or intramuscularly into severe combined immunodeficiency mice. Histologic and quantitative image analysis revealed that the urethras in pSMC-treated rats contained abundant elastic fibers and thicker muscle layers compared with the control rats. Western blot confirmed increased elastin/collagen III content in the urethra and bladder of the H9-pSMC-treated rats compared with controls. iPSC-pSMC treatment also showed similar trends in elastin and collagen III. Human elastin gene expression was not detectable in rodent tissues, suggesting that the extracellular matrix synthesis resulted from the native rodent tissues rather than from the implanted human cells. Immunofluorescence staining and in vivo bioluminescence imaging confirmed long-term engraftment of pSMCs into the host urethra and the persistence of the smooth muscle phenotype. Taken together, the data suggest that hPSC-derived pSMCs facilitate restoration of urethral sphincter function by direct smooth muscle cell regeneration and by inducing native tissue elastin/collagen III remodeling. The present study provides evidence that a pure population of human smooth muscle progenitor cells (pSMCs) derived from human pluripotent stem cells (hPSCs) (human

  5. High calcium bioglass enhances differentiation and survival of endothelial progenitor cells, inducing early vascularization in critical size bone defects.

    PubMed

    Eldesoqi, Karam; Seebach, Caroline; Nguyen Ngoc, Christina; Meier, Simon; Nau, Christoph; Schaible, Alexander; Marzi, Ingo; Henrich, Dirk

    2013-01-01

    Early vascularization is a prerequisite for successful bone healing and endothelial progenitor cells (EPC), seeded on appropriate biomaterials, can improve vascularization. The type of biomaterial influences EPC function with bioglass evoking a vascularizing response. In this study the influence of a composite biomaterial based on polylactic acid (PLA) and either 20 or 40% bioglass, BG20 and BG40, respectively, on the differentiation and survival of EPCs in vitro was investigated. Subsequently, the effect of the composite material on early vascularization in a rat calvarial critical size defect model with or without EPCs was evaluated. Human EPCs were cultured with β-TCP, PLA, BG20 or BG40, and seeding efficacy, cell viability, cell morphology and apoptosis were analysed in vitro. BG40 released the most calcium, and improved endothelial differentiation and vitality best. This effect was mimicked by adding an equivalent amount of calcium to the medium and was diminished in the presence of the calcium chelator, EGTA. To analyze the effect of BG40 and EPCs in vivo, a 6-mm diameter critical size calvarial defect was created in rats (n = 12). Controls (n = 6) received BG40 and the treatment group (n = 6) received BG40 seeded with 5×10(5) rat EPCs. Vascularization after 1 week was significantly improved when EPCs were seeded onto BG40, compared to implanting BG40 alone. This indicates that Ca(2+) release improves EPC differentiation and is useful for enhanced early vascularization in critical size bone defects.

  6. High Calcium Bioglass Enhances Differentiation and Survival of Endothelial Progenitor Cells, Inducing Early Vascularization in Critical Size Bone Defects

    PubMed Central

    Nguyen Ngoc, Christina; Meier, Simon; Nau, Christoph; Schaible, Alexander; Marzi, Ingo; Henrich, Dirk

    2013-01-01

    Early vascularization is a prerequisite for successful bone healing and endothelial progenitor cells (EPC), seeded on appropriate biomaterials, can improve vascularization. The type of biomaterial influences EPC function with bioglass evoking a vascularizing response. In this study the influence of a composite biomaterial based on polylactic acid (PLA) and either 20 or 40% bioglass, BG20 and BG40, respectively, on the differentiation and survival of EPCs in vitro was investigated. Subsequently, the effect of the composite material on early vascularization in a rat calvarial critical size defect model with or without EPCs was evaluated. Human EPCs were cultured with β-TCP, PLA, BG20 or BG40, and seeding efficacy, cell viability, cell morphology and apoptosis were analysed in vitro. BG40 released the most calcium, and improved endothelial differentiation and vitality best. This effect was mimicked by adding an equivalent amount of calcium to the medium and was diminished in the presence of the calcium chelator, EGTA. To analyze the effect of BG40 and EPCs in vivo, a 6-mm diameter critical size calvarial defect was created in rats (n = 12). Controls (n = 6) received BG40 and the treatment group (n = 6) received BG40 seeded with 5×105 rat EPCs. Vascularization after 1 week was significantly improved when EPCs were seeded onto BG40, compared to implanting BG40 alone. This indicates that Ca2+ release improves EPC differentiation and is useful for enhanced early vascularization in critical size bone defects. PMID:24244419

  7. Ex vivo expanded human cord blood-derived hematopoietic progenitor cells induce lung growth and alveolarization in injured newborn lungs.

    PubMed

    Mao, Quanfu; Chu, Sharon; Ghanta, Sailaja; Padbury, James F; De Paepe, Monique E

    2013-03-23

    We investigated the capacity of expanded cord blood-derived CD34+ hematopoietic progenitor cells to undergo respiratory epithelial differentiation ex vivo, and to engraft and attenuate alveolar disruption in injured newborn murine lungs in vivo. Respiratory epithelial differentiation was studied in CD34+ cells expanded in the presence of growth factors and cytokines ("basic" medium), in one group supplemented with dexamethasone ("DEX"). Expanded or freshly isolated CD34+ cells were inoculated intranasally in newborn mice with apoptosis-induced lung injury. Pulmonary engraftment, lung growth and alveolarization were studied at 8 weeks post-inoculation. SP-C mRNA expression was seen in 2/7 CD34+ cell isolates expanded in basic media and in 6/7 isolates expanded in DEX, associated with cytoplasmic SP-C immunoreactivity and ultrastructural features suggestive of type II cell-like differentiation. Administration of expanding CD34+ cells was associated with increased lung growth and, in animals treated with DEX-exposed cells, enhanced alveolar septation. Freshly isolated CD34+ cells had no effect of lung growth or remodeling. Lungs of animals treated with expanded CD34+ cells contained intraalveolar aggregates of replicating alu-FISH-positive mononuclear cells, whereas epithelial engraftment was extremely rare. Expanded cord blood CD34+ cells can induce lung growth and alveolarization in injured newborn lungs. These growth-promoting effects may be linked to paracrine or immunomodulatory effects of persistent cord blood-derived mononuclear cells, as expanded cells showed limited respiratory epithelial transdifferentiation.

  8. Irradiated human endothelial progenitor cells induce bystander killing in human non-small cell lung and pancreatic cancer cells.

    PubMed

    Turchan, William T; Shapiro, Ronald H; Sevigny, Garrett V; Chin-Sinex, Helen; Pruden, Benjamin; Mendonca, Marc S

    2016-08-01

    Purpose To investigate whether irradiated human endothelial progenitor cells (hEPC) could induce bystander killing in the A549 non-small cell lung cancer (NSCLC) cells and help explain the improved radiation-induced tumor cures observed in A549 tumor xenografts co-injected with hEPC. Materials and methods We investigated whether co-injection of CBM3 hEPC with A549 NSCLC cells would alter tumor xenograft growth rate or tumor cure after a single dose of 0 or 5 Gy of X-rays. We then utilized dual chamber Transwell dishes, to test whether medium from irradiated CBM3 and CBM4 hEPC would induce bystander cell killing in A549 cells, and as an additional control, in human pancreatic cancer MIA PaCa-2 cells. The CBM3 and CBM4 hEPC were plated into the upper Transwell chamber and the A549 or MIA PaCa-2 cells were plated in the lower Transwell chamber. The top inserts with the CBM3 or CBM4 hEPC cells were subsequently removed, irradiated, and then placed back into the Transwell dish for 3 h to allow for diffusion of any potential bystander factors from the irradiated hEPC in the upper chamber through the permeable membrane to the unirradiated cancer cells in the lower chamber. After the 3 h incubation, the cancer cells were re-plated for clonogenic survival. Results We found that co-injection of CBM3 hEPC with A549 NSCLC cells significantly increased the tumor growth rate compared to A549 cells alone, but paradoxically also increased A549 tumor cure after a single dose of 5 Gy of X-rays (p < 0.05). We hypothesized that irradiated hEPC may be inducing bystander killing in the A549 NSCLC cells in tumor xenografts, thus improving tumor cure. Bystander studies clearly showed that exposure to the medium from irradiated CBM3 and CBM4 hEPC induced significant bystander killing and decreased the surviving fraction of A549 and MIA PaCa-2 cells to 0.46 (46%) ± 0.22 and 0.74 ± 0.07 (74%) respectively (p < 0.005, p < 0.0001). In addition, antibody depletion

  9. Nebivolol exerts beneficial effects on endothelial function, early endothelial progenitor cells, myocardial neovascularization, and left ventricular dysfunction early after myocardial infarction beyond conventional β1-blockade.

    PubMed

    Sorrentino, Sajoscha A; Doerries, Carola; Manes, Costantina; Speer, Thimoteus; Dessy, Chantal; Lobysheva, Irina; Mohmand, Wazma; Akbar, Razma; Bahlmann, Ferdinand; Besler, Christian; Schaefer, Arnd; Hilfiker-Kleiner, Denise; Lüscher, Thomas F; Balligand, Jean-Luc; Drexler, Helmut; Landmesser, Ulf

    2011-02-01

    The aim of this study was to investigate whether nebivolol has added effects on left ventricular (LV) dysfunction and remodeling early after myocardial infarction (MI) beyond its β₁-receptor-blocking properties. Nebivolol is a third-generation selective β₁-adrenoreceptor antagonist that stimulates endothelial cell nitric oxide (NO) production and prevents vascular reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. Both endothelial NO synthase-derived NO production and NADPH oxidase activation are critical modulators of LV dysfunction early after MI. Mice with extensive anterior MI (n = 90) were randomized to treatment with nebivolol (10 mg/kg/day), metoprolol-succinate (20 mg/kg/day), or placebo for 30 days starting on day 1 after surgery. Infarct size was similar among the groups. Both β₁-adrenergic receptor antagonists caused a similar decrease in heart rate. Nebivolol therapy improved endothelium-dependent vasorelaxation and increased early endothelial progenitor cells 4 weeks after MI compared with metoprolol and placebo. Nebivolol, but not metoprolol, inhibited cardiac NADPH oxidase activation after MI, as detected by electron spin resonance spectroscopy analysis. Importantly, nebivolol, but not metoprolol, improved LV dysfunction 4 weeks after MI (LV ejection fraction: nebivolol vs. metoprolol vs. placebo: 32 ± 4% vs. 17 ± 6% vs. 19 ± 4%; nebivolol vs. metoprolol: p < 0.05) and was associated with improved survival 4 weeks post-MI compared with placebo. Nebivolol had a significantly more pronounced inhibitory effect on cardiomyocyte hypertrophy after MI compared with metoprolol. Nebivolol improves LV dysfunction and survival early after MI likely beyond the effects provided by conventional β₁-receptor blockade. Nebivolol induced effects on NO-mediated endothelial function, early endothelial progenitor cells and inhibition of myocardial NADPH oxidase likely contribute to these beneficial effects of nebivolol early

  10. SCF promotes dental pulp progenitor migration, neovascularization, and collagen remodeling – potential applications as a homing factor in dental pulp regeneration

    PubMed Central

    Pan, Shuang; Dangaria, Smit; Gopinathan, Gokul; Yan, Xiulin; Lu, Xuanyu; Kolokythas, Antonia; Niu, Yumei; Luan, Xianghong

    2014-01-01

    Stem cell factor (SCF) is a powerful chemokine that binds to the c-Kit receptor CD117 and has shown promise as a homing agent capable of progenitor cell recruitment. In the present study we have documented high levels of both SCF and its receptor c-Kit in differentiating dental pulp (DP) cells and in the sub-odontoblastic layer of Höhl. In vitro studies using human DP progenitors revealed a significant increase in cell proliferation after100nM SCF application, explained by a 2-fold upregulation in cyclin D3 and FGF2 cell cycle regulators, and a 7-fold increase in CDK4 expression. DP cell migration in the presence of SCF was up-regulated 2.7-fold after a 24 hour culture period, and this effect was accompanied by cytoskeletal rearrangement, a 1.5-fold increase in polymeric F-actin over G-actin, and a 1.8-fold increase in RhoA expression. Explaining the signaling effect of SCF on DP migration, PI3K/Akt and MEK/ERK pathway inhibitors were demonstrated to significantly reduce DP cell migration, while SCF alone doubled the number of migrated cells. ERK and AKT phosphorylation were dramatically upregulated already 3-5 minutes after SCF addition to the culture medium and declined thereafter, classifying SCF as a fast acting chemokine. When applied as an agent to promote tissue regeneration in subcutaneously implanted collagen sponges, SCF resulted in a 7-fold increase in the cell number in the implanted tissue construct, a more than 9-fold increase in capillaries, as well as collagen sponge remodeling and collagen fiber neogenesis. Together, these studies demonstrate the suitability of SCF as a potent aid in the regeneration of dental pulp and other mesenchymal tissues, capable of inducing cell homing, angiogenesis, and tissue remodeling. PMID:23703692

  11. Müller glial cells induce stem cell properties in retinal progenitors in vitro and promote their further differentiation into photoreceptors.

    PubMed

    Simón, María V; De Genaro, Pablo; Abrahan, Carolina E; de los Santos, Beatriz; Rotstein, Nora P; Politi, Luis E

    2012-02-01

    Using stem cells to replace lost neurons is a promising strategy for treating retinal neurodegenerative diseases. Among their multiple functions, Müller glial cells are retina stem cells, with a robust regenerative potential in lower vertebrates, which is much more restricted in mammals. In rodents, most retina progenitors exit the cell cycle immediately after birth, differentiate as neurons, and then cannot reenter the cell cycle. Here we demonstrate that, in mixed cultures with Müller glial cells, rat retina progenitor cells expressed stem cell properties, maintained their proliferative potential, and were able to preserve these properties and remain mitotically active after several consecutive passages. Notably, these progenitors retained the capacity to differentiate as photoreceptors, even after successive reseedings. Müller glial cells markedly stimulated differentiation of retina progenitors; these cells initially expressed Crx and then developed as mature photoreceptors that expressed characteristic markers, such as opsin and peripherin. Moreover, they were light responsive, insofar as they decreased their cGMP levels when exposed to light, and they also showed high-affinity glutamate uptake, a characteristic of mature photoreceptors. Our present findings indicate that, in addition to giving rise to new photoreceptors, Müller glial cells might instruct a pool of undifferentiated cells to develop and preserve stem cell characteristics, even after successive reseedings, and then stimulate their differentiation as functional photoreceptors. This complementary mechanism might contribute to enlarge the limited regenerative capacity of mammalian Müller cells.

  12. Sulindac Sulfide Reverses Aberrant Self-Renewal of Progenitor Cells Induced by the AML-Associated Fusion Proteins PML/RARα and PLZF/RARα

    PubMed Central

    Steinert, Gunnar; Oancea, Claudia; Roos, Jessica; Hagemeyer, Heike; Maier, Thorsten; Ruthardt, Martin; Puccetti, Elena

    2011-01-01

    Chromosomal translocations can lead to the formation of chimeric genes encoding fusion proteins such as PML/RARα, PLZF/RARα, and AML-1/ETO, which are able to induce and maintain acute myeloid leukemia (AML). One key mechanism in leukemogenesis is increased self renewal of leukemic stem cells via aberrant activation of the Wnt signaling pathway. Either X-RAR, PML/RARα and PLZF/RARα or AML-1/ETO activate Wnt signaling by upregulating γ-catenin and β-catenin. In a prospective study, a lower risk of leukemia was observed with aspirin use, which is consistent with numerous studies reporting an inverse association of aspirin with other cancers. Furthermore, a reduction in leukemia risk was associated with use of non-steroidal anti-inflammatory drug (NSAID), where the effects on AML risk was FAB subtype-specific. To better investigate whether NSAID treatment is effective, we used Sulindac Sulfide in X-RARα-positive progenitor cell models. Sulindac Sulfide (SSi) is a derivative of Sulindac, a NSAID known to inactivate Wnt signaling. We found that SSi downregulated both β-catenin and γ-catenin in X-RARα-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RARα-positive HSCs. The data presented herein show that SSi inhibits the leukemic cell growth as well as hematopoietic progenitors cells (HPCs) expressing PML/RARα, and it indicates that Sulindac is a valid molecular therapeutic approach that should be further validated using in vivo leukemia models and in clinical settings. PMID:21811629

  13. Sulindac sulfide reverses aberrant self-renewal of progenitor cells induced by the AML-associated fusion proteins PML/RARα and PLZF/RARα.

    PubMed

    Steinert, Gunnar; Oancea, Claudia; Roos, Jessica; Hagemeyer, Heike; Maier, Thorsten; Ruthardt, Martin; Puccetti, Elena

    2011-01-01

    Chromosomal translocations can lead to the formation of chimeric genes encoding fusion proteins such as PML/RARα, PLZF/RARα, and AML-1/ETO, which are able to induce and maintain acute myeloid leukemia (AML). One key mechanism in leukemogenesis is increased self renewal of leukemic stem cells via aberrant activation of the Wnt signaling pathway. Either X-RAR, PML/RARα and PLZF/RARα or AML-1/ETO activate Wnt signaling by upregulating γ-catenin and β-catenin. In a prospective study, a lower risk of leukemia was observed with aspirin use, which is consistent with numerous studies reporting an inverse association of aspirin with other cancers. Furthermore, a reduction in leukemia risk was associated with use of non-steroidal anti-inflammatory drug (NSAID), where the effects on AML risk was FAB subtype-specific. To better investigate whether NSAID treatment is effective, we used Sulindac Sulfide in X-RARα-positive progenitor cell models. Sulindac Sulfide (SSi) is a derivative of Sulindac, a NSAID known to inactivate Wnt signaling. We found that SSi downregulated both β-catenin and γ-catenin in X-RARα-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RARα-positive HSCs. The data presented herein show that SSi inhibits the leukemic cell growth as well as hematopoietic progenitors cells (HPCs) expressing PML/RARα, and it indicates that Sulindac is a valid molecular therapeutic approach that should be further validated using in vivo leukemia models and in clinical settings.

  14. Conditioned media from human ovarian cancer endothelial progenitor cells induces ovarian cancer cell migration by activating epithelial-to-mesenchymal transition.

    PubMed

    Teng, L; Peng, S; Guo, H; Liang, H; Xu, Z; Su, Y; Gao, L

    2015-11-01

    Bone marrow-derived endothelial progenitor cells (EPCs) migrate to and engraft at ovarian cancer sites. Understanding the interactions between ovarian cancer cells and EPCs is fundamental for determining whether to harness EPC-tumor interactions for delivery of therapeutic agents or target them for intervention. Ovarian cancer cell lines (SKOV-3 and OVCAR-3) were cultured alone or in EPC-conditioned media (EPC-CM). Migration of ovarian cancer cells was detected by transwell chamber. N-cadherin and E-cadherin expression were analyzed by real-time reverse transcription PCR and western blot. EPC-CM can increase transforming growth factor-beta (TGF-β) secretion in SKOV-3 and OVCAR-3 cells. EPC-CM induced loss of ovarian cancer cell-cell junctions, downregulation of E-cadherin, upregulation of N-cadherin and acquisition of a fibroblastic phenotype, consistent with an epithelial-to-mesenchymal transition (EMT). The specific TGF-β inhibitor SB431542 abolished the SKOV-3 and OVCAR-3 ovarian cancer cell migration induced by EPC-CM. In SKOV-3 and OVCAR-3 cells, EPC-CM downregulated E-cadherin and concurrently upregulated N-cadherin. EPC-CM upregulated the expression of transcriptional repressors of E-cadherin, Snail and Twist. Treatment with SB431542 abolished the effects of EPC-CM on the relative expression levels of cadherin, Snail and Twist. This study demonstrates that TGF-β has a role in EPC-CM-induced ovarian cancer migration by activating EMT.

  15. Endothelial FoxM1 Mediates Bone Marrow Progenitor Cell-Induced Vascular Repair and Resolution of Inflammation following Inflammatory Lung Injury

    PubMed Central

    Zhao, Yidan D.; Huang, Xiaojia; Yi, Fan; Dai, Zhiyu; Qian, Zhijian; Tiruppathi, Chinnaswamy; Tran, Khiem; Zhao, You-Yang

    2015-01-01

    Adult stem cell treatment is a potential novel therapeutic approach for acute respiratory distress syndrome. Given the extremely low rate of cell engraftment, it is believed that these cells exert their beneficial effects via paracrine mechanisms. However, the endogenous mediator(s) in the pulmonary vasculature remains unclear. Employing the mouse model with endothelial cell (EC)-restricted disruption of FoxM1 (FoxM1 CKO), here we show that endothelial expression of the reparative transcriptional factor FoxM1 is required for the protective effects of bone marrow progenitor cells (BMPC) against LPS-induced inflammatory lung injury and mortality. BMPC treatment resulted in rapid induction of FoxM1 expression in WT but not FoxM1 CKO lungs. BMPC-induced inhibition of lung vascular injury, resolution of lung inflammation, and survival, as seen in WT mice, were abrogated in FoxM1 CKO mice following LPS challenge. Mechanistically, BMPC treatment failed to induce lung EC proliferation in FoxM1 CKO mice, which was associated with impaired expression of FoxM1 target genes essential for cell cycle progression. We also observed that BMPC treatment enhanced endothelial barrier function in WT, but not in FoxM1-deficient EC monolayers. Restoration of β-catenin expression in FoxM1-deficient ECs normalized endothelial barrier enhancement in response to BMPC treatment. These data demonstrate the requisite role of endothelial FoxM1 in the mechanism of BMPC-induced vascular repair to restore vascular integrity and accelerate resolution of inflammation, thereby promoting survival following inflammatory lung injury. PMID:24578354

  16. Circulating Progenitor Cells and Scleroderma

    PubMed Central

    2010-01-01

    Scleroderma (systemic sclerosis) is a disease of unknown origins that involves tissue ischemia and fibrosis in the skin and internal organs such as the lungs. The tissue ischemia is due to a lack of functional blood vessels and an inability to form new blood vessels. Bone marrow–derived circulating endothelial progenitor cells play a key role in blood vessel repair and neovascularization. Scleroderma patients appear to have defects in the number and function of circulating endothelial progenitor cells. Scleroderma patients also develop fibrotic lesions, possibly as the result of tissue ischemia. Fibroblast-like cells called fibrocytes that differentiate from a different pool of bone marrow–derived circulating progenitor cells seem to be involved in this process. Manipulating the production, function, and differentiation of circulating progenitor cells represents an exciting new possibility for treating scleroderma. PMID:18638425

  17. Polymeric materials for neovascularization

    NASA Astrophysics Data System (ADS)

    DeVolder, Ross John

    Revascularization therapies have emerged as a promising strategy to treat various acute and chronic wounds, cardiovascular diseases, and tissue defects. It is common to either administer proangiogenic growth factors, such as vascular endothelial growth factor (VEGF), or transplant cells that endogenously express multiple proangiogenic factors. Additionally, these strategies utilize a wide variety of polymeric systems, including hydrogels and biodegradable plastics, to deliver proangiogenic factors in a sophisticated manner to maintain a sustained proangiogenic environment. Despite some impressive results in rebuilding vascular networks, it is still a challenging task to engineer mature and functional neovessels in target tissues, because of the increasing complexities involved with neovascularization applications. To resolve these challenges, this work aims to design a wide variety of proangiogenic biomaterial systems with tunable properties used for neovascularization therapies. This thesis describes the design of several biomaterial systems used for the delivery of proangiogenic factors in neovascularization therapies, including: an electrospun/electrosprayed biodegradable plastic patch used for directional blood vessel growth (Chapter 2), an alginate-g-pyrrole hydrogel system that biochemically stimulates cellular endogenous proangiogenic factor expression (Chapter 3), an enzyme-catalyzed alginate-g-pyrrole hydrogel system for VEGF delivery (Chapter 4), an enzyme-activated alginate-g-pyrrole hydrogel system with systematically controllable electrical and mechanical properties (Chapter 5), and an alginate-g-pyrrole hydrogel that enables the decoupled control of electrical conductivity and mechanical rigidity and is use to electrically stimulate cellular endogenous proangiogenic factor expression (Chapter 6). Overall, the biomaterial systems developed in this thesis will be broadly useful for improving the quality of a wide array of molecular and cellular based

  18. Management of neovascular glaucoma.

    PubMed

    Ajvazi, Halil; Goranci, Ilhami; Lutaj, Pajtim

    2013-01-01

    Neovascular glaucoma is an atrophic optic neuropathy resulting from the neovascularization of the iridocorneal angle increasing the intraocular pressure. To show the incidence of NVG in comparison to the other types of glaucoma and to compare with the relevant literature data and other referent clinics. In this study were included 116 patients with NVG, of whom 75 or 64.7% male and 41 or 35.3% female, treated from January 2003 until February 2013. Visual acuity damages from NVG, were classified as big damages with 84.7% of cases and minor damages with 15.3% of cases. Cases with heavy damages were the cases with blindness, L+P+/- up to V = 0.3 and cases with slightly damages with V = 0.4-1.0. NVG caused by PDR with 52 cases or 44.8% and CRVO with 12 cases or 10.3%. We should be focused on prevention of diabetic retinopathy which requires interdisciplinary cooperation. In cases when diabetic retinopathy is present, we have to advise patients to undergo PRP as soon as possible, since it is the only way to prevent NVG and heavy consequences.

  19. Chemotaxis and transendothelial migration of CD34(+) hematopoietic progenitor cells induced by the inflammatory mediator leukotriene D4 are mediated by the 7-transmembrane receptor CysLT1.

    PubMed

    Bautz, F; Denzlinger, C; Kanz, L; Möhle, R

    2001-06-01

    Recent studies suggest that bone marrow (BM)-derived chemotactic mediators such as chemokines play key roles in hematopoietic stem cell trafficking. Lipid mediators, particularly leukotrienes, are involved in leukocyte chemotaxis during inflammation but have also been detected in the normal BM. Therefore, the effects of leukotrienes on hematopoietic progenitor cells were analyzed. Cysteinyl leukotrienes, particularly leukotriene D4 (LTD4), induced strong intracellular calcium fluxes and actin polymerization in mobilized and BM CD34(+) progenitors. Chemotaxis and in vitro transendothelial migration of CD34(+) and more primitive CD34(+)/CD38(-) cells were 2-fold increased by LTD4 at an optimum concentration of 25 to 50 nM. Accordingly, CD34(+) cells expressed the 7-transmembrane LTD4 receptor CysLT1 by reverse transcriptase-polymerase chain reaction and Western blot. Effects of LTD4 were suppressed by the CysLT1 receptor antagonist MK-571 and reduced by pertussis toxin. In contrast, LTB4 induced strong responses only in mature granulocytes. LTD4-induced calcium fluxes were also observed in granulocytes but were not reduced by MK-571, suggesting that these effects were mediated by other receptors (eg, CysLT2) rather than by CysLT1. In addition, expression of 5-lipoxygenase, the key enzyme of leukotriene biosynthesis, was detected in both hematopoietic progenitor cells and mature leukocytes. The study concludes that the functionally active LTD4 receptor CysLT1 is preferentially expressed in immature hematopoietic progenitor cells. LTD4 released in the BM might regulate progenitor cell trafficking and could also act as an autocrine mediator of hematopoiesis. This would be a first physiologic effect of cysteinyl leukotrienes apart from the many known pathophysiologic actions related to allergy and inflammation. (Blood. 2001;97:3433-3440)

  20. Implants for draining neovascular glaucoma.

    PubMed Central

    Molteno, A C; Van Rooyen, M M; Bartholomew, R S

    1977-01-01

    The implant design, surgical technique, and pharmacological methods of controlling bleb fibrosis, used to treat neovascular glaucoma, are described, together with the results of 14 operations performed on 12 eyes. Images PMID:843508

  1. Investigation of inhibitory effects on EPC-mediated neovascularization by different bisphosphonates for cancer therapy

    PubMed Central

    ZIEBART, THOMAS; ZIEBART, JOHANNA; GAUSS, LEONIE; PABST, ANDREAS; ACKERMANN, MAXIMILIAN; SMEETS, RALF; KONERDING, MORITZ A.; WALTER, CHRISTIAN

    2013-01-01

    Bisphosphonates (BPs) are potent drugs, used in metastatic cancer-like prostate or breast carcinoma. In recent studies, besides reduced bone remodeling, influences on angiogenesis and neovascularization were reported. Since BPs have the tendency to accumulate in the bones, the biological effect of various nitrogen- and non-nitrogen BPs on endothelial progenitor cells (EPCs) that originated from bone marrow and mobilized under physiological and pathophysiological conditions, such as tumor neovascularization, was investigated. EPCs subsequent to 72-h treatment with different concentrations of bisphosphonates comprised the non-nitrogen-containing BP clodronate and the nitrogen-containing BPs ibandronate, pamidronate and zoledronate. After incubation, biological activity was measured by using the migration boyden chamber assay and measurement of the colony-forming ability. Nitrogen-containing BPs inhibited the migration ability and differentiation of EPCs in a dose-dependent manner, as compared to the non-treated control groups. More specifically, the nitrogen-containing BP zoledronate significantly inhibited angiogenesis and neovascularization. Clodronate was less distinct on EPC function. To underline the importance of neovascularization in the context of tumor angiogenesis, EPC functions were significantly influenced in a dose-dependent manner by nitrogen-containing BPs. From these findings, we conclude that especially the nitrogen-containing BPs, such as zoledronate, are potential anticancer agents through the inhibition of neovascularization. PMID:24649016

  2. Neovascularization in Left Atrial Myxoma

    PubMed Central

    Dubey, Laxman; Chaurasia, Amit Kumar

    2012-01-01

    Abstract We report a case with a left atrial mass who underwent coronary angiography to rule out coronary artery disease. Coronary angiography revealed an anomalous tortuous vascular structure originating from the left circumflex coronary artery to the left atrial tumor suggestive of neovascularization. Preoperative coronary angiography is useful for coronary artery evaluation and also provides additional information regarding the feeding vessel supplying the mass. PMID:24757609

  3. [Neovascular glaucoma--etipathogeny and diagnosis].

    PubMed

    Călugăru, D; Călugăru, M

    2012-01-01

    Neovascular glaucoma is defined as an iris and/or anterior chamber angle neovascularization associated with increased intraocular presure. It is a secondary glaucoma most frequently determined by a severe retinal ischemia. The most common diseases responsible for the development of neovascular glaucoma are diabetic retinopathy, ischemic central retinal vein occlusion and ocular ischemic syndrome; the uncommon causes include ocular radiation, ocular tumors, uveitis and other miscellaneous conditions. Vascular endothelial growth factor is an important and probably predominant agent in the pathogenesis of both intraocular neovascularization and neovascular glaucoma. The evolution of clinical and histopathological changes from predisposing conditions to the occurrence of rubeosis iridis as well as neovacular glaucoma is divided into four grades that is prerubeotic, preglaucomatous, open-angle and angle closure glaucoma stages.

  4. Biology and Flow Cytometry of Proangiogenic Hematopoietic Progenitors Cells

    PubMed Central

    Rose, Jonathan A.; Erzurum, Serpil; Asosingh, Kewal

    2015-01-01

    During development hematopoiesis and neovascularization are closely linked to each other via a common bipotent stem cell called the hemangioblast that gives rise to both hematopoietic cells and endothelial cells. In postnatal life this functional connection between the vasculature and hematopoiesis is maintained by a subset of hematopoietic progenitor cells endowed with the capacity to differentiate into potent proangiogenic cells. These proangiogenic hematopoietic progenitors comprise a specific subset of bone marrow-derived cells that homes to sites of neovascularization and possess potent paracrine angiogenic activity. There is emerging evidence that this subpopulation of hematopoietic progenitors plays a critical role in vascular health and disease. Their angiogenic activity is distinct from putative “endothelial progenitor cells” that become structural cells of the endothelium by differentiation into endothelial cells. Proangiogenic hematopoietic progenitor cell research requires multi-disciplinary expertise in flow cytometry, hematology and vascular biology. This review provides a comprehensive overview of proangiogenic hematopoietic progenitor cell biology and flow cytometric methods to detect these cells in the peripheral blood circulation and bone marrow. PMID:25418030

  5. Human tears reveal insights into corneal neovascularization.

    PubMed

    Zakaria, Nadia; Van Grasdorff, Sigi; Wouters, Kristien; Rozema, Jos; Koppen, Carina; Lion, Eva; Cools, Nathalie; Berneman, Zwi; Tassignon, Marie-José

    2012-01-01

    Corneal neovascularization results from the encroachment of blood vessels from the surrounding conjunctiva onto the normally avascular cornea. The aim of this study is to identify factors in human tears that are involved in development and/or maintenance of corneal neovascularization in humans. This could allow development of diagnostic tools for monitoring corneal neovascularization and combination monoclonal antibody therapies for its treatment. In an observational case-control study we enrolled a total of 12 patients with corneal neovascularization and 10 healthy volunteers. Basal tears along with reflex tears from the inferior fornix, superior fornix and using a corneal bath were collected along with blood serum samples. From all patients, ocular surface photographs were taken. Concentrations of the pro-angiogenic cytokines interleukin (IL)-6, IL-8, Vascular Endothelial Growth Factor (VEGF), Monocyte Chemoattractant Protein 1 (MCP-1) and Fas Ligand (FasL) were determined in blood and tear samples using a flow cytometric multiplex assay. Our results show that the concentration of pro-angiogenic cytokines in human tears are significantly higher compared to their concentrations in serum, with highest levels found in basal tears. Interestingly, we could detect a significantly higher concentration of IL- 6, IL-8 and VEGF in localized corneal tears of patients with neovascularized corneas when compared to the control group. This is the first study of its kind demonstrating a significant difference of defined factors in tears from patients with neovascularized corneas as compared to healthy controls. These results provide the basis for future research using animal models to further substantiate the role of these cytokines in the establishment and maintenance of corneal neovascularization.

  6. Human Tears Reveal Insights into Corneal Neovascularization

    PubMed Central

    Wouters, Kristien; Rozema, Jos; Koppen, Carina; Lion, Eva; Cools, Nathalie; Berneman, Zwi; Tassignon, Marie-José

    2012-01-01

    Corneal neovascularization results from the encroachment of blood vessels from the surrounding conjunctiva onto the normally avascular cornea. The aim of this study is to identify factors in human tears that are involved in development and/or maintenance of corneal neovascularization in humans. This could allow development of diagnostic tools for monitoring corneal neovascularization and combination monoclonal antibody therapies for its treatment. In an observational case-control study we enrolled a total of 12 patients with corneal neovascularization and 10 healthy volunteers. Basal tears along with reflex tears from the inferior fornix, superior fornix and using a corneal bath were collected along with blood serum samples. From all patients, ocular surface photographs were taken. Concentrations of the pro-angiogenic cytokines interleukin (IL)-6, IL-8, Vascular Endothelial Growth Factor (VEGF), Monocyte Chemoattractant Protein 1 (MCP-1) and Fas Ligand (FasL) were determined in blood and tear samples using a flow cytometric multiplex assay. Our results show that the concentration of pro-angiogenic cytokines in human tears are significantly higher compared to their concentrations in serum, with highest levels found in basal tears. Interestingly, we could detect a significantly higher concentration of IL- 6, IL-8 and VEGF in localized corneal tears of patients with neovascularized corneas when compared to the control group. This is the first study of its kind demonstrating a significant difference of defined factors in tears from patients with neovascularized corneas as compared to healthy controls. These results provide the basis for future research using animal models to further substantiate the role of these cytokines in the establishment and maintenance of corneal neovascularization. PMID:22590547

  7. The role of biomaterial properties in peri-implant neovascularization

    NASA Astrophysics Data System (ADS)

    Raines, Andrew Lawrence

    An understanding of the interactions between orthopaedic and dental implant surfaces with the surrounding host tissue is critical in the design of next generation implants to improve osseointegration and clinical success rates. Critical to the process of osseointegration is the rapid establishment of a patent neovasculature in the peri-implant space to allow for the delivery of oxygen, nutrients, and progenitor cells. The central aim of this thesis is to understand how biomaterials regulate cellular and host tissue response to elicit a pro-angiogenic microenvironment at the implant/tissue interface. To address this question, the studies performed in this thesis aim to (1) determine whether biomaterial surface properties can modulate the production and secretion of pro-angiogenic growth factors by cells, (2) determine the role of integrin and VEGF-A signaling in the angiogenic response of cells to implant surface features, and (3) to determine whether neovascularization in response to an implanted biomaterial can be modulated in vivo. The results demonstrate that biomaterial surface microtopography and surface energy can increase the production of pro-angiogenic growth factors by osteoblasts and that these growth factors stimulate the differentiation of endothelial cells in a paracrine manner and the results suggest that signaling through specific integrin receptors affects the production of angiogenic growth factors by osteoblast-like cells. Further, using a novel in vivo model, the results demonstrate that a combination of a rough surface microtopography and high surface energy can improve bone-to-implant contact and neovascularization. The results of these studies also suggest that VEGF-A produced by osteoblast-like cells has both an autocrine and paracrine effect. VEGF-A silenced cells exhibited reduced production of both pro-angiogenic and osteogenic growth factors in response to surface microtopgraphy and surface energy, and conditioned media from VEGF

  8. NADPH Oxidase-Derived Overproduction of Reactive Oxygen Species Impairs Postischemic Neovascularization in Mice with Type 1 Diabetes

    PubMed Central

    Ebrahimian, Téni G; Heymes, Christophe; You, Dong; Blanc-Brude, Olivier; Mees, Barend; Waeckel, Ludovic; Duriez, Micheline; Vilar, José; Brandes, Ralph P.; Levy, Bernard I.; Shah, Ajay M.; Silvestre, Jean-Sébastien

    2006-01-01

    We hypothesized that diabetes-induced oxidative stress may affect postischemic neovascularization. The response to unilateral femoral artery ligation was studied in wild-type or gp91phox-deficient control or type 1 diabetic mice or in animals treated with the anti-oxidant N-acetyl-l-cysteine (NAC) or with in vivo electrotransfer of a plasmid encoding dominant-negative Rac1 (50 μg) for 21 days. Postischemic neovascularization was reduced in diabetic mice in association with down-regulated vascular endothelial growth factor-A protein levels. In diabetic animals vascular endothelial growth factor levels and postischemic neovascularization were restored to nondiabetic levels by the scavenging of reactive oxygen species (ROS) by NAC administration or the inhibition of ROS generation by gp91phox deficiency or by administration of dominant-negative Rac1. Finally, diabetes reduced the ability of adherent bone marrow-derived mononuclear cells (BM-MNCs) to differentiate into endothelial progenitor cells. Treatment with NAC (3 mmol/L), apocynin (200 μmol/L), or the p38MAPK inhibitor LY333351 (10 μmol/L) up-regulated the number of endothelial progenitor cell colonies derived from diabetic BM-MNCs by 1.5-, 1.6-, and 1.5-fold, respectively (P < 0.05). In the ischemic hindlimb model, injection of diabetic BM-MNCs isolated from NAC-treated or gp91phox-deficient diabetic mice increased neovascularization by ∼1.5-fold greater than untreated diabetic BM-MNCs (P < 0.05). Thus, inhibition of NADPH oxidase-derived ROS overproduction improves the angiogenic and vasculogenic processes and restores postischemic neovascularization in type 1 diabetic mice. PMID:16877369

  9. NADPH oxidase-derived overproduction of reactive oxygen species impairs postischemic neovascularization in mice with type 1 diabetes.

    PubMed

    Ebrahimian, Téni G; Heymes, Christophe; You, Dong; Blanc-Brude, Olivier; Mees, Barend; Waeckel, Ludovic; Duriez, Micheline; Vilar, José; Brandes, Ralph P; Levy, Bernard I; Shah, Ajay M; Silvestre, Jean-Sébastien

    2006-08-01

    We hypothesized that diabetes-induced oxidative stress may affect postischemic neovascularization. The response to unilateral femoral artery ligation was studied in wild-type or gp91(phox)-deficient control or type 1 diabetic mice or in animals treated with the anti-oxidant N-acetyl-l-cysteine (NAC) or with in vivo electrotransfer of a plasmid encoding dominant-negative Rac1 (50 microg) for 21 days. Postischemic neovascularization was reduced in diabetic mice in association with down-regulated vascular endothelial growth factor-A protein levels. In diabetic animals vascular endothelial growth factor levels and postischemic neovascularization were restored to nondiabetic levels by the scavenging of reactive oxygen species (ROS) by NAC administration or the inhibition of ROS generation by gp91(phox) deficiency or by administration of dominant-negative Rac1. Finally, diabetes reduced the ability of adherent bone marrow-derived mononuclear cells (BM-MNCs) to differentiate into endothelial progenitor cells. Treatment with NAC (3 mmol/L), apocynin (200 micromol/L), or the p38MAPK inhibitor LY333351 (10 micromol/L) up-regulated the number of endothelial progenitor cell colonies derived from diabetic BM-MNCs by 1.5-, 1.6-, and 1.5-fold, respectively (P < 0.05). In the ischemic hindlimb model, injection of diabetic BM-MNCs isolated from NAC-treated or gp91(phox)-deficient diabetic mice increased neovascularization by approximately 1.5-fold greater than untreated diabetic BM-MNCs (P < 0.05). Thus, inhibition of NADPH oxidase-derived ROS overproduction improves the angiogenic and vasculogenic processes and restores postischemic neovascularization in type 1 diabetic mice.

  10. Perspectives of choroidal neovascularization therapy.

    PubMed

    Caputo, M; Zirpoli, H; Di Benedetto, R; De Nadai, K; Tecce, M F

    2011-02-01

    Vision loss secondary to Choroidal Neovascularization (CNV) is becoming a major disease condition in developed world. CNV is typically secondary to Age-related Macular Degeneration (AMD) and these conditions are major, and also substantially increasing, causes of blindness among aged people. Several therapeutic options are currently available to treat CNV with variable efficacy on disease progress. Among existing treatments there are laser photocoagulation, photodynamic therapies, local corticosteroids and, more recently, the use of anti-angiogenic factors. Although by these treatments very effective results are obtained and their further improvement is still possible, it is also reasonable and necessary to look for more successful and definitive alternatives. The research in this direction is already very active and it can be expected that applications of the more recent molecular technologies will bring important advances also for CNV. These will likely regard the use of gene therapy and of new target specific factors. Gene therapies methodologies are rapidly becoming closer to current clinical use and, since the eye is a particularly favourable organ for drug delivery, their ocular use is probably going to be among the first successful applications of these techniques. In addition to its specific technology, gene therapy requires the knowledge of specific genes to be modulated to adequately affect pathogenesis and progression of the disease in which has to be applied. This will also be true for the use of novel target specific drugs such as antibodies and other molecules able to affect cellular factors and pathways also related to disease development. For this reason, a major direction of future CNV therapies will be the identification of specific gene, gene products, metabolic pathways and metabolites related to the disease. This information, in addition to be suitable for gene and target specific therapies, will also allow the development of new procedures to

  11. Gene Therapies for Neovascular Age-Related Macular Degeneration.

    PubMed

    Pechan, Peter; Wadsworth, Samuel; Scaria, Abraham

    2014-12-18

    Pathological neovascularization is a key component of the neovascular form (also known as the wet form) of age-related macular degeneration (AMD) and proliferative diabetic retinopathy. Several preclinical studies have shown that antiangiogenesis strategies are effective for treating neovascular AMD in animal models. Vascular endothelial growth factor (VEGF) is one of the main inducers of ocular neovascularization, and several clinical trials have shown the benefits of neutralizing VEGF in patients with neovascular AMD or diabetic macular edema. In this review, we summarize several preclinical and early-stage clinical trials with intraocular gene therapies, which have the potential to reduce or eliminate the repeated intravitreal injections that are currently required for the treatment of neovascular AMD.

  12. CHOROIDAL NEOVASCULARIZATION SECONDARY TO ALEXANDRITE LASER EXPOSURE.

    PubMed

    Wang, Rui; Wykoff, Charles C; Christie, Lynsey; Croft, Daniel E; Major, James C; Fish, Richard H; Brown, David M

    2016-01-01

    To report macular photic trauma after accidental occupational exposure to a 750-nm Alexandrite laser and management of secondary choroidal neovascularization. Institutional review board-approved retrospective case report. A 30-year-old woman presented with immediate vision loss in her left eye after direct inadvertent exposure to a single discharge from an occupational 750-nm Alexandrite laser used for laser hair removal. Baseline Snellen visual acuity was 20/40 in the involved left eye. One week after the initial exposure, the patient experienced subjective visual decline to 20/50, was treated with oral prednisone, and then developed a subretinal hemorrhage (SRH) in the setting of choroidal neovascularization 2 weeks later, or 3 weeks after initial trauma. The patient subsequently received 5 intravitreal ranibizumab injections over 25 weeks with resolution of the SRH. Final visual acuity was 20/50. The present case documents development and management of subretinal hemorrhage associated with choroidal neovascularization following macular photic trauma after accidental occupational to a 750-nm Alexandrite laser.

  13. Photoacoustic detection of neovascularities in skin graft

    NASA Astrophysics Data System (ADS)

    Yamazaki, Mutsuo; Sato, Shunichi; Saitoh, Daizo; Ishihara, Miya; Okada, Yoshiaki; Ashida, Hiroshi; Obara, Minoru

    2005-04-01

    We previously proposed a new method for monitoring adhesion of skin graft by measuring photoacoustic (PA) signal originated from the neovascularities. In this study, immunohistochemical staining (IHC) with CD31 antibody was performed for grafted skin tissue to observe neovascularity, and the results were compared with PA signals. We also used a laser Doppler imaging (LDI) to observe blood flow in the grafted skin, and sensitivity of PA measurement and that of LDI were compared. In rat autograft models, PA signals were measured for the grafted skin at postgrafting times of 0-48 h. At 6 h postgrafting, PA signal was observed in the skin depth region of 500-600 mm, while the results of IHC showed that angiogenesis occurred at the depth of about 600 mm. Depths at which PA signal and angiogenesis were observed decreased with postgrafting time. These indicate that the PA signal observed at 6 h postgrafting originated from the neovascularities in the skin graft. Results of LDI showed no blood-originated signal before 48 h postgrafting. These findings suggest that PA measurement is effective in monitoring the adhesion of skin graft in early stage after transplantation.

  14. Ocular Sarcoidosis Limited to Retinal Vascular Ischemia and Neovascularization

    PubMed Central

    Dyer, Gawain; Shaikh, Saad

    2016-01-01

    A 59-year-old Caucasian male experienced progressive vision loss secondary to retinal vascular ischemia and neovascularization. At no time did he present with uveitis or vasculitis, and his serology tests were all negative. He was soon after diagnosed with sarcoidosis by hilar lymph node lung biopsy. Our patient demonstrates an atypical presentation of ocular sarcoidosis, manifesting solely as neovascularization and retinal vascular ischemia. Ophthalmologists should consider proliferative sarcoid retinopathy in patients with neovascularization. PMID:27928517

  15. Photodynamic therapy for treatment subretinal neovascularization

    NASA Astrophysics Data System (ADS)

    Avetisov, Sergey E.; Budzinskaja, Maria V.; Kiseleva, Tatyana N.; Balatskaya, Natalia V.; Gurova, Irina V.; Loschenov, Viktor B.; Shevchik, Sergey A.; Kuzmin, Sergey G.; Vorozhtsov, Georgy N.

    2007-07-01

    This work are devoted our experience with photodynamic therapy (PDT) with <> for patients with choroidal neovascularization (CNV). 18 patients with subfoveal CNV in age-related macular degeneration (AMD), 24 patients with subfoveal CNV in pathological myopia (PM) and 4 patients with subfoveal CNV associated with toxoplasmic retinochoroiditis were observed. CNV was 100% classic in all study patients. Standardized protocol refraction, visual acuity testing, ophthalmologic examinations, biomicroscopy, fluorescein angiography, and ultrasonography were performed before treatment and 1 month, 3 months, 6 months, and 1 year after treatment; were used to evaluate the results of photodynamic therapy with <> (0.02% solution of mixture sulfonated aluminium phtalocyanine 0.05 mg/kg, intravenously). A diode laser (<>, Inc, Moscow) was used operating in the range of 675 nm. Need for retreatment was based on fluorescein angiographic evidence of leakage at 3-month follow-up intervals. At 3, 6, 9 month 26 (56.5%) patients had significant improvement in the mean visual acuity. At the end of the 12-month minimal fluorescein leakage from choroidal neovascularization was seen in 12 (26.1%) patients and the mean visual acuity was slightly worse than 0.2 which was not statistically significant as compared with the baseline visual acuity. Patients with fluorescein leakage from CNV underwent repeated PDT with <>. 3D-mode ultrasound shown the decreasing thickness of chorioretinal complex in CNV area. Photodynamic therapy with <> can safely reduce the risk of severe vision loss in patients with predominantly classic subfoveal choroidal neovascularization secondary to AMD, PM and toxoplasmic retinochoroiditis.

  16. Enrichment and terminal differentiation of striated muscle progenitors in vitro

    SciTech Connect

    Becher, Ulrich M.; Breitbach, Martin; Sasse, Philipp; Garbe, Stephan; Ven, Peter F.M. van der; Fuerst, Dieter O.; Fleischmann, Bernd K.

    2009-10-01

    Enrichment and terminal differentiation of mammalian striated muscle cells is severely hampered by fibroblast overgrowth, de-differentiation and/or lack of functional differentiation. Herein we report a new, reproducible and simple method to enrich and terminally differentiate muscle stem cells and progenitors from mice and humans. We show that a single gamma irradiation of muscle cells induces their massive differentiation into structurally and functionally intact myotubes and cardiomyocytes and that these cells can be kept in culture for many weeks. Similar results are also obtained when treating skeletal muscle-derived stem cells and progenitors with Mitomycin C.

  17. Hyperoxia, Endothelial Progenitor Cell Mobilization, and Diabetic Wound Healing

    PubMed Central

    Liu, Zhao-Jun

    2008-01-01

    Abstract Diabetic foot disease is a major health problem, which affects 15% of the 200 million patients with diabetes worldwide. Diminished peripheral blood flow and decreased local neovascularization are critical factors that contribute to the delayed or nonhealing wounds in these patients. The correction of impaired local angiogenesis may be a key component in developing therapeutic protocols for treating chronic wounds of the lower extremity and diabetic foot ulcers. Endothelial progenitor cells (EPCs) are the key cellular effectors of postnatal neovascularization and play a central role in wound healing, but their circulating and wound-level numbers are decreased in diabetes, implicating an abnormality in EPC mobilization and homing mechanisms. The deficiency in EPC mobilization is presumably due to impairment of eNOS-NO cascade in bone marrow (BM). Hyperoxia, induced by a clinically relevant hyperbaric oxygen therapy (HBO) protocol, can significantly enhance the mobilization of EPCs from the BM into peripheral blood. However, increased circulating EPCs failed to reach to wound tissues. This is partly a result of downregulated production of SDF-1α in local wound lesions with diabetes. Administration of exogenous SDF-1α into wounds reversed the EPC homing impairment and, with hyperoxia, synergistically enhanced EPC mobilization, homing, neovascularization, and wound healing. Antioxid. Redox Signal. 10, 1869–1882. PMID:18627349

  18. Progenitor Cell Dysfunctions Underlie Some Diabetic Complications

    PubMed Central

    Rodrigues, Melanie; Wong, Victor W.; Rennert, Robert C.; Davis, Christopher R.; Longaker, Michael T.; Gurtner, Geoffrey C.

    2016-01-01

    Stem cells and progenitor cells are integral to tissue homeostasis and repair. They contribute to health through their ability to self-renew and commit to specialized effector cells. Recently, defects in a variety of progenitor cell populations have been described in both preclinical and human diabetes. These deficits affect multiple aspects of stem cell biology, including quiescence, renewal, and differentiation, as well as homing, cytokine production, and neovascularization, through mechanisms that are still unclear. More important, stem cell aberrations resulting from diabetes have direct implications on tissue function and seem to persist even after return to normoglycemia. Understanding how diabetes alters stem cell signaling and homeostasis is critical for understanding the complex pathophysiology of many diabetic complications. Moreover, the success of cell-based therapies will depend on a more comprehensive understanding of these deficiencies. This review has three goals: to analyze stem cell pathways dysregulated during diabetes, to highlight the effects of hyperglycemic memory on stem cells, and to define ways of using stem cell therapy to overcome diabetic complications. PMID:26079815

  19. Carotid intraplaque neovascularization quantification software (CINQS).

    PubMed

    Akkus, Zeynettin; van Burken, Gerard; van den Oord, Stijn C H; Schinkel, Arend F L; de Jong, Nico; van der Steen, Antonius F W; Bosch, Johan G

    2015-01-01

    Intraplaque neovascularization (IPN) is an important biomarker of atherosclerotic plaque vulnerability. As IPN can be detected by contrast enhanced ultrasound (CEUS), imaging-biomarkers derived from CEUS may allow early prediction of plaque vulnerability. To select the best quantitative imaging-biomarkers for prediction of plaque vulnerability, a systematic analysis of IPN with existing and new analysis algorithms is necessary. Currently available commercial contrast quantification tools are not applicable for quantitative analysis of carotid IPN due to substantial motion of the carotid artery, artifacts, and intermittent perfusion of plaques. We therefore developed a specialized software package called Carotid intraplaque neovascularization quantification software (CINQS). It was designed for effective and systematic comparison of sets of quantitative imaging biomarkers. CINQS includes several analysis algorithms for carotid IPN quantification and overcomes the limitations of current contrast quantification tools and existing carotid IPN quantification approaches. CINQS has a modular design which allows integrating new analysis tools. Wizard-like analysis tools and its graphical-user-interface facilitate its usage. In this paper, we describe the concept, analysis tools, and performance of CINQS and present analysis results of 45 plaques of 23 patients. The results in 45 plaques showed excellent agreement with visual IPN scores for two quantitative imaging-biomarkers (The area under the receiver operating characteristic curve was 0.92 and 0.93).

  20. Low-dose ionizing radiation induces therapeutic neovascularization in a pre-clinical model of hindlimb ischemia.

    PubMed

    Ministro, Augusto; de Oliveira, Paula; Nunes, Raquel J; Dos Santos Rocha, André; Correia, Adriana; Carvalho, Tânia; Rino, José; Faísca, Pedro; Becker, Jorg D; Goyri-O'Neill, João; Pina, Filomena; Poli, Esmeralda; Silva-Santos, Bruno; Pinto, Fausto; Mareel, Marc; Serre, Karine; Constantino Rosa Santos, Susana

    2017-06-01

    We have previously shown that low-dose ionizing radiation (LDIR) induces angiogenesis but there is no evidence that it induces neovascularization in the setting of peripheral arterial disease. Here, we investigated the use of LDIR as an innovative and non-invasive strategy to stimulate therapeutic neovascularization using a model of experimentally induced hindlimb ischemia (HLI). After surgical induction of unilateral HLI, both hindlimbs of female C57BL/6 mice were sham-irradiated or irradiated with four daily fractions of 0.3 Gy, in consecutive days and allowed to recover. We demonstrate that LDIR, significantly improved blood perfusion in the murine ischemic limb by stimulating neovascularization, as assessed by laser Doppler flow, capillary density, and collateral vessel formation. LDIR significantly increased the circulating levels of VEGF, PlGF, and G-CSF, as well as the number of circulating endothelial progenitor cells (EPCs) mediating their incorporation to ischemic muscles. These effects were dependent upon LDIR exposition on the ischemic niche (thigh and shank regions). In irradiated ischemic muscles, these effects were independent of the recruitment of monocytes and macrophages. Importantly, LDIR induced a durable and simultaneous up-regulation of a repertoire of pro-angiogenic factors and their receptors in endothelial cells (ECs), as evident in ECs isolated from the irradiated gastrocnemius muscles by laser capture microdissection. This specific mechanism was mediated via vascular endothelial growth factor (VEGF) receptor signaling, since VEGF receptor inhibition abrogated the LDIR-mediated gene up-regulation and impeded the increase in capillary density. Finally, the vasculature in an irradiated non-ischemic bed was not affected and after 52 week of LDIR exposure no differences in the incidence of morbidity and mortality were seen. These findings disclose an innovative, non-invasive strategy to induce therapeutic neovascularization in a mouse

  1. Swept Source OCT Angiography of Neovascular Macular Telangiectasia Type 2

    PubMed Central

    Zhang, Qinqin; Wang, Ruikang K.; Chen, Chieh-Li; Legarreta, Andrew D.; Durbin, Mary K.; An, Lin; Sharma, Utkarsh; Stetson, Paul F.; Legarreta, John E.; Roisman, Luiz; Gregori, Giovanni; Rosenfeld, Philip J.

    2015-01-01

    Objective To image subretinal neovascularization in proliferative macular telangiectasia type 2 (MacTel2) using swept source optical coherence tomography based microangiography (OMAG). Study Design Patients with MacTel2 were enrolled in a prospective, observational study known as the MacTel Project and evaluated using a high-speed 1050nm swept-source OCT (SS-OCT) prototype system. The OMAG algorithm generated en face flow images from three retinal layers, as well as the region bounded by the outer retina and Bruch’s membrane, the choriocapillaris, and the remaining choroidal vasculature. The en face OMAG images were compared to images from fluorescein angiography (FA) and indocyanine green angiography (ICGA). Results Three eyes with neovascular MacTel2 were imaged. The neovascularization was best identified from the en face OMAG images that included a layer between the outer retinal boundary and Bruch’s membrane. OMAG images identified these abnormal vessels better than FA and were comparable to the images obtained using ICGA. In all three cases, OMAG identified choroidal vessels communicating with the neovascularization, and these choroidal vessels were evident in the two cases with ICGA imaging. In one case, monthly injections of bevacizumab reduced the microvascular complexity of the neovascularization, as well as the telangiectatic changes within the retinal microvasculature. In another case, less frequent bevacizumab therapy was associated with growth of the subretinal neovascular complex. Conclusions OMAG imaging provided detailed, depth-resolved information about subretinal neovascularization in MacTel2 eyes demonstrating superiority to FA imaging and similarities to ICGA imaging for documenting the retinal microvascular changes, the size and extent of the neovascular complex, the communications between the neovascular complex and the choroidal circulation, and the response to monthly bevacizumab therapy. PMID:26457402

  2. Risk of choroidal neovascularization among the uveitides

    PubMed Central

    Baxter, Sally L.; Pistilli, Maxwell; Pujari, Siddharth S.; Liesegang, Teresa L.; Suhler, Eric B.; Thorne, Jennifer E.; Foster, C. Stephen; Jabs, Douglas A.; Levy-Clarke, Grace A.; Nussenblatt, Robert B.; Rosenbaum, James T.; Kempen, John H.

    2013-01-01

    Purpose To evaluate the risk, risk factors, and visual impact of choroidal neovascularization (CNV) in uveitis cases. Design Retrospective cohort study Methods Standardized medical record review at five tertiary centers. Results Among 15,137 uveitic eyes (8,868 patients), CNV was rare in the cases of anterior or intermediate uveitis. Among the 4,041 eyes (2,307 patients) with posterior or panuveitis, 81 (2.0%) presented with CNV. Risk factors included posterior uveitis in general and specific uveitis syndromes affecting the outer retina/retinal pigment epithelium (RPE)/choroid interface. Among the 2,364 eyes (1,357 patients) with posterior or panuveitis and free of CNV at the time of cohort entry, the cumulative two-year incidence of CNV was 2.7% (95% confidence interval (95%CI): 1.8-3.5%). Risk factors for incident CNV included currently active inflammation (adjusted HR [aHR] 2.13, 95%CI: 1.26-3.60), preretinal neovascularization (aHR 3.19, 95%CI: 1.30-7.80), and prior diagnosis of CNV in the contralateral eye (aHR 5.79, 95%CI: 2.77-12.09). Among specific syndromes, the incidence was greater in Vogt-Koyanagi-Harada Syndrome (aHR 3.37, 95%CI: 1.52-7.46), and punctate inner choroiditis (aHR 8.67, 95%CI: 2.83-26.54). Incident CNV was associated with two lines’ loss of visual acuity (+0.19 logMAR units, 95%CI: 0.079–0.29) from the preceding visit. Conclusions CNV is an uncommon complication of uveitis associated with visual impairment, which more commonly occurs in forms affecting the outer retina/RPE/choroid interface, during periods of inflammatory activity, in association with preretinal neovascularization, and in second eyes of patients with unilateral CNV. Because CNV is treatable, a systematic approach to early detection in high-risk patients may be appropriate. PMID:23795984

  3. Retinitis pigmentosa associated with peripheral sea fan neovascularization.

    PubMed

    Kadayifçilar, S; Eldem, B; Kiratli, H

    2000-10-01

    To describe a case with retinitis pigmentosa associated with sea fan type retinal neovascularization. Complete ocular examination including fluorescein angiography was performed in a 9-year-old girl. Ophthalmoscopically, in addition to arteriolar narrowing and bone corpuscular pigmentation of both retinae, a vascular lesion with surrounding intraretinal exudation was noted in the upper equatorial region of the right eye. On fluorescein angiography, the lesion stained in the form of a sea fan neovascularization. Sea fan type of neovascularization can be seen in association with retinitis pigmentosa. Fluorescein angiography is important in identifying the exact nature of such a lesion.

  4. [Micro-trephination of the limbus in neovascular glaucoma].

    PubMed

    Sergienko, N M; Torchinskaia, N V

    2001-01-01

    Microtrephination of the limb was carried out for neovascular glaucoma on 112 eyes. The technique of the operation is described and its results are analyzed. Electric microtrephine (0.6 mm) allows making perforations in the limb as oblique microchannels connecting the anterior chamber and the subconjunctival space. Mitomycin C, an antimetabolic drug, was used for neovascularization control near the channels and filtration pad. High efficiency, low invasiveness, and low incidence of postoperative complications recommend this operation as an alternative method for the treatment of neovascular glaucoma.

  5. Beals-Hecht syndrome and choroidal neovascularization.

    PubMed

    Gallego-Pinazo, Roberto; López-Lizcano, Ruth; Millán, José María; Arevalo, J Fernando; Mullor, J Luis; Díaz-Llopis, Manuel

    2010-08-09

    To describe a case of choroidal neovascularization (CNV) in a female diagnosed with Beals-Hecht syndrome. A retrospective, interventional case is described in a 26-year-old female complaining of metamorphopsia and visual loss in her left eye (counting fingers). The fluorescein angiogram and the optical coherence tomography supported the diagnosis of CNV. Intravitreal ranibizumab was administered. After the third intravitreal ranibizumab, her visual acuity improved to 0.8 and the morphology of the macular area was restored. To our knowledge this is the first report of CNV in Beals-Hecht syndrome treated with ranibizumab. Self-monitoring by periodically performing Amsler grid test is strongly recommended in these patients in order to achieve an early diagnosis of eventual CNV and avoid visual acuity loss.

  6. Targeting Neovascularization in Ischemic Retinopathy: Recent Advances

    PubMed Central

    Al-Shabrawey, Mohamed; Elsherbiny, Mohamed; Nussbaum, Julian; Othman, Amira; Megyerdi, Sylvia; Tawfik, Amany

    2014-01-01

    Pathological retinal neovascularization (RNV) is a common micro-vascular complication in several retinal diseases including retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration and central vein occlusion. The current therapeutic modalities of RNV are invasive and although they may slow or halt the progression of the disease they are unlikely to restore normal acuity. Therefore, there is an urgent need to develop treatment modalities, which are less invasive and therefore associated with fewer procedural complications and systemic side effects. This review article summarizes our understanding of the pathophysiology and current treatment of RNV in ischemic retinopathies; lists potential therapeutic targets; and provides a framework for the development of future treatment modalities. PMID:25598837

  7. Neovascular glaucoma after helium ion irradiation for uveal melanoma

    SciTech Connect

    Kim, M.K.; Char, D.H.; Castro, J.L.; Saunders, W.M.; Chen, G.T.; Stone, R.D.

    1986-02-01

    Neovascular glaucoma developed in 22 of 169 uveal melanoma patients treated with helium ion irradiation. Most patients had large melanomas; no eyes containing small melanomas developed anterior segment neovascularization. The mean onset of glaucoma was 14.1 months (range, 7-31 months). The incidence of anterior segment neovascularization increased with radiation dosage; there was an approximately three-fold increase at 80 GyE versus 60 GyE of helium ion radiation (23% vs. 8.5%) (P less than 0.05). Neovascular glaucoma occurred more commonly in larger tumors; the incidence was not affected by tumor location, presence of subretinal fluid, nor rate of tumor regression. Fifty-three percent of patients had some response with intraocular pressures of 21 mmHg or less to a combination of antiglaucoma treatments.

  8. Genetic modification of corneal neovascularization in Dstncorn1 mice

    PubMed Central

    Kawakami-Schulz, Sharolyn V.; Sattler, Shannon G.; Doebley, Anna-Lisa; Ikeda, Akihiro; Ikeda, Sakae

    2013-01-01

    Mutations in the gene for destrin (Dstn), an actin depolymerizing factor, lead to corneal abnormalities in mice. A null mutation in Dstn, termed Dstncorn1, isolated and maintained in the A.BY background (A.BY Dstncorn1), results in corneal epithelial hyperproliferation, inflammation and neovascularization. We previously reported that neovascularization in the cornea of Dstncorn1 on the C57BL/6 background (B6.A.BY-Dstncorn1) mice is significantly reduced when compared to A.BY Dstncorn1 mice, suggesting the existence of genetic modifier(s). The purpose of this study is to identify the genetic basis of difference in cornea neovascularization between A.BY Dstncorn1 and B6.A.BY-Dstncorn1 mice. We generated N2 mice for a whole genome scan by backcrossing F1 progeny (A.BY Dstncorn1 X B6.A.BY-Dstncorn1) to B6.A.BY-Dstncorn1 mice. N2 progeny were quantitatively phenotyped for the extent of corneal neovascularization and genotyped for markers across the mouse genome. We identified significant association of variability in corneal neovascularization with a locus on chromosome 3 (Chr3). The validity of identified quantitative trait locus (QTL) was tested using B6 consomic mice carrying Chr3 from A/J mice. Dstncorn1 mice from F1 and F2 intercrosses (B6.A.BY- Dstncorn1 x C57BL/6J-Chr 3A/J/NaJ) were phenotyped for the extent of corneal neovascularization. This analysis showed that mice carrying the A/J allele at the QTL show significantly increased neovascularization. Our results indicate the existence of a modifier that genetically interacts with the Dstn gene. This modifier demonstrates allelic differences between C57BL6 and A.BY or A/J. The modifier is sufficient to increase neovascularization in Dstncorn1 mice. PMID:23929036

  9. Resident vascular progenitor cells.

    PubMed

    Torsney, Evelyn; Xu, Qingbo

    2011-02-01

    Homeostasis of the vessel wall is essential for maintaining its function, including blood pressure and patency of the lumen. In physiological conditions, the turnover rate of vascular cells, i.e. endothelial and smooth muscle cells, is low, but markedly increased in diseased situations, e.g. vascular injury after angioplasty. It is believed that mature vascular cells have an ability to proliferate to replace lost cells normally. On the other hand, recent evidence indicates stem/progenitor cells may participate in vascular repair and the formation of neointimal lesions in severely damaged vessels. It was found that all three layers of the vessels, the intima, media and adventitia, contain resident progenitor cells, including endothelial progenitor cells, mesenchymal stromal cells, Sca-1+ and CD34+ cells. Data also demonstrated that these resident progenitor cells could differentiate into a variety of cell types in response to different culture conditions. However, collective data were obtained mostly from in vitro culture assays and phenotypic marker studies. There are many unanswered questions concerning the mechanism of cell differentiation and the functional role of these cells in vascular repair and the pathogenesis of vascular disease. In the present review, we aim to summarize the data showing the presence of the resident progenitor cells, to highlight possible signal pathways orchestrating cell differentiation toward endothelial and smooth muscle cells, and to discuss the data limitations, challenges and controversial issues related to the role of progenitors. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".

  10. Neovascularization and functional recovery after intracerebral hemorrhage is conditioned by the Tp53 Arg72Pro single-nucleotide polymorphism

    PubMed Central

    Rodríguez, Cristina; Sobrino, Tomás; Agulla, Jesús; Bobo-Jiménez, Verónica; Ramos-Araque, María E; Duarte, Juan J; Gómez-Sánchez, José C; Bolaños, Juan P; Castillo, José; Almeida, Ángeles

    2017-01-01

    Intracerebral hemorrhage (ICH) is a devastating subtype of stroke that lacks effective therapy and reliable prognosis. Neovascularization following ICH is an essential compensatory response that mediates brain repair and modulates the clinical outcome of stroke patients. However, the mechanism that dictates this process is unknown. Bone marrow-derived endothelial progenitor cells (EPCs) promote endothelial repair and contribute to ischemia-induced neovascularization. The human Tp53 gene harbors a common single-nucleotide polymorphism (SNP) at codon 72, which yields an arginine-to-proline amino-acidic substitution (Arg72Pro) that modulates the apoptotic activity of the p53 protein. Previously, we found that this SNP controls neuronal susceptibility to ischemia-induced apoptosis in vitro. Here, we evaluated the impact of the Tp53 Arg72Pro SNP on vascular repair and functional recovery after ICH. We first analyzed EPC mobilization and functional outcome based on the modified Rankin scale scores in a hospital-based cohort of 78 patients with non-traumatic ICH. Patients harboring the Pro allele of the Tp53 Arg72Pro SNP showed higher levels of circulating EPC-containing CD34+ cells, EPC-mobilizing cytokines – vascular endothelial growth factor and stromal cell-derived factor-1α – and good functional outcome following ICH, when compared with the homozygous Arg allele patients, which is compatible with increased neovascularization. To assess directly whether Tp53 Arg72Pro SNP regulated neovascularization after ICH, we used the humanized Tp53 Arg72Pro knock-in mice, which were subjected to the collagenase-induced ICH. The brain endothelial cells of the Pro allele-carrying mice were highly resistant to ICH-mediated apoptosis, which facilitated cytokine-mediated EPC mobilization, cerebrovascular repair and functional recovery. However, these processes were not observed in the Arg allele-carrying mice. These results reveal that the Tp53 Arg72Pro SNP determines

  11. Neovascularization and functional recovery after intracerebral hemorrhage is conditioned by the Tp53 Arg72Pro single-nucleotide polymorphism.

    PubMed

    Rodríguez, Cristina; Sobrino, Tomás; Agulla, Jesús; Bobo-Jiménez, Verónica; Ramos-Araque, María E; Duarte, Juan J; Gómez-Sánchez, José C; Bolaños, Juan P; Castillo, José; Almeida, Ángeles

    2017-01-01

    Intracerebral hemorrhage (ICH) is a devastating subtype of stroke that lacks effective therapy and reliable prognosis. Neovascularization following ICH is an essential compensatory response that mediates brain repair and modulates the clinical outcome of stroke patients. However, the mechanism that dictates this process is unknown. Bone marrow-derived endothelial progenitor cells (EPCs) promote endothelial repair and contribute to ischemia-induced neovascularization. The human Tp53 gene harbors a common single-nucleotide polymorphism (SNP) at codon 72, which yields an arginine-to-proline amino-acidic substitution (Arg72Pro) that modulates the apoptotic activity of the p53 protein. Previously, we found that this SNP controls neuronal susceptibility to ischemia-induced apoptosis in vitro. Here, we evaluated the impact of the Tp53 Arg72Pro SNP on vascular repair and functional recovery after ICH. We first analyzed EPC mobilization and functional outcome based on the modified Rankin scale scores in a hospital-based cohort of 78 patients with non-traumatic ICH. Patients harboring the Pro allele of the Tp53 Arg72Pro SNP showed higher levels of circulating EPC-containing CD34(+) cells, EPC-mobilizing cytokines - vascular endothelial growth factor and stromal cell-derived factor-1α - and good functional outcome following ICH, when compared with the homozygous Arg allele patients, which is compatible with increased neovascularization. To assess directly whether Tp53 Arg72Pro SNP regulated neovascularization after ICH, we used the humanized Tp53 Arg72Pro knock-in mice, which were subjected to the collagenase-induced ICH. The brain endothelial cells of the Pro allele-carrying mice were highly resistant to ICH-mediated apoptosis, which facilitated cytokine-mediated EPC mobilization, cerebrovascular repair and functional recovery. However, these processes were not observed in the Arg allele-carrying mice. These results reveal that the Tp53 Arg72Pro SNP determines

  12. Effect of endogenous bone marrow derived stem cells induced by AMD-3100 on expanded ischemic flap.

    PubMed

    Jeong, Hii-Sun; Lee, Hye-Kyung; Tark, Kwan-Chul; Lew, Dae-Hyun; Koh, Yoon-Woo; Kim, Chul-Hoon; Seo, In-Suck

    2014-11-01

    The purpose of this study was to devise an expanded ischemic flap model and to investigate the role of AMD-3100 (Plerixafor, chemokine receptor 4 inhibitor) in this model by confirming its effect on mobilization of stem cells from the bone marrow. Male Sprague-Dawley rats were used as an animal research model. The mobilization of stem cells from the bone marrow was confirmed in the AMD-3100-treated group. The fractions of endothelial progenitor cells (EPC) and the vascular endothelial growth factor receptor (VEGFR) 2+ cells in the peripheral blood were increased in groups treated with AMD-3100. The expression of vascular endothelial growth factor (VEGF) was increased in response to expansion or AMD injection. The expression of stromal cell derived factor (SDF)-1 and VEGFR2 were increased only in unexpanded flap treated with AMD-3100. Treatment with AMD-3100 increased both the number and area of blood vessels. However, there were no statistically significant differences in the survival area or physiologic microcirculation in rats from the other groups. This endogenous neovascularization induced by AMD-3100 may be a result of the increase in both the area and number of vessels, as well as paracrine augmentation of the expression of VEGF and EPCs. However, the presence of a tissue expander under the flap could block the neovascularization between the flap and the recipient regardless of AMD-3100 treatment and expansion.

  13. Diagnostic Challenges in Inflammatory Choroidal Neovascular Membranes.

    PubMed

    Bansal, Reema; Bansal, Pooja; Gupta, Amod; Gupta, Vishali; Dogra, Mangat R; Singh, Ramandeep; Katoch, Deeksha

    2017-08-01

    To describe the clinical presentations of inflammatory choroidal neovascular membranes (CNVMs) and factors leading to their delayed diagnosis. Retrospective analysis of chart records and digital images of 60 patients (73 eyes) with inflammatory CNVM (January 1998 to December 2013) to obtain demographic and clinical details, particularly the time of the first documentation of inflammatory CNVM by the uveitis specialist, time of its actual appearance on digital images, and the earliest clinical indicators of a CNVM. In total, 14 (19.2%) eyes had a delayed diagnosis of inflammatory CNVMs, of which five developed significant visual loss. The earliest clinical indicators of CNVM that were overlooked initially due to their subtle appearance, included a tiny subretinal hemorrhage (five eyes), peripapillary halo/fluid/scar (eight eyes), and a subfoveal scar (one eye). The causes of uveitis in these eyes included Vogt-Koyanagi-Harada disease (five eyes, 35.7%), tubercular uveitis (five eyes, 35.7%), idiopathic (three eyes, 21.4%), and sympathetic ophthalmia (one eye, 7.1%). Presence of significant background fundus scarring, sunset glow fundus, visually significant cataract, poorly dilating pupil, media haze due to vitritis, cystoid macular edema, and multiple chorioretinal scars in these eyes probably predisposed to delayed detection of an underlying CNVM. A high index of suspicion and comparison of serial fundus photographs to identify the earliest clues of inflammatory CNVMs are important to prevent diagnostic delays and poorer outcomes.

  14. Redox Regulation of Stem/Progenitor Cells and Bone Marrow Niche

    PubMed Central

    Urao, Norifumi; Ushio-Fukai, Masuko

    2013-01-01

    Bone marrow (BM)-derived stem and progenitor cell functions including self-renewal, differentiation, survival, migration, proliferation and mobilization are regulated by unique cell-intrinsic signals and -extrinsic signals provided by their microenvironment, also termed the ‘niche’. Reactive oxygen species (ROS), especially hydrogen peroxide (H2O2), play important roles in regulating stem and progenitor cell function in various physiologic and pathologic responses. The low level of H2O2 in quiescent hematopoietic stem cells (HSCs) contributes to maintain their stemness, whereas a higher level of H2O2 within HSCs or their niche promotes differentiation, proliferation, migration, and survival of HSCs or stem/progenitor cells. Major sources of ROS are NADPH oxidase and mitochondria. In response to ischemic injury, ROS derived from NADPH oxidase are increased in the BM microenvironment, which is required for hypoxia and HIF1α expression and expansion throughout the BM. This, in turn, promotes progenitor cell expansion and mobilization from BM, leading to reparative neovascularization and tissue repair. In pathophysiological states such as aging, atherosclerosis, heart failure, hypertension and diabetes, excess amounts of ROS create an inflammatory and oxidative microenvironment, which induces cell damage and apoptosis of stem and progenitor cells. Understanding the molecular mechanisms of how ROS regulate the functions of stem and progenitor cells and their niche in physiological and pathological conditions will lead to the development of novel therapeutic strategies. PMID:23085514

  15. Parametric imaging of tumor perfusion and neovascular morphology using ultrasound

    NASA Astrophysics Data System (ADS)

    Hoyt, Kenneth

    2015-03-01

    A new image processing strategy is detailed for the simultaneous measurement of tumor perfusion and neovascular morphology parameters from a sequence of dynamic contrast-enhanced ultrasound (DCE-US) images. A technique for locally mapping tumor perfusion parameters using skeletonized neovascular data is also introduced. Simulated images were used to test the neovascular skeletonization technique and variance (error) of relevant parametric estimates. Preliminary DCE-US image datasets were collected in 6 female patients diagnosed with invasive breast cancer and using a Philips iU22 ultrasound system equipped with a L9-3 MHz transducer and Definity contrast agent. Simulation data demonstrates that neovascular morphology parametric estimation is reproducible albeit measurement error can occur at a lower signal-to-noise ratio (SNR). Experimental results indicate the feasibility of our approach to performing both tumor perfusion and neovascular morphology measurements from DCE-US images. Future work will expand on our initial clinical findings and also extent our image processing strategy to 3-dimensional space to allow whole tumor characterization.

  16. Neovascular growth in an experimental alkali corneal burn model.

    PubMed

    Figueroa-Ortiz, L C; Martín Rodríguez, O; García-Ben, A; García-Campos, J

    2014-08-01

    To analyse the length and area of corneal surface occupied by vessels, and their location in an experimental model of alkali burn-induced corneal neovascularization. An injury to the central cornea of the right eye in 91 Sprague-Dawley rats was induced using a silver nitrate pencil. The rats were divided in 7 groups that were sacrificed 2, 4, 6, 8, 10, 12 and 14 days post-injury, and then perfused with a mixture of Chinese ink in PBS -phosphate buffer saline-. Corneas were flat-mounted processed and divided in 4 quadrants. Corneal neovascular growth parameters (length and area) and the location of these vessels were performed blind. The results were statistically analysed. Neovascular growth was observed from day 2, reaching its maximum peak in length and area on the 12th day post-injury. A slight reduction in corneal neovascularization was observed after this day. The vessels were initially located in the middle third of the stroma and tended to be observed in the anterior third during the course of the experiment. Neovascularisation was observed on day 2 post-injury in all sectors of corneal surface. Neovascular growth was uniform during the experiment. Neovessels were located in the middle and anterior third of the cornea. Copyright © 2012 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

  17. Lack of netrin-4 modulates pathologic neovascularization in the eye

    PubMed Central

    Kociok, Norbert; Crespo-Garcia, Sergio; Liang, Yong; Klein, Sabrina V.; Nürnberg, Christina; Reichhart, Nadine; Skosyrski, Sergej; Moritz, Eva; Maier, Anna-Karina; Brunken, William J.; Strauß, Olaf; Koch, Manuel; Joussen, Antonia M.

    2016-01-01

    Netrins are a family of matrix-binding proteins that function as guidance signals. Netrin-4 displays pathologic roles in tumorigenesis and neovascularization. To answer the question whether netrin-4 acts either pro- or anti-angiogenic, angiogenesis in the retina was assessed in Ntn-4−/− mice with oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV), mimicking hypoxia-mediated neovascularization and inflammatory mediated angiogenesis. The basement membrane protein netrin-4 was found to be localised to mature retinal blood vessels. Netrin-4, but not netrin-1 mRNA expression, increased in response to relative hypoxia and recovered to normal levels at the end of blood vessel formation. No changes in the retina were found in normoxic Ntn-4−/− mice. In OIR, Ntn-4−/− mice initially displayed larger avascular areas which recovered faster to revascularization. Ganzfeld electroretinography showed faster recovery of retinal function in Ntn-4−/− mice. Expression of netrin receptors, Unc5H2 (Unc-5 homolog B, C. elegans) and DCC (deleted in colorectal carcinoma), was found in Müller cells and astrocytes. Laser-induced neovascularization in Nnt-4−/− mice did not differ to that in the controls. Our results indicate a role for netrin-4 as an angiogenesis modulating factor in O2-dependent vascular homeostasis while being less important during normal retinal developmental angiogenesis or during inflammatory neovascularization. PMID:26732856

  18. Choroidal neovascularization in a child with traumatic choroidal rupture: clinical and ultrastructural findings.

    PubMed

    Abri, Adele; Binder, Susanne; Pavelka, Margit; Tittl, Michael; Neumüller, Josef

    2006-07-01

    Choroidal neovascularization in children is uncommon and mostly associated with inflammation, infectious diseases or trauma. The clinical and histological findings of a choroidal neovascular membrane that developed in a 9-year-old boy after traumatic choroidal rupture are reported.

  19. The Crab Nebula's progenitor

    NASA Technical Reports Server (NTRS)

    Nomoto, K.; Sugimoto, D.; Sparks, W. M.; Fesen, R. A.; Gull, T. R.; Miyaji, S.

    1982-01-01

    The initial mass of the Crab Nebula's progenitor star is estimated by comparing the observed nebular chemical abundances with detailed evolutionary calculations for 2.4- and 2.6-solar-mass helium cores of stars with masses of 8 to 10 solar masses. The results indicate that the mass of the Crab's progenitor was between the upper limit of about 8 solar masses for carbon deflagration and the lower limit of about 9.5 solar masses set by the dredge-up of the helium layer before the development of the helium-burning convective region. A scenario is outlined for the evolution of the progenitor star. It is suggested that the Crab Nebula was probably the product of an electron-capture supernova.

  20. Angiotensin Type 1 Receptor Blocker Reduces Intimal Neovascularization and Plaque Growth in Apolipoprotein E–Deficient Mice

    PubMed Central

    Cheng, Xian Wu; Song, Haizhen; Sasaki, Takeshi; Hu, Lina; Inoue, Aiko; Bando, Yasuko K.; Shi, Guo-Ping; Kuzuya, Masafumi; Okumura, Kenji; Murohara, Toyoaki

    2012-01-01

    The interactions between the renin-angiotensin system and neovascularization in atherosclerotic plaque development are unclear. We investigated the effects of angiotensin II type 1 receptor antagonism in the pathogenesis of atherosclerosis in apolipoprotein E–deficient (ApoE−/−) mice with a special focus on plaque neovascularization. ApoE−/− mice fed a high-fat diet were randomly assigned to 1 of 2 groups and administered vehicle or olmesartan for 12 weeks. Quantification of plaque areas at the aortic root and in the thoracic and abdominal aorta revealed that, in all 3 of the regions, olmesartan reduced intimal neovessel density and the mRNA levels of toll-like receptor (TLR) 2 and TLR4. Olmesartan increased the levels of collagen and elastin, reduced the level of macrophages in the aortic root, and reduced the mRNA and the activity of matrix metalloproteinase (MMP) 2 in aortic roots and thoracic aortas. Aortic ring assay revealed that olmesartan-treated ApoE−/− mice had a markedly lower angiogenic response than that of untreated ApoE−/− mice. Bone marrow–derived endothelial progenitor cell-like c-Kit+ cells from olmesartan-treated ApoE−/− mice showed marked impairment of cellular functions and lower expression of TLR2/TLR4 and MMP-2 compared with those of untreated controls. MMP-2 deficiency reduced intimal neovessel density and atherosclerotic lesion formation. Olmesartan and small-interfering RNA targeting TLR2 reduced the levels of TLR2, and MMP-2 mRNA induced angiotensin II in cultured endothelial cells. Angiotensin II type 1 receptor antagonism appears to inhibit intimal neovascularization in ApoE−/− mice, partly by reducing TLR2/TLR4-mediated inflammatory action and MMP activation, thus decreasing atherosclerotic plaque growth and increasing plaque instability. PMID:21464389

  1. Treatment of choroidal neovascularization in high myopia.

    PubMed

    Montero, Javier A; Ruiz-Moreno, Jose M

    2010-05-01

    High myopia affects approximately 2% of general population, and is a major cause of legal blindness in many developed countries. Choroidal neovascularization (CNV) is the most common vision-threatening complication of high myopia. Different therapeutic approaches have been attempted such as thermal laser photocoagulation, surgery and photodynamic therapy with verteporfin (PDT). The visual outcome of these therapies has been reported to be better than the natural history of the condition. However, the limited visual acuity improvement after PDT monotherapy and the appearance of subretinal fibrosis and chorioretinal atrophy prompted the association of other therapies. In the past few years a tremendous advance in the knowledge of the mechanisms underling CNV secondary to high myopia and age related macular degeneration has been achieved, leading to new therapeutic targets and novel drugs and combined therapies. These new therapeutic weapons have been designed to achieve a selective shut down of choroidal new vessels. Recent reviews have been published on the natural history and therapies for myopic CNV. Ohno-Matsui reported on the natural history of the condition as well as the outcome of laser photocoagulation, surgical extraction of CNV, foveal translocation and photodynamic therapy on myopic CNV in the short-term. Soubrane et al reviewed the new advances on surgery, laser photocoagulation and PDT, considering some of the potential effects of triamcinolone, pegaptanib and ranibizumab in CNV secondary to age related macular degeneration (AMD). Novack et al reported on the pharmacological therapy of CNV in AMD. The aim of this review is to summarize the recent advances in myopic CNV pathophysiology and the new therapeutic targets and drugs that are changing the clinical management of myopic CNV.

  2. Cell trafficking of endothelial progenitor cells in tumor progression.

    PubMed

    de la Puente, Pilar; Muz, Barbara; Azab, Feda; Azab, Abdel Kareem

    2013-07-01

    Blood vessel formation plays an essential role in many physiologic and pathologic processes, including normal tissue growth and healing, as well as tumor progression. Endothelial progenitor cells (EPC) are a subtype of stem cells with high proliferative potential that are capable of differentiating into mature endothelial cells, thus contributing to neovascularization in tumors. In response to tumor-secreted cytokines, EPCs mobilize from the bone marrow to the peripheral blood, home to the tumor site, and differentiate to mature endothelial cells and secrete proangiogenic factors to facilitate vascularization of tumors. In this review, we summarize the expression of surface markers, cytokines, receptors, adhesion molecules, proteases, and cell signaling mechanisms involved in the different steps (mobilization, homing, and differentiation) of EPC trafficking from the bone marrow to the tumor site. Understanding the biologic mechanisms of EPC cell trafficking opens a window for new therapeutic targets in cancer.

  3. Co-culture of Retinal and Endothelial Cells Results in the Modulation of Genes Critical to Retinal Neovascularization.

    PubMed

    Kumar, Ravindra; Harris-Hooker, Sandra; Kumar, Ritesh; Sanford, Gary

    2011-11-23

    Neovascularization (angiogenesis) is a multistep process, controlled by opposing regulatory factors, which plays a crucial role in several ocular diseases. It often results in vitreous hemorrhage, retinal detachment, neovascularization glaucoma and subsequent vision loss. Hypoxia is considered to be one of the key factors to trigger angiogenesis by inducing angiogenic factors (like VEGF) and their receptors mediated by hypoxia inducible factor-1 (HIF-1α) a critical transcriptional factor. Another factor, nuclear factor kappa B (NFκB) also regulates many of the genes required for neovascularization, and can also be activated by hypoxia. The aim of this study was to elucidate the mechanism of interaction between HRPC and HUVEC that modulates a neovascularization response. Human retinal progenitor cells (HRPC) and human umbilical vein endothelial cells (HUVEC) were cultured/co-cultured under normoxia (control) (20% O2) or hypoxia (1% O2) condition for 24 hr. Controls were monolayer cultures of each cell type maintained alone. We examined the secretion of VEGF by ELISA and influence of conditioned media on blood vessel growth (capillary-like structures) via an angiogenesis assay. Total RNA and protein were extracted from the HRPC and HUVEC (cultured and co-cultured) and analyzed for the expression of VEGF, VEGFR-2, NFκB and HIF-1α by RT-PCR and Western blotting. The cellular localization of NFκB and HIF-1α were studied by immunofluorescence and Western blotting. We found that hypoxia increased exogenous VEGF expression 4-fold in HRPC with a further 2-fold increase when cultured with HUVEC. Additionally, we found that hypoxia induced the expression of the VEGF receptor (VEGFR-2) for HRPC co-cultured with HUVEC. Hypoxia treatment significantly enhanced (8- to 10-fold higher than normoxia controls) VEGF secretion into media whether cells were cultured alone or in a co-culture. Also, hypoxia was found to result in a 3- and 2-fold increase in NFκB and HIF-1α m

  4. Intrastromal Delivery of Bevacizumab Using Microneedles to Treat Corneal Neovascularization

    PubMed Central

    Kim, Yoo C.; Grossniklaus, Hans E.; Edelhauser, Henry F.; Prausnitz, Mark R.

    2014-01-01

    Purpose. This study tested the hypothesis that highly targeted intrastromal delivery of bevacizumab using coated microneedles allows dramatic dose sparing compared with subconjunctival and topical delivery for treatment of corneal neovascularization. Methods. Stainless steel microneedles 400 μm in length were coated with bevacizumab. A silk suture was placed in the cornea approximately 1 mm from the limbus to induce corneal neovascularization in the eyes of New Zealand white rabbits that were divided into different groups: untreated, microneedle delivery, topical eye drop, and subconjunctival injection of bevacizumab. All drug treatments were initiated 4 days after suture placement and area of neovascularization was measured daily by digital photography for 18 days. Results. Eyes treated once with 4.4 μg bevacizumab using microneedles reduced neovascularization compared with untreated eyes by 44% (day 18). Eyes treated once with 2500 μg bevacizumab using subconjunctival injection gave similar results to microneedle-treated eyes. Eyes treated once with 4.4 μg subconjunctival bevacizumab showed no significant effect compared with untreated eyes. Eyes treated with 52,500 μg bevacizumab by eye drops three times per day for 14 days reduced the neovascularization area compared with untreated eyes by 6% (day 18), which was significantly less effective than the single microneedle treatment. Visual exam and histological analysis showed no observable effect of microneedle treatment on corneal transparency or microanatomical structure. Conclusions. This study shows that microneedles can target drug delivery to corneal stroma in a minimally invasive way and demonstrates effective suppression of corneal neovascularization after suture-induced injury using a much lower dose compared with conventional methods. PMID:25212779

  5. Clinical correlates of common corneal neovascular diseases: a literature review

    PubMed Central

    Abdelfattah, Nizar Saleh; Amgad, Mohamed; Zayed, Amira A; Salem, Hamdy; Elkhanany, Ahmed E; Hussein, Heba; Abd El-Baky, Nawal

    2015-01-01

    A large subset of corneal pathologies involves the formation of new blood and lymph vessels (neovascularization), leading to compromised visual acuity. This article aims to review the clinical causes and presentations of corneal neovascularization (CNV) by examining the mechanisms behind common CNV-related corneal pathologies, with a particular focus on herpes simplex stromal keratitis, contact lenses-induced keratitis and CNV secondary to keratoplasty. Moreover, we reviewed CNV in the context of different types of corneal transplantation and keratoprosthesis, and summarized the most relevant treatments available so far. PMID:25709930

  6. Endothelial Progenitor Cells in Sprouting Angiogenesis: Proteases Pave the Way.

    PubMed

    Laurenzana, A; Fibbi, G; Margheri, F; Biagioni, A; Luciani, C; Del Rosso, M; Chillà, A

    2015-01-01

    Sprouting angiogenesis consists of the expansion and remodelling of existing vessels, where the vascular sprouts connect each other to form new vascular loops. Endothelial Progenitor Cells (EPCs) are a subtype of stem cells, with high proliferative potential, able to differentiate into mature Endothelial Cells (ECs) during the neovascularization process. In addition to this direct structural role EPCs improve neovascularization, also secreting numerous pro-angiogenic factors able to enhance the proliferation, survival and function of mature ECs, and other surrounding progenitor cells. While sprouting angiogenesis by mature ECs involves resident ECs, the vasculogenic contribution of EPCs is a high hurdle race. Bone marrowmobilized EPCs have to detach from the stem cell niche, intravasate into bone marrow vessels, reach the hypoxic area or tumour site, extravasate and incorporate into the new vessel lumen, thus complementing the resident mature ECs in sprouting angiogenesis. The goal of this review is to highlight the role of the main protease systems able to control each of these steps. The pivotal protease systems here described, involved in vascular patterning in sprouting angiogenesis, are the matrix-metalloproteinases (MMPs), the serineproteinases urokinase-type plasminogen activator (uPA) associated with its receptor (uPAR) and receptorassociated plasminogen/plasmin, the neutrophil elastase and the cathepsins. Since angiogenesis plays a critical role not only in physiological but also in pathological processes, such as in tumours, controlling the contribution of EPCs to the angiogenic process, through the regulation of the protease systems involved, could yield new opportunities for the therapeutic prospect of efficient control of pathological angiogenesis.

  7. Bone marrow transplantation transfers age-related susceptibility to neovascular remodeling in murine laser-induced choroidal neovascularization.

    PubMed

    Espinosa-Heidmann, Diego G; Malek, Goldis; Mettu, Priyatham S; Caicedo, Alejandro; Saloupis, Peter; Gach, Sarah; Dunnon, Askia K; Hu, Peng; Spiga, Maria-Grazia; Cousins, Scott W

    2013-11-13

    Neovascular remodeling (NVR), the progression of small capillaries into large-caliber arterioles with perivascular fibrosis, represents a major therapeutic challenge in neovascular age-related macular degeneration (AMD). Neovascular remodeling occurs after laser-induced choroidal neovascularization (CNV) in aged but not young mice. Additionally, bone marrow-derived cells, including macrophages, endothelial precursor cells, and mesenchymal precursor cells, contribute to CNV severity. In this study, we investigated the impact of aged bone marrow transplantation (BMT) on the degree of fibrosis, size, and vascular morphology of CNV lesions in a mouse model of laser-induced CNV. Young (2 months) and old (16 months) mice were transplanted with green fluorescent protein (GFP)-labeled bone marrow isolated from either young or old donors. Laser CNV was induced 1 month following transplant, and eyes were analyzed via choroidal flat mounts and immunohistochemistry 1 month postlaser. The identity of cells infiltrating CNV lesions was determined using specific markers for the labeled transplanted cells (GFP+), macrophages (F4/80+), perivascular mesenchymal-derived cells (smooth muscle actin, SMA+), and endothelial cells (CD31+). Bone marrow transplantation from aged mice transferred susceptibility to NVR into young recipients. Inversely, transplantation of young marrow into old mice prevented NVR, preserving small size and minimal fibrosis. Mice with NVR demonstrated a greater relative contribution of marrow-derived SMA+ perivascular mesenchymal cells as compared to other cells. Our findings indicate that the status of bone marrow is an important determining factor of neovascular severity. Furthermore, we find that perivascular mesenchymal cells, rather than endothelial cells, derived from aged bone marrow may contribute to increased CNV severity in this murine model of experimental neovascularization.

  8. Bone Marrow Transplantation Transfers Age-Related Susceptibility to Neovascular Remodeling in Murine Laser-Induced Choroidal Neovascularization

    PubMed Central

    Espinosa-Heidmann, Diego G.; Malek, Goldis; Mettu, Priyatham S.; Caicedo, Alejandro; Saloupis, Peter; Gach, Sarah; Dunnon, Askia K.; Hu, Peng; Spiga, Maria-Grazia; Cousins, Scott W.

    2013-01-01

    Purpose. Neovascular remodeling (NVR), the progression of small capillaries into large-caliber arterioles with perivascular fibrosis, represents a major therapeutic challenge in neovascular age-related macular degeneration (AMD). Neovascular remodeling occurs after laser-induced choroidal neovascularization (CNV) in aged but not young mice. Additionally, bone marrow–derived cells, including macrophages, endothelial precursor cells, and mesenchymal precursor cells, contribute to CNV severity. In this study, we investigated the impact of aged bone marrow transplantation (BMT) on the degree of fibrosis, size, and vascular morphology of CNV lesions in a mouse model of laser-induced CNV. Methods. Young (2 months) and old (16 months) mice were transplanted with green fluorescent protein (GFP)-labeled bone marrow isolated from either young or old donors. Laser CNV was induced 1 month following transplant, and eyes were analyzed via choroidal flat mounts and immunohistochemistry 1 month postlaser. The identity of cells infiltrating CNV lesions was determined using specific markers for the labeled transplanted cells (GFP+), macrophages (F4/80+), perivascular mesenchymal-derived cells (smooth muscle actin, SMA+), and endothelial cells (CD31+). Results. Bone marrow transplantation from aged mice transferred susceptibility to NVR into young recipients. Inversely, transplantation of young marrow into old mice prevented NVR, preserving small size and minimal fibrosis. Mice with NVR demonstrated a greater relative contribution of marrow-derived SMA+ perivascular mesenchymal cells as compared to other cells. Conclusions. Our findings indicate that the status of bone marrow is an important determining factor of neovascular severity. Furthermore, we find that perivascular mesenchymal cells, rather than endothelial cells, derived from aged bone marrow may contribute to increased CNV severity in this murine model of experimental neovascularization. PMID:24135751

  9. Relationship between neovascularization and clinical severity in Achilles tendinopathy in 556 paired measurements.

    PubMed

    De Jonge, S; Warnaars, J L F; De Vos, R J; Weir, A; van Schie, H T M; Bierma-Zeinstra, S M A; Verhaar, J A N; Tol, J L

    2014-10-01

    Neovascularization is frequently observed in tendinopathy. Previous studies have focused on the role of neovascularization in Achilles tendinopathy, but have been conducted in small series. It is still unclear whether the degree of neovascularization is related to severity of symptoms. The purpose was to study the relationship between ultrasonographic neovascularization and clinical severity in patients with Achilles tendinopathy. In this prospective cohort study, data on 127 patients (141 tendons) were assembled from databases of three clinical trials. All patients followed an eccentric exercise program. The Öhberg neovascularization score (0-4+) and Victorian Institute of Sports Assessment-Achilles (VISA-A) score (split into domains: pain, function and activity) were collected during baseline and follow-up. The relationship between neovascularization and VISA-A score was calculated. At baseline, 107 tendons (76%) showed some degree of neovascularization. In 556 coupled measurements, neovascularization was weakly related to the VISA-A score [Exp (B) 1.017, 95% confidence interval (CI), 1.007-1.026]. No significant relationship was found between neovascularization and the pain domain (P = 0.277) and the activity domain (P = 0.283), but there was between neovascularization and the function domain of the VISA-A score [Exp (B) = 1.067, 95% CI 1.018-1.119]. In conclusion, neovascularization in Achilles tendinopathy is weakly related to clinical severity, mainly based on the function domain of the VISA-A score.

  10. [Intravitreal ranibizumab therapy for choroidal neovascularization secondary to pathological myopia].

    PubMed

    Lukács, Regina; Sándor, Gábor; Resch, Miklós; Szabó, Antal; Barcsay, György; Ecsedy, Mónika; Szepessy, Zsuzsanna; Nagy, Zoltán Zsolt; Papp, András

    2017-04-01

    Pathological myopia is one of the leading causes of vision loss worldwide, especially among young people of working age. Choroidal neovascularization is one of the most important cause of visual impairment in pathological myopia. To evaluate the efficacy of intravitreal ranibizumab for the treatment of myopic choroidal neovascularization. In this retrospective analysis 14 eyes of 14 patients (mean age: 61 ± 17 years) with myopic choroidal neovascularization were treated with intravitreal ranibizumab as needed. Best-corrected visual acuity, thickness of choroidal neovascularization lesion and the number of injections were assessed. The mean visual acuity changed from 55.8 ± 19.3 letters to 64.8 + 15.5 at 12 months (p = 0.0414), and 62.6 ± 16.3 during follow-up time (p = 0.2896). Mean follow-up time was 19.7 ± 23.9 months, average number of injections was 2.8 ± 2.1. Visual acuity declined in four patients despite the treatment. Intravitreal ranibizumab is an effective therapy in pathological myopia. Some patients experience deterioration of visual acuity despite of treatment. Orv. Hetil., 2017, 158(15), 579-586.

  11. A Mouse Model for Laser-induced Choroidal Neovascularization.

    PubMed

    Shah, Ronil S; Soetikno, Brian T; Lajko, Michelle; Fawzi, Amani A

    2015-12-27

    The mouse laser-induced choroidal neovascularization (CNV) model has been a crucial mainstay model for neovascular age-related macular degeneration (AMD) research. By administering targeted laser injury to the RPE and Bruch's membrane, the procedure induces angiogenesis, modeling the hallmark pathology observed in neovascular AMD. First developed in non-human primates, the laser-induced CNV model has come to be implemented into many other species, the most recent of which being the mouse. Mouse experiments are advantageously more cost-effective, experiments can be executed on a much faster timeline, and they allow the use of various transgenic models. The miniature size of the mouse eye, however, poses a particular challenge when performing the procedure. Manipulation of the eye to visualize the retina requires practice of fine dexterity skills as well as simultaneous hand-eye-foot coordination to operate the laser. However, once mastered, the model can be applied to study many aspects of neovascular AMD such as molecular mechanisms, the effect of genetic manipulations, and drug treatment effects. The laser-induced CNV model, though useful, is not a perfect model of the disease. The wild-type mouse eye is otherwise healthy, and the chorio-retinal environment does not mimic the pathologic changes in human AMD. Furthermore, injury-induced angiogenesis does not reflect the same pathways as angiogenesis occurring in an age-related and chronic disease state as in AMD. Despite its shortcomings, the laser-induced CNV model is one of the best methods currently available to study the debilitating pathology of neovascular AMD. Its implementation has led to a deeper understanding of the pathogenesis of AMD, as well as contributing to the development of many of the AMD therapies currently available.

  12. Lung Epithelial Progenitor Cells

    PubMed Central

    Rawlins, Emma L.

    2008-01-01

    The current enthusiasm for stem cell research stems from the hope that damaged or diseased tissues may one day be repaired through the manipulation of endogenous or exogenous stem cells. The postnatal human respiratory system is highly accessible and provides unique opportunities for the application of such techniques. Several putative adult lung epithelial stem cells have been identified in the mouse model system. However, their in vivo capabilities to contribute to different lineages, and their control mechanisms, remain unclear. If stem cell–based therapies are to be successful in the lung, it is vitally important that we understand the normal behavior of adult lung stem cells, and how this is regulated. Lung embryonic progenitor cells are much better defined and characterized than their adult counterparts. Moreover, experiments on a variety of developing tissues are beginning to uncover general mechanisms by which embryonic progenitors influence final organ size and structure. This provides a framework for the study of lung embryonic progenitor cells, facilitating experimental design and interpretation. A similar approach to investigating adult lung stem cells could produce rapid advances in the field. PMID:18684716

  13. Propranolol inhibits endothelial progenitor cell homing: a possible treatment mechanism of infantile hemangioma.

    PubMed

    Zou, Hai-Xiao; Jia, Jun; Zhang, Wen-Feng; Sun, Zhi-Jun; Zhao, Yi-Fang

    2013-01-01

    Propranolol effectively treats infantile hemangioma, but its mechanisms of action remain poorly understood. Although the antiangiogenesis role of propranolol has been previously demonstrated, several lines of evidence suggest that this therapeutic agent may affect the neovascular formation in infantile hemangioma by targeting vasculogenesis. In addition, the homing of endothelial progenitor cells to the lesion of infantile hemangioma plays an important role during the process of vasculogenesis. The purpose of this study was to investigate whether propranolol inhibits the vasculogenesis in infantile hemangioma by targeting endothelial progenitor cells recruitment. Endothelial progenitor cells were treated with different concentrations (0, 1, 5, 10, 20, 40, 60, 80, 100 μM) of propranolol for indicated times (24, 48, 72 h). Cell proliferation and viability were assessed by MTT assay and trypan blue staining. Cell migration was determined by wound healing assay and Boyden chamber assay. The expression levels of extracellular signal regulated kinase, phospho-extracellular signal regulated kinase, Akt, and phospho-Akt were measured by Western blot analysis to explore the molecular mechanism of propranolol on endothelial progenitor cells. In addition, the expression of CXCR4 was measured by Western blot and reverse transcriptase polymerase chain reaction. Propranolol did not significantly affect the proliferation of endothelial progenitor cells. It inhibited stromal-cell-derived factor 1α-induced migration of endothelial progenitor cells through the Akt and MAPK pathways and the expression of CXCR4 in a dose- and time-dependent manner. In addition, the expression of CXCR4 was suppressed by propranolol most likely through the Akt and MAPK pathways. Propranolol inhibits stromal-cell-derived factor 1α-induced endothelial progenitor cell homing by suppressing the expression of CXCR4 most likely through the Akt and MAPK pathways. Copyright © 2013 Elsevier Inc. All rights

  14. Thrombospondin-2 Expression During Retinal Vascular Development and Neovascularization

    PubMed Central

    Fei, Ping; Palenski, Tammy L.; Wang, Shoujian; Gurel, Zafer; Hankenson, Kurt D.; Sorenson, Christine M.

    2015-01-01

    Abstract Purpose: To determine thrombospondin-2 (TSP2) expression and its impact on postnatal retinal vascular development and retinal neovascularization. Methods: The TSP2-deficient (TSP2−/−) mice and a line of TSP2 reporter mice were used to assess the expression of TSP2 during postnatal retinal vascular development and neovascularization. The postnatal retinal vascularization was evaluated using immunostaining of wholemount retinas prepared at different postnatal days by collagen IV staining and/or TSP2 promoter driven green fluorescent protein (GFP) expression. The organization of astrocytes was evaluated by glial fibrillary acidic protein (GFAP) staining. Retinal vascular densities were determined using trypsin digestion preparation of wholemount retinas at 3- and 6-weeks of age. Retinal neovascularization was assessed during the oxygen-induced ischemic retinopathy (OIR). Choroidal neovascularization (CNV) was assessed using laser-induced CNV. Results: Using the TSP2-GFP reporter mice, we observed significant expression of TSP2 mRNA in retinas of postnatal day 5 (P5) mice, which increased by P7 and remained high up to P42. Similar results were observed in retinal wholemount preparations, and western blotting for GFP with the highest level of GFP was observed at P21. In contrast to high level of mRNA at P42, the GFP fluorescence or protein level was dramatically downregulated. The primary retinal vasculature developed at a faster rate in TSP2−/− mice compared with TSP2+/+ mice up to P5. However, the developing retinal vasculature in TSP2+/+ mice caught up with that of TSP2−/− mice after P7. No significant differences in retinal vascular density were observed at 3- or 6-weeks of age. TSP2−/− mice also exhibited a similar sensitivity to the hyperoxia-mediated vessel obliteration and similar level of neovascularization during OIR as TSP2+/+ mice. Lack of TSP2 expression minimally affected laser-induced CNV compared with TSP2+/+ mice. Conclusions

  15. Neovascularization Potential of Blood Outgrowth Endothelial Cells From Patients With Stable Ischemic Heart Failure Is Preserved.

    PubMed

    Dauwe, Dieter; Pelacho, Beatriz; Wibowo, Arief; Walravens, Ann-Sophie; Verdonck, Kristoff; Gillijns, Hilde; Caluwe, Ellen; Pokreisz, Peter; van Gastel, Nick; Carmeliet, Geert; Depypere, Maarten; Maes, Frederik; Vanden Driessche, Nina; Droogne, Walter; Van Cleemput, Johan; Vanhaecke, Johan; Prosper, Felipe; Verfaillie, Catherine; Luttun, Aernout; Janssens, Stefan

    2016-04-18

    Blood outgrowth endothelial cells (BOECs) mediate therapeutic neovascularization in experimental models, but outgrowth characteristics and functionality of BOECs from patients with ischemic cardiomyopathy (ICMP) are unknown. We compared outgrowth efficiency and in vitro and in vivo functionality of BOECs derived from ICMP with BOECs from age-matched (ACON) and healthy young (CON) controls. We isolated 3.6±0.6 BOEC colonies/100×10(6) mononuclear cells (MNCs) from 60-mL blood samples of ICMP patients (n=45; age: 66±1 years; LVEF: 31±2%) versus 3.5±0.9 colonies/100×10(6) MNCs in ACON (n=32; age: 60±1 years) and 2.6±0.4 colonies/100×10(6) MNCs in CON (n=55; age: 34±1 years), P=0.29. Endothelial lineage (VEGFR2(+)/CD31(+)/CD146(+)) and progenitor (CD34(+)/CD133(-)) marker expression was comparable in ICMP and CON. Growth kinetics were similar between groups (P=0.38) and not affected by left ventricular systolic dysfunction, maladaptive remodeling, or presence of cardiovascular risk factors in ICMP patients. In vitro neovascularization potential, assessed by network remodeling on Matrigel and three-dimensional spheroid sprouting, did not differ in ICMP from (A)CON. Secretome analysis showed a marked proangiogenic profile, with highest release of angiopoietin-2 (1.4±0.3×10(5) pg/10(6) ICMP-BOECs) and placental growth factor (5.8±1.5×10(3) pg/10(6) ICMP BOECs), independent of age or ischemic disease. Senescence-associated β-galactosidase staining showed comparable senescence in BOECs from ICMP (5.8±2.1%; n=17), ACON (3.9±1.1%; n=7), and CON (9.0±2.8%; n=13), P=0.19. High-resolution microcomputed tomography analysis in the ischemic hindlimb of nude mice confirmed increased arteriogenesis in the thigh region after intramuscular injections of BOECs from ICMP (P=0.025; n=8) and CON (P=0.048; n=5) over vehicle control (n=8), both to a similar extent (P=0.831). BOECs can be successfully culture-expanded from patients with ICMP. In contrast to impaired

  16. [Subretinal neovascular membrane in angioid streaks treated with intravitreal bevacizumab].

    PubMed

    García-López, A; González-Castaño, C

    2014-05-01

    Angioid streaks are breaks in Bruch's membrane that may be associated, among others, with pseudoxanthoma elasticum. Its most common complication is the development of subretinal neovascular membranes (SRNVM) and the decreased vision this entails. A 28 year old woman with angioid streaks and SRNVM in the left eye, who received 3 injections of intravitreal bevacizumab, with rapid improvement in vision and stability during 11 months follow up. The finding of angioid streaks led to the diagnosis of pseudoxanthoma elasticum. Intravitreal bevacizumab should be considered as an effective treatment option for choroidal neovascularization associated with angioid streaks. Copyright © 2012 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

  17. Neovascular glaucoma in a child: an unusual presentation of medulloepithelioma

    PubMed Central

    Kassa, Enoch; Li, Helen; Sun, Yang

    2014-01-01

    A healthy 12 month old infant without significant medical history presented with left eye redness for one week. Ophthalmic examination showed elevated intraocular pressure with iris neovascularization in the affected eye with increased optic nerve cupping. Scleral depression revealed a ciliary body mass in the supratemporal quadrant. A large, non-pigmented, vascular mass was noted; biopsy results showed multilayered cords, tubules, and sheets resembling primitive medullary epithelium arising from the ciliary body. The patient was diagnosed with medulloepithelioma. The patient underwent enucleation of the affected eye. Medulloepithelioma is a rare but important cause of neovascular glaucoma in the pediatric population. This case will focus on the characteristics of medulloepthelioma and the differential diagnosis for a non-pigmented ciliary body mass in a child. PMID:27625938

  18. Neovascular glaucoma treatment with extraction of anterior chamber fibrovascular tissue.

    PubMed

    Nadal, Jeroni; Carreras, Elisa; Kudsieh, Bachar; Canut, Maribel

    2013-08-01

    The use of antibody to vascular endothelial growth factor to treat neovascular glaucoma yields good anatomic results in most cases. However, this type of glaucoma can cause angle closure with decompensation of intraocular pressure secondary to fibrovascular tissue contraction in the anterior chamber. Our surgical technique treats the cause by removing the anterior chamber fibrous complex after administration of antibody to vascular endothelial growth factor, thus restoring the chamber angle.

  19. Fracture induced mobilization and incorporation of bone marrow-derived endothelial progenitor cells for bone healing.

    PubMed

    Matsumoto, Tomoyuki; Mifune, Yutaka; Kawamoto, Atsuhiko; Kuroda, Ryosuke; Shoji, Taro; Iwasaki, Hiroto; Suzuki, Takahiro; Oyamada, Akira; Horii, Miki; Yokoyama, Ayumi; Nishimura, Hiromi; Lee, Sang Yang; Miwa, Masahiko; Doita, Minoru; Kurosaka, Masahiro; Asahara, Takayuki

    2008-04-01

    We recently reported that systemic administration of peripheral blood (PB) CD34+ cells, an endothelial progenitor cell (EPC)-enriched population, contributed to fracture healing via vasculogenesis/angiogenesis. However, pathophysiological role of EPCs in fracture healing process has not been fully clarified. Therefore, we investigated the hypothesis whether mobilization and incorporation of bone marrow (BM)-derived EPCs may play a pivotal role in appropriate fracture healing. Serial examinations of Laser doppler perfusion imaging and histological capillary density revealed that neovascularization activity at the fracture site peaked at day 7 post-fracture, the early phase of endochondral ossifification. Fluorescence-activated cell sorting (FACS) analysis demonstrated that the frequency of BM cKit+Sca1+Lineage- (Lin-) cells and PB Sca1+Lin- cells, which are EPC-enriched fractions, significantly increased post-fracture. The Sca1+ EPC-derived vasuculogenesis at the fracture site was confirmed by double immunohistochemistry for CD31 and Sca1. BM transplantation from transgenic donors expressing LacZ transcriptionally regulated by endothelial cell-specific Tie-2 promoter into wild type also provided direct evidence that EPCs contributing to enhanced neovascularization at the fracture site were specifically derived from BM. Animal model of systemic administration of PB Sca1+Lin- Green Fluorescent Protein (GFP)+ cells further confirmed incorporation of the mobilized EPCs into the fracture site for fracture healing. These findings indicate that fracture may induce mobilization of EPCs from BM to PB and recruitment of the mobilized EPCs into fracture sites, thereby augment neovascularization during the process of bone healing. EPCs may play an essential role in fracture healing by promoting a favorable environment through neovascularization in damaged skeletal tissue.

  20. Topical ranibizumab as a treatment of corneal neovascularization.

    PubMed

    Ferrari, Giulio; Dastjerdi, Mohammad H; Okanobo, Andre; Cheng, Sheng-Fu; Amparo, Francisco; Nallasamy, Nambi; Dana, Reza

    2013-07-01

    To examine the effect of topical ranibizumab on clinically stable corneal neovascularization (NV). This was a prospective, open-label, monocentric, uncontrolled noncomparative study. Ten eyes of 9 patients with corneal NV received topical ranibizumab (1%) 4 times a day for 3 weeks with a follow-up period of 16 weeks. The main corneal NV outcome measures were: neovascular area, the area occupied by the corneal neovessels; vessel caliber (VC), the mean diameter of the corneal neovessels; and invasion area (IA), the fraction of the total cornea area covered by the vessels. This study was conducted at the Massachusetts Eye and Ear Infirmary, Boston, MA. Statistically significant decreases in neovascular area (55.3%, P < 0.001), which lasted through 16 weeks, and VC (59%, P < 0.001), which continued to improve up to week 16, were observed after treatment. No significant decrease was observed in IA (12.3%, P = 0.49). There was no statistically significant change in visual acuity or intraocular pressure. No adverse events ascribed to the treatment were noted. Topical application of ranibizumab is effective in reducing the severity of corneal NV in the context of established corneal NV, mostly through decrease in VC rather than IA.

  1. Topical Ranibizumab as a Treatment of Corneal Neovascularization

    PubMed Central

    Ferrari, Giulio; Dastjerdi, Mohammad H.; Okanobo, Andre; Cheng, Sheng-Fu; Amparo, Francisco; Nallasamy, Nambi; Dana, Reza

    2014-01-01

    Purpose To examine the effect of topical ranibizumab on clinically stable corneal neovascularization (NV). Methods This was a prospective, open-label, monocentric, uncontrolled, non-comparative study. Ten eyes of 9 patients with corneal NV received topical ranibizumab (1%) 4 times a day for 3 weeks with a follow-up of 16 weeks. The main corneal neovascularization outcome measures were: neovascular area (NA), the area occupied by the corneal neovessels; vessel caliber (VC), the mean diameter of the corneal neovessels; and invasion area (IA), the fraction of the total cornea area covered by the vessels. This study was conducted at the Massachusetts Eye and Ear Infirmary, Boston, MA, USA. Results Statistically significant decreases in NA (55.3%, P<0.001), which lasted through 16 weeks, and VC (59%, P<0.001), which continued to improve up to week 16, were observed after treatment. No significant decrease was observed in IA (12.3%, P=0.49). There was no statistically significant change in visual acuity or intraocular pressure. No adverse events ascribed to the treatment were noted. Conclusions Topical application of ranibizumab is effective in reducing the severity of corneal NV in the context of established corneal NV, mostly through decrease in VC rather than IA. PMID:23407316

  2. Secondary glaucoma in CAPN5-associated neovascular inflammatory vitreoretinopathy

    PubMed Central

    Cham, Abdourahman; Bansal, Mayank; Banda, Himanshu K; Kwon, Young; Tlucek, Paul S; Bassuk, Alexander G; Tsang, Stephen H; Sobol, Warren M; Folk, James C; Yeh, Steven; Mahajan, Vinit B

    2016-01-01

    Objective The objective of this study was to review the treatment outcomes of patients with secondary glaucoma in cases of autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), a hereditary autoimmune uveitis due to mutations in CAPN5. Patients and methods A retrospective, observational case series was assembled from ADNIV patients with secondary glaucoma. The main outcome measures were intraocular pressure (IOP), visual acuity, use of antiglaucoma medications, ocular surgeries, and adverse outcomes. Perimetry and optic disk optical coherence tomography (OCT) were also analyzed. Results Nine eyes of five ADNIV patients with secondary glaucoma were reviewed. Each received a fluocinolone acetonide (FA) implant for the management of posterior uveitis. Following implantation, no eyes developed neovascular glaucoma. Five eyes (in patients 1, 2, and 5) required Ahmed glaucoma valve surgery for the management of steroid-responsive glaucoma. Patient 2 also developed angle closure with iris bombe and underwent laser peripheral iridotomy. Patient 4 had both hypotony and elevated IOP that required periodic antiglaucoma medication in the FA-implanted eye. Patient 3 did not develop steroid-response glaucoma in either eye. Optic disk examinations were obscured by fibrosis and better assessed with OCT. Conclusion ADNIV patients show combined mechanism secondary glaucoma best assessed by OCT of the optic disk. The FA implants have reduced uveitic and neovascular glaucoma. Nevertheless, IOP management remains complex due to steroid-response glaucoma, angle closure glaucoma, and hypotony. PMID:27390515

  3. Characterization of a Mouse Model of Hyperglycemia and Retinal Neovascularization

    PubMed Central

    Rakoczy, Elizabeth P.; Rahman, Ireni S. Ali; Binz, Nicolette; Li, Cai-Rui; Vagaja, Nermina N.; de Pinho, Marisa; Lai, Chooi-May

    2010-01-01

    One of the limitations of research into diabetic retinopathy is the lack of suitable animal models. To study how the two important factors—hyperglycemia and vascular endothelial growth factor—interact in diabetic retinopathy, the Akimba mouse (Ins2AkitaVEGF+/−) was generated by crossing the Akita mouse (Ins2Akita) with the Kimba mouse (VEGF+/+). C57Bl/6 and the parental and Akimba mouse lines were characterized by biometric measurements, histology, immunohistochemistry, and Spectralis Heidelberg retinal angiography and optical coherence tomography. The Akimba line not only retained the characteristics of the parental strains, such as developing hyperglycemia and retinal neovascularization, but developed higher blood glucose levels at a younger age and had worse kidney-body weight ratios than the Akita line. With aging, the Akimba line demonstrated enhanced photoreceptor cell loss, thinning of the retina, and more severe retinal vascular pathology, including more severe capillary nonperfusion, vessel constriction, beading, neovascularization, fibroses, and edema, compared with the Kimba line. The vascular changes were associated with major histocompatibility complex class II+ cellular staining throughout the retina. Together, these observations suggest that hyperglycemia resulted in higher prevalences of edema and exacerbated the vascular endothelial growth factor-driven neovascular and retinal changes in the Akimba line. Thus, the Akimba line could become a useful model for studying the interplay between hyperglycemia and vascular endothelial growth factor and for testing treatment strategies for potentially blinding complications, such as edema. PMID:20829433

  4. Optical coherence tomography angiography in pediatric choroidal neovascularization

    PubMed Central

    Veronese, Chiara; Maiolo, Chiara; Huang, David; Jia, Yali; Armstrong, Grayson W.; Morara, Mariachiara; Ciardella, Antonio P.

    2016-01-01

    Purpose To report two cases of pediatric choroidal neovascularization (CNV) and the associated neo-vascular and retinal findings identified on Optical Coherence Tomography Angiography (OCTA) imaging. Methods A 14-year-old boy with handheld laser-induced maculopathy-related CNV and a 13-year-old boy with idiopathic CNV were evaluated with visual acuity testing, slit-lamp exam, fundus photography, fluorescein angiography, indocyanine green angiography, spectral domain optical coherence tomography, and OCTA. Results Macular CNV were identified in both pediatric patients using OCTA imaging. The first case demonstrated a classic pediatric type II CNV with a “tree-like” pattern and a single vessel in-growth site, while the second case demonstrated a type I CNV with a “glomerular” pattern. Conclusion Distinct choroidal neovascular patterns were visualized in these two cases of pediatric CNV when compared to adult subtypes. OCTA is a noninvasive imaging modality capable of evaluating and characterizing pediatric CNV and their associated vascular patterns. PMID:27990495

  5. A new role for cofilin in retinal neovascularization

    PubMed Central

    Kumar, Raj; Janjanam, Jagadeesh; Singh, Nikhlesh K.; Rao, Gadiparthi N.

    2016-01-01

    ABSTRACT Pak1 plays an important role in several cellular processes, including cell migration, but its role in pathological angiogenesis is not known. Here, we have determined its role in pathological retinal angiogenesis using an oxygen-induced retinopathy (OIR) model. VEGFA induced phosphorylation of Pak1 and its effector cofilin in a manner that was dependent on time as well as p38MAPKβ (also known as MAPK11) in human retinal microvascular endothelial cells (HRMVECs). Depletion of the levels of any of these molecules inhibited VEGFA-induced HRMVEC F-actin stress fiber formation, migration, proliferation, sprouting and tube formation. In accordance with these observations, hypoxia induced Pak1 and cofilin phosphorylation with p38MAPKβ being downstream to Pak1 and upstream to cofilin in mouse retina. Furthermore, Pak1 deficiency abolished hypoxia-induced p38MAPKβ and cofilin phosphorylation and abrogated retinal endothelial cell proliferation, tip cell formation and neovascularization. In addition, small interfering RNA (siRNA)-mediated downregulation of p38MAPKβ or cofilin levels in the wild-type mouse retina also diminished endothelial cell proliferation, tip cell formation and neovascularization. Taken together, these observations suggest that, although the p38MAPKβ–Pak1–cofilin axis is required for HRMVEC migration, proliferation, sprouting and tubulogenesis, Pak1–p38MAPKβ–cofilin signaling is also essential for hypoxia-induced mouse retinal endothelial cell proliferation, tip cell formation and neovascularization. PMID:26857814

  6. Evaluation of artificial dermis neovascularization in an avascular wound.

    PubMed

    Baynosa, Richard C; Browder, Leslie K; Jones, Seth R; Oliver, Jill A; Van Der Harten, Carol A; Stephenson, Linda L; Wang, Wei Z; Khiabani, Kayvan T; Zamboni, William A

    2009-09-01

    Soft tissue coverage for avascular wounds is necessary in reconstructive surgery. Several authors have demonstrated successful treatment of problem wounds using artificial dermis. This study evaluates in an animal model the potential for neovascularization of artificial dermis in devascularized and avascular wound beds. Forty rats were assigned to four groups: (1) control, full-thickness skin graft was replaced on the vascular wound bed; (2) Integra, Integra placed over the full-thickness wound; (3) fascia, the spinotrapezius fascia exposed and Integra placed over the wound; and (4) fascia/Parafilm, a Parafilm layer placed under the raised fascia with Integra over the fascia. Laser Doppler readings were taken at baseline over the intact skin and then over the created wound beds. Biopsies of the full-thickness skin graft and the neodermis were obtained on postoperative day 14 and histologically evaluated for neovascularization. The laser Doppler readings confirmed the nature of the surgically created, poorly vascularized and avascular wound beds. Subsequent biopsies of the artificial dermis in these wound beds, however, demonstrated active neovascularization. This study demonstrates that Integra artificial dermis can serve as an effective dermal substitute in avascular wounds. Lateral ingrowth of capillaries into the dermal substitute may explain the successful integration of this artificial dermis.

  7. Assessment of therapeutic options for reducing alkali burn-induced corneal neovascularization and inflammation.

    PubMed

    Bakunowicz-Łazarczyk, Alina; Urban, Beata

    2016-03-01

    This article aims to review and provide the current knowledge of the possibilities of topical treatment of corneal neovascularization due to alkali burns, evidenced by laboratory experiments, in vitro studies, and clinical trials published in the specialized literature. Authors present clinically relevant treatment of corneal neovascularization used in clinical practice, potential antiangiogenic topical therapeutics against corneal neovascularization, which are under investigation, and anti-angiogenic gene-therapy.

  8. Local delivery of VEGF and SDF enhances endothelial progenitor cell recruitment and resultant recovery from ischemia.

    PubMed

    Anderson, Erin M; Kwee, Brian J; Lewin, Sarah A; Raimondo, Theresa; Mehta, Manav; Mooney, David J

    2015-04-01

    Biomaterials may improve outcomes of endothelial progenitor-based therapies for the treatment of ischemic cardiovascular disease, due to their ability to direct cell behavior. We hypothesized that local, sustained delivery of exogenous vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF) from alginate hydrogels could increase recruitment of systemically infused endothelial progenitors to ischemic tissue, and subsequent neovascularization. VEGF and SDF were found to enhance in vitro adhesion and migration of outgrowth endothelial cells (OECs) and circulating angiogenic cells (CACs), two populations of endothelial progenitors, by twofold to sixfold, and nearly doubled recruitment to both ischemic and nonischemic muscle tissue in vivo. Local delivery of VEGF and SDF to ischemic hind-limbs in combination with systemic CAC delivery significantly improved functional perfusion recovery over OEC delivery, or either treatment alone. Compared with OECs, CACs were more responsive to VEGF and SDF treatment, promoted in vitro endothelial sprout formation in a paracrine manner more potently, and demonstrated greater influence on infiltrating inflammatory cells in vivo. These studies demonstrate that accumulation of infused endothelial progenitors can be enriched using biomaterial-based delivery of VEGF and SDF, and emphasize the therapeutic benefit of using CACs for the treatment of ischemia.

  9. Peripapillary subretinal neovascularization in sarcoidosis: remission and exacerbation during oral corticosteroid therapy.

    PubMed

    Abe, Koji; Shiraki, Kunihiko; Yasunari, Takaharu; Kohno, Takeya; Miki, Tokuhiko

    2002-01-01

    In sarcoidosis, peripapillary subretinal neovascularization is rare. The role of corticosteroid therapy for subretinal neovascularization is controversial. A 38-year-old female patient weighing 38 kg with histologically diagnosed sarcoidosis presented with peripapillary subretinal neovascularization, retinal phlebitis, a hyperemic disc, and snowball vitreous opacities in the left eye. Oral betamethasone therapy at an initial dose of 3 mg/day reduced the size of subretinal neovascular membrane, and the membrane became fibrous. Despite the total initial 140 mg of betamethasone given over 2.5 months and the additional total 700 mg of prednisolone given over the next 2 months, the subretinal neovascularization recurred. Six months after the first recurrence, a second recurrence developed during the tapering-off period of oral corticosteroid therapy. At the second recurrence, the oral corticosteroid therapy was ineffective in reducing the size of the neovascular membrane. In our patient, oral corticosteroids temporarily suppressed peripapillary subretinal neovascularization but failed to prevent extension of neovascular membrane to the fovea because of recurrent sarcoidosis. Over time, oral corticosteroids appear to lose their effectiveness for treating repeated recurrence of peripapillary subretinal neovascularization associated with sarcoidosis.

  10. Peripapillary subretinal neovascularization and serous macular detachment. Association with congenital optic nerve pits.

    PubMed

    Borodic, G E; Gragoudas, E S; Edward, W O; Brockhurst, R J

    1984-02-01

    Congenital anomalous disc changes were associated with acquired macular detachment and peripapillary choroidal neovascularization in two cases. The anomalous disc changes resembled optic nerve pits. In one case, the peripapillary choroidal neovascularization was treated with argon laser photocoagulation, with subsequent reattachment of the macula and considerable improvement in the visual acuity. Although the pathogenesis of macular detachment occurring with optic nerve pits is usually not disclosed by fluorescein angiography, leakage from choroidal neovascularization can occur with this congenital defect and may contribute to the formation of a neurosensory macular detachment. If found, choroidal neovascularization may represent a remedial cause for visual loss in a condition with an otherwise poor prognosis.

  11. Peripheral retinal neovascularization in recurrent cicatricial toxoplasmic retinochoroiditis: case series report.

    PubMed

    Rodríguez, Álvaro; Gómez, Flor Edith; Valencia, Marcela; Rodríguez, Francisco

    2015-01-01

    To report cases of retinal neovascularization in association with cicatricial plaques of congenital recurrent toxoplasmic retinochoroiditis. This was a retrospective review of retinologist records. Four cases found were documented with diagnostic techniques, mainly fluorescein angiography, optical coherence tomography and laboratory confirmation. Management included focal laser photocoagulation and pars plana vitrectomy. In 4 cases, one presented spontaneous involution of neovascularization and vitreous hemorrhage. Three cases of neovascularization responded to laser photocoagulation and 2 cases to pars plana vitrectomy. Three cases regained 20/25 vision. Peripheral neovascularization associated with plaques of cicatricial toxoplasmic retinochoroiditis has been rarely reported. Therefore, a routine careful examination of fundus periphery is recommended.

  12. Dramatic Inhibition of Retinal and Choroidal Neovascularization by Oral Administration of a Kinase Inhibitor

    PubMed Central

    Seo, Man Seong; Kwak, Nohoon; Ozaki, Hiroaki; Yamada, Haruhiko; Okamoto, Naoyuki; Yamada, Eri; Fabbro, Doriano; Hofmann, Francesco; Wood, Jeanette M.; Campochiaro, Peter A.

    1999-01-01

    The most common cause of new blindness in young patients is retinal neovascularization, and in the elderly is choroidal neovascularization. Therefore, there has been a great deal of attention focused on the development of new treatments for these disease processes. Previous studies have demonstrated partial inhibition of retinal neovascularization in animal models using antagonists of vascular endothelial growth factor or other signaling molecules implicated in the angiogenesis cascade. These studies have indicated potential for drug treatment, but have left many questions unanswered. Is it possible to completely inhibit retinal neovascularization using drug treatment with a mode of administration that is feasible to use in patients? Do agents that inhibit retinal neovascularization have any effect on choroidal neovascularization? In this study, we demonstrate complete inhibition of retinal neovascularization in mice with oxygen-induced ischemic retinopathy by oral administration of a partially selective kinase inhibitor that blocks several members of the protein kinase C family, along with vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases. The drug also blocks normal vascularization of the retina during development but has no identifiable adverse effects on mature retinal vessels. In addition, the kinase inhibitor causes dramatic inhibition of choroidal neovascularization in a laser-induced murine model. These data provide proof of concept that pharmacological treatment is a viable approach for therapy of both retinal and choroidal neovascularization. PMID:10362799

  13. Apelin Is Required for Non-Neovascular Remodeling in the Retina

    PubMed Central

    McKenzie, Jenny A.G.; Fruttiger, Marcus; Abraham, Sabu; Lange, Clemens A.K.; Stone, Jay; Gandhi, Pranita; Wang, Xiaomeng; Bainbridge, James; Moss, Stephen E.; Greenwood, John

    2012-01-01

    Retinal pathologies are frequently accompanied by retinal vascular responses, including the formation of new vessels by angiogenesis (neovascularization). Pathological vascular changes may also include less well characterized traits of vascular remodeling that are non-neovascular, such as vessel pruning and the emergence of dilated and tortuous vessel phenotypes (telangiectasis). The molecular mechanisms underlying neovascular growth versus non-neovascular remodeling are poorly understood. We therefore undertook to identify novel regulators of non-neovascular remodeling in the retina by using the dystrophic Royal College of Surgeons (RCS) rat and the retinal dystrophy 1 (RD1) mouse, both of which display pronounced non-neovascular remodeling. Gene expression profiling of isolated retinal vessels from these mutant rodent models and wild-type controls revealed 60 differentially expressed genes. These included the genes for apelin (Apln) and for its receptor (Aplnr), both of which were strongly up-regulated in the mutants. Crossing RD1 mice into an Apln-null background substantially reduced vascular telangiectasia. In contrast, Apln gene deletion had no effect in two models of neovascular pathology [laser-induced choroidal neovascularization and the very low density lipoprotein receptor (Vldlr)-knockout mouse]. These findings suggest that in these models apelin has minimal effect on sprouting retinal angiogenesis, but contributes significantly to pathogenic non-neovascular remodeling. PMID:22067912

  14. The effect of subconjunctival suramin on corneal neovascularization in rabbits.

    PubMed

    Lee, Hyun Soo; Chung, Sung Kun

    2010-01-01

    To evaluate the effect of subconjunctival injection of suramin on corneal neovascularization in rabbits. Corneal neovascularization was induced by silk suturing of the corneal stroma in 40 eyes of 40 male New Zealand white rabbits. Five days after suture placement, all rabbits were randomly divided into 4 groups of 10 rabbits and were treated subconjunctivally with balanced salt solution 0.1 mL (group 1), suramin 0.1 mL (10 mg/mL and 100 mg/mL, groups 2 and 3, respectively), and bevacizumab 2.5 mg/0.1 mL (group 4). Digital photographs of eyes were obtained and analyzed on days 7, 14, and 28 after subconjunctival injections. In addition, vascular endothelial growth factor (VEGF) enzyme-linked immunosorbent assay (ELISA) and immunohistochemical analyses were used to estimate the level of VEGF and the expression of VEGF and basic FGF in neovascularized cornea, respectively. The neovascularized area in control was increased significantly for 14 days after subconjunctival injection, but slightly decreased on day 28. On days 7 and 14, group 4 exhibited greater antiangiogenic effect than group 3, but group 3 exhibited greater antiangiogenic effect than group 4 on day 28. VEGF ELISA analysis showed the mean concentration of VEGF in group 4 was significantly lower than with other treatments for the first 14 days, but the mean concentration of VEGF in group 4 was similar to that with group 3 on day 28. Immunohistochemical analysis showed that the expressions of both VEGF and basic fibroblast growth factor (FGF) were reduced in group 3 and that bevacizumab reduced VEGF expression relative to basic FGF on day 28. Subconjunctival suramin 100 mg/mL exhibited less antiangiogenic effect than bevacizumab 2.5 mg during the early period of treatment, but it had a longer effect than that of bevacizumab later. Therefore, the combination of subconjunctival bevacizumab and suramin may provide a more potent effect in early treatment as well as a longer antiangiogenic effect in

  15. Ultrasound imaging of breast tumor perfusion and neovascular morphology.

    PubMed

    Hoyt, Kenneth; Umphrey, Heidi; Lockhart, Mark; Robbin, Michelle; Forero-Torres, Andres

    2015-09-01

    A novel image processing strategy is detailed for simultaneous measurement of tumor perfusion and neovascular morphology parameters from a sequence of dynamic contrast-enhanced ultrasound (DCE-US) images. After normalization and tumor segmentation, a global time-intensity curve describing contrast agent flow was analyzed to derive surrogate measures of tumor perfusion (i.e., peak intensity, time-to-peak intensity, area under the curve, wash-in rate, wash-out rate). A maximum intensity image was generated from these same segmented image sequences, and each vascular component was skeletonized via a thinning algorithm. This skeletonized data set and collection of vessel segments were then investigated to extract parameters related to the neovascular network and physical architecture (i.e., vessel-to-tissue ratio, number of bifurcations, vessel count, average vessel length and tortuosity). An efficient computation of local perfusion parameters was also introduced and operated by averaging time-intensity curve data over each individual neovascular segment. Each skeletonized neovascular segment was then color-coded by these local measures to produce a parametric map detailing spatial properties of tumor perfusion. Longitudinal DCE-US image data sets were collected in six patients diagnosed with invasive breast cancer using a Philips iU22 ultrasound system equipped with a L9-3 transducer and Definity contrast agent. Patients were imaged using US before and after contrast agent dosing at baseline and again at weeks 6, 12, 18 and 24 after treatment started. Preliminary clinical results suggested that breast tumor response to neoadjuvant chemotherapy may be associated with temporal and spatial changes in DCE-US-derived parametric measures of tumor perfusion. Moreover, changes in neovascular morphology parametric measures may also help identify any breast tumor response (or lack thereof) to systemic treatment. Breast cancer management from early detection to therapeutic

  16. High proliferative potential endothelial colony-forming cells contribute to hypoxia-induced pulmonary artery vasa vasorum neovascularization

    PubMed Central

    Nijmeh, Hala; Balasubramaniam, Vivek; Burns, Nana; Ahmad, Aftab; Stenmark, Kurt R.

    2014-01-01

    Angiogenic expansion of the vasa vasorum (VV) is an important contributor to pulmonary vascular remodeling in the pathogenesis of pulmonary hypertension (PH). High proliferative potential endothelial progenitor-like cells have been described in vascular remodeling and angiogenesis in both systemic and pulmonary circulations. However, their role in hypoxia-induced pulmonary artery (PA) VV expansion in PH is not known. We hypothesized that profound PA VV neovascularization observed in a neonatal calf model of hypoxia-induced PH is due to increased numbers of subsets of high proliferative cells within the PA adventitial VV endothelial cells (VVEC). Using a single cell clonogenic assay, we found that high proliferative potential colony-forming cells (HPP-CFC) comprise a markedly higher percentage in VVEC populations isolated from the PA of hypoxic (VVEC-Hx) compared with control (VVEC-Co) calves. VVEC-Hx populations that comprised higher numbers of HPP-CFC also demonstrated markedly higher expression levels of CD31, CD105, and c-kit than VVEC-Co. In addition, significantly higher expression of CD31, CD105, and c-kit was observed in HPP-CFC vs. the VVEC of the control but not of hypoxic animals. HPP-CFC exhibited migratory and tube formation capabilities, two important attributes of angiogenic phenotype. Furthermore, HPP-CFC-Co and some HPP-CFC-Hx exhibited elevated telomerase activity, consistent with their high replicative potential, whereas a number of HPP-CFC-Hx exhibited impaired telomerase activity, suggestive of their senescence state. In conclusion, our data suggest that hypoxia-induced VV expansion involves an emergence of HPP-CFC populations of a distinct phenotype with increased angiogenic capabilities. These cells may serve as a potential target for regulating VVEC neovascularization. PMID:24508729

  17. High proliferative potential endothelial colony-forming cells contribute to hypoxia-induced pulmonary artery vasa vasorum neovascularization.

    PubMed

    Nijmeh, Hala; Balasubramaniam, Vivek; Burns, Nana; Ahmad, Aftab; Stenmark, Kurt R; Gerasimovskaya, Evgenia V

    2014-04-01

    Angiogenic expansion of the vasa vasorum (VV) is an important contributor to pulmonary vascular remodeling in the pathogenesis of pulmonary hypertension (PH). High proliferative potential endothelial progenitor-like cells have been described in vascular remodeling and angiogenesis in both systemic and pulmonary circulations. However, their role in hypoxia-induced pulmonary artery (PA) VV expansion in PH is not known. We hypothesized that profound PA VV neovascularization observed in a neonatal calf model of hypoxia-induced PH is due to increased numbers of subsets of high proliferative cells within the PA adventitial VV endothelial cells (VVEC). Using a single cell clonogenic assay, we found that high proliferative potential colony-forming cells (HPP-CFC) comprise a markedly higher percentage in VVEC populations isolated from the PA of hypoxic (VVEC-Hx) compared with control (VVEC-Co) calves. VVEC-Hx populations that comprised higher numbers of HPP-CFC also demonstrated markedly higher expression levels of CD31, CD105, and c-kit than VVEC-Co. In addition, significantly higher expression of CD31, CD105, and c-kit was observed in HPP-CFC vs. the VVEC of the control but not of hypoxic animals. HPP-CFC exhibited migratory and tube formation capabilities, two important attributes of angiogenic phenotype. Furthermore, HPP-CFC-Co and some HPP-CFC-Hx exhibited elevated telomerase activity, consistent with their high replicative potential, whereas a number of HPP-CFC-Hx exhibited impaired telomerase activity, suggestive of their senescence state. In conclusion, our data suggest that hypoxia-induced VV expansion involves an emergence of HPP-CFC populations of a distinct phenotype with increased angiogenic capabilities. These cells may serve as a potential target for regulating VVEC neovascularization.

  18. Hydroxysafflor yellow A promotes neovascularization and cardiac function recovery through HO-1/VEGF-A/SDF-1α cascade.

    PubMed

    Wei, Guo; Yin, Ying; Duan, Jialin; Guo, Chao; Zhu, Yanrong; Wang, Yanhua; Xi, Miaomiao; Wen, Aidong

    2017-04-01

    The present study was to investigate the proangiogenic and cardioprotective effects of hydroxysafflor yellow A (HSYA) against myocardial infarction (MI) injury and the underlying mechanisms. MI model was induced by ligation of the left coronary artery in normal and heme oxygenase-1 (HO-1) knockout mice and the ones receiving vascular endothelial growth factor-A (VEGF-A) or stromal cell-derived factor-1α (SDF-1α) antagonists. They were treated with three doses or single dose of HSYA for 28days. The cardiac function, endothelial progenitor cells (EPCs) mobilization, angiogenesis, the expression of HO-1, VEGF-A, SDF-1α and apoptosis or fibrosis related proteins in the peri-infarct area were evaluated at respective times. We further examined the effect of HSYA on EPCs CXC chemokiner receptor 4 (CXCR4) expression and the role of SDF-1α on EPCs function in vitro. HSYA could dose dependently reduce left ventricular function impairment, myocardial apoptosis and fibrosis, and promote EPCs mobilization and myocardial neovascularization. Further, HO-1 knockout abolished HSYA-induced up-regulation of HO-1, VEGF-A and SDF-1α. VEGF antagonist significantly reduced HSYA-increased VEGF-A and SDF-1α levels and SDF-1 antagonist abolished HSYA-simulated up-regulation of SDF-1α. Meanwhile, HO-1 knockout, administration of VEGF and SDF-1 antibodies abrogated HSYA-promoted expression of the marker proteins of newborn microvessels and cardiac functional recovery. In vitro, HSYA dose dependently promoted (CXCR4) expression on EPCs. SDF-1α significantly accelerated EPCs function which was reversed by CXCR4 antagonist. HSYA could promote EPCs function through the HO-1/VEGF-A/SDF-1α signaling cascade, which contributed largely to myocardial neovascularization and further improved cardiac function in MI mice. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  19. Role of liver progenitors in liver regeneration.

    PubMed

    Best, Jan; Manka, Paul; Syn, Wing-Kin; Dollé, Laurent; van Grunsven, Leo A; Canbay, Ali

    2015-02-01

    During massive liver injury and hepatocyte loss, the intrinsic regenerative capacity of the liver by replication of resident hepatocytes is overwhelmed. Treatment of this condition depends on the cause of liver injury, though in many cases liver transplantation (LT) remains the only curative option. LT for end stage chronic and acute liver diseases is hampered by shortage of donor organs and requires immunosuppression. Hepatocyte transplantation is limited by yet unresolved technical difficulties. Since currently no treatment is available to facilitate liver regeneration directly, therapies involving the use of resident liver stem or progenitor cells (LPCs) or non-liver stem cells are coming to fore. LPCs are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. Non-liver stem cells include embryonic stem cells (ES cells) and mesenchymal stem cells (MSCs). In the first section, we aim to provide an overview of the role of putative cytokines, growth factors, mitogens and hormones in regulating LPC response and briefly discuss the prognostic value of the LPC response in clinical practice. In the latter section, we will highlight the role of other (non-liver) stem cells in transplantation and discuss advantages and disadvantages of ES cells, induced pluripotent stem cells (iPS), as well as MSCs.

  20. Inhibition of pathological retinal neovascularization by semaphorin 3A

    PubMed Central

    Yu, Wenzhen; Bai, Yujing; Han, Na; Wang, Fei; Zhao, Min; Huang, Lvzhen

    2013-01-01

    Objective Pathological retinal angiogenesis is a major cause of vision loss. Semaphorin 3A (Sema3A), a chemorepellent guidance protein, plays crucial roles in neural and vascular patterning. To identify its role in retinal neovascularization, we investigated its antiangiogenic effects. Methods Human umbilical vein endothelial cells (HUVECs) were used for the in vitro study, and an oxygen-induced retinopathy (OIR) mouse model was used for the in vivo study. The HUVECs were incubated with Sema3A, and cell proliferation, migration, apoptosis, cell cycle, tube formation, and c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (p38 MAPK) signaling pathways were measured using Cell Counting Kit-8, Transwell, flow cytometry, Matrigel assays, and western blot. C57BL/6J mouse pups were exposed to 75% oxygen for 5 days and then brought to room air and injected with Sema3A intravitreously. At postnatal day 18, the retinal nonperfused areas were measured. The in vitro and in vivo vascular endothelial growth factor-165 (VEGF165) secretion was measured using enzyme-linked immunosorbent assay. Results Sema3A not only inhibited VEGF165-induced proliferation, but also induced cell cycle arrest in a dose-dependent manner. Furthermore, Sema3A inhibited migration and tube formation, both in general and in VEGF165-containing culture medium. Using an enzyme-linked immunosorbent assay, we showed that Sema3A did not affect VEGF165 secretion, but it did impede VEGF165 function. Additionally, Sema3A significantly inhibited the phosphorylation of the JNK and p38MAPK signaling pathways. When administered intravitreously, Sema3A reduced the pathological vascular changes seen in the retinal neovascularization OIR model. Conclusions These results suggest that the administration of Sema3A could be a useful therapeutic strategy for preventing hypoxia/ischemic-induced retinal neovascularization. PMID:23825919

  1. RAGE Regulates Immune Cell Infiltration and Angiogenesis in Choroidal Neovascularization

    PubMed Central

    McVicar, Carmel; Ward, Michael; Colhoun, Liza; Quinn, Michael; Bierhaus, Angelika; Xu, Heping; Stitt, Alan W.

    2014-01-01

    Purpose RAGE regulates pro-inflammatory responses in diverse cells and tissues. This study has investigated if RAGE plays a role in immune cell mobilization and choroidal neovascular pathology that is associated with the neovascular form of age-related macular degeneration (nvAMD). Methods RAGE null (RAGE−/−) mice and age-matched wild type (WT) control mice underwent laser photocoagulation to generate choroidal neovascularization (CNV) lesions which were then analyzed for morphology, S100B immunoreactivity and inflammatory cell infiltration. The chemotactic ability of bone marrow derived macrophages (BMDMs) towards S100B was investigated. Results RAGE expression was significantly increased in the retina during CNV of WT mice (p<0.001). RAGE−/− mice exhibited significantly reduced CNV lesion size when compared to WT controls (p<0.05). S100B mRNA was upregulated in the lasered WT retina but not RAGE−/− retina and S100B immunoreactivity was present within CNV lesions although levels were less when RAGE−/− mice were compared to WT controls. Activated microglia in lesions were considerably less abundant in RAGE−/− mice when compared to WT counterparts (p<0.001). A dose dependent chemotactic migration was observed in BMDMs from WT mice (p<0.05–0.01) but this was not apparent in cells isolated from RAGE−/− mice. Conclusions RAGE-S100B interactions appear to play an important role in CNV lesion formation by regulating pro-inflammatory and angiogenic responses. This study highlights the role of RAGE in inflammation-mediated outer retinal pathology. PMID:24586862

  2. Neovascularization and pain in abnormal patellar tendons of active jumping athletes.

    PubMed

    Cook, Jill L; Malliaras, Peter; De Luca, Jason; Ptasznik, Ronald; Morris, Meg E; Goldie, Patricia

    2004-09-01

    The aim of this study was to investigate tendon pain in abnormal patellar tendons with and without neovascularization. Comparative design. Multidisciplinary tendon study group at a competitive volleyball venue. One hundred eleven volleyball players volunteered to participate in the study. Subjects' patellar tendons were imaged with ultrasound, with and without Doppler. Tendons that were imaging abnormal were categorized according the presence of tendon neovascularization. Subjects completed 3 pain scales that examined function (Victorian Institute of Sport Assessment score, 100-point maximum), pain with tendon load (decline squat, visual analogue scale, 100-mm maximum), and maximum pain for the previous week (visual analogue scale, 100-mm maximum). A 1-tailed Mann-Whitney U test compared pain scores in abnormal tendons without neovascularization to abnormal tendons with neovascularization. Functional scores were lower (Victorian Institute of Sport score, median, 78; P = 0.045) and pain scores under tendon load were greater (decline squat pain, median, 19; P = 0.048) in subjects with abnormal tendons with neovascularization than subjects with abnormal tendons without neovascularization (Victorian Institute of Sport Assessment score, median, 87; decline squat pain, median, 0). This study indicates that the presence of neovascularization in abnormal patellar tendons is associated with greater tendon pain compared with abnormal tendons without neovascularization in active jumping athletes.

  3. Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuate neovascularization

    PubMed Central

    Yanai, Ryoji; Mulki, Lama; Hasegawa, Eiichi; Takeuchi, Kimio; Sweigard, Harry; Suzuki, Jun; Gaissert, Philipp; Vavvas, Demetrios G.; Sonoda, Koh-Hei; Rothe, Michael; Schunck, Wolf-Hagen; Miller, Joan W.; Connor, Kip M.

    2014-01-01

    Ocular neovascularization, including age-related macular degeneration (AMD), is a primary cause of blindness in individuals of industrialized countries. With a projected increase in the prevalence of these blinding neovascular diseases, there is an urgent need for new pharmacological interventions for their treatment or prevention. Increasing evidence has implicated eicosanoid-like metabolites of long-chain polyunsaturated fatty acids (LCPUFAs) in the regulation of neovascular disease. In particular, metabolites generated by the cytochrome P450 (CYP)–epoxygenase pathway have been shown to be potent modulators of angiogenesis, making this pathway a reasonable previously unidentified target for intervention in neovascular ocular disease. Here we show that dietary supplementation with ω-3 LCPUFAs promotes regression of choroidal neovessels in a well-characterized mouse model of neovascular AMD. Leukocyte recruitment and adhesion molecule expression in choroidal neovascular lesions were down-regulated in mice fed ω-3 LCPUFAs. The serum of these mice showed increased levels of anti-inflammatory eicosanoids derived from eicosapentaenoic acid and docosahexaenoic acid. 17,18-epoxyeicosatetraenoic acid and 19,20-epoxydocosapentaenoic acid, the major CYP-generated metabolites of these primary ω-3 LCPUFAs, were identified as key lipid mediators of disease resolution. We conclude that CYP-derived bioactive lipid metabolites from ω-3 LCPUFAs are potent inhibitors of intraocular neovascular disease and show promising therapeutic potential for resolution of neovascular AMD. PMID:24979774

  4. OCT Angiography Identification of Choroidal Neovascularization Secondary to Acute Zonal Occult Outer Retinopathy.

    PubMed

    Levison, Ashleigh L; Baynes, Kimberly; Lowder, Careen Y; Srivastava, Sunil K

    2016-01-01

    A 74-year-old female with acute zonal occult outer retinopathy presented with a new lesion suspicious for choroidal neovascularization (CNV) in her right eye. Optical coherence tomography angiography (OCTA) confirmed the presence of CNV. OCTA is a new imaging technique that may help guide diagnosis and management of choroidal neovascular membranes in uveitic diseases.

  5. PATTERNS OF FUNDUS AUTOFLUORESCENCE DEFECTS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION SUBTYPES.

    PubMed

    Ozkok, Ahmet; Sigford, Douglas K; Tezel, Tongalp H

    2016-11-01

    To test define characteristic fundus autofluorescence patterns of different exudative age-related macular degeneration subtypes. Cross-sectional study. Fifty-two patients with choroidal neovascularization because of three different neovascular age-related macular degeneration subtypes were included in the study. Macular and peripheral fundus autofluorescence patterns of study subjects were compared in a masked fashion. Fundus autofluorescence patterns of all three neovascular age-related macular degeneration subtypes revealed similar patterns. However, peripapillary hypo-autofluorescence was more common among patients with polypoidal choroidal vasculopathy (88.2%) compared with patients with retinal angiomatous proliferation (12.5%) and patients without retinal angiomatous proliferation and polypoidal choroidal vasculopathy (21.1%) (P < 0.0001). Presence of peripapillary fundus autofluorescence defects in neovascular age-related macular degeneration maybe suggestive of polypoidal choroidal vasculopathy as a variant of neovascular age-related macular degeneration.

  6. Therapeutic Effects of PPARα Agonist on Ocular Neovascularization in Models Recapitulating Neovascular Age-Related Macular Degeneration.

    PubMed

    Qiu, Fangfang; Matlock, Greg; Chen, Qian; Zhou, Kelu; Du, Yanhong; Wang, Xiang; Ma, Jian-Xing

    2017-10-01

    This study was designed to evaluate effects of fenofibric acid (Feno-FA), a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, on ocular neovascularization (NV) in models recapitulating neovascular age-related macular degeneration (AMD), and to explore whether the effects are PPARα dependent. Laser-induced choroidal NV (CNV) in rats and very low-density lipoprotein receptor knockout (Vldlr-/-) mice received daily intraperitoneal injections of Feno-FA or vehicle. Vascular leakage was examined by fundus fluorescein angiography and permeability assay using Evans blue as tracer. In CNV rats, severity of CNV was evaluated by CNV areas and CNV volume. In Vldlr-/- mice, subretinal NV (SRNV) and intraretinal NV (IRNV) were quantified in choroid flat mount and retina flat mount, respectively. Inflammatory factors were measured using Western blotting and retinal leukostasis assay. Further, Pparα-/- mice and age-matched wild-type (WT) mice were used for laser-induced CNV and treated with Feno-FA to explore the underlying mechanism. Feno-FA significantly reduced vascular leakage in CNV rats and Vldlr-/- mice, reduced CNV volume in laser-induced CNV rats, and suppressed SRNV and IRNV in Vldlr-/- mice. In addition, Feno-FA downregulated the expression of inflammatory factors, including VEGF, TNF-α, and intercellular cell adhesion molecule-1 (ICAM-1), in the eyecups of CNV rats and decreased adherent retinal leukocytes in Vldlr-/- mice. Furthermore, Pparα-/- mice developed more severe CNV compared with WT mice, and PPARα knockout abolished the beneficial effects of Feno-FA on CNV. Feno-FA has therapeutic effects on ocular NV in models recapitulating neovascular AMD through a PPARα-dependent mechanism.

  7. SDF-1α-induced dual pairs of E-selectin/ligand mediate endothelial progenitor cell homing to critical ischemia

    PubMed Central

    Liu, Zhao-Jun; Tian, Runxia; Li, Yan; Zhang, Leiming; Shao, Hongwei; Yang, Cuixia; Velazquez, Omaida C.

    2016-01-01

    Homing of endothelial progenitor cells (EPC) to the ischemic tissues is a key event in neovascularization and tissue regeneration. In response to ischemic insult, injured tissues secrete several chemo-cytokines, including stromal cell-derived factor-1α (SDF-1α), which triggers mobilization and homing of bone marrow-derived EPC (BMD-EPC). We previously reported that SDF-1α-induced EPC homing is mediated by a panel of adhesion molecules highly or selectively expressed on the activated endothelium in ischemic tissues, including E-selectin. Elevated E-selectin on wound vasculature serve as docking sites for circulating EPC, which express counterpart E-selectin ligands. Here, we show that SDF-1α presented in wound tissue and released into circulation can act both locally and remotely to induce ischemic tissue endothelium and BMD-EPC to express both E-selectin and its ligands. By performing BM transplantation using E-selectin−/− and E-selectin+/+ mice as the donors and recipients respectively, we demonstrate that upregulated dual E-selectin/ligand pairs reciprocally expressed on ischemic tissue endothelium and BMD-EPC act as double-locks to secure targeted EPC- endothelium interactions by which to facilitate EPC homing and promote neovascularization and tissue repair. These findings describe a novel mechanism for BMD-EPC homing and indicate that dual E-selectin/ligand pairs may be effective targets/tools for therapeutic neovascularization and targeted cell delivery. PMID:27713493

  8. SDF-1α-induced dual pairs of E-selectin/ligand mediate endothelial progenitor cell homing to critical ischemia.

    PubMed

    Liu, Zhao-Jun; Tian, Runxia; Li, Yan; Zhang, Leiming; Shao, Hongwei; Yang, Cuixia; Velazquez, Omaida C

    2016-10-07

    Homing of endothelial progenitor cells (EPC) to the ischemic tissues is a key event in neovascularization and tissue regeneration. In response to ischemic insult, injured tissues secrete several chemo-cytokines, including stromal cell-derived factor-1α (SDF-1α), which triggers mobilization and homing of bone marrow-derived EPC (BMD-EPC). We previously reported that SDF-1α-induced EPC homing is mediated by a panel of adhesion molecules highly or selectively expressed on the activated endothelium in ischemic tissues, including E-selectin. Elevated E-selectin on wound vasculature serve as docking sites for circulating EPC, which express counterpart E-selectin ligands. Here, we show that SDF-1α presented in wound tissue and released into circulation can act both locally and remotely to induce ischemic tissue endothelium and BMD-EPC to express both E-selectin and its ligands. By performing BM transplantation using E-selectin(-/-) and E-selectin(+/+) mice as the donors and recipients respectively, we demonstrate that upregulated dual E-selectin/ligand pairs reciprocally expressed on ischemic tissue endothelium and BMD-EPC act as double-locks to secure targeted EPC- endothelium interactions by which to facilitate EPC homing and promote neovascularization and tissue repair. These findings describe a novel mechanism for BMD-EPC homing and indicate that dual E-selectin/ligand pairs may be effective targets/tools for therapeutic neovascularization and targeted cell delivery.

  9. PPARα Is Essential for Microparticle-Induced Differentiation of Mouse Bone Marrow-Derived Endothelial Progenitor Cells and Angiogenesis

    PubMed Central

    Benameur, Tarek; Tual-Chalot, Simon; Andriantsitohaina, Ramaroson; Martínez, María Carmen

    2010-01-01

    Background Bone marrow-derived endothelial progenitor cells (EPCs) are critical for neovascularization. We hypothesized that microparticles (MPs), small fragments generated from the plasma membrane, can activate angiogenic programming of EPCs. Methodology/Principal Findings We studied the effects of MPs obtained from wild type (MPsPPARα+/+) and knock-out (MPsPPARα−/−) mice on EPC differentiation and angiogenesis. Bone marrow-derived cells were isolated from WT or KO mice and were cultured in the presence of MPsPPARα+/+ or MPsPPARα−/− obtained from blood of mice. Only MPsPPARα+/+ harboring PPARα significantly increased EPC, but not monocytic, differentiation. Bone marrow-derived cells treated with MPsPPARα+/+ displayed increased expression of pro-angiogenic genes and increased in vivo angiogenesis. MPsPPARα+/+ increased capillary-like tube formation of endothelial cells that was associated with enhanced expressions of endothelial cell-specific markers. Finally, the effects of MPsPPARα+/+ were mediated by NF-κB-dependent mechanisms. Conclusions/Significance Our results underscore the obligatory role of PPARα carried by MPs for EPC differentiation and angiogenesis. PPARα-NF-κB-Akt pathways may play a pivotal stimulatory role for neovascularization, which may, at least in part, be mediated by bone marrow-derived EPCs. Improvement of EPC differentiation may represent a useful strategy during reparative neovascularization. PMID:20811625

  10. Nanotechnology in corneal neovascularization therapy--a review.

    PubMed

    Gonzalez, Lilian; Loza, Raymond J; Han, Kyu-Yeon; Sunoqrot, Suhair; Cunningham, Christy; Purta, Patryk; Drake, James; Jain, Sandeep; Hong, Seungpyo; Chang, Jin-Hong

    2013-03-01

    Nanotechnology is an up-and-coming branch of science that studies and designs materials with at least one dimension sized from 1-100 nm. These nanomaterials have unique functions at the cellular, atomic, and molecular levels. The term "nanotechnology" was first coined in 1974. Since then, it has evolved dramatically and now consists of distinct and independent scientific fields. Nanotechnology is a highly studied topic of interest, as nanoparticles can be applied to various fields ranging from medicine and pharmacology, to chemistry and agriculture, to environmental science and consumer goods. The rapidly evolving field of nanomedicine incorporates nanotechnology with medical applications, seeking to give rise to new diagnostic means, treatments, and tools. Over the past two decades, numerous studies that underscore the successful fusion of nanotechnology with novel medical applications have emerged. This has given rise to promising new therapies for a variety of diseases, especially cancer. It is becoming abundantly clear that nanotechnology has found a place in the medical field by providing new and more efficient ways to deliver treatment. Ophthalmology can also stand to benefit significantly from the advances in nanotechnology research. As it relates to the eye, research in the nanomedicine field has been particularly focused on developing various treatments to prevent and/or reduce corneal neovascularization among other ophthalmologic disorders. This review article aims to provide an overview of corneal neovascularization, currently available treatments, and where nanotechnology comes into play.

  11. Prognostic Factor Analysis of Intraocular Pressure with Neovascular Glaucoma.

    PubMed

    Nakano, Satoko; Nakamuro, Takako; Yokoyama, Katsuhiko; Kiyosaki, Kunihiro; Kubota, Toshiaki

    2016-01-01

    Purpose. To perform multivariate analysis for identifying independent predictors of elevated intraocular pressure (IOP) with neovascular glaucoma (NVG), including antivascular endothelial growth factor (VEGF) intravitreal injections. Methods. We retrospectively reviewed 142 NVG patients (181 eyes) with ischemic retinal diseases [proliferative diabetic retinopathy (PDR) in 134 eyes, retinal vein occlusion (RVO) in 29, and ocular ischemic syndrome in 18]. We analyzed age, gender, initial/final LogMAR VA, initial/final IOP, extent of iris and/or angle neovascularization, treatments, preexisting complications, concurrent medications, and follow-up duration. Results. The mean follow-up duration was 23.8 ± 18.8 months. At the final follow-up, 125 (72.3%) eyes had IOP ≤ 21 mmHg. NVG patients with RVO had a higher degree of angle closure and higher IOP. NVG with PDR had better IOP and LogMAR VA. Angle closure had the greatest impact on final IOP. Greater than 90% of patients treated with trabeculectomy with mitomycin C (LEC) had persistent declines in IOP (≤21 mmHg). Stand-alone and combination anti-VEGF therapies were not associated with improved long-term prognosis of IOP. Conclusions. Angle closure was found to have the greatest effect on NVG-IOP prognosis. When target IOP values are not obtained after adequate PRP with or without anti-VEGF, early LEC may improve the prognosis of IOP.

  12. Prognostic Factor Analysis of Intraocular Pressure with Neovascular Glaucoma

    PubMed Central

    Nakamuro, Takako; Yokoyama, Katsuhiko; Kiyosaki, Kunihiro

    2016-01-01

    Purpose. To perform multivariate analysis for identifying independent predictors of elevated intraocular pressure (IOP) with neovascular glaucoma (NVG), including antivascular endothelial growth factor (VEGF) intravitreal injections. Methods. We retrospectively reviewed 142 NVG patients (181 eyes) with ischemic retinal diseases [proliferative diabetic retinopathy (PDR) in 134 eyes, retinal vein occlusion (RVO) in 29, and ocular ischemic syndrome in 18]. We analyzed age, gender, initial/final LogMAR VA, initial/final IOP, extent of iris and/or angle neovascularization, treatments, preexisting complications, concurrent medications, and follow-up duration. Results. The mean follow-up duration was 23.8 ± 18.8 months. At the final follow-up, 125 (72.3%) eyes had IOP ≤ 21 mmHg. NVG patients with RVO had a higher degree of angle closure and higher IOP. NVG with PDR had better IOP and LogMAR VA. Angle closure had the greatest impact on final IOP. Greater than 90% of patients treated with trabeculectomy with mitomycin C (LEC) had persistent declines in IOP (≤21 mmHg). Stand-alone and combination anti-VEGF therapies were not associated with improved long-term prognosis of IOP. Conclusions. Angle closure was found to have the greatest effect on NVG-IOP prognosis. When target IOP values are not obtained after adequate PRP with or without anti-VEGF, early LEC may improve the prognosis of IOP. PMID:27579175

  13. Attenuation of Choroidal Neovascularization by β2-Adrenergic Receptor Antagonism

    PubMed Central

    Lavine, Jeremy A.; Sang, Yanzhi; Wang, Shoujian; Ip, Michael S.; Sheibani, Nader

    2013-01-01

    Objectives To determine if β-adrenergic blockade inhibits choroidal neovascularization (CNV) in a mouse model of laser-induced CNV, and to investigate the mechanism by which β-adrenoreceptor antagonism blunts CNV. Methods The impact of β-adrenoreceptor blockade on CNV was determined using the laser-induced CNV model. Briefly, mice were subjected to laser burns, inducing CNV, and treated with daily intraperitoneal injections of propranolol. Neovascularization was measured on choroidal-sclera flat mounts using intercellular adhesion molecule-2 immunofluorescence staining. The impact of β-adrenergic receptor signaling on expression of vascular endothelial growth factor (VEGF) was investigated using primary mouse choroidal endothelial cells (ChEC) and retinal pigment epithelial (RPE) cells. These cells were incubated with β-adrenoreceptor agonists and/or antagonists, and assayed for VEGF mRNA and protein levels. Results Propranolol-treated mice demonstrated a 50% reduction in laser-induced CNV. Norepinephrine treatment stimulated VEGF mRNA expression and protein secretion in both ChEC and RPE cells. This effect was blocked by β2-adrenoreceptor antagonism and mimicked by β2-adrenergic receptor agonists. Conclusions and Clinical Relevance β-Adrenergic blockade attenuated CNV. β2-Adrenergic receptors regulated VEGF expression in ChEC and RPE cells. Antagonists of β-adrenergic receptors are safe and well tolerated in patients with glaucoma and cardiovascular disease. Thus, blockade of β-adrenoreceptors may provide a new avenue to inhibit VEGF expression in CNV. PMID:23303344

  14. Inflammatory choroidal neovascular membrane after healed tuberculous choroidal granuloma

    PubMed Central

    Lodhi, Sikander A. K.; Saifuddin, Khadija; Devulapally, Santhosh

    2017-01-01

    Objective: To present a case of choroidal granuloma masquerading as intraocular tumor that healed on anti-tuberculous treatment but led to the development of inflammatory choroidal neovascular membrane (CNVM). Method: A 42-year-old female patient with past history of hysterectomy presented with diminution of vision in the right eye. Fundus examination in the right eye showed a yellowish white choroidal mass with associated bullous retinal detachment superotemporal to fovea. Left eye fundus was normal. Fundus flourescein angiography showed early and late hyperflourescence with late pooling in serous detachments. Complete systemic evaluation did not yield a clue to diagnosis. Positron emission tomography scan (PET scan) showed enlarged lymph nodes in cervical, mediastinal and peritoneal regions. Lymph node biopsy showed caseating granulomas. Results: The granuloma subsided and a scar formed 5 months after starting anti-tuberculous treatment with improvement in vision. Six months later, the vision deteriorated again with the development of a choroidal neovascular membrane (CNVM) at the margin of the scar. The CNVM resolved and all the signs of activity subsided after giving intravitreal antivascular endothelial growth factor (anti-VEGF) injections. Conclusions: Making a diagnosis of tuberculous granuloma in a case of choroidal mass lesion is a challenge. PET scan helps in identifying metabolically active lymph nodes appropriate for biopsy. Healed scars of tuberculous choroid lesions should be followed closely to detect the development of CNVM. PMID:28293535

  15. Human Adult Vena Saphena Contains Perivascular Progenitor Cells Endowed With Clonogenic and Proangiogenic Potential

    PubMed Central

    Campagnolo, Paola; Cesselli, Daniela; Zen, Ayman Al Haj; Beltrami, Antonio Paolo; Kränkel, Nicolle; Katare, Rajesh; Angelini, Gianni; Emanueli, Costanza; Madeddu, Paolo

    2010-01-01

    Background Clinical trials in ischemic patients showed the safety and benefit of autologous bone marrow progenitor cell transplantation. Non–bone marrow progenitor cells with proangiogenic capacities have been described, yet they remain clinically unexploited owing to their scarcity, difficulty of access, and low ex vivo expansibility. We investigated the presence, antigenic profile, expansion capacity, and proangiogenic potential of progenitor cells from the saphenous vein of patients undergoing coronary artery bypass surgery. Methods and Results CD34-positive cells, negative for the endothelial marker von Willebrand factor, were localized around adventitial vasa vasorum. After dissection of the vein from surrounding tissues and enzymatic digestion, CD34-positive/CD31-negative cells were isolated by selective culture, immunomagnetic beads, or fluorescence-assisted cell sorting. In the presence of serum, CD34-positive/CD31-negative cells gave rise to a highly proliferative population that expressed pericyte/mesenchymal antigens together with the stem cell marker Sox2 and showed clonogenic and multilineage differentiation capacities. We called this population “saphenous vein–derived progenitor cells” (SVPs). In culture, SVPs integrated into networks formed by endothelial cells and supported angiogenesis through paracrine mechanisms. Reciprocally, endothelial cell–released factors facilitated SVP migration. These interactive responses were inhibited by Tie-2 or platelet-derived growth factor-BB blockade. Intramuscular injection of SVPs in ischemic limbs of immunodeficient mice improved neovascularization and blood flow recovery. At 14 days after transplantation, proliferating SVPs were still detectable in the recipient muscles, where they established N-cadherin–mediated physical contact with the capillary endothelium. Conclusions SVPs generated from human vein CD34-positive/CD31-negative progenitor cells might represent a new therapeutic tool for

  16. SCORE Study Report #11: Incidences of Neovascular Events in Eyes with Retinal Vein Occlusion

    PubMed Central

    Chan, Clement K.; Ip, Michael S.; VanVeldhuisen, Paul C.; Oden, Neal L.; Scott, Ingrid U.; Tolentino, Michael J.; Blodi, Barbara A.

    2010-01-01

    Purpose To investigate in The Standard Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) Study: 1) incidences of neovascular events and retinal capillary nonperfusion (abbreviated as “nonperfusion”), and their relationship with treatment groups; 2) neovascular incidences by nonperfusion status; and 3) pertinent baseline factors for their potential risk for neovascular events. Design Two multi-center, randomized clinical trials: one evaluating participants with central retinal vein occlusion (CRVO) and the other evaluating participants with branch retinal vein occlusion (BRVO). Participants At 36 months, data were available for 81 participants with CRVO and 128 with BRVO. Intervention Standard care (observation or grid photocoagulation) versus 1 mg or 4 mg intravitreal triamcinolone. Main Outcome Measures Neovascularization of the iris (NVI), neovascular glaucoma (NVG), disc or retinal neovascularization (NVD/NVE), pre-retinal or vitreous hemorrhage (PRH/VH), and nonperfusion. Results Cumulative 36-month incidences for CRVO and BRVO eyes, respectively, were: 8.5% and 2.4% for NVI or NVG; 8.8 % and 7.6% for NVD/NVE or PRH/VH. There were no differences in incidences of neovascular events or risk of nonperfusion when comparing the 3 treatment groups within diseases. For CRVO at 36 months, 16.6% of eyes with ≥ 5.5 disc areas of nonperfusion vs. 4.0% of eyes with < 5.5 disc areas of nonperfusion developed NVG (P= 0.0003); for BRVO at 36 months, 14.6% versus 2.4% developed NVD/NVE (P < 0.0001). Nonperfusion was the only significant baseline factor for neovascularization in BRVO, with the risk of a neovascular event increasing with greater disc areas of nonperfusion, and the highest risk noted at ≥ 5.5 disc areas. Conclusions In the SCORE Study, triamcinolone treatment was not associated with lower incidences of neovascular events or nonperfusion status compared with observation or grid photocoagulation. Cumulative 36-month incidences for most

  17. Mesenchymal progenitor cells for the osteogenic lineage.

    PubMed

    Ono, Noriaki; Kronenberg, Henry M

    2015-09-01

    Mesenchymal progenitors of the osteogenic lineage provide the flexibility for bone to grow, maintain its function and homeostasis. Traditionally, colony-forming-unit fibroblasts (CFU-Fs) have been regarded as surrogates for mesenchymal progenitors; however, this definition cannot address the function of these progenitors in their native setting. Transgenic murine models including lineage-tracing technologies based on the cre-lox system have proven to be useful in delineating mesenchymal progenitors in their native environment. Although heterogeneity of cell populations of interest marked by a promoter-based approach complicates overall interpretation, an emerging complexity of mesenchymal progenitors has been revealed. Current literatures suggest two distinct types of bone progenitor cells; growth-associated mesenchymal progenitors contribute to explosive growth of bone in early life, whereas bone marrow mesenchymal progenitors contribute to the much slower remodeling process and response to injury that occurs mainly in adulthood. More detailed relationships of these progenitors need to be studied through further experimentation.

  18. Identification of E-Selectin as a Novel Target for the Regulation of Post-Natal Neovascularization: Implications for Diabetic Wound Healing

    PubMed Central

    Liu, Zhao-Jun; Tian, Runxia; An, Weijun; Zhuge, Ying; Li, Yan; Shao, Hongwei; Habib, Bianca; Livingstone, Alan S.; Velazquez, Omaida C.

    2012-01-01

    Objectives We previously reported that stromal cell-derived factor-1α (SDF-1α, a homing signal for recruiting endothelial progenitor cells (EPC) to areas of neovascularization), is down-regulated in diabetic wounds 1. We now investigate signals whereby mature endothelial cells (EC) and circulating EPC achieve SDF-1α-mediated EPC homing. Methods SDF-1α in diabetic wounds were therapeutically increased by injection of SDF-1α–engineered bone marrow-derived fibroblasts versus control cells (N= 48 (20, NOD), (28, STZ-C57)). PCR-array gene expression differences were validated by Western blotting and immunohistochemistry. The role of adhesion molecule(s) in mediating SDF-1α-induced EPC homing and wound healing was furthered studied using antagonists in vitro and in vivo. Results Increasing wound SDF-1α via cell-base therapy promotes healing in diabetic mice (~20% increase in healing rates by day 3, p=0.006). SDF-1α increased EC-EPC adhesion and specifically upregulated E-selectin expression in human microvascular EC (2.3-fold increase, p<0.01). This effect was also significant in blood vessels of the experimental mice and resulted in increased wound neovascularization. The regulatory effects of SDF-1α on EC-EPC adhesion and EPC homing were specifically mediated by E-selectin, as the application of E-selectin antagonists significantly inhibited SDF-1α-induced EC-EPC adhesion, EPC homing, wound neovascularization, and wound healing. Conclusions SDF-1α–engineered cell-based therapy promotes diabetic wound healing in mice by specifically upregulating E-selectin expression in mature EC leading to increase EC-EPC adhesion, EPC homing and increased wound neovascularization. These findings provide novel insight into the signals underlying the biological effect of SDF-1α on EPC homing and point to E-selectin as a new potential target for therapeutic manipulation of EPC trafficking in diabetic wound healing. PMID:20881769

  19. Intrasilicone bevacizumab injection for iris neovascularization after vitrectomy for proliferative diabetic retinopathy.

    PubMed

    Salman, Abdelrahman G

    2013-01-01

    To evaluate the efficacy and safety of intrasilicone injection of bevacizumab for the treatment of iris neovascularization after vitrectomy for proliferative diabetic retinopathy. Bevacizumab 1.25 mg/0.05 ml was injected into silicone oil in 15 eyes of 11 patients with iris neovascularization which had developed 2.5-6 months after vitrectomy and silicone oil tamponade. The main outcome measures were regression of iris neovascularization, intraocular pressure elevation, and visual acuity. In all eyes, iris neovascularization regressed and postinjection intraocular pressure was controlled within 7 days postinjection. Visual acuity improved in 12 eyes. In 4 patients, iris neovascularization recurred within 10 weeks after the injection and they were successfully treated with a second intrasilicone bevacizumab injection of the same dose. Intrasilicone injection of bevacizumab is safe and effective in the treatment of patients with iris neovascularization after vitrectomy for advanced proliferative diabetic retinopathy. Further studies on greater numbers of patients and more advanced neovascularization are recommended. Copyright © 2012 S. Karger AG, Basel.

  20. Reduced survival in patients with early-stage non-small-cell lung cancer is associated with high pleural endothelial progenitor cell levels.

    PubMed

    Pirro, Matteo; Cagini, Lucio; Mannarino, Massimo R; Andolfi, Marco; Potenza, Rossella; Paciullo, Francesco; Bianconi, Vanessa; Frangione, Maria Rosaria; Bagaglia, Francesco; Puma, Francesco; Mannarino, Elmo

    2016-12-01

    Endothelial progenitor cells are capable of contributing to neovascularization in tumours. In patients with either malignant or transudative pleural effusion, we tested the presence of pleural endothelial progenitor cells. We also measured the number of endothelial progenitor cells in post-surgery pleural drainage of either patients with early non-small-cell lung cancer or control patients with benign lung disease undergoing pulmonary resection. The prospective influence of post-surgery pleural-drainage endothelial progenitor cells on cancer recurrence/survival was investigated. Pleural endothelial progenitor cell levels were quantified by fluorescence-activated cell sorting analysis in pleural effusion of 15 patients with late-stage non-small-cell lung cancer with pleural involvement and in 15 control patients with congestive heart failure. Also, pleural-drainage endothelial progenitor cells were measured in pleural-drainage fluid 48 h after surgery in 64 patients with early-stage non-small-cell lung cancer and 20 benign lung disease patients undergoing pulmonary resection. Cancer recurrence and survival was evaluated in patients with high pleural-drainage endothelial progenitor cell levels. The number of pleural endothelial progenitor cells was higher in non-small-cell lung cancer pleural effusion than in transudative pleural effusion. Also, pleural-drainage endothelial progenitor cell levels were higher in patients with non-small-cell lung cancer than in patients with benign lung disease undergoing pulmonary resection (P < 0.05). Non-small-cell lung cancer patients with high pleural-drainage endothelial progenitor cell levels had a significantly 4.9 higher rate of cancer recurrence/death than patients with lower pleural-drainage endothelial progenitor cell levels, irrespective of confounders. Endothelial progenitor cells are present in the pleural effusion and are higher in patients with late-stage non-small-cell lung cancer with pleural involvement than in

  1. Neovascularization prevalence in the supraspinatus of patients with rotator cuff tendinopathy.

    PubMed

    Kardouni, Joseph R; Seitz, Amee L; Walsworth, Matthew K; Michener, Lori A

    2013-11-01

    A high prevalence of neovascularity in lower extremity tendinopathies has been reported. Neovascularity in those with rotator cuff tendinopathy exclusively has not been examined. The objective was to determine the prevalence of neovascularization in patients with rotator cuff tendinopathy compared with asymptomatic controls. Single-blind cross-sectional study. Research laboratory. Participants (n = 40; age = 44.9 years, 23-62 years; 20 females) with rotator cuff tendinopathy (n = 20) but without full-thickness rotator cuff tears, and asymptomatic controls that were age, gender, and hand dominance matched (n = 20) to the patients. The participants laying in supine had their shoulder positioned in internal rotation and extension. Ultrasound images were collected of the supraspinatus tendon and subacromial bursae in the transverse and longitudinal planes using a linear transducer in color Doppler mode. Images were assessed for neovascularization by 2 trained raters who were blinded to group (rotator cuff tendinopathy or asymptomatic group). No statistically significant difference in neovascularization was identified between participants with and without rotator cuff tendinopathy (χ = 0.13, df = 1, P = 0.72). Neovascularization was identified in 6 of 20 patients with rotator cuff tendinopathy (30%) and 5 of 20 asymptomatic control participants (25%). The authors found no differences in neovascularization rate in patients with rotator cuff tendinopathy (30%) and asymptomatic controls (25%). The study indicates that neovascularization is not related to presence of symptomatic tendinopathy in those with rotator cuff tendinopathy. Neovascularization may not be a relevant sonographic finding to aid the clinical assessment of those with rotator cuff tendinopathy.

  2. Embryonic Heart Progenitors and Cardiogenesis

    PubMed Central

    Brade, Thomas; Pane, Luna S.; Moretti, Alessandra; Chien, Kenneth R.; Laugwitz, Karl-Ludwig

    2013-01-01

    The mammalian heart is a highly specialized organ, comprised of many different cell types arising from distinct embryonic progenitor populations during cardiogenesis. Three precursor populations have been identified to contribute to different myocytic and nonmyocytic cell lineages of the heart: cardiogenic mesoderm cells (CMC), the proepicardium (PE), and cardiac neural crest cells (CNCCs). This review will focus on molecular cues necessary for proper induction, expansion, and lineage-specific differentiation of these progenitor populations during cardiac development in vivo. Moreover, we will briefly discuss how the knowledge gained on embryonic heart progenitor biology can be used to develop novel therapeutic strategies for the management of congenital heart disease as well as for improvement of cardiac function in ischemic heart disease. PMID:24086063

  3. In vitro culture of stress erythroid progenitors identifies distinct progenitor populations and analogous human progenitors

    PubMed Central

    Xiang, Jie; Wu, Dai-Chen; Chen, Yuanting

    2015-01-01

    Tissue hypoxia induces a systemic response designed to increase oxygen delivery to tissues. One component of this response is increased erythropoiesis. Steady-state erythropoiesis is primarily homeostatic, producing new erythrocytes to replace old erythrocytes removed from circulation by the spleen. In response to anemia, the situation is different. New erythrocytes must be rapidly made to increase hemoglobin levels. At these times, stress erythropoiesis predominates. Stress erythropoiesis is best characterized in the mouse, where it is extramedullary and utilizes progenitors and signals that are distinct from steady-state erythropoiesis. In this report, we use an in vitro culture system that recapitulates the in vivo development of stress erythroid progenitors. We identify cell-surface markers that delineate a series of stress erythroid progenitors with increasing maturity. In addition, we use this in vitro culture system to expand human stress erythroid progenitor cells that express analogous cell-surface markers. Consistent with previous suggestions that human stress erythropoiesis is similar to fetal erythropoiesis, we demonstrate that human stress erythroid progenitors express fetal hemoglobin upon differentiation. These data demonstrate that similar to murine bone marrow, human bone marrow contains cells that can generate BMP4-dependent stress erythroid burst-forming units when cultured under stress erythropoiesis conditions. PMID:25608563

  4. [Choroidal neovascularization secondary to angioid streaks: A familial case report].

    PubMed

    Benitez-Herreros, J; Camara-Gonzalez, C; Lopez-Guajardo, L; Beckford-Torngren, C; Pareja-Esteban, J

    2014-05-01

    We report a familial case of 2 brothers that suffered choroidal neovascularization (CNV) secondary to angioid streaks. They were both treated with a monthly intravitreal injection of ranibizumab (Lucentis(®)) for 3 months. Visual acuity was stabilized and fluorescein angiography revealed complete resolution of CNV. Neither recurrent CNV lesion nor new hemorrhages were reported during the follow-up period. The use of intravitreal ranibizumab for the treatment of CNV in patients with angioid streaks has shown favorable results. However, further studies with a longer follow-up and larger number of patients are necessary to more precisely determine the results of this therapy. Copyright © 2012 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

  5. Diospyros kaki Extract Inhibits Alkali Burn-Induced Corneal Neovascularization.

    PubMed

    Yang, Sung Jae; Jo, Hyoung; Kim, Kyung-A; Ahn, Hong Ryul; Kang, Suk Woo; Jung, Sang Hoon

    2016-01-01

    The purpose of this study was to evaluate the effect of ethanol extract of Diospyros kaki (EEDK) leaves on corneal neovascularization (CoNV) in rats. One week after the alkali burns in the corneas, the CoNV area coverage in the CoNV-positive control group, 100 mg/kg EEDK group, and 200 mg/kg EEDK group was 43.3% ± 5.5%, 337.7% ± 2.5%, and 27.2% ± 4.3%, respectively. The areas of CoNV in the EEDK-treated groups were significantly different from those of the CoNV group. EEDK significantly attenuated the upregulation of vascular endothelial growth factor, fibroblast growth factor, interleukin-6, and matrix metalloproteinase-2 (MMP-2) protein levels. Orally administrated D. kaki inhibited CoNV development in rats.

  6. Focal choroidal excavaction associated with idiopathic choroidal neovascularization.

    PubMed

    Sánchez-Vicente, J L; Rueda-Rueda, T; Martínez-Borrego, A C; Moruno-Rodríguez, A; Molina-Socola, F E; Contreras-Díaz, M; Medina-Tapia, A; Muñoz-Morales, A; López-Herrero, F

    2017-06-02

    The case is presented of a 45 year-old man with a focal choroidal excavation associated with choroidal neovascularisation not included in the area of excavation. Clinical features were analysed using retinography, fluorescein angiography, optical coherence tomography, and optical coherence tomography angiography. The patient was treated with 3 intravitreal injections of bevacizumab, with a good response. Focal choroidal excavation can be associated with choroidal neovascularization not included in the area of excavation. Multimodal imaging provides a complete description of clinical features, before and after treatment. Copyright © 2017 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

  7. Neovascular glaucoma after vitrectomy in patients with proliferative diabetic retinopathy

    PubMed Central

    Kwon, Jin-woo; Jee, Donghyun; La, Tae Yoon

    2017-01-01

    Abstract To evaluate the prevalence and risk factors of neovascular glaucoma (NVG) after vitrectomy in patients with vitreous hemorrhage associated with proliferative diabetic retinopathy (PDR). This retrospective, noncomparative, observational study included 127 eyes of 127 patients with PDR who received vitrectomy with a follow-up period of at least 6 months. The prevalence of NVG and associated risk factors were assessed including sex, age, previous panretinal photocoagulation, baseline intraocular pressure, combined phacovitrectomy, and pretreatment with intravitreal bevacizumab (IVB) before vitrectomy for the treatment of vitreous hemorrhage. NVG developed in 15 (11.8%) of 127 patients. Of the 15 eyes with NVG, 11 cases (73.3%) postoperatively developed NVG within 6 months. Postoperative NVG was associated with preoperative IVB treatment (odds ratio, 4.43; P = 0.019). The prevalence of NVG after vitrectomy was 11.8%, and an associated risk factor for NVG was preoperative IVB for the treatment of vitreous hemorrhage. PMID:28272234

  8. Diospyros kaki Extract Inhibits Alkali Burn-Induced Corneal Neovascularization

    PubMed Central

    Yang, Sung Jae; Jo, Hyoung; Kim, Kyung-A; Ahn, Hong Ryul; Kang, Suk Woo

    2016-01-01

    Abstract The purpose of this study was to evaluate the effect of ethanol extract of Diospyros kaki (EEDK) leaves on corneal neovascularization (CoNV) in rats. One week after the alkali burns in the corneas, the CoNV area coverage in the CoNV-positive control group, 100 mg/kg EEDK group, and 200 mg/kg EEDK group was 43.3% ± 5.5%, 337.7% ± 2.5%, and 27.2% ± 4.3%, respectively. The areas of CoNV in the EEDK-treated groups were significantly different from those of the CoNV group. EEDK significantly attenuated the upregulation of vascular endothelial growth factor, fibroblast growth factor, interleukin-6, and matrix metalloproteinase-2 (MMP-2) protein levels. Orally administrated D. kaki inhibited CoNV development in rats. PMID:26348484

  9. Synthesis and Biological Evaluation of Novel Homoisoflavonoids for Retinal Neovascularization

    PubMed Central

    Lee, Hyungjun; Sulaiman, Rania S.; An, Hongchan; Magaña, Carlos; Shadmand, Mehdi; Vayl, Alexandra; Rajashekhar, Gangaraju; Kim, Eun-Yeong; Suh, Young-Ger; Lee, Kiho

    2016-01-01

    Eye diseases characterized by excessive angiogenesis such as wet age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity are major causes of blindness. Cremastranone is an anti-angiogenic, naturally occurring homoisoflavanone with efficacy in retinal and choroidal neovascularization models and antiproliferative selectivity for endothelial cells over other cell types. We undertook a cell-based structure-activity relationship study to develop more potent cremastranone analogs, with improved antiproliferative selectivity for retinal endothelial cells. Phenylalanyl-incorporated homoisoflavonoids showed improved activity and remarkable selectivity for retinal microvascular endothelial cells. A lead compound inhibited angiogenesis in vitro without inducing apoptosis, and had efficacy in the oxygen-induced retinopathy model in vivo. PMID:26035340

  10. Radiation Therapy for Neovascular Age-related Macular Degeneration

    SciTech Connect

    Kishan, Amar U.; Modjtahedi, Bobeck S.; Morse, Lawrence S.; Lee, Percy

    2013-03-01

    In the enormity of the public health burden imposed by age-related macular degeneration (ARMD), much effort has been directed toward identifying effective and efficient treatments. Currently, anti-vascular endothelial growth factor (VEGF) injections have demonstrated considerably efficacy in treating neovascular ARMD, but patients require frequent treatment to fully benefit. Here, we review the rationale and evidence for radiation therapy of ARMD. The results of early photon external beam radiation therapy are included to provide a framework for the sequential discussion of evidence for the usage of stereotactic radiation therapy, proton therapy, and brachytherapy. The evidence suggests that these 3 modern modalities can provide a dose-dependent benefit in the treatment of ARMD. Most importantly, preliminary data suggest that all 3 can be used in conjunction with anti-VEGF therapeutics, thereby reducing the frequency of anti-VEGF injections required to maintain visual acuity.

  11. Specific role of impaired glucose metabolism and diabetes mellitus in endothelial progenitor cell characteristics and function.

    PubMed

    Yiu, Kai-Hang; Tse, Hung-Fat

    2014-06-01

    The disease burden of diabetes mellitus (DM) and its associated cardiovascular complications represent a growing and major global health problem. Recent studies suggest that circulating exogenous endothelial progenitor cells (EPCs) play an important role in endothelial repair and neovascularization at sites of injury or ischemia. Both experimental and clinical studies have demonstrated that hyperglycemia related to DM can induce alterations to EPCs. The reduction and dysfunction of EPCs related to DM correlate with the occurrence and severity of microvascular and macrovascular complications, suggesting a close mechanistic link between EPC dysfunction and impaired vascular function/repair in DM. These alterations to EPCs, likely mediated by multiple pathophysiological mechanisms, including inflammation, oxidative stress, and alterations in Akt and the nitric oxide pathway, affect EPCs at multiple stages: differentiation and mobilization in the bone marrow, trafficking and survival in the circulation, and homing and neovascularization. Several different therapeutic approaches have consequently been proposed to reverse the reduction and dysfunction of EPCs in DM and may represent a novel therapeutic approach to prevent and treat DM-related cardiovascular complications.

  12. Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization.

    PubMed

    Chakroborty, Debanjan; Chowdhury, Uttio Roy; Sarkar, Chandrani; Baral, Rathindranath; Dasgupta, Partha Sarathi; Basu, Sujit

    2008-04-01

    Mobilization of endothelial progenitor cells (EPCs) from the bone marrow and their subsequent participation in neovessel formation are implicated in tumor growth and neovascularization. As the neurotransmitter dopamine (DA) modulates adult endothelial cell function, we hypothesized that DA might have a regulatory role in mobilization of EPCs from the bone marrow niche. We show that there was a significant decrease in bone marrow DA content and an increase in EPC mobilization in tumor-bearing mice associated with tumor neovascularization. DA treatment of tumor-bearing mice inhibited EPC mobilization and tumor growth through its D2 receptors, as DA treatment failed to inhibit EPC mobilization in tumor-bearing mice treated with a specific DA D2 receptor antagonist and in tumor-bearing mice lacking the D2 receptor. In addition, we found that DA, through D2 receptors, exerted its inhibitory effect on EPC mobilization through suppression of VEGFA-induced ERK1/ERK2 phosphorylation and MMP-9 synthesis. These findings reveal a new link between DA and EPC mobilization and suggest a novel use for DA and D2 agents in the treatment of cancer and other diseases involving neovessel formation.

  13. New Treatment Modalities for Neovascular Age-Related Macular Degeneration.

    PubMed

    Schlottmann, Patricio G; Alezzandrini, Arturo A; Zas, Marcelo; Rodriguez, Francisco J; Luna, José D; Wu, Lihteh

    2017-09-14

    Age-related macular degeneration (AMD) is considered one of the main causes of severe vision loss in older adults. The neovascular form (nAMD) is an advanced stage, which is responsible for the most severe vision loss. Vascular endothelial growth factor (VEGF) is at present the main factor that leads to the development of a neovascular membrane and the increased leakage from the membrane to the retina. At present, anti-VEGF therapy is the only treatment that achieves vision gains in many patients and halts progression in most of them. VEGF blockade can be achieved with several molecules and various treatment regimens, which have been studied with excellent results. Unfortunately, real-world data has shown to be far less efficacious than clinical trials. This gap between clinical trials and real-world results is an unmet medical need that supports the necessity of new treatment modalities for nAMD. Of the various treatments being studied, anti-VEGFs of higher efficacy and longer durability are those more advanced in their development. Brolucizumab and abicipar pegol are 2 new anti-VEGF drugs that had positive results in phase 2 studies and are being tested in phase 3 trials at present. Other promising therapies are antiangiopoietin 2 molecules, which are in phase 2 development. At earlier stages of development but with promising results are squalamine, anti-VEGF-C and -D, and gene therapy. The future will give retina specialists a broad armamentarium with which patients may achieve high visual gains for the long term with a low treatment burden. Copyright 2017 Asia-Pacific Academy of Ophthalmology.

  14. Ranibizumab and bevacizumab for neovascular age-related macular degeneration.

    PubMed

    Martin, Daniel F; Maguire, Maureen G; Ying, Gui-shuang; Grunwald, Juan E; Fine, Stuart L; Jaffe, Glenn J

    2011-05-19

    Clinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data. In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart. Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern. At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further

  15. A Simple Optical Coherence Tomography Quantification Method for Choroidal Neovascularization

    PubMed Central

    Sulaiman, Rania S.; Quigley, Judith; Qi, Xiaoping; O'Hare, Michael N.; Grant, Maria B.; Boulton, Michael E.

    2015-01-01

    Abstract Purpose: Therapeutic efficacy is routinely assessed by measurement of lesion size using flatmounted choroids and confocal microscopy in the laser-induced choroidal neovascularization (L-CNV) rodent model. We investigated whether optical coherence tomography (OCT) quantification, using an ellipsoid volume measurement, was comparable to standard ex vivo evaluation methods for this model and whether this approach could be used to monitor treatment-related lesion changes. Methods: Bruch's membrane was ruptured by argon laser in the dilated eyes of C57BL/6J mice, followed by intravitreal injections of anti-VEGF164 or vehicle, or no injection. In vivo OCT images were acquired using Micron III or InVivoVue systems at 7, 10, and/or 14 days post-laser and neovascular lesion volume was calculated as an ellipsoid. Subsequently, lesion volume was compared to that calculated from confocal Z-stack images of agglutinin-stained choroidal flatmounts. Results: Ellipsoid volume measurement of orthogonal 2-dimensional OCT images obtained from different imaging systems correlated with ex vivo lesion volumes for L-CNV (Spearman's ρ=0.82, 0.75, and 0.82 at days 7, 10, and 14, respectively). Ellipsoid volume calculation allowed temporal monitoring and evaluation of CNV lesions in response to antivascular endothelial growth factor treatment. Conclusions: Ellipsoid volume measurements allow rapid, quantitative use of OCT for the assessment of CNV lesions in vivo. This novel method can be used with different OCT imaging systems with sensitivity to distinguish between treatment conditions. It may serve as a useful adjunct to the standard ex vivo confocal quantification, to assess therapeutic efficacy in preclinical models of CNV, and in models of other ocular diseases. PMID:26060878

  16. Aflibercept for neovascular age-related macular degeneration

    PubMed Central

    Sarwar, Salman; Clearfield, Elizabeth; Soliman, Mohamed Kamel; Sadiq, Mohammad Ali; Baldwin, Andrew J; Hanout, Mostafa; Agarwal, Aniruddha; Sepah, Yasir J; Do, Diana V; Nguyen, Quan Dong

    2016-01-01

    Background Central vision loss caused by age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. Neovascular AMD is characterized by choroidal neovascularization (CNV). Growth of new blood vessels in patients with neovascular AMD is driven by a complex process that involves a signal protein called vascular endothelial growth factor A (VEGF-A). Anti-VEGF drugs that block this protein include ranibizumab, bevacizumab, and aflibercept. Objectives To assess and compare the effectiveness and safety of intravitreal injections of aflibercept versus ranibizumab, bevacizumab, or sham for treatment of patients with neovascular AMD. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (Issue 11, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2015), EMBASE (January 1980 to November 2015), PubMed (1948 to November 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to November 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched December 4, 2014), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on November 30, 2015. Selection criteria We included randomized controlled trials (RCTs) in which aflibercept monotherapy was compared with ranibizumab, bevacizumab, or sham for participants with neovascular AMD who were treatment-naive. Data collection and analysis We used standard methodological procedures of The Cochrane Collaboration for screening, data abstraction, and study assessment. Two review authors

  17. Critical Role of the Nitric Oxide/Reactive Oxygen Species Balance in Endothelial Progenitor Dysfunction

    PubMed Central

    Fleissner, Felix

    2011-01-01

    Abstract Endothelial injury and dysfunction are critical events in the pathogenesis of cardiovascular disease. During these processes, an impaired balance of nitric oxide bioavailability and oxidative stress is mechanistically involved. Circulating angiogenic cells (including early and late outgrowth endothelial progenitor cells (EPC)) contribute to formation of new blood vessels, neovascularization, and homeostasis of the vasculature, and are highly sensitive for misbalance between NO and oxidative stress. We here review the role of the endothelial nitric oxide synthase and oxidative stress producing enzyme systems in EPC during cardiovascular disease. We also focus on the underlying molecular mechanisms and potential emerging drug- and gene-based therapeutic strategies to improve EPC function in cardiovascular diseased patients. Antioxid. Redox Signal. 15, 933–948. PMID:20712407

  18. Ephrin-B2–Activated Peripheral Blood Mononuclear Cells From Diabetic Patients Restore Diabetes-Induced Impairment of Postischemic Neovascularization

    PubMed Central

    Broquères-You, Dong; Leré-Déan, Carole; Merkulova-Rainon, Tatiana; Mantsounga, Chris S.; Allanic, David; Hainaud, Patricia; Contrères, Jean-Olivier; Wang, Yu; Vilar, José; Virally, Marie; Mourad, Jean-Jacques; Guillausseau, Pierre-Jean; Silvestre, Jean-Sébastien; Lévy, Bernard I.

    2012-01-01

    We hypothesized that in vitro treatment of peripheral blood mononuclear cells (PB-MNCs) from diabetic patients with ephrin-B2/Fc (EFNB2) improves their proangiogenic therapeutic potential in diabetic ischemic experimental models. Diabetes was induced in nude athymic mice by streptozotocin injections. At 9 weeks after hyperglycemia, 105 PB-MNCs from diabetic patients, pretreated by EFNB2, were intravenously injected in diabetic mice with hindlimb ischemia. Two weeks later, the postischemic neovascularization was evaluated. The mechanisms involved were investigated by flow cytometry analysis and in vitro cell biological assays. Paw skin blood flow, angiographic score, and capillary density were significantly increased in ischemic leg of diabetic mice receiving EFNB2-activated diabetic PB-MNCs versus those receiving nontreated diabetic PB-MNCs. EFNB2 bound to PB-MNCs and increased the adhesion and transmigration of PB-MNCs. Finally, EFNB2-activated PB-MNCs raised the number of circulating vascular progenitor cells in diabetic nude mice and increased the ability of endogenous bone marrow MNCs to differentiate into cells with endothelial phenotype and enhanced their proangiogenic potential. Therefore, EFNB2 treatment of PB-MNCs abrogates the diabetes-induced stem/progenitor cell dysfunction and opens a new avenue for the clinical development of an innovative and accessible strategy in diabetic patients with critical ischemic diseases. PMID:22596048

  19. [Prevention of recurrent varicose veins after surgery caused by phenomenon of neovascularization].

    PubMed

    Kas'ian, D A; Gutsu, E V; Ivanov, V A; Kuliuk, V S; Dontsu, I I

    2010-01-01

    The aim of study was to evaluate the effectiveness of surgical "barrier techniques" in prevention of phenomenon of inguinal neovascularization in patients with varicose veins of lower limbs. There were 68 patients (80 limbs) treated with flush ligation of saphenofemoral junction, stripping of great saphenous vein and avulsion of varicosities. Patients were divided in three groups: I (no "barrier techniques")--40 limbs; II (anatomical barrier)--20 limbs and III (synthetic barrier)--20 limbs. Duplex ultrasound was performed at interval of 24 months postoperatively. Signs of neovascularization were found more frequently in group I--22.5% of limbs vs 7.5% of limbs in patients with utilization of "barrier techniques". There were types B1, B2a and B2b of neovascularization only, according to Fischer classification. We conclude that use of a "barrier techniques", either anatomic or synthetic, is associated with a decreased incidence of neovascularization at the level of the saphenofemoral junction compared with a control group.

  20. SOX17 Regulates Conversion of Human Fibroblasts Into Endothelial Cells and Erythroblasts by Dedifferentiation Into CD34(+) Progenitor Cells.

    PubMed

    Zhang, Lianghui; Jambusaria, Ankit; Hong, Zhigang; Marsboom, Glenn; Toth, Peter T; Herbert, Brittney-Shea; Malik, Asrar B; Rehman, Jalees

    2017-06-20

    The mechanisms underlying the dedifferentiation and lineage conversion of adult human fibroblasts into functional endothelial cells have not yet been fully defined. Furthermore, it is not known whether fibroblast dedifferentiation recapitulates the generation of multipotent progenitors during embryonic development, which give rise to endothelial and hematopoietic cell lineages. Here we established the role of the developmental transcription factor SOX17 in regulating the bilineage conversion of fibroblasts by the generation of intermediate progenitors. CD34(+) progenitors were generated after the dedifferentiation of human adult dermal fibroblasts by overexpression of pluripotency transcription factors. Sorted CD34(+) cells were transdifferentiated into induced endothelial cells and induced erythroblasts using lineage-specific growth factors. The therapeutic potential of the generated cells was assessed in an experimental model of myocardial infarction. Induced endothelial cells expressed specific endothelial cell surface markers and also exhibited the capacity for cell proliferation and neovascularization. Induced erythroblasts expressed erythroid surface markers and formed erythroid colonies. Endothelial lineage conversion was dependent on the upregulation of the developmental transcription factor SOX17, whereas suppression of SOX17 instead directed the cells toward an erythroid fate. Implantation of these human bipotential CD34(+) progenitors into nonobese diabetic/severe combined immunodeficiency (NOD-SCID) mice resulted in the formation of microvessels derived from human fibroblasts perfused with mouse and human erythrocytes. Endothelial cells generated from human fibroblasts also showed upregulation of telomerase. Cell implantation markedly improved vascularity and cardiac function after myocardial infarction without any evidence of teratoma formation. Dedifferentiation of fibroblasts to intermediate CD34(+) progenitors gives rise to endothelial cells and

  1. Optical Coherence Tomography Angiography Demonstration of Choroidal Neovascularization in Malattia Leventinese.

    PubMed

    Corbelli, Eleonora; Corvi, Federico; Carnevali, Adriano; Querques, Lea; Zucchiatti, Ilaria; Bandello, Francesco; Querques, Giuseppe

    2016-06-01

    In a case of Malattia Leventinese, optical coherence tomography angiography led to the diagnosis of type 1 neovascularization, despite absence of evidence on conventional dye-based angiography. The authors hypothesize that, at least in some cases, accumulation of subretinal fluid in Malattia Leventinese could be due to a subretinal pigment epithelium (RPE) neovascular component rather than creation of hydrophobic barrier at the RPE and Bruch's membrane. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:602-604.].

  2. Short-term topical bevacizumab in the treatment of stable corneal neovascularization.

    PubMed

    Cheng, Sheng-Fu; Dastjerdi, Mohammad H; Ferrari, Giulio; Okanobo, Andre; Bower, Kraig S; Ryan, Denise S; Amparo, Francisco; Stevenson, William; Hamrah, Pedram; Nallasamy, Nambi; Dana, Reza

    2012-12-01

    To evaluate the safety and efficacy of topical bevacizumab in the treatment of corneal neovascularization. Prospective, nonrandomized, interventional case series. setting: Institutional, multicenter clinical trial. study population: Twenty eyes from 20 patients with stable corneal neovascularization. intervention procedures: Patients were treated with topical 1.0% bevacizumab for 3 weeks and were monitored for a total of 24 weeks. main outcome measures: Primary outcome measures included: neovascular area, defined as the area of the corneal vessels themselves; vessel caliber, defined as the mean corneal vessel diameter; and invasion area, defined as the fraction of the total cornea into which the vessels extended. The occurrence of ocular and systemic adverse events was monitored closely. As compared with the baseline visit, patients exhibited a statistically significant improvement in neovascular area by week 6 (P = .007) and in vessel caliber by week 12 (P = .006). At the final visit, neovascular area, vessel caliber, and invasion area were reduced by 47.5%, 36.2%, and 20%, respectively. The decreases in neovascular area and vessel caliber were statistically significant (P < .001 and P = .003, respectively); however, the reduction in invasion area did not reach statistical significance (P = .06). There were no significant changes in the secondary outcomes, and there were no adverse events. Short-term topical bevacizumab treatment reduced the extent of stable corneal neovascularization as measured by neovascular area and vessel caliber with no associated adverse events. Interestingly, the degree of treatment efficacy was inversely proportional to the baseline invasion area. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Correlation between neovascular lesion type and clinical characteristics of nonneovascular fellow eyes in patients with unilateral, neovascular age-related macular degeneration.

    PubMed

    Marsiglia, Marcela; Boddu, Sucharita; Chen, Christine Y; Jung, Jesse J; Mrejen, Sarah; Gallego-Pinazo, Roberto; Freund, K Bailey

    2015-05-01

    To investigate the association between the type of neovascularization (NV) and the clinical characteristics of nonneovascular fellow eyes in patients with unilateral, neovascular age-related macular degeneration. Eighty-three patients with treatment-naive, unilateral, neovascular age-related macular degeneration were retrospectively analyzed. Neovascular lesions were classified using both fluorescein angiography and optical coherence tomography as Type 1 (subretinal pigment epithelium), 2 (subretinal), 3 (intraretinal), or mixed NV. The associations between NV lesion type and baseline clinical and imaging characteristics of the fellow eye, including central geographic atrophy, noncentral geographic atrophy, pigmentary changes, soft drusen, cuticular drusen, reticular pseudodrusen, and subfoveal choroidal thickness, were examined. Subfoveal choroidal thickness was defined as thin if thickness was <120 μm. In the fellow eyes of patients with treatment-naive, unilateral, neovascular age-related macular degeneration, Type 3 NV had an increased adjusted odds ratio of reticular pseudodrusen (15.361, P < 0.001) and thin subfoveal choroidal thickness (21.537, P < 0.001) as well as a tendency toward an increased adjusted odds ratio of central geographic atrophy (4.775, P = 0.028). Fellow eyes of patients with Type 1 NV showed a decreased adjusted odds ratio of reticular pseudodrusen (0.233, P = 0.007) and thin subfoveal choroidal thickness (0.080, P = 0.005). In patients with unilateral, neovascular age-related macular degeneration, certain nonneovascular features of the fellow eye correlate with the NV lesion composition based on type, as anatomically classified utilizing both fluorescein angiography and optical coherence tomography. Patients with Type 3 NV were more likely to have reticular pseudodrusen and/or thin subfoveal choroidal thickness in the fellow eye compared with those with Type 1 NV. Patients with Type 3 NV also showed a trend toward increased central

  4. Girdin and its phosphorylation dynamically regulate neonatal vascular development and pathological neovascularization in the retina.

    PubMed

    Ito, Takanori; Komeima, Keiichi; Yasuma, Tetsuhiro; Enomoto, Atsushi; Asai, Naoya; Asai, Masato; Iwase, Sayoko; Takahashi, Masahide; Terasaki, Hiroko

    2013-02-01

    Vascular endothelial growth factor (VEGF) is recognized as a principal mediator of vessel growth. VEGF regulates various endothelial cellular processes, including cell migration, proliferation, and survival, through the serine threonine protein kinase Akt. The Akt substrate girdin, an actin-binding protein, is known to regulate VEGF-mediated postnatal angiogenesis. However, the role of girdin and its phosphorylation in neonatal retinal vascular development and ocular pathological neovascularization in vivo has not been elucidated. In the present study, therefore, we investigated these processes using Girdin(+/-) mice lacking one copy of the girdin gene and girdin S1416A knockin (Girdin-KI(SA/SA)) mice in which the phosphorylation site of girdin is completely disrupted. We used three mouse models of pathological ocular neovascularization: oxygen-induced retinopathy (a mouse model of ischemic retinopathies), laser-induced choroidal neovascularization, and a human VEGF transgenic mouse that overexpresses human VEGF specifically in photoreceptor cells and generates pathological neovascularization in the retina. Neonatal vascular development was delayed and pathological neovascularization was decreased in both Girdin(+/-) mice and Girdin-KI(SA/SA) mice. These results demonstrate that girdin and its phosphorylation play an important role in neonatal vascular development and in pathological neovascularization in the retina. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  5. The potential of nanomedicine therapies to treat neovascular disease in the retina

    PubMed Central

    2010-01-01

    Neovascular disease in the retina is the leading cause of blindness in all age groups. Thus, there is a great need to develop effective therapeutic agents to inhibit and prevent neovascularization in the retina. Over the past decade, anti-VEGF therapeutic agents have entered the clinic for the treatment of neovascular retinal disease, and these agents have been effective for slowing and preventing the progression of neovascularization. However, the therapeutic benefits of anti-VEGF therapy can be diminished by the need for prolonged treatment regimens of repeated intravitreal injections, which can lead to complications such as endophthalmitis, retinal tears, and retinal detachment. Recent advances in nanoparticle-based drug delivery systems offer the opportunity to improve bioactivity and prolong bioavailability of drugs in the retina to reduce the risks associated with treating neovascular disease. This article reviews recent advances in the development of nanoparticle-based drug delivery systems which could be utilized to improve the treatment of neovascular disease in the retina. PMID:20932321

  6. Spontaneous Regression of Choroidal Neovascularization in a Patient with Pattern Dystrophy

    PubMed Central

    Goleni, Flamur; Livir-Rallatos, Gerasimos; Livir-Rallatos, Charalampos; Zafirakis, Panagiotis; Allen Fishman, Gerald

    2016-01-01

    Purpose. To present a case of a patient with pattern dystrophy (PD) associated choroidal neovascularization (CNV) that resolved spontaneously without treatment. Methods. A 69-year-old male patient was referred to our unit, for evaluation of a recent visual loss (metamorphopsias) in his left eye. Fundus examination, fundus autofluorescence imaging, and fluorescein angiography showed a choroidal neovascular membrane in his left eye. Since visual acuity was satisfactory the patient elected observation. Clinical examination and OCT testing were repeated at 6 and 12 months after presentation. Results. Visual acuity remained stable at the level of 0.9 (baseline BCVA) during the follow-up period (12 months). Repeat OCT testing showed complete spontaneous regression of the choroidal neovascular membrane without evidence of intra- or subretinal fluid in both follow-up visits. Conclusions. Spontaneous regression of choroidal neovascularization can occur in patients with retinal dystrophies and associated choroidal neovascular membranes. The decision to treat or observe these patients relies strongly on the presenting visual acuity, since, in isolated instances, spontaneous resolution of choroidal neovascularization may occur. PMID:27847664

  7. Interleukin-12 inhibits pathological neovascularization in mouse model of oxygen-induced retinopathy

    PubMed Central

    Zhou, Yedi; Yoshida, Shigeo; Kubo, Yuki; Kobayashi, Yoshiyuki; Nakama, Takahito; Yamaguchi, Muneo; Ishikawa, Keijiro; Nakao, Shintaro; Ikeda, Yasuhiro; Ishibashi, Tatsuro; Sonoda, Koh-Hei

    2016-01-01

    Hypoxia-induced retinal neovascularization is a major pathological condition in many vision-threatening diseases. In the present study, we determined whether interleukin (IL)-12, a cytokine that regulates angiogenesis, plays a role in the neovascularization in a mouse model of oxygen-induced retinopathy (OIR). We found that the expressions of the mRNAs of both IL-12p35 and IL-12p40 were significantly reduced in the OIR retinas compared to that of the room air-raised control. The sizes of the avascular areas and neovascular tufts were larger in IL-12p40 knock-out (KO) mice than that in wild type (WT) mice. In addition, an intravitreal injection of recombinant IL-12 reduced both avascular areas and neovascular tufts. IL-12 injection enhanced the expressions of interferon-gamma (IFN-γ) and other downstream chemokines. In an in vitro system, IL-12 had no significant effect on tube formation of human retinal microvascular endothelial cells (HRECs). Moreover, a blockade of IFN-γ suppressed the inhibitory effect of IL-12 on pathological neovascularization. These results suggest that IL-12 plays important roles in inhibiting pathological retinal neovascularization. PMID:27312090

  8. Anterior segment changes following intravitreal bevacizumab injection for treatment of neovascular glaucoma

    PubMed Central

    Canut, MI; Alvarez, A; Nadal, J; Abreu, R; Abreu, JA; Pulido, JS

    2011-01-01

    Background: The purpose of this study was to describe anterior segment changes in a prospective, interventional, noncomparative case series of patients with neovascular glaucoma secondary to proliferative diabetic retinopathy treated with intravitreal bevacizumab. Methods: Five consecutive patients with neovascular glaucoma and a refractory, symptomatic elevation of intraocular pressure and pronounced anterior segment congestion received intravitreal bevacizumab 1.25 mg/0.05 mL. Follow-up examinations were performed at 4–16 weeks by the same specialists, with testing performed at hour 48, week 1, and months 1, 3, and 6 after intravitreal bevacizumab. Results: We observed a significant difference (P = 0.021) between initial and mean neovascularization at three months in all the quadrants. At three months, median intraocular pressure was 19 ± 5.38 (range 12–26) mmHg. In three of the five cases, diode laser cyclophotocoagulation was required, and in one case a trabeculectomy was performed. One patient showed complete synechial angle closure 48 hours after treatment which required cyclodestructive procedures to normalize intraocular pressure. Conclusion: Intravitreal bevacizumab achieves complete regression of neovascularization in neovascular glaucoma secondary to proliferative diabetic retinopathy, and this regression is stable when associated with treatment of the underlying disease and should be investigated more thoroughly as an adjunct in the management of neovascular glaucoma. PMID:21629579

  9. Inhibition of corneal neovascularization with a nutrient mixture containing lysine, proline, ascorbic acid, and green tea extract.

    PubMed

    Shakiba, Yadollah; Mostafaie, Ali

    2007-10-01

    Corneal neovascularization is a significant, sight-threatening complication of many ocular surface disorders. Various growth factors and proteinases are involved in corneal neovascularization. The data supporting a causal role for vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) are extensive. Inhibition of VEGF and MMPs is a main strategy for treating corneal neovascularization. Several findings have shown that corneal neovascularization can be reduced by using anti-VEGF and anti-MMPs agents. Efficacy of a nutrient mixture (NM) containing lysine, proline, ascorbic acid, and green tea extract has been demonstrated for reducing VEGF and MMPs secretion by various cells. Moreover, NM can inhibit endothelial cell migration and capillary tube formation. We herein note that topical application of NM is potentially useful for inhibiting corneal neovascularization and restoration of corneal clarity. Further investigations in animal models are needed to place NM alongside corneal neovascularization therapeutics.

  10. Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain.

    PubMed

    Ben-Shaanan, T L; Ben-Hur, T; Yanai, J

    2008-02-01

    Grafting of neural progenitors has been shown to reverse a wide variety of neurobehavioral defects. While their role of replacing injured cells and restoring damaged circuitries has been shown, it is widely accepted that this cannot be the only mechanism, as therapy can occur even when an insufficient number of transplanted cells are found. We hypothesized that one major mechanism by which transplanted neural progenitors exert their therapeutic effect is by enhancing endogenous cells production. Consequently, in an allographic model of transplantation, prenatally heroin-exposed genetically heterogeneous (HS) mice were made defective in their hippocampal neurobehavioral function by exposing their mothers to heroin (10 mg kg(-1) heroin on gestation days 9-18). Hippocampal damage was confirmed by deficient performance in the Morris maze (P<0.009), and decreased production of endogenous cells in the dentate gyrus by 39% was observed. On postnatal day 35, they received an HS-derived neural progenitors transplant followed by repeated bromodeoxyuridine injections. The transplant returned endogenous cells production to normal levels (P<0.006) and reversed the behavioral defects (P<0.03), despite the fact that only 0.0334% of the transplanted neural progenitors survived and that they differentiated mainly to astrocytes. An immunological study demonstrated the presence of macrophages and T cells as a possible explanation for the paucity of the transplanted cells. This study suggests one mechanism for the therapeutic action of neural progenitors, the enhancement of the production of endogenous cells, pointing to future clinical applications in this direction by use of neural progenitors or by analogous cell-inducing techniques.

  11. Combinatorial human progenitor cell transplantation optimizes islet regeneration through secretion of paracrine factors.

    PubMed

    Bell, Gillian I; Meschino, Michael T; Hughes-Large, Jennifer M; Broughton, Heather C; Xenocostas, Anargyros; Hess, David A

    2012-07-20

    Transplanted human bone marrow (BM) and umbilical cord blood (UCB) progenitor cells activate islet-regenerative or revascularization programs depending on the progenitor subtypes administered. Using purification of multiple progenitor subtypes based on a conserved stem cell function, high aldehyde dehydrogenase (ALDH) activity (ALDH(hi)), we have recently shown that transplantation of BM-derived ALDH(hi) progenitors improved systemic hyperglycemia and augmented insulin secretion by increasing islet-associated proliferation and vascularization, without increasing islet number. Conversely, transplantation of culture-expanded multipotent-stromal cells (MSCs) derived from BM ALDH(hi) cells augmented total beta cell mass via formation of beta cell clusters associated with the ductal epithelium, without sustained islet vascularization. To identify paracrine effectors produced by islet-regenerative MSCs, culture-expanded BM ALDH(hi) MSCs were transplanted into streptozotocin-treated nonobese diabetic/severe combine immune deficient (SCID) mice and segregated into islet-regenerative versus nonregenerative cohorts based on hyperglycemia reduction, and subsequently compared for differential production of mRNA and secreted proteins. Regenerative MSCs showed increased expression of matrix metalloproteases, epidermal growth factor receptor (EGFR)-activating ligands, and downstream effectors of Wnt signaling. Regenerative MSC supernatant also contained increased levels of pro-angiogenic versus pro-inflammatory cytokines, and augmented the expansion of ductal epithelial but not beta cells in vitro. Conversely, co-culture with UCB ALDH(hi) cells induced beta cell but not ductal epithelial cell proliferation. Sequential transplantation of MSCs followed by UCB ALDH(hi) cells improved hyperglycemia and glucose tolerance by increasing beta cell mass associated with the ductal epithelium and by augmenting intra-islet capillary densities. Thus, combinatorial human progenitor cell

  12. Polymorphisms in the VEGFA and VEGFR-2 genes and neovascular age-related macular degeneration

    PubMed Central

    Fang, Amy M.; Lee, Aaron Y.; Kulkarni, Mukti; Osborn, Melissa P.

    2009-01-01

    Purpose Genetic factors influence an individual’s risk for developing neovascular age-related macular degeneration (AMD), a leading cause of irreversible blindness. Previous studies on the potential genetic link between AMD and vascular endothelial growth factor (VEGF), a key regulator of angiogenesis and vascular permeability, have yielded conflicting results. In the present case-control association study, we aimed to determine whether VEGF or its main receptor tyrosine kinase VEGFR-2 is genetically associated with neovascular AMD. Methods A total of 515 Caucasian patients with neovascular AMD and 253 ethically-matched controls were genotyped for polymorphisms in the VEGFA and VEGFR-2 genes. A tagging single nucleotide polymorphism (tSNP) approach was employed to cover each gene plus two kilobases on each side, spanning the promoter and 3′ untranslated regions. SNPs with a minimum allele frequency of 10% were covered by seven tSNPs in VEGFA and 20 tSNPs in VEGFR-2. Two VEGFA SNPs previously linked with AMD, rs1413711 and rs3025039, were also analyzed. Results The 29 VEGFA and VEGFR-2 SNPs analyzed in our cohort demonstrated no significant association with neovascular AMD. A single rare haplotype in the VEGFR-2 gene was associated with the presence of neovascular AMD (p=0.034). Conclusions This study is the first to investigate the association of VEGFR-2 polymorphisms with AMD and evaluates VEGFA genetic variants in the largest neovascular AMD cohort to date. Despite the angiogenic and permeability-enhancing effects of VEGF/VEGFR-2 signaling, we found minimal evidence of a significant link between polymorphisms in the VEGFA and VEGFR-2 genes and neovascular AMD. PMID:20019880

  13. Different roles played by periostin splice variants in retinal neovascularization.

    PubMed

    Nakama, Takahito; Yoshida, Shigeo; Ishikawa, Keijiro; Kobayashi, Yoshiyuki; Abe, Takaya; Kiyonari, Hiroshi; Shioi, Go; Katsuragi, Naruto; Ishibashi, Tatsuro; Morishita, Ryuichi; Taniyama, Yoshiaki

    2016-12-01

    Retinal neovascularization (NV) due to retinal ischemia is one of the major causes of vision reduction in patients with different types of retinal diseases although anti-vascular endothelial growth factor (anti-VEGF) therapy can partially reduce the size of the retinal NV. We recently reported that periostin plays an important role in the development of NV and the formation of preretinal fibrovascular membranes, but the role of the splice variants of periostin on retinal NV has not been determined. We examined the expressions of periostin splice variants in the ischemic retinas of a mouse model of oxygen-induced retinal NV. We also studied the function of periostin splice variants on retinal NV using periostin knock out mice, and the effects of anti-periostin antibodies on retinal NV. Our results showed that the expressions of the periostin splice variants were increased in ischemic retinas. The degree of increase of periostin lacking exon 17 was the highest among the periostin splice variants examined. Both genetic ablation of periostin exons 17 and 21 and antibodies for periostin exons 17 and 21 affected preretinal pathological NV. Inhibition of exon 17 of periostin had the greatest effect in reducing preretinal pathological NV. These findings suggest a causal link between periostin splice variants and retinal NV, and an intravitreal injection of antibody for exon 17 and exon 21 of periostin should be considered to inhibit preretinal pathological NV.

  14. Overload and neovascularization of shoulder tendons in volleyball players

    PubMed Central

    2012-01-01

    Background In overhead sports like volleyball, the onset of a rotator cuff tendinopathy due to functional overload is a common observation. An angiofibroblastic etiopathogenesis has been hypothesized, whereby a greater anaerobic metabolism occurs in critical zones of the tendon with a lower degree of vascularization; this would induce collagen and extracellular matrix degradation, that could then trigger a compensatory neovascularization response. We performed a clinical observational study of 80 elite volleyball players, monitoring the perfusion values of the supraspinatus tendons by oximetry. Results No statistically significant differences were found between the oximetry data and age, sex or years of sports activity, nor when comparing the right and left arm or the dominant and non-dominant arm. A statistically significant difference was found for the dominant arm values in relation to the competitive role, higher values being obtained in outside hitters (62.7%) than middle hitters (53.7%) (p = 0.01), opposite hitters (55.5%) (p = 0.02) and libero players (54.4%) (p = 0.008), whereas there were no differences in setters (56.2%) (p > 0.05). Conclusions The different tendon vascularization values found in players with different roles in the team may be attributed to a response to the specific biomechanical demands posed by the different overhead throwing roles. PMID:22853746

  15. An Angiogenic Role for Adrenomedullin in Choroidal Neovascularization

    PubMed Central

    Sakimoto, Susumu; Kidoya, Hiroyasu; Kamei, Motohiro; Naito, Hisamichi; Yamakawa, Daishi; Sakaguchi, Hirokazu; Wakabayashi, Taku; Nishida, Kohji; Takakura, Nobuyuki

    2013-01-01

    Purpose Adrenomedullin (ADM) has been shown to take part in physiological and pathological angiogenesis. The purpose of this study was to investigate whether ADM signaling is involved in choroidal neovascularization (CNV) using a mouse model. Methods and Results CNV was induced by laser photocoagulation in 8-week-old C57BL/6 mice. ADM mRNA expression significantly increased following treatment, peaking 4 days thereafter. The expression of ADM receptor (ADM-R) components (CRLR, RAMP2 and RAMP 3) was higher in CD31+CD45− endothelial cells (ECs) than CD31−CD45− non-ECs. Inflammatory stimulation upregulated the expression of ADM not only in cell lines but also in cells in primary cultures of the choroid/retinal pigment epithelium complex. Supernatants from TNFα-treated macrophage cell lines potentiated the proliferation of ECs and this was partially suppressed by an ADM antagonist, ADM (22–52). Intravitreous injection of ADM (22–52) or ADM neutralizing monoclonal antibody (mAb) after laser treatment significantly reduced the size of CNV compared with vehicle-treated controls (p<0.01). Conclusions ADM signaling is involved in laser-induced CNV formation, because both an ADM antagonist and ADM mAb significantly inhibited it. Suppression of ADM signaling might be a valuable alternative treatment for CNV associated with age-related macular degeneration. PMID:23520487

  16. Effect of pitavastatin on experimental choroidal neovascularization in rats.

    PubMed

    Sagara, Nina; Kawaji, Takahiro; Takano, Akiomi; Inomata, Yasuya; Inatani, Masaru; Fukushima, Mikiko; Tanihara, Hidenobu

    2007-06-01

    The association between the use of statins and age-related macular degeneration (AMD), a leading cause of blindness, has been evaluated in many clinical studies; however, the results have been contradictory. We evaluated the effect of pitavastatin administration on laser-induced experimental choroidal neovascularization (CNV) in rats. Brown Norway rats received pitavastatin (1.0mg/kg per day) for 1day prior to laser-induced CNV and continued to receive the drug for 14days. Fluorescein angiograms were graded by masked observers. CNV area and thickness were assessed by fluorescein isothiocyanate-labeled dextran angiography and histology, respectively. Vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (Ccl-2; also known as MCP-1), and intercellular adhesion molecule-1 (ICAM-1) mRNA levels were measured using reverse-transcription polymerase chain reaction (RT-PCR) and real-time quantitative RT-PCR. Pitavastatin-treated rats had significantly less fluorescence leakage compared with the vehicle-treated rats estimated by CNV score using fluorescein angiography. Both the area and the thickness of CNV in pitavastatin-treated rats were significantly reduced compared with the vehicle-treated rats. Gene expression of VEGF, Ccl-2, and ICAM-1 were significantly decreased by pitavastatin administration in experimental CNV. Thus, we demonstrated that the therapeutic dose of pitavastatin for human hypocholesterolemia effectively suppressed experimental CNV in rats. The use of pitavastatin may be helpful in preventing CNV development in AMD patients.

  17. Attenuation of Choroidal Neovascularization by Histone Deacetylase Inhibitor

    PubMed Central

    Chan, Nymph; He, Shikun; Spee, Christine K.; Ishikawa, Keijiro; Hinton, David R.

    2015-01-01

    Choroidal neovascularization (CNV) is a blinding complication of age-related macular degeneration that manifests as the growth of immature choroidal blood vessels through Bruch’s membrane, where they can leak fluid or hemorrhage under the retina. Here, we demonstrate that the histone deacetylase inhibitor (HDACi) trichostatin A (TSA) can down-regulate the pro-angiogenic hypoxia-inducible factor-1α and vascular endothelial growth factor (VEGF), and up-regulate the anti-angiogenic and neuro-protective pigment epithelium derived factor in human retinal pigment epithelial (RPE) cells. Most strikingly, TSA markedly down-regulates the expression of VEGF receptor-2 in human vascular endothelial cells and, thus, can knock down pro-angiogenic cell signaling. Additionally, TSA suppresses CNV-associated wound healing response and RPE epithelial-mesenchymal transdifferentiation. In the laser-induced model of CNV using C57Bl/6 mice, systemic administration of TSA significantly reduces fluorescein leakage and the size of CNV lesions at post—laser days 7 and 14 as well as the immunohistochemical expression of VEGF, VEGFR2, and smooth muscle actin in CNV lesions at post-laser day 7. This report suggests that TSA, and possibly HDACi’s in general, should be further evaluated for their therapeutic potential for the treatment of CNV. PMID:25807249

  18. Stereotactic radiotherapy in neovascular age-related macular degeneration

    PubMed Central

    Ranjbar, Mahdy; Kurz, Maximilian; Holzhey, Annekatrin; Melchert, Corinna; Rades, Dirk; Grisanti, Salvatore

    2016-01-01

    Abstract Stereotactic radiotherapy (SRT) is a new approach to treat neovascular age-related macular degeneration (nAMD). The INTREPID trial suggested that SRT could reduce the frequency of regular intravitreal injections (IVIs) with antivascular endothelial growth factor drugs, which are necessary to control disease activity. However, the efficacy of SRT in nAMD and resulting morphological changes have not been validated under real-life circumstances, an issue, which we would like to address in this retrospective analysis. Patients who met the INTREPID criteria for best responders were eligible for SRT. A total of 32 eyes of 32 patients were treated. Thereafter, patients were examined monthly for 12 months and received pro re nata IVI of aflibercept or ranibizumab. Outcome measures were: mean number of injections, best-corrected visual acuity, and morphological changes of the outer retina-choroid complex as well as patient safety. Mean number of IVI decreased by almost 50% during the 12 months after SRT compared to the year before, whereas visual acuity increased by one line (logMAR). Morphological evaluation showed that most changes affect outer retinal layers. Stereotactic radiotherapy significantly reduced IVI retreatment in nAMD patients under real-life circumstances. Therefore, SRT might be the first step to stop visual loss as a result of IVI undertreatment, which is a major risk. PMID:28033280

  19. Segmentation of choroidal neovascularization in fundus fluorescein angiograms.

    PubMed

    Abdelmoula, Walid M; Shah, Syed M; Fahmy, Ahmed S

    2013-05-01

    Choroidal neovascularization (CNV) is a common manifestation of age-related macular degeneration (AMD). It is characterized by the growth of abnormal blood vessels in the choroidal layer causing blurring and deterioration of the vision. In late stages, these abnormal vessels can rupture the retinal layers causing complete loss of vision at the affected regions. Determining the CNV size and type in fluorescein angiograms is required for proper treatment and prognosis of the disease. Computer-aided methods for CNV segmentation is needed not only to reduce the burden of manual segmentation but also to reduce inter- and intraobserver variability. In this paper, we present a framework for segmenting CNV lesions based on parametric modeling of the intensity variation in fundus fluorescein angiograms. First, a novel model is proposed to describe the temporal intensity variation at each pixel in image sequences acquired by fluorescein angiography. The set of model parameters at each pixel are used to segment the image into regions of homogeneous parameters. Preliminary results on datasets from 21 patients with Wet-AMD show the potential of the method to segment CNV lesions in close agreement with the manual segmentation.

  20. Mesenteric Neovascularization with Distraction-Induced Intestinal Growth: Enterogenesis

    PubMed Central

    Ralls, Matthew W.; Sueyoshi, Ryo; Herman, Richard S.; Utter, Brent; Czarnocki, Isabel; Si, Nancy; Luntz, Jonathan; Brei, Diann; Teitelbaum, Daniel H.

    2012-01-01

    Background Distraction-induced enterogenesis, whereby the intestine lengthens with application of linear forces, is an emerging area which may provide a unique treatment for short bowel syndrome (SBS). With an increase in overall tissue mass, there is an increase in oxygen and nutrient demand. We hypothesized that a neovascularization within the mesentery is necessary to support the growing small bowel. Methods A curvilinear hydraulic device was used to induce growth within the small bowel of Yorkshire pigs, and the intestine was harvested after 14 days. High-resolution, gross pictures were recorded of the mesentery at implantation and at harvest, and CT imaging of the bowel and mesentery was performed at harvest after dye injection. Results After 2 weeks of distraction, an average of 72.5% (8.7cm) bowel lengthening was achieved. Gross images of the mesentery between major vessels showed a blossoming of the microvasculature and this was confirmed by CT imaging with 3D reconstruction. Mesenteric sample taken from the distracted segment had a 4-fold increase in the volume of microvasculature versus controls. Conclusion Enterogenesis results not only in increased bowel length, but significant increase in the mesenteric microvascularity. Presumably, this sustains the lengthened segment after application of longitudinal forces. PMID:23229341

  1. PROGENITORS OF RECOMBINING SUPERNOVA REMNANTS

    SciTech Connect

    Moriya, Takashi J.

    2012-05-01

    Usual supernova remnants have either ionizing plasma or plasma in collisional ionization equilibrium, i.e., the ionization temperature is lower than or equal to the electron temperature. However, the existence of recombining supernova remnants, i.e., supernova remnants with ionization temperature higher than the electron temperature, has been recently confirmed. One suggested way to have recombining plasma in a supernova remnant is to have a dense circumstellar medium at the time of the supernova explosion. If the circumstellar medium is dense enough, collisional ionization equilibrium can be established in the early stage of the evolution of the supernova remnant and subsequent adiabatic cooling, which occurs after the shock wave gets out of the dense circumstellar medium, makes the electron temperature lower than the ionization temperature. We study the circumstellar medium around several supernova progenitors and show which supernova progenitors can have a circumstellar medium dense enough to establish collisional ionization equilibrium soon after the explosion. We find that the circumstellar medium around red supergiants (especially massive ones) and the circumstellar medium dense enough to make Type IIn supernovae can establish collisional ionization equilibrium soon after the explosion and can evolve to become recombining supernova remnants. Wolf-Rayet stars and white dwarfs have the possibility to be recombining supernova remnants but the fraction is expected to be very small. As the occurrence rate of the explosions of red supergiants is much higher than that of Type IIn supernovae, the major progenitors of recombining supernova remnants are likely to be red supergiants.

  2. Gamma-Ray Burst Progenitors

    NASA Astrophysics Data System (ADS)

    Levan, Andrew; Crowther, Paul; de Grijs, Richard; Langer, Norbert; Xu, Dong; Yoon, Sung-Chul

    2016-12-01

    We review our current understanding of the progenitors of both long and short duration gamma-ray bursts (GRBs). Constraints can be derived from multiple directions, and we use three distinct strands; (i) direct observations of GRBs and their host galaxies, (ii) parameters derived from modelling, both via population synthesis and direct numerical simulation and (iii) our understanding of plausible analog progenitor systems observed in the local Universe. From these joint constraints, we describe the likely routes that can drive massive stars to the creation of long GRBs, and our best estimates of the scenarios that can create compact object binaries which will ultimately form short GRBs, as well as the associated rates of both long and short GRBs. We further discuss how different the progenitors may be in the case of black hole engine or millisecond-magnetar models for the production of GRBs, and how central engines may provide a unifying theme between many classes of extremely luminous transient, from luminous and super-luminous supernovae to long and short GRBs.

  3. Specific disruption of Lnk in murine endothelial progenitor cells promotes dermal wound healing via enhanced vasculogenesis, activation of myofibroblasts, and suppression of inflammatory cell recruitment.

    PubMed

    Lee, Jun Hee; Ji, Seung Taek; Kim, Jaeho; Takaki, Satoshi; Asahara, Takayuki; Hong, Young-Joon; Kwon, Sang-Mo

    2016-10-28

    Although endothelial progenitor cells (EPCs) contribute to wound repair by promoting neovascularization, the mechanism of EPC-mediated wound healing remains poorly understood due to the lack of pivotal molecular targets of dermal wound repair. We found that genetic targeting of the Lnk gene in EPCs dramatically enhances the vasculogenic potential including cell proliferation, migration, and tubule-like formation as well as accelerates in vivo wound healing, with a reduction in fibrotic tissue and improved neovascularization via significant suppression of inflammatory cell recruitment. When injected into wound sites, Lnk (-/-) EPCs gave rise to a significant number of new vessels, with remarkably increased survival of transplanted cells and decreased recruitment of cytotoxic T cells, macrophages, and neutrophils, but caused activation of fibroblasts in the wound-remodeling phase. Notably, in a mouse model of type I diabetes, transplanted Lnk (-/-) EPCs induced significantly better wound healing than Lnk (+/+) EPCs did. The specific targeting of Lnk may be a promising EPC-based therapeutic strategy for dermal wound healing via improvement of neovascularization but inhibition of excessive inflammation as well as activation of myofibroblasts during dermal tissue remodeling.

  4. Pivotal Cytoprotective Mediators and Promising Therapeutic Strategies for Endothelial Progenitor Cell-Based Cardiovascular Regeneration

    PubMed Central

    Kim, Sujin

    2016-01-01

    Cardiovascular diseases (CVDs), including atherosclerosis, stroke, and myocardial infarction, is a major cause of death worldwide. In aspects of cell therapy against CVD, it is generally accepted that endothelial progenitor cells (EPCs) are potent neovascular modulators in ischemic tissues. In response to ischemic injury signals, EPCs located in a bone marrow niche migrate to injury sites and form new vessels by secreting various vasculogenic factors including VEGF, SDF-1, and FGF, as well as by directly differentiating into endothelial cells. Nonetheless, in ischemic tissues, most of engrafted EPCs do not survive under harsh ischemic conditions and nutrient depletion. Therefore, an understanding of diverse EPC-related cytoprotective mediators underlying EPC homeostasis in ischemic tissues may help to overcome current obstacles for EPC-mediated cell therapy for CVDs. Additionally, to enhance EPC's functional capacity at ischemic sites, multiple strategies for cell survival should be considered, that is, preconditioning of EPCs with function-targeting drugs including natural compounds and hormones, virus mediated genetic modification, combined therapy with other stem/progenitor cells, and conglomeration with biomaterials. In this review, we discuss multiple cytoprotective mediators of EPC-based cardiovascular repair and propose promising therapeutic strategies for the treatment of CVDs. PMID:28090210

  5. Human endothelial stem/progenitor cells, angiogenic factors and vascular repair

    PubMed Central

    Watt, Suzanne M.; Athanassopoulos, Athanasios; Harris, Adrian L.; Tsaknakis, Grigorios

    2010-01-01

    Neovascularization or new blood vessel formation is of utmost importance not only for tissue and organ development and for tissue repair and regeneration, but also for pathological processes, such as tumour development. Despite this, the endothelial lineage, its origin, and the regulation of endothelial development and function either intrinsically from stem cells or extrinsically by proangiogenic supporting cells and other elements within local and specific microenvironmental niches are still not fully understood. There can be no doubt that for most tissues and organs, revascularization represents the holy grail for tissue repair, with autologous endothelial stem/progenitor cells, their proangiogenic counterparts and the products of these cells all being attractive targets for therapeutic intervention. Historically, a great deal of controversy has surrounded the identification and origin of cells and factors that contribute to revascularization, the use of such cells or their products as biomarkers to predict and monitor tissue damage and repair or tumour progression and therapeutic responses, and indeed their efficacy in revascularizing and repairing damaged tissues. Here, we will review the role of endothelial progenitor cells and of supporting proangiogenic cells and their products, principally in humans, as diagnostic and therapeutic agents for wound repair and tissue regeneration. PMID:20843839

  6. Implementation studies of ranibizumab for neovascular age-related macular degeneration.

    PubMed

    Bloch, Sara Brandi

    2013-11-01

    The pathogenesis of AMD is associated with age changes plus pathological changes involving oxidative stress and an altered inflammatory response leading to injury of retinal pigment epithelial cells and the adjacent choroidea and photoreceptor cells. AMD is divided into early, intermediate and advanced AMD. The advanced form of AMD is further divided into non-neovascular AMD and neovascular AMD. The diagnosis of neovascular AMD is based on FA and clinical characteristics of the eyes. The CNV lesions are by their growth pattern divided into type 1 CNV lesions, which grow primarily beneath the RPE, and type 2 CNV lesions, which have penetrated the RPE and evolve within the subretinal space. The natural course of neovascular AMD leads to visual disability in a majority of cases within the first years after onset, primarily caused by the development of subfoveal fibrous tissue and atrophy of the RPE. The prognosis of visual acuity in neovascular AMD has been markedly improved by the introduction of an intravitreal administered VEGF inhibitor (ranibizumab) given on a monthly basis. Treatment with ranibizumab for neovascular AMD was introduced in Denmark in 2006 under a fully reimbursed national healthcare plan. Treatment with ranibizumab is given in a variable dosing regimen that varies from the monthly dosing regimen administered in the studies that led to the approval of ranibizumab for neovascular AMD in Europe. The main objectives of this PhD thesis were to evaluate and potentially improve treatment with ranibizumab in a variable OCT guided regimen for neovascular AMD. Another intension of this PhD thesis was to prepare the conditions for future research to further improve the visual prognosis in neovascular AMD treated with anti-VEGF agents. The first study revealed that vision was improved in eyes with active neovascular AMD treated for 1 year in a variable ranibizumab treatment regimen as compared to PDT and the natural course of the disease. We assumed by

  7. The prevalence of neovascularity in patients clinically diagnosed with rotator cuff tendinopathy.

    PubMed

    Lewis, Jeremy S; Raza, Syed A; Pilcher, James; Heron, Christine; Poloniecki, Jan D

    2009-12-21

    Shoulder dysfunction is common and pathology of the rotator cuff tendons and subacromial bursa are considered to be a major cause of pain and morbidity. Although many hypotheses exist there is no definitive understanding as to the origin of the pain arising from these structures. Research investigations from other tendons have placed intra-tendinous neovascularity as a potential mechanism of pain production. The prevalence of neovascularity in patients with a clinical diagnosis of rotator cuff tendinopathy is unknown. As such the primary aim of this pilot study was to investigate if neovascularity could be identified and to determine the prevalence of neovascularity in the rotator cuff tendons and subacromial bursa in subjects with unilateral shoulder pain clinically assessed to be rotator cuff tendinopathy. The secondary aims were to investigate the association between the presence of neovascularity and pain, duration of symptoms, and, neovascularity and shoulder function. Patients with a clinical diagnosis of unilateral rotator cuff tendinopathy referred for a routine diagnostic ultrasound (US) scan in a major London teaching hospital formed the study population. At referral patients were provided with an information document. On the day of the scan (on average, at least one week later) the patients agreeing to participate were taken through the consent process and underwent an additional clinical examination prior to undergoing a bilateral grey scale and colour Doppler US examination (symptomatic and asymptomatic shoulder) using a Philips HDI 5000 Sono CT US machine. The ultrasound scans were performed by one of two radiologists who recorded their findings and the final assessment was made by a third radiologist blinded both to the clinical examination and the ultrasound examination. The findings of the radiologists who performed the scans and the blinded radiologist were compared and any disagreements were resolved by consensus. Twenty-six patients agreed to

  8. Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review

    PubMed Central

    Yang, Shiqi; Zhao, Jingke; Sun, Xiaodong

    2016-01-01

    As a progressive chronic disease, age-related macular degeneration (AMD) is the leading cause of irreversible vision impairment worldwide. Experimental and clinical evidence has demonstrated that vascular endothelial growth factor (VEGF) plays a vital role in the formation of choroidal neovascularization. Intravitreal injections of anti-VEGF agents have been recommended as a first-line treatment for neovascular AMD. However, persistent fluid or recurrent exudation still occurs despite standardized anti-VEGF therapy. Patients suffering from refractory or recurrent neovascular AMD may develop mechanisms of resistance to anti-VEGF therapy, which results in a diminished therapeutic effect. Until now, there has been no consensus on the definitions of refractory neovascular AMD and recurrent neovascular AMD. This article aims at clarifying these concepts to evaluate the efficacy of switching drugs, which contributes to making clinical decision more scientifically. Furthermore, insight into the causes of resistance to anti-VEGF therapy would be helpful for developing possible therapeutic approaches, such as combination therapy and multi-target treatment that can overcome this resistance. PMID:27330279

  9. Strategies for improving early detection and diagnosis of neovascular age-related macular degeneration

    PubMed Central

    Keane, Pearse A; de Salvo, Gabriella; Sim, Dawn A; Goverdhan, Srini; Agrawal, Rupesh; Tufail, Adnan

    2015-01-01

    Treatment of the neovascular form of age-related macular degeneration (AMD) has been revolutionized by the introduction of such agents as ranibizumab, bevacizumab, and aflibercept. As a result, the incidence of legal blindness occurring secondary to AMD has fallen dramatically in recent years in many countries. While these agents have undoubtedly been successful in reducing visual impairment and blindness, patients with neovascular AMD typically lose some vision over time, and often lose the ability to read, drive, or perform other important activities of daily living. Efforts are therefore under way to develop strategies that allow for earlier detection and treatment of this disease. In this review, we begin by providing an overview of the rationale for, and the benefits of, early detection and treatment of neovascular AMD. To achieve this, we begin by providing an overview of the pathophysiology and natural history of choroidal neovascularization, before reviewing the evidence from both clinical trials and “real-world” outcome studies. We continue by highlighting an area that is often overlooked: the importance of patient education and awareness for early AMD detection. We conclude the review by reviewing an array of both established and emerging technologies for early detection of choroidal neovascularization, ranging from Amsler chart testing, to hyperacuity testing, to advanced imaging techniques, such as optical coherence tomography. PMID:25733802

  10. Intrachoroidal Neovascularization in Transgenic Mice Overexpressing Vascular Endothelial Growth Factor in the Retinal Pigment Epithelium

    PubMed Central

    Schwesinger, Catherine; Yee, Charles; Rohan, Richard M.; Joussen, Antonia M.; Fernandez, Antonio; Meyer, Tobias N.; Poulaki, Vassiliki; Ma, Joseph J. K.; Redmond, T. Michael; Liu, Suyan; Adamis, Anthony P.; D’Amato, Robert J.

    2001-01-01

    Choroidal neovascularization in age-related macular degeneration is a frequent and poorly treatable cause of vision loss in elderly Caucasians. This choroidal neovascularization has been associated with the expression of vascular endothelial growth factor (VEGF). In current animal models choroidal neovascularization is induced by subretinal injection of growth factors or vectors encoding growth factors such as VEGF, or by disruption of the Bruch’s membrane/retinal pigment epithelium complex with laser treatment. We wished to establish a transgenic murine model of age-related macular degeneration, in which the overexpression of VEGF by the retinal pigment epithelium induces choroidal neovascularization. A construct consisting of a tissue-specific murine retinal pigment epithelium promoter (RPE65 promoter) coupled to murine VEGF164 cDNA with a rabbit β-globin-3′ UTR was introduced into the genome of albino mice. Transgene mRNA was expressed in the retinal pigment epithelium at all ages peaking at 4 months. The expression of VEGF protein was increased in both the retinal pigment epithelium and choroid. An increase of intravascular adherent leukocytes and vessel leakage was observed. Histopathology revealed intrachoroidal neovascularization that did not penetrate through an intact Bruch’s membrane. These results support the hypothesis that additional insults to the integrity of Bruch’s membrane are required to induce growth of choroidal vessels into the subretinal space as seen in age-related macular degeneration. This model may be useful to screen for inhibitors of choroidal vessel growth. PMID:11238064

  11. Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review.

    PubMed

    Yang, Shiqi; Zhao, Jingke; Sun, Xiaodong

    2016-01-01

    As a progressive chronic disease, age-related macular degeneration (AMD) is the leading cause of irreversible vision impairment worldwide. Experimental and clinical evidence has demonstrated that vascular endothelial growth factor (VEGF) plays a vital role in the formation of choroidal neovascularization. Intravitreal injections of anti-VEGF agents have been recommended as a first-line treatment for neovascular AMD. However, persistent fluid or recurrent exudation still occurs despite standardized anti-VEGF therapy. Patients suffering from refractory or recurrent neovascular AMD may develop mechanisms of resistance to anti-VEGF therapy, which results in a diminished therapeutic effect. Until now, there has been no consensus on the definitions of refractory neovascular AMD and recurrent neovascular AMD. This article aims at clarifying these concepts to evaluate the efficacy of switching drugs, which contributes to making clinical decision more scientifically. Furthermore, insight into the causes of resistance to anti-VEGF therapy would be helpful for developing possible therapeutic approaches, such as combination therapy and multi-target treatment that can overcome this resistance.

  12. Implications of the anatomical classification of the neovascular form of age-related macular degeneration.

    PubMed

    Gallego-Pinazo, R; Monje-Fernández, L; García-Marín, N; Andreu-Fenoll, M; Dolz-Marco, R

    2017-02-01

    To present the clinical relevance of the anatomical classification of the neovascular form of Age-Related Macular Degeneration (AMD). Critical analysis of the current situation in the management of patients with neovascular AMD, by reviewing the available scientific evidence with regards to the classification of the types of neovascular lesion by angiography and optical coherence tomography (OCT). The classification of the neovascular lesion type secondary to AMD by OCT in type 1 lesions (under the pigment epithelium), type 2 (subretinal), and type 3 (retinal angiomatous proliferation), provides an added value in allowing to establish a long-term visual prognosis, an estimate of the number of treatments that a certain case may require, and a stratification of the risk for secondary geographic atrophy. Incorporating OCT to the initial qualitative analysis of cases with neovascular AMD offers an added value superior to that provided by the angiography, with the relevant clinical implications. Copyright © 2016 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

  13. Endothelial microRNA-150 is an intrinsic suppressor of pathologic ocular neovascularization

    PubMed Central

    Liu, Chi-Hsiu; Sun, Ye; Li, Jie; Gong, Yan; Tian, Katherine T.; Evans, Lucy P.; Morss, Peyton C.; Fredrick, Thomas W.; Saba, Nicholas J.; Chen, Jing

    2015-01-01

    Pathologic ocular neovascularization commonly causes blindness. It is critical to identify the factors altered in pathologically proliferating versus normally quiescent vessels to develop effective targeted therapeutics. MicroRNAs regulate both physiological and pathological angiogenesis through modulating expression of gene targets at the posttranscriptional level. However, it is not completely understood if specific microRNAs are altered in pathologic ocular blood vessels, influencing vascular eye diseases. Here we investigated the potential role of a specific microRNA, miR-150, in regulating ocular neovascularization. We found that miR-150 was highly expressed in normal quiescent retinal blood vessels and significantly suppressed in pathologic neovessels in a mouse model of oxygen-induced proliferative retinopathy. MiR-150 substantially decreased endothelial cell function including cell proliferation, migration, and tubular formation and specifically suppressed the expression of multiple angiogenic regulators, CXCR4, DLL4, and FZD4, in endothelial cells. Intravitreal injection of miR-150 mimic significantly decreased pathologic retinal neovascularization in vivo in both wild-type and miR-150 knockout mice. Loss of miR-150 significantly promoted angiogenesis in aortic rings and choroidal explants ex vivo and laser-induced choroidal neovascularization in vivo. In conclusion, miR-150 is specifically enriched in quiescent normal vessels and functions as an endothelium-specific endogenous inhibitor of pathologic ocular neovascularization. PMID:26374840

  14. TYPE 2 (SUBRETINAL) NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION ASSOCIATED WITH PURE RETICULAR PSEUDODRUSEN PHENOTYPE.

    PubMed

    Naysan, Jonathan; Jung, Jesse J; Dansingani, Kunal K; Balaratnasingam, Chandrakumar; Freund, K Bailey

    2016-03-01

    To report the association of pure type 2 neovascularization (NV) in age-related macular degeneration occurring almost exclusively in patients with reticular pseudodrusen. An observational retrospective cohort study of all eyes receiving antivascular endothelial growth factor therapy for newly diagnosed neovascular age-related macular degeneration by a single practitioner over a 6-year period. Only patients with treatment-naive, pure type 2 NV who also had either pre-neovascular imaging of the study eye or imaging of a nonneovascular fellow eye available to determine baseline characteristics including drusen type and choroidal thickness were incuded. Of 694 patients treated for neovascular age-related macular degeneration, only 8 met the inclusion criteria with pure type 2 NV. Of these, 7 (88%) had exclusively reticular pseudodrusen (5 in the nonneovascular fellow eye, 2 in the study eye before developing NV). Six (75%) patients in the affected neovascular eye and 6 (75%) in the fellow nonneovascular eye had choroidal thickness <120 μm. Mean follow-up was 46 months (range, 3.0-63.3). Best-corrected vision improved from 20/89 (range, 20/30-20/796) at baseline to 20/60 (range, 20/20-20/399) at last follow-up. Pure type 2 NV is rare in age-related macular degeneration, occurring almost exclusively in patients with reticular pseudodrusen and thin choroids.

  15. Pharmacologically active microcarriers for endothelial progenitor cell support and survival.

    PubMed

    Musilli, Claudia; Karam, Jean-Pierre; Paccosi, Sara; Muscari, Claudio; Mugelli, Alessandro; Montero-Menei, Claudia N; Parenti, Astrid

    2012-08-01

    The regenerative potential of endothelial progenitor cell (EPC)-based therapies is limited due to poor cell viability and minimal retention following application. Neovascularization can be improved by means of scaffolds supporting EPCs. The aim of the present study was to investigate whether human early EPCs (eEPCs) could be efficiently cultured on pharmacologically active microcarriers (PAMs), made with poly(d,l-lactic-coglycolic acid) and coated with adhesion/extracellular matrix molecules. They may serve as a support for stem cells and may be used as cell carriers providing a controlled delivery of active protein such as the angiogenic factor, vascular endothelial growth factor-A (VEGF-A). eEPC adhesion to fibronectin-coated PAMs (FN-PAMs) was assessed by means of microscopic evaluation and by means of Alamar blue assay. Phospho ERK(1/2) and PARP-1 expression was measured by means of Western blot to assess the survival effects of FN-PAMs releasing VEGF-A (FN-VEGF-PAMs). The Alamar blue assay or a modified Boyden chamber assay was employed to assess proliferative or migratory capacity, respectively. Our data indicate that eEPCs were able to adhere to empty FN-PAMs within a few hours. FN-VEGF-PAMs increased the ability of eEPCs to adhere to them and strongly supported endothelial-like phenotype and cell survival. Moreover, the release of VEGF-A by FN-PAMs stimulated in vitro HUVEC migration and proliferation. These data strongly support the use of PAMs for supporting eEPC growth and survival and for stimulating resident mature human endothelial cells.

  16. Role of NADPH Oxidase-4 in Human Endothelial Progenitor Cells

    PubMed Central

    Hakami, Nora Y.; Ranjan, Amaresh K.; Hardikar, Anandwardhan A.; Dusting, Greg J.; Peshavariya, Hitesh M.

    2017-01-01

    Introduction: Endothelial progenitor cells (EPCs) display a unique ability to promote angiogenesis and restore endothelial function in injured blood vessels. NADPH oxidase 4 (NOX4)-derived hydrogen peroxide (H2O2) serves as a signaling molecule and promotes endothelial cell proliferation and migration as well as protecting against cell death. However, the role of NOX4 in EPC function is not completely understood. Methods: EPCs were isolated from human saphenous vein and mammary artery discarded during bypass surgery. NOX4 gene and protein expression in EPCs were measured by real time-PCR and Western blot analysis respectively. NOX4 gene expression was inhibited using an adenoviral vector expressing human NOX4 shRNA (Ad-NOX4i). H2O2 production was measured by Amplex red assay. EPC migration was evaluated using a transwell migration assay. EPC proliferation and viability were measured using trypan blue counts. Results: Inhibition of NOX4 using Ad-NOX4i reduced Nox4 gene and protein expression as well as H2O2 formation in EPCs. Inhibition of NOX4-derived H2O2 decreased both proliferation and migration of EPCs. Interestingly, pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) decreased NOX4 expression and reduced survival of EPCs. However, the survival of EPCs was further diminished by TNF-α in NOX4-knockdown cells, suggesting that NOX4 has a protective role in EPCs. Conclusion: These findings suggest that NOX4-type NADPH oxidase is important for proliferation and migration functions of EPCs and protects against pro-inflammatory cytokine induced EPC death. These properties of NOX4 may facilitate the efficient function of EPCs which is vital for successful neovascularization. PMID:28386230

  17. Modeling Renal Progenitors – Defining the Niche

    PubMed Central

    Tanigawa, Shunsuke; Perantoni, Alan O.

    2016-01-01

    Significant recent advances in methodologies for the differentiation of pluripotent stem cells to renal progenitors as well as the definition of niche conditions for sustaining those progenitors have dramatically enhanced our understanding of their biology and developmental programing, prerequisites for establishing viable approaches to renal regeneration. In this article, we review the evolution of culture techniques and models for the study of metanephric development, describe the signaling mechanisms likely to be driving progenitor self-renewal, and discuss current efforts to generate de novo functional tissues, providing in depth protocols and niche conditions for the stabilization of the nephronic Six2+ progenitor. PMID:26856661

  18. Anti-vascular endothelial growth factor for neovascular glaucoma

    PubMed Central

    Simha, Arathi; Braganza, Andrew; Abraham, Lekha; Samuel, Prasanna; Lindsley, Kristina

    2014-01-01

    Background Neovascular glaucoma (NVG) is a potentially blinding secondary glaucoma. It is caused by the formation of abnormal new blood vessels which prevent normal drainage of aqueous from the anterior segment of the eye. Anti-vascular endothelial growth factor (anti-VEGF) agents are specific inhibitors of the primary mediators of neovascularization. Studies have reported the effectiveness of anti-VEGFs for the control of intraocular pressure (IOP) in NVG. Objectives To compare the IOP lowering effects of intraocular anti-VEGF agents to no anti-VEGF treatment, as an adjunct to existing modalities for the treatment of NVG. Search methods We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 12), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to January 2013), EMBASE (January 1980 to January 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to January 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov/) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 11 January 2013. Selection criteria We included randomized controlled trials (RCTs) and quasi-RCTs of people treated with anti-VEGF agents for NVG. Data collection and analysis Two authors independently assessed the search results for trials to be included in the review. Discrepancies were resolved by discussion with a third author. Since no trial met our inclusion criteria, no assessment of risk of bias or meta-analysis was undertaken. Main results No RCTs were found that met the inclusion criteria for this review. Two RCTs of anti-VEGF agents for treating NVG were not included in the

  19. Risk of Retinal Neovascularization in Cases of Uveitis.

    PubMed

    Patel, Apurva K; Newcomb, Craig W; Liesegang, Teresa L; Pujari, Siddharth S; Suhler, Eric B; Thorne, Jennifer E; Foster, C Stephen; Jabs, Douglas A; Levy-Clarke, Grace A; Nussenblatt, Robert B; Rosenbaum, James T; Sen, H Nida; Artornsombudh, Pichaporn; Kothari, Srishti; Kempen, John H

    2016-03-01

    To evaluate the risk of and risk factors for retinal neovascularization (NV) in cases of uveitis. Retrospective cohort study. Patients with uveitis at 4 US academic ocular inflammation subspecialty practices. Data were ascertained by standardized chart review. Prevalence data analysis used logistic regression. Incidence data analysis used survival analysis with time-updated covariates where appropriate. Prevalence and incidence of NV. Among uveitic eyes of 8931 patients presenting for initial evaluation, 106 of 13,810 eyes had NV (prevalence = 0.77%, 95% confidence interval [CI], 0.60-0.90). Eighty-eight more eyes developed NV over 26,465 eye-years (incidence, 0.33%/eye-year; 95% CI, 0.27-0.41). Factors associated with incident NV include age <35 years compared with >35 years (adjusted hazard ratio [aHR], 2.4; 95% CI, 1.5-3.9), current cigarette smoking (aHR, 1.9; 95% CI, 1.1-3.4), and systemic lupus erythematosus (aHR, 3.5, 95% CI, 1.1-11). Recent diagnosis of uveitis was associated with an increased incidence of NV (compared with patients diagnosed >5 years ago, aHR, 2.4 [95% CI, 1.1-5.0] and aHR, 2.6 [95% CI, 1.2-6.0] for diagnosis within <1 year vs. 1-5 years, respectively). Compared with anterior uveitis, intermediate uveitis (aHR, 3.1; 95% CI, 1.5-6.6), posterior uveitis (aHR, 5.2; 95% CI, 2.5-11), and panuveitis (aHR, 4.3; 95% CI, 2.0-9.3) were associated with a similar degree of increased NV incidence. Active (aHR, 2.1, 95% CI, 1.2-3.7) and slightly active (aHR, 2.4, 95% CI, 1.3-4.4) inflammation were associated with an increased incidence of NV compared with inactive inflammation. Neovascularization incidence also was increased with retinal vascular occlusions (aHR, 10, 95% CI, 3.0-33), retinal vascular sheathing (aHR, 2.6, 95% CI, 1.4-4.9), and exudative retinal detachment (aHR, 4.1, 95% CI, 1.3-13). Diabetes mellitus was associated with a somewhat increased incidence of retinal NV (aHR, 2.3, 95% CI, 1.1-4.9), and systemic hypertension (aHR 1.5, 95% CI, 0

  20. Objective Area Measurement Technique for Choroidal Neovascularization from Fluorescein Angiography

    PubMed Central

    Guthrie, Micah J.; Osswald, Christian R.; Valio, Nicole L.; Mieler, William F.; Kang-Mieler, Jennifer J.

    2014-01-01

    The purpose of this study was to develop a non-biased method of quantitatively measuring choroidal neovascularization (CNV) areas based on late-phase fluorescein angiography (FA) images. Experimental CNV was induced in Long Evans rats by laser disruption of the Bruch’s membrane. FA was performed weekly for 5 weeks. Multi-Otsu thresholding (MOT) was used to quantify CNV in late-phase FA images from both experimental rodent CNV and wet age-related macular degeneration patients (wAMD). Images were automatically thresholded into three levels based on the image histogram, with the highest level containing CNV. To determine the technique’s ability to quantify CNV areas, rats were given either triamcinolone acetonide or dexamethasone sodium phosphate to treat CNV and compared to untreated rats. The rat CNV lesion areas measured from 5-week histology sections from each treatment group were compared to areas measured from the corresponding FA images. MOT was able to detect statistical decreases in rodent CNV area in the treatment groups versus control from weeks 3 through 5. The ratio of CNV area measured from histology to area measured from FA images was not statistically different between groups. Finally, to determine the usefulness of MOT on pathological morphologies of CNV, MOT was performed on late-phase FA images from patients with classic and diffuse CNV. The technique was able to segment classical CNV in wAMD patients, but performed poorly with diffuse CNV. MOT provides a robust, objective, and quantifiable area measurement of CNV lesion area in both experimentally-induced and pathological CNV. The results indicate that MOT could be a useful research tool in helping evaluate the effects of therapeutics on CNV growth. PMID:24316422

  1. Improved assessment of laser-induced choroidal neovascularization

    PubMed Central

    Toma, Hassanain S.; Barnett, Joshua M.; Penn, John S.; Kim, Stephen J.

    2011-01-01

    The primary objective of this study was to develop and evaluate new methods of analyzing laser-induced choroidal neovascularization (CNV), in order to make recommendations for improving the reporting of experimental CNV in the literature. Six laser burns of sufficient power to rupture Bruch's membrane were concentrically placed in each eye of 18 adult Norway rats. Eyes received intravitreal injections of either triamcinolone acetonide, ketorolac, or balanced salt solution (BSS). Fluorescein angiography (FA) was performed 2 and 3 weeks after injection, followed by choroidal flat mount preparation. Vascular leakage on FAs and vascular budding on choroidal mounts were quantified by measuring either the cross-sectional area of each CNV lesion contained within the best-fitting polygon using Adobe Photoshop (Lasso Technique or Quick Selection Technique), or the area of bright pixels within a lesion using Image-Pro Plus. On choroidal mounts, the Lasso Technique and Image-Pro Plus detected a significant difference in lesion size between either ketorolac or triamcinolone when compared to BSS, while the Quick Selection Technique did not (Lasso Technique, 0.78 and 0.64; Image-Pro Plus, 0.77 and 0.65). On FA, the Lasso Technique and Quick Selection Technique detected a significant difference in lesion size between either ketorolac or triamcinolone when compared to BSS, while Image-Pro Plus did not (Lasso Tool, 0.81 and 0.54; Quick Selection Tool, 0.76 and 0.57). Choroidal mounts and FA are both valuable for imaging experimental CNV. Adobe Photoshop and Image-Pro Plus are both able to detect subtle differences in CNV lesion size, when images are not manipulated. The combination of choroidal mounts and FA provides a more comprehensive assessment of CNV anatomy and physiology. PMID:20553963

  2. Modifying Choroidal Neovascularization Development with a Nutritional Supplement in Mice

    PubMed Central

    Ivanescu, Alina Adriana; Fernández-Robredo, Patricia; Heras-Mulero, Henar; Sádaba-Echarri, Luis Manuel; García-García, Laura; Fernández-García, Vanessa; Moreno-Orduna, Maite; Redondo-Exposito, Aitor; Recalde, Sergio; García-Layana, Alfredo

    2015-01-01

    We examined the effect of nutritional supplements (modified Age Related Eye Disease Study (AREDS)-II formulation containing vitamins, minerals, lutein, resveratrol, and omega-3 fatty acids) on choroidal neovascularization (CNV). Supplements were administered alone and combined with intravitreal anti-VEGF in an early-CNV (diode laser-induced) murine model. Sixty mice were evenly divided into group V (oral vehicle, intravitreal saline), group S (oral supplement, intravitreal saline), group V + aVEGF (oral vehicle, intravitreal anti-VEGF), and group S + aVEGF (oral supplement, intravitreal anti-VEGF). Vehicle and nutritional supplements were administered daily for 38 days beginning 10 days before laser. Intravitreal injections were administered 48 h after laser. Fluorescein angiography (FA) and flat-mount CD31 staining evaluated leakage and CNV lesion area. Expression of VEGF, MMP-2 and MMP-9 activity, and NLRP3 were evaluated with RT-PCR, zymography, and western-blot. Leakage, CNV size, VEGF gene and protein expression were lower in groups V + aVEGF, S + aVEGF, and S than in V (all p < 0.05). Additionally, MMP-9 gene expression differed between groups S + aVEGF and V (p < 0.05) and MMP-9 activity was lower in S + aVEGF than in V and S (both p < 0.01). Levels of MMP-2 and NLRP3 were not significantly different between groups. Nutritional supplements either alone or combined with anti-VEGF may mitigate CNV development and inhibit retinal disease involving VEGF overexpression and CNV. PMID:26153682

  3. Chorioretinal Coloboma Complications: Retinal Detachment and Choroidal Neovascular Membrane

    PubMed Central

    Hussain, Rehan M.; Abbey, Ashkan M.; Shah, Ankoor R.; Drenser, Kimberly A.; Trese, Michael T.; Capone, Antonio

    2017-01-01

    Purpose: To report the chorioretinal coloboma, and its association with increased risk of retinal detachment (RD) and choroidal neovascularization (CNV). Methods: This retrospective case series included eyes with chorioretinal coloboma diagnosed between 1995 and 2014 with a focus on RD and CNV as related complications. Cases of CNV were managed with laser photocoagulation or intravitreal injection of bevacizumab. For eyes with CNV, therapeutic success was defined as resolution of the subretinal hemorrhage on fundus examination and resolution of the subretinal and intraretinal fluid on optical coherence tomography (OCT). For eyes with RD, anatomic success following surgical intervention was defined as attachment of the retina at the last follow-up visit. Results: Fifty-one eyes of 31 patients with chorioretinal coloboma were identified for review. Bilateral chorioretinal coloboma was present in 64.5% of subjects. RD developed in 15 eyes (29.4%). Among 15 eyes with RD, 4 eyes (27%) had retinal breaks identified within the coloboma, 5 eyes (33%) had retinal breaks outside the coloboma, 2 eyes (13%) showed retinal breaks both inside and outside the coloboma, and in 4 eyes (27%) the causative retinal break was not localized. The overall rate of anatomic success after RD repair was 85.7%. CNV developed in 7 eyes (13.7%) and was located along the margin of the coloboma in all cases. CNV was bilateral in 2 of the 5 affected individuals (40%). Conclusion: RD and CNV were present in a high percentage of eyes with chorioretinal coloboma in these series. The frequent finding of retinal breaks outside the coloboma bed suggests that vitreoretinal interface abnormalities may play a role in development of RD in these eyes. PMID:28299000

  4. Ketorolac inhibits choroidal neovascularization by suppression of retinal VEGF

    PubMed Central

    Kim, Stephen J.; Toma, Hassanain S.; Barnett, Joshua M.; Penn, John S.

    2011-01-01

    We assessed the effect of topical ketorolac on laser-induced choroidal neovascularization (CNV), measured retinal PGE2 and VEGF levels after laser treatment, and determined the effect of ketorolac on PGE2 and VEGF production. Six laser burns were placed in eyes of rats which then received topical ketorolac 0.4% or artificial tears four times daily until sacrifice. Fluorescein angiography (FA) was performed at 2 and 3 weeks and retinal pigment epithelium-choroid-sclera flat mounts were prepared. The retina and vitreous were isolated at 1, 3, 5, 7, and 14 days after laser treatment and tested for VEGF and PGE2. Additional animals were lasered and treated with topical ketorolac or artificial tears and tested at 3 and 7 days for retinal and vitreous VEGF and PGE2. Ketorolac reduced CNV on FA by 27% at 2 weeks (P < 0.001) and 25% at 3 weeks (P < 0.001). Baseline retina and vitreous PGE2 levels were 29.4 μg/g and 16.5 μg/g respectively, and reached 51.2 μg/g and 26.9 μg/g respectively, 24 h after laser treatment (P < 0.05). Retinal VEGF level was 781 pg/g 24 h after laser treatment and reached 931 pg/g by 7 days (P < 0.01). Ketorolac reduced retinal PGE2 by 35% at 3 days (P < 0.05) and 29% at 7 days (P < 0.001) and retinal VEGF by 31% at 3 days (P = 0.10) and 19% at 7 days (P < 0.001). Topical ketorolac inhibited CNV and suppressed retinal PGE2 and VEGF production. PMID:20659449

  5. Inhibitory role of adiponectin peptide I on rat choroidal neovascularization

    PubMed Central

    Lyzogubov, Valeriy V.; Tytarenko, Ruslana G.; Bora, Nalini S.; Bora, Puran S.

    2013-01-01

    Age-related macular degeneration (AMD) is a leading cause of central blindness in elderly population. Wet type of AMD is characterized by extensive growth of new vessels. One of the effective strategies to treat wet AMD is to limit the choroidal neovascularization (CNV). We studied effect of adiponectin peptide I (APNpI) on new vessel growth in laser-induced rat model of wet AMD and on rat choroidal endothelial cell (CEC) culture. CNV size and vessel density was investigated by microscopy. Immunohistochemical staining (IHC) for Von Willebrand Factor (vWF), APN, APN receptors 1 (AdipoR1), 2 (AdipoR2), VEGF, VEGF receptor 2 (VEGF-R2), proliferating cell nuclear antigen (PCNA) was performed in CNV area. The mRNA expression of VEGF and VEGF-R2 in RPE-choroid was investigated by RT-PCR and real-time PCR. APNpI inhibited area of CNV by 4 fold, number of vWF positive vessels by 99% and area of subretinal tissue by 40%. The expression of VEGF and VEGF-R2 at mRNA and protein levels were decreased after APNpI treatment in vivo. Proliferative index (PCNA) was 5 fold less in laser spots of APNpI treated rats compared to controls. In conclusion, APNpI inhibited formation of new vessels in rat model of CNV by decreasing VEGF, VEGF-R2 expression and cell proliferation. Thus, APNpI may have potential therapeutic use for AMD treatment since it significantly inhibited CNV. PMID:22633972

  6. Monocytes/Macrophages Mobilization Orchestrate Neovascularization after Localized Colorectal Irradiation.

    PubMed

    Loinard, Céline; Vilar, José; Milliat, Fabien; Lévy, Bernard; Benderitter, Marc

    2017-05-01

    In patients undergoing radiotherapy for cancer, radiation dose to healthy tissue can occur, causing microvascular damage. Monocytes that have been shown to promote tissue revascularization comprise the subsets: CD11b(+)Ly6G(-)7/4(hi)/monocytes(hi) and CD11b(+)Ly6G(-)7/4(lo)/monocytes(lo). We hypothesized that monocytes were implicated in postirradiation blood vessel formation. C57Bl6 mice underwent localized colorectal irradiation and were sacrificed at different times after exposure. Bone marrow, spleen, blood and colon were collected. Fourteen days postirradiation, colons expressed proangiogenic actors and adhesion molecules. Monocytes(hi), which were the main subset of infiltrating monocytes, mobilized to the blood from spleen and bone marrow, peaking at day 14 postirradiation, and were associated with lymphocyte Th1 polarization. At day 28 postirradiation, angiographic score and capillary density increased by ∼1.8-fold, and then returned to nonirradiated levels at day 60. Clodronate-mediated depletion of circulating monocytes prior to irradiation resulted in a ∼1.4-fold decrease in angiographic score and capillary density compared to the nontreated control. Histological analysis of the colon in clodronate-treated mice revealed a massive decrease of macrophage and lymphocyte infiltration as well as reduced collagen deposition in crypt area at day 21. However, late depletion of monocytes from day 25 postirradiation had no effect on fibrotic process. These findings demonstrate a central role for monocyte/macrophage activation in the orchestration of a neovascularization mechanism after localized colorectal irradiation.

  7. Improved assessment of laser-induced choroidal neovascularization.

    PubMed

    Toma, Hassanain S; Barnett, Joshua M; Penn, John S; Kim, Stephen J

    2010-12-01

    The primary objective of this study was to develop and evaluate new methods of analyzing laser-induced choroidal neovascularization (CNV), in order to make recommendations for improving the reporting of experimental CNV in the literature. Six laser burns of sufficient power to rupture Bruch's membrane were concentrically placed in each eye of 18 adult Norway rats. Eyes received intravitreal injections of either triamcinolone acetonide, ketorolac, or balanced salt solution (BSS). Fluorescein angiography (FA) was performed 2 and 3 weeks after injection, followed by choroidal flat mount preparation. Vascular leakage on FAs and vascular budding on choroidal mounts were quantified by measuring either the cross-sectional area of each CNV lesion contained within the best-fitting polygon using Adobe Photoshop (Lasso Technique or Quick Selection Technique), or the area of bright pixels within a lesion using Image-Pro Plus. On choroidal mounts, the Lasso Technique and Image-Pro Plus detected a significant difference in lesion size between either ketorolac or triamcinolone when compared to BSS, while the Quick Selection Technique did not (Lasso Technique, 0.78 and 0.64; Image-Pro Plus, 0.77 and 0.65). On FA, the Lasso Technique and Quick Selection Technique detected a significant difference in lesion size between either ketorolac or triamcinolone when compared to BSS, while Image-Pro Plus did not (Lasso Tool, 0.81 and 0.54; Quick Selection Tool, 0.76 and 0.57). Choroidal mounts and FA are both valuable for imaging experimental CNV. Adobe Photoshop and Image-Pro Plus are both able to detect subtle differences in CNV lesion size, when images are not manipulated. The combination of choroidal mounts and FA provides a more comprehensive assessment of CNV anatomy and physiology.

  8. Ocular neovascularization associated with central and hemicentral retinal vein occlusion.

    PubMed

    Hayreh, Sohan Singh; Zimmerman, M Bridget

    2012-09-01

    To investigate the incidence of ocular neovascularization (NV) in central and hemicentral retinal vein occlusion. The study comprised consecutive 912 (673 nonischemic and 239 ischemic) central retinal vein occlusion and 190 (147 nonischemic, 43 ischemic) hemicentral retinal vein occlusion eyes. Ophthalmic evaluation at initial and follow-up visits included recording visual acuity, visual fields, and detailed anterior segment and fundus examinations and fluorescein fundus angiography. In ischemic central retinal vein occlusion, within 6 months from time of onset, the cumulative probability of development of iris NV was 49%, angle NV 37%, NV glaucoma 29%, retinal NV 9%, and disk NV 6%. More severe peripheral retinal hemorrhages were significantly associated with iris NV (P = 0.005), angle NV (P = 0.0004), and NV glaucoma (P = 0.012). Eyes that developed disk NV had more cotton wool spots (P = 0.058) than those without. In ischemic hemicentral retinal vein occlusion, within 12 months of onset, the cumulative probability of development of retinal NV was 29%, disk NV 12%, and iris NV 12%; within 6 months of onset, angle NV was found in 10% and NV glaucoma in 5%. Anterior chamber flare was associated with anterior segment NV and may precede the development of NV. Patients who developed NV were significantly younger, and there was a greater prevalence of NV glaucoma in patients with primary open angle glaucoma. In ischemic central retinal vein occlusion, anterior segment NV is much more common than posterior segment NV, and the cumulative chance of developing anterior segment NV is maximum during the first 6 months. In ischemic hemicentral retinal vein occlusion, posterior segment NV is much more common than anterior segment NV.

  9. Optical Coherence Tomography Angiography Study of Choroidal Neovascularization Associated With Focal Choroidal Excavation.

    PubMed

    Chawla, Rohan; Mittal, Kanhaiya; Vohra, Rajpal

    2016-10-01

    The authors report the use of optical coherence tomography angiography (OCTA) (DRI OCT Triton; Topcon, Tokyo, Japan) to localize, characterize, and confirm the presence of a choroidal neovascular membrane in a patient of focal choroidal excavation (FCE) with recent-onset metamorphopsia and visual blurring. En face OCTA images just above the level of the retinal pigment epithelium-Bruch's membrane complex typically showed the presence of a glomerulus-like neovascular network with an adjacent dark area suggestive of a Type 2 choroidal neovascularization (CNV). OCTA was found to be a very useful, noninvasive, and quick imaging modality to detect secondary CNV formation in a case of FCE. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:969-971.].

  10. Sulodexide inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy

    PubMed Central

    Jo, Hyoung; Jung, Sang Hoon; Kang, Jun; Yim, Hye Bin; Kang, Kui Dong

    2014-01-01

    Sulodexide is a mixed glycosaminoglycan composed of heparin and dermatan sulfate. In this study, the anti-angiogenic effect of sulodexide was investigated using an oxygen-induced retinopathy (OIR) mouse model. The retinas of sham-injected OIR mice (P17) had a distinctive central area of nonperfusion, and this area was significantly decreased in sulodexide-injected mice. The number of neovascular tufts measured by SWIFT_NV and mean neovascular lumen number were significantly decreased in sulodexide-injected mice. Hyperbaric oxygen exposure resulted in increased levels of VEGF, MMP-2 and MMP-9, and when mice were treated with sulodexide, a dose-dependent reduction in VEGF, MMP-2 and MMP-9 levels was observed. Our results clearly demonstrate the anti-angiogenic effect of sulodexide and highlight sulodexide as a candidate supplementary substance to be used for the treatment of ocular pathologies that involve neovascularization. [BMB Reports 2014; 47(11): 637-642] PMID:24602608

  11. Sulodexide inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy.

    PubMed

    Jo, Hyoung; Jung, Sang Hoon; Kang, Jun; Yim, Hye Bin; Kang, Kui Dong

    2014-11-01

    Sulodexide is a mixed glycosaminoglycan composed of heparin and dermatan sulfate. In this study, the anti-angiogenic effect of sulodexide was investigated using an oxygen-induced retinopathy (OIR) mouse model. The retinas of sham-injected OIR mice (P17) had a distinctive central area of nonperfusion, and this area was significantly decreased in sulodexide-injected mice. The number of neovascular tufts measured by SWIFT_NV and mean neovascular lumen number were significantly decreased in sulodexide-injected mice. Hyperbaric oxygen exposure resulted in increased levels of VEGF, MMP-2 and MMP-9, and when mice were treated with sulodexide, a dose-dependent reduction in VEGF, MMP-2 and MMP-9 levels was observed. Our results clearly demonstrate the anti-angiogenic effect of sulodexide and highlight sulodexide as a candidate supplementary substance to be used for the treatment of ocular pathologies that involve neovascularization.

  12. Fluorocoxib A enables targeted detection of cyclooxygenase-2 in laser-induced choroidal neovascularization

    NASA Astrophysics Data System (ADS)

    Uddin, Md. Jashim; Moore, Chauca E.; Crews, Brenda C.; Daniel, Cristina K.; Ghebreselasie, Kebreab; McIntyre, J. Oliver; Marnett, Lawrence J.; Jayagopal, Ashwath

    2016-09-01

    Ocular angiogenesis is a blinding complication of age-related macular degeneration and other retinal vascular diseases. Clinical imaging approaches to detect inflammation prior to the onset of neovascularization in these diseases may enable early detection and timely therapeutic intervention. We demonstrate the feasibility of a previously developed cyclooxygenase-2 (COX-2) targeted molecular imaging probe, fluorocoxib A, for imaging retinal inflammation in a mouse model of laser-induced choroidal neovascularization. This imaging probe exhibited focal accumulation within laser-induced neovascular lesions, with minimal detection in proximal healthy tissue. The selectivity of the probe for COX-2 was validated in vitro and by in vivo retinal imaging with nontargeted 5-carboxy-X-rhodamine dye, and by blockade of the COX-2 active site with nonfluorescent celecoxib prior to injection of fluorocoxib A. Fluorocoxib A can be utilized for imaging COX-2 expression in vivo for further validation as an imaging biomarker in retinal diseases.

  13. Endothelial progenitor cells in atherosclerosis

    PubMed Central

    Du, Fuyong; Zhou, Jun; Gong, Ren; Huang, Xiao; Pansuria, Meghana; Virtue, Anthony; Li, Xinyuan; Wang, Hong; Yang, Xiao-Feng

    2012-01-01

    Endothelial progenitor cells (EPCs) are involved in the maintenance of endothelial homoeostasis and in the process of new vessel formation. Experimental and clinical studies have shown that atherosclerosis is associated with reduced numbers and dysfunction of EPCs; and that medications alone are able to partially reverse the impairment of EPCs in patients with atherosclerosis. Therefore, novel EPC-based therapies may provide enhancement in restoring EPCs’ population and improvement of vascular function. Here, for a better understanding of the molecular mechanisms underlying EPC impairment in atherosclerosis, we provide a comprehensive overview on EPC characteristics, phenotypes, and the signaling pathways underlying EPC impairment in atherosclerosis. PMID:22652782

  14. Lack of association between VAP-1/SSAO activity and corneal neovascularization in a rabbit model.

    PubMed

    Énzsöly, Anna; Markó, Katalin; Tábi, Tamás; Szökő, Éva; Zelkó, Romána; Tóth, Miklós; Petrash, J Mark; Mátyus, Péter; Németh, János

    2013-06-01

    The aim of this study is to determine the efficacy of a potent and specific vascular adhesive protein-1/semicarbazide-sensitive amine oxidase (VAP-1/SSAO) inhibitor, LJP 1207, as a potential antiangiogenic and anti-inflammatory agent in the therapy of corneal neovascularization. Corneal neovascularization was induced with intrastromal suturing in rabbits (n = 20). Topical treatment with VAP-1/SSAO inhibitor LJP 1207 (n = 5, 4 times a day), bevacizumab (n = 5, daily), their combination (n = 5) and vehicle only (n = 5, 4 times a day) were applied postoperatively for 2 weeks. The development and extent of corneal neovascularization were evaluated by digital image analysis. At the end of the observation period, the level of corneal and serum VAP-1/SSAO activity was measured fluorometrically and radiochemically. The corneal VAP-1/SSAO activity was significantly elevated in the suture-challenged vehicle-treated group (3,075 ± 1,009 pmol/mg/h) as compared to unoperated controls (464.2 ± 135 pmol/mg/h, p < 0.001). Treatment with LJP 1207 resulted in slower early phase neovascularization compared to vehicle-treated animals (not significant). At days 7-14, there was no significant difference in the extent of corneal neovascularization between inhibitor- and vehicle-treated corneas, even though inhibitor treatment caused a normalization of corneal VAP-1/SSAO activity (885 ± 452 pmol/mg/h). Our results demonstrate that the significant elevation of VAP-1/SSAO activity due to corneal injury can be prevented with VAP-1/SSAO inhibitor LJP 1207 treatment. However, normalization of VAP-1/SSAO activity in this model does not prevent the development of corneal neovascularization.

  15. Short-Term Topical Bevacizumab in the Treatment of Stable Corneal Neovascularization

    PubMed Central

    Cheng, Sheng-Fu; Dastjerdi, Mohammad H.; Ferrari, Giulio; Okanobo, Andre; Bower, Kraig S.; Ryan, Denise S.; Amparo, Francisco; Stevenson, William; Hamrah, Pedram; Nallasamy, Nambi; Dana, Reza

    2012-01-01

    Purpose To evaluate the safety and efficacy of topical bevacizumab in the treatment of corneal neovascularization (NV). Design Prospective, non-randomized, interventional case series. Methods Setting Institutional, multicenter clinical trial. Study Population Twenty eyes from 20 patients with stable corneal NV. Intervention Procedures Patients were treated with topical 1.0% for 3 weeks and monitored for a total of 24 weeks. Main Outcome Measures Primary outcome measures included: neovascular area, defined as the area of the corneal vessels themselves; vessel caliber, defined as the mean corneal vessel diameter; and invasion area, defined as the fraction of the total cornea into which the vessels extended. The occurrence of ocular and systemic adverse events was closely monitored. Results As compared to the baseline visit, patients exhibited a statistically significant improvement in neovascular area by week 6 (P = .007) and vessel caliber by week 12 (P = .006). At the final visit, neovascular area, vessel caliber, and invasion area were reduced by 47.5%, 36.2%, and 20%, respectively. The decreases in neovascular area and vessel caliber were statistically significant (P < .001 and P = .003, respectively); however, the reduction in invasion area did not reach statistical significance (P = .06). There were no significant changes in the secondary outcomes and there were no adverse events. Conclusions Short-term topical bevacizumab treatment reduced the extent of stable corneal NV as measured by neovascular area and vessel caliber with no associated adverse events. Interestingly, the degree of treatment efficacy was inversely proportional to the baseline invasion area. PMID:22967868

  16. Antiangiogenic activity of a bevacizumab-loaded polyurethane device in animal neovascularization models.

    PubMed

    Ferreira, A E R; Castro, B F M; Vieira, L C; Cassali, G D; Souza, C M; Fulgêncio, G O; Ayres, E; Oréfice, R L; Jorge, R; Silva-Cunha, A; Fialho, S L

    2017-03-01

    To evaluate the antiangiogenic activity of bevacizumab-loaded polyurethane using two animal models of neovascularization. The percentage of blood vessels was evaluated in a chicken chorioallantoic membrane model (n=42) and in the rabbit cornea (n=24) with neovascularization induced by alkali injury. In each model, the animals were randomly divided into the groups treated with the bevacizumab-loaded polyurethane device, phosphate-buffered-saline (negative control) and bevacizumab commercial solution (positive control). Clinical examination, as well as histopathological and immunohistochemical evaluation, were performed in the rabbit eyes. Microvascular density in hot spot areas was determined in semi-thin sections of corneal tissue by hematoxylin-eosin staining and factor VIII immunohistochemistry. Immunohistochemical analysis was also performed to evaluate VEGF expression. In the evaluated models, the use of bevacizumab (Avastin(®)) and the bevacizumab-loaded polyurethane device led to similar results with regard to inhibition of neovascularization. In the chorioallantoic membrane model, the bevacizumab-loaded polyurethane device reduced angiogenesis by 50.27% when compared to the negative control group. In the rabbit model of corneal neovascularization, the mean density of vessels/field was reduced by 46.87% on analysis of factor VIII immunohistochemistry photos in the bevacizumab-loaded polyurethane device group as compared to the negative control (PBS) sections. In both models, no significant difference could be identified between the bevacizumab-loaded polyurethane device and the positive control group, leading to similar results with regard to inhibition of neovascularization. The present study shows that the bevacizumab-loaded polyurethane device may release bevacizumab and inhibit neovascularization similarly to commercial bevacizumab solution in the short-term. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  17. The inhibitory effect of thalidomide analogue on corneal neovascularization in rabbits.

    PubMed

    Lee, You Kyung; Chung, Sung Kun

    2013-08-01

    To evaluate the effect of thalidomide analogue CC-3052 on corneal neovascularization in the rabbit model. Corneal neovascularization was induced in 15 rabbits by a silk suture in the corneal stroma. At 1 week after suturing, 30 eyes were divided into 5 groups of 6 eyes each. Three groups were treated with topical CC-3052 at 3 different concentrations: 0.25% (group 1), 0.5% (group 2), and 1.0% (group 3). All treatments were performed twice a day for a week. A 0.5% concentration of CC-3052 was injected subconjunctivally once in group 4. In group 5, a topical balanced salt solution was added twice a day for a week as the experimental control group. Rabbit corneas were photographed by a digital camera and examined by the operating microscope. Half of the corneal specimens were analyzed histopathologically, and the other half were used to measure the concentration of tumor necrosis factor α and vascular endothelial growth factor (VEGF) messenger RNA by reverse transcriptase-polymerase chain reaction. The neovascularized area was decreased in all treatment groups compared with the control group. There was a significant difference in the percentage and score of corneal neovascularization between the control and all treatment groups. Inflammation, fibroblast, neovascularization, and anti-VEGF antibody intensities were significantly lower in the control group. The concentration of VEGF and tumor necrosis factor α was significantly lower in the control group. There was no difference between the treatment groups. Topical and subconjunctival administration of thalidomide analogue CC-3052 was found to be effective for the inhibition of corneal neovascularization.

  18. Acute iritis induced by granulocyte colony-stimulating factor used for mobilization in a volunteer unrelated peripheral blood progenitor cell donor.

    PubMed

    Parkkali, T; Volin, L; Sirén, M K; Ruutu, T

    1996-03-01

    We describe a volunteer unrelated peripheral blood progenitor cell donor with previously diagnosed dermatitis herpetiformis in whom the administration of G-CSF for the mobilization of precursor cells induced acute iritis. G-CSF has been administered to healthy people with minimal side-effects but when used in patients with autoimmune disorders worsening of symptoms or new manifestations may be a potential concern.

  19. THE GOAL OF VALUE-BASED MEDICINE ANALYSES: COMPARABILITY. THE CASE FOR NEOVASCULAR MACULAR DEGENERATION

    PubMed Central

    Brown, Gary C.; Brown, Melissa M.; Brown, Heidi C.; Kindermann, Sylvia; Sharma, Sanjay

    2007-01-01

    Purpose To evaluate the comparability of articles in the peer-reviewed literature assessing the (1) patient value and (2) cost-utility (cost-effectiveness) associated with interventions for neovascular age-related macular degeneration (ARMD). Methods A search was performed in the National Library of Medicine database of 16 million peer-reviewed articles using the key words cost-utility, cost-effectiveness, value, verteporfin, pegaptanib, laser photocoagulation, ranibizumab, and therapy. All articles that used an outcome of quality-adjusted life-years (QALYs) were studied in regard to (1) percent improvement in quality of life, (2) utility methodology, (3) utility respondents, (4) types of costs included (eg, direct healthcare, direct nonhealthcare, indirect), (5) cost bases (eg, Medicare, National Health Service in the United Kingdom), and (6) study cost perspective (eg, government, societal, third-party insurer). To qualify as a value-based medicine analysis, the patient value had to be measured using the outcome of the QALYs conferred by respective interventions. As with value-based medicine analyses, patient-based time tradeoff utility analysis had to be utilized, patient utility respondents were necessary, and direct medical costs were used. Results Among 21 cost-utility analyses performed on interventions for neovascular macular degeneration, 15 (71%) met value-based medicine criteria. The 6 others (29%) were not comparable owing to (1) varying utility methodology, (2) varying utility respondents, (3) differing costs utilized, (4) differing cost bases, and (5) varying study perspectives. Among value-based medicine studies, laser photocoagulation confers a 4.4% value gain (improvement in quality of life) for the treatment of classic subfoveal choroidal neovascularization. Intravitreal pegaptanib confers a 5.9% value gain (improvement in quality of life) for classic, minimally classic, and occult subfoveal choroidal neovascularization, and photodynamic therapy

  20. Imaging polarimetry in patients with neovascular age-related macular degeneration

    PubMed Central

    Elsner, Ann E.; Weber, Anke; Cheney, Michael C.; VanNasdale, Dean A.; Miura, Masahiro

    2007-01-01

    Imaging polarimetry was used to examine different components of neovascular membranes in age-related macular degeneration. Retinal images were acquired with a scanning laser polarimeter. An innovative pseudo-color scale, based on cardinal directions of color, displayed two types of image information: relative phases and magnitudes of birefringence. Membranes had relative phase changes that did not correspond to anatomical structures in reflectance images. Further, membrane borders in depolarized light images had significantly higher contrasts than those in reflectance images. The retinal birefringence in neovascular membranes indicates optical activity consistent with molecular changes rather than merely geometrical changes. PMID:17429494

  1. Regulation of signaling events involved in the pathophysiology of neovascular AMD.

    PubMed

    Wang, Haibo; Hartnett, M Elizabeth

    2016-01-01

    Neovascular age-related macular degeneration (AMD) is a complex disease in which an individual's genetic predisposition is affected by aging and environmental stresses, which trigger signaling pathways involving inflammation, oxidation, and/or angiogenesis in the RPE cells and choroidal endothelial cells (CECs), to lead to vision loss from choroidal neovascularization. Antiangiogenic therapies have greatly improved clinical outcomes in the last decade; however, vision improves in less than half of patients treated for neovascular AMD, and treatments remain inadequate for atrophic AMD. Many studies focus on genetic predisposition or the association of outcomes in trials of human neovascular AMD but are unable to evaluate the effects between different cell types involved in AMD and the signaling events that take place to cause pathologic biologic events. This manuscript complements other reviews in that it describes what is known generally in human AMD studies and clinical trials testing methods to inhibit vascular endothelial growth factor (VEGF inhibitors) and presents pathologic signaling events that develop in two important cell types, the RPE cells and the CECs, when stimulated by stresses or placed into conditions similar to what is currently understood to occur in neovascular AMD. This manuscript complements other reviews by discussing signaling events that are activated by cell-cell or cell-matrix interactions. These considerations are particularly important when considering growth factors, such as VEGF, which are important in physiologic and pathologic processes, or GTPases that are present but active only if GTP bound. In either case, it is essential to understand the role of signaling activation to distinguish what is pathologic from what is physiologic. Particularly important is the essential role of activated Rac1 in CEC transmigration of the RPE monolayer, an important step in blindness associated with neovascular AMD. Other concepts discussed include

  2. PSGL-1-mediated activation of EphB4 increases the proangiogenic potential of endothelial progenitor cells.

    PubMed

    Foubert, Philippe; Silvestre, Jean-Sébastien; Souttou, Boussad; Barateau, Véronique; Martin, Coralie; Ebrahimian, Téni G; Leré-Déan, Carole; Contreres, Jean Olivier; Sulpice, Eric; Levy, Bernard I; Plouët, Jean; Tobelem, Gérard; Le Ricousse-Roussanne, Sophie

    2007-06-01

    Endothelial progenitor cell (EPC) transplantation has beneficial effects for therapeutic neovascularization; however, only a small proportion of injected cells home to the lesion and incorporate into the neocapillaries. Consequently, this type of cell therapy requires substantial improvement to be of clinical value. Erythropoietin-producing human hepatocellular carcinoma (Eph) receptors and their ephrin ligands are key regulators of vascular development. We postulated that activation of the EphB4/ephrin-B2 system may enhance EPC proangiogenic potential. In this report, we demonstrate in a nude mouse model of hind limb ischemia that EphB4 activation with an ephrin-B2-Fc chimeric protein increases the angiogenic potential of human EPCs. This effect was abolished by EphB4 siRNA, confirming that it is mediated by EphB4. EphB4 activation enhanced P selectin glycoprotein ligand-1 (PSGL-1) expression and EPC adhesion. Inhibition of PSGL-1 by siRNA reversed the proangiogenic and adhesive effects of EphB4 activation. Moreover, neutralizing antibodies to E selectin and P selectin blocked ephrin-B2-Fc-stimulated EPC adhesion properties. Thus, activation of EphB4 enhances EPC proangiogenic capacity through induction of PSGL-1 expression and adhesion to E selectin and P selectin. Therefore, activation of EphB4 is an innovative and potentially valuable therapeutic strategy for improving the recruitment of EPCs to sites of neovascularization and thereby the efficiency of cell-based proangiogenic therapy.

  3. CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction.

    PubMed

    Jujo, Kentaro; Hamada, Hiromichi; Iwakura, Atsushi; Thorne, Tina; Sekiguchi, Haruki; Clarke, Trevor; Ito, Aiko; Misener, Sol; Tanaka, Toshikazu; Klyachko, Ekaterina; Kobayashi, Koichi; Tongers, Jörn; Roncalli, Jérôme; Tsurumi, Yukio; Hagiwara, Nobuhisa; Losordo, Douglas W

    2010-06-15

    We hypothesized that a small molecule CXCR4 antagonist, AMD3100 (AMD), could augment the mobilization of bone marrow (BM)-derived endothelial progenitor cells (EPCs), thereby enhancing neovascularization and functional recovery after myocardial infarction. Single-dose AMD injection administered after the onset of myocardial infarction increased circulating EPC counts and myocardial vascularity, reduced fibrosis, and improved cardiac function and survival. In mice transplanted with traceable BM cells, AMD increased BM-derived cell incorporation in the ischemic border zone. In contrast, continuous infusion of AMD, although increasing EPCs in the circulation, worsened outcome by blocking EPC incorporation. In addition to its effects as a CXCR4 antagonist, AMD also up-regulated VEGF and matrix metalloproteinase 9 (MMP-9) expression, and the benefits of AMD were not observed in the absence of MMP-9 expression in the BM. These findings suggest that AMD3100 preserves cardiac function after myocardial infarction by enhancing BM-EPC-mediated neovascularization, and that these benefits require MMP-9 expression in the BM, but not in the ischemic region. Our results indicate that AMD3100 could be a potentially useful therapy for the treatment of myocardial infarction.

  4. Growth inhibition of formed corneal neovascularization following Fosaprepitant treatment.

    PubMed

    Bignami, Fabio; Lorusso, Anna; Rama, Paolo; Ferrari, Giulio

    2017-02-15

    The aim of this study was to test the efficacy of Neurokinin-1 Receptor (NK-1R) antagonist -Fosaprepitant- in inducing regression of established corneal neovascularization (CNV). Twenty C57BL/6 mice underwent alkali burn. Seven days later, when corneal neovessels had developed, they received Fosaprepitant 10 mg/ml, administered topically six times a day in the right eye for 10 days. In parallel, a group of 20 causticated mice was treated with normal saline, as control. A second independent experiment was also performed (n = 10/group). Finally, ten healthy mice received the same topical treatment for 10 days to evaluate Fosaprepitant safety. Haemangiogenesis and lymphangiogenesis were measured by means of vesselj plugin (imagej). Secondary endpoints, such as leucocyte infiltration, corneal opacity and corneal fluorescein staining were also evaluated. Inflammatory cell composition was assessed by flow cytometry. Differences between groups were assessed using unpaired t-test, Mann-Whitney U-test or two-way anova, as appropriate. Topical Fosaprepitant administration induced a significant reduction of (i) CD31(+) blood corneal neovessels (-27%, p = 0.0132), (ii) LYVE1(+) lymphatic corneal neovessels (-31%, p = 0.0118) and (iii) CD45(+) leucocyte infiltration (-36%; p = 0.0237). The second independent experiment confirmed these data. Moreover, Fosaprepitant-treated corneas showed a reduction in opacity, no impairment in corneal fluorescein staining and decreased infiltration of neutrophils (-72%, p < 0.05) and macrophages (-75%, p < 0.01). Finally, topical Fosaprepitant was not toxic to the ocular surface: no signs of conjunctivitis, opacity, perforations or corneal fluorescein staining were detected. Similarly, corneal TUJ1(+) nerve density was not affected. Our data suggest that NK-1R antagonists, such as Fosaprepitant, could be a new, promising therapeutic tool to inhibit CNV after this has been established. © 2017 Acta Ophthalmologica Scandinavica

  5. Suppression of Experimental Choroidal Neovascularization by Curcumin in Mice

    PubMed Central

    Xie, Ping; Zhang, WeiWei; Yuan, Songtao; Chen, Zhiqiang; Yang, Qin; Yuan, DongQing; Wang, Feng; Liu, QingHuai

    2012-01-01

    Purpose To investigate the effects of curcumin on the development of experimental choroidal neovascularization (CNV) with underlying cellular and molecular mechanisms. Methods C57BL/6N mice were pretreated with intraperitoneal injections of curcumin daily for 3 days prior to laser-induced CNV, and the drug treatments were continued until the end of the study. The CNV area was analyzed by fluorescein-labeled dextran angiography of retinal pigment epithelium (RPE)-choroid flat mounts on day 7 and 14, and CNV leakage was evaluated by fluorescein angiography (FA) on day 14 after laser photocoagulation. The infiltration of F4/80 positive macrophages and GR-1 positive granulocytes were evaluated by immunohistochemistry on RPE-choroid flat mounts on day 3. Their expression in RPE-choroid complex was quantified by real-time PCR (F4/80) and Western blotting (GR-1) on day 3. RPE-choroid levels of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1, and intercellular adhesion molecule (ICAM)-1 were examined by ELISA on day 3. Double immunostaining of F4/80 and VEGF was performed on cryo-sections of CNV lesions on day 3. The expression of nuclear factor (NF)-κB and hypoxia-inducible factor (HIF)−1α in the RPE-choroid was determined by Western blotting. Results Curcumin-treated mice had significantly less CNV area (P<0.05) and CNV leakage (P<0.001) than vehicle-treated mice. Curcumin treatment led to significant inhibition of F4/80 positive macrophages (P<0.05) and GR-1 positive granulocytes infiltration (P<0.05). VEGF mainly expressed in F4/80 positive macrophages in laser injury sites, which was suppressed by curcumin treatment (P<0.01). Curcumin inhibited the RPE-choroid levels of TNF-α (P<0.05), MCP-1 (P<0.05) and ICAM-1 (P<0.05), and suppressed the activation of NF-κB in nuclear extracts (P<0.05) and the activation of HIF−1α (P<0.05). Conclusion Curcumin treatment led to the suppression of CNV development

  6. Celastrol nanoparticles inhibit corneal neovascularization induced by suturing in rats

    PubMed Central

    Li, Zhanrong; Yao, Lin; Li, Jingguo; Zhang, Wenxin; Wu, Xianghua; Liu, Yi; Lin, Miaoli; Su, Wenru; Li, Yongping; Liang, Dan

    2012-01-01

    Purpose Celastrol, a traditional Chinese medicine, is widely used in anti-inflammation and anti-angiogenesis research. However, the poor water solubility of celastrol restricts its further application. This paper aims to study the effect of celastrol nanoparticles (CNPs) on corneal neovascularization (CNV) and determine the possible mechanism. Methods To improve the hydrophilicity of celastrol, celastrol-loaded poly(ethylene glycol)-block-poly(ɛ-caprolactone) nanopolymeric micelles were developed. The characterization of CNPs was measured by dynamic light scattering and transmission electron microscopy analysis. Celastrol loading content and release were assessed by ultraviolet-visible analysis and high performance liquid chromatography, respectively. In vitro, human umbilical vein endothelial cell proliferation and capillary-like tube formation were assayed. In vivo, suture-induced CNV was chosen to evaluate the effect of CNPs on CNV in rats. Immunohistochemistry for CD68 assessed the macrophage infiltration of the cornea on day 6 after surgery. Real-time quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay were used to evaluate the messenger ribonucleic acid and protein levels, respectively, of vascular endothelial growth factor, matrix metalloproteinase 9, and monocyte chemoattractant protein 1 in the cornea. Results The mean diameter of CNPs with spherical shape was 48 nm. The celastrol loading content was 7.36%. The release behavior of CNPs in buffered solution (pH 7.4) showed a typical two-phase release profile. CNPs inhibited the proliferation of human umbilical vein endothelial cells in a dose-independent manner and suppressed the capillary structure formation. After treatment with CNPs, the length and area of CNV reduced from 1.16 ± 0.18 mm to 0.49 ± 0.12 mm and from 7.71 ± 0.94 mm2 to 2.29 ± 0.61 mm2, respectively. Macrophage infiltration decreased significantly in the CNP-treated corneas. CNPs reduced

  7. Multimodal imaging and diagnosis of myopic choroidal neovascularization in Caucasians

    PubMed Central

    Milani, Paolo; Massacesi, Amedeo; Moschini, Stefania; Setaccioli, Marco; Bulone, Ennio; Tremolada, Gemma; Ciaccia, Stefano; Mantovani, Elena; Morale, Daniela; Bergamini, Fulvio

    2016-01-01

    Purpose To investigate myopic choroidal neovascularization (mCNV) by fluorescein angiography (FA), spectral-domain optical coherence tomography (SD-OCT), near-infrared (NIR) reflectance, and autofluorescence (AF). Methods This retrospective study included 65 eyes of 62 Caucasian patients with a mean age of 66.72 years (95% confidence interval [CI] 63–70 years) and a mean refraction of −9.72 diopters (95% CI −8.74 to −10.70 diopters). Results Most of the mCNV cases were foveal-juxtafoveal (60/65, 92.3%), with thickening of the corresponding retina (62/65, 95.3%) and leakage on FA (44/65, 67.6%). No retinal fluid was detectable in 32 (49.2%) eyes and there was no hemorrhage in 25 (38.4%) eyes. Papillary chorioretinal atrophy was evident in 58 (89.2%), a shadowing effect in 48 (73.8%), and an epiretinal membrane in 38 (58.4%) eyes. If an area of macular chorioretinal atrophy was present, mCNV frequently developed adjacent to it and was hyperfluorescent rather than with leakage (P⩽0.001). In eyes with edema or hemorrhage, hyper-reflective foci were more frequent (P⩽0.005). NIR and AF features were indeterminable in 19 (29.2%) and 27 (41.5%) eyes, respectively. The predominant feature was black or grayish on NIR (34/65, 52.3%) and patchy (hypo- and hyperfluorescence was observed) on AF (25/65, 38.4%). FA and SD-OCT correctly detected mCNV in 49 (75.3%) and 48 (73.8%) eyes, respectively, whereas NIR and AF exhibited limited diagnostic sensitivity. Doubtful diagnosis was associated with hyperfluorescent mCNV (P⩽0.001), absence of retinal fluid and epiretinal membrane (P⩽0.05), and presence of macular chorioretinal atrophy (P⩽0.01). Conclusion Tomographic, angiographic, AF, and NIR features of mCNV are described in this study. Combination of SD-OCT and FA is recommendable for diagnosis. PMID:27672306

  8. Inhibition of corneal neovascularization by vascular endothelia growth inhibitor gene

    PubMed Central

    Wang, Hong; Wang, Bing; Zhang, Zhen-Hai

    2010-01-01

    AIM To evaluate the effect of Effectene™ lipofectine mediated plasmids encoding human pcDNA4-vascular endothelia growth inhibitor (pcDNA4-VEGI) gene on corneal neovascularization (CNV). METHODS Forty New Zealand albino rabbits were sutured by 5-0 silk on the superior cornea to establish the animal model and divided into 4 random group, ten per each group: group A: transfected by pcDNA4-VEGI gene mediated by Effectene™ lipofectine transfection, group B: by Plasmid pcDNA4, group C: by Effectene™, and group D: by normal saline. Length and area of CNV were measured under slit lamp every day after transfection, immunohistochemistry was used to detected the expression of VEGI protein in cornea at 3, 7, 14 and 21 days. RESULTS Average occurrence of CNV in the pcDNA4-VEGI gene transfected group (group A) was 6.3 days, in plasmid pcDNA4 control group (group B) was 3.1 days, in Effectene™ lipofectine control group (group C) was 3.2 days, in normal saline control group (group D) was 3.2 days. Differences between groups A and B, C, D were statistically significant (P<0.01), while differences in groups B, C and D were meaningless (P>0.05). Lenth and average area of CNV in each period in group A was meaningful different from that in groups B, C, and D (P<0.01), while differences in group B, C and D were meaningless (P>0.05). Immunohistochemistry result: VEGI positive cells could be seen in epithelium, stroma, endothelium and the cliff of CNV in group A at 3 days after transfection. VEGI cells changed with the decrease of CNV. None positive cells were in the control groups (groups B, C and D) all the time. CONCLUSION Effectene™ lipofectine transfection technique can be effectively used in transfecting pcDNA4-VEGI gene into rabbit cornea and the lenth and areas of CNV can be inhibited by VEGI gene. PMID:22553552

  9. Three specific antigens to isolate endothelial progenitor cells from human liposuction material.

    PubMed

    Hager, Gudrun; Holnthoner, Wolfgang; Wolbank, Susanne; Husa, Anna-Maria; Godthardt, Kathrin; Redl, Heinz; Gabriel, Christian

    2013-11-01

    Human endothelial progenitor cells (EPC) play an important role in regenerative medicine and contribute to neovascularization on vessel injury. They are usually enriched from peripheral blood, cord blood and bone marrow. In human fat tissue, EPC are rare and their isolation remains a challenge. Fat tissue was prepared by collagenase digestion, and the expression of specific marker proteins was evaluated by flow cytometry in the stromal vascular fraction (SVF). For enrichment, magnetic cell sorting was performed with the use of CD133 microbeads and EPC were cultured until colonies appeared. A second purification was performed with CD34; additional isolation steps were performed with the use of a combination of CD34 and CD31 microbeads. Enriched cells were investigated by flow cytometry for the expression of endothelial specific markers, by Matrigel assay and by the uptake of acetylated low-density lipoprotein. The expression pattern confirmed the heterogeneous nature of the SVF, with rare numbers of CD133+ detectable. EPC gained from the SVF by magnetic enrichment showed cobblestone morphology of outgrowth endothelial cells and expressed the specific markers CD31, CD144, vascular endothelial growth factor (VEGF)R2, CD146, CD73 and CD105. Functional integrity was confirmed by uptake of acetylated low-density lipoprotein and the formation of tube-like structures on Matrigel. Rare EPC can be enriched from human fat tissue by magnetic cell sorting with the use of a combination of microbeads directed against CD133, an early EPC marker, CD34, a stem cell marker, and CD31, a typical marker for endothelial cells. In culture, they differentiate into EC and hence could have the potential to contribute to neovascularization in regenerative medicine. Copyright © 2013 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  10. Effects of mesenchymal stem cell-derived cytokines on the functional properties of endothelial progenitor cells.

    PubMed

    Kamprom, Witchayaporn; Kheolamai, Pakpoom; U-Pratya, Yaowalak; Supokawej, Aungkura; Wattanapanitch, Methichit; Laowtammathron, Chuti; Issaragrisil, Surapol

    2016-01-01

    Human mesenchymal stem cell (hMSC) is a potential source for cell therapy due to its property to promote tissue repair. Although, it has been known that hMSCs promote tissue repair via angiogenic cytokines, the interaction between hMSC-derived cytokines and the endothelial progenitor cells (EPCs), which play an important role in tissue neovascularization, is poorly characterized. We investigate the effect of cytokine released from different sources of hMSCs including bone marrow and gestational tissues on the EPC functions in vitro. The migration, extracellular matrix invasion and vessel formation of EPCs were studied in the presence or absence of cytokines released from various sources of hMSCs using transwell culture system. The migration of EPCs was highest when co-culture with secretory factors from placenta-derived hMSCs (PL-hMSCs) compared to those co-culture with other sources of hMSCs. For invasion and vessel formation, secretory factors from bone marrow-derived hMSCs (BM-hMSCs) could produce the maximal enhancement compared to other sources. We further identified the secreted cytokines and found that the migratory-enhancing cytokine from PL-hMSCs was PDGF-BB while the enhancing cytokine from BM-hMSCs on invasion was IGF-1. For vessel formation, the cytokines released from BM-hMSCs were IGF1 and SDF-1. In conclusion, hMSCs can release angiogenic cytokines which increase the migration, invasion and vessel forming capacity of EPCs. We can then use hMSCs as a source of angiogenic cytokines to induce neovascularization in injured/ischemic tissues.

  11. Progenitors of Supernovae Type Ia

    NASA Astrophysics Data System (ADS)

    Toonen, S.; Nelemans, G.; Bours, M.; Portegies Zwart, S.; Claeys, J.; Mennekens, N.; Ruiter, A.

    2013-01-01

    Despite the significance of Type Ia supernovae (SNeIa) in many fields in astrophysics, SNeIa lack a theoretical explanation. The standard scenarios involve thermonuclear explosions of carbon/oxygen white dwarfs approaching the Chandrasekhar mass; either by accretion from a companion or by a merger of two white dwarfs. We investigate the contribution from both channels to the SNIa rate with the binary population synthesis (BPS) code SeBa in order to constrain binary processes such as the mass retention efficiency of WD accretion and common envelope evolution. We determine the theoretical rates and delay time distribution of SNIa progenitors and in particular study how assumptions affect the predicted rates.

  12. Red supergiants as supernova progenitors

    NASA Astrophysics Data System (ADS)

    Davies, Ben

    2017-09-01

    It is now well-established from pre-explosion imaging that red supergiants (RSGs) are the direct progenitors of Type-IIP supernovae. These images have been used to infer the physical properties of the exploding stars, yielding some surprising results. In particular, the differences between the observed and predicted mass spectrum has provided a challenge to our view of stellar evolutionary theory. However, turning what is typically a small number of pre-explosion photometric points into the physical quantities of stellar luminosity and mass requires a number of assumptions about the spectral appearance of RSGs, as well as their evolution in the last few years of life. Here I will review what we know about RSGs, with a few recent updates on how they look and how their appearance changes as they approach supernova. This article is part of the themed issue 'Bridging the gap: from massive stars to supernovae'.

  13. Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium.

    PubMed

    Tang, Yao Liang; Zhao, Qiang; Zhang, Y Clare; Cheng, Leilei; Liu, Mingya; Shi, Jianhui; Yang, Yin Zeng; Pan, Chuizhen; Ge, Junbo; Phillips, M Ian

    2004-01-15

    Neovascularization induced by vascular endothelial growth factor (VEGF) represents an appealing approach for treating ischemic heart disease. However, VEGF therapy has been associated with transient therapeutic effects and potential risk for hemangioma growth. Adult mesenchymal stem cells (MSCs) derived from bone marrow are a promising source for tissue regeneration and repair. In order to achieve a safe and persistent angiogenic effect, we have explored the potential of autologous MSCs transplantation to enhance angiogenesis and cardiac function of ischemic hearts. One week after myocardial infarction induced by occlusion of left anterior descending artery, autologous MSCs expanded in vitro was administrated intramyocardially into the infarct area of the same donor rats. By 2 months, MSCs implantation significantly elevated VEGF expression levels, accompanied by increased vascular density and regional blood flow in the infarct zone. The neovascularization resulted in a decreased apoptosis of hypertrophied myocytes and markedly improved the left ventricular contractility (ejection fraction: 79.9+/-7.6% vs. 37.2+/-6.9% in control animals). Therefore, mechanisms underlying MSCs improvement of cardiac functions may involve neovascularization induced by differentiation of MSCs to endothelial cells and para-secretion of growth factors, in addition to the apoptosis reduction and previously reported cardiomyocytes regeneration. Two months after cell transplantation, there are significant improvement of left ventricular function. Hence, autologous MSCs transplantation may represent a promising therapeutic strategy free of ethical concerns and immune rejection, for neovascularization in ischemic heart diseases.

  14. Bevacizumab in choroidal neovascularization secondary to Indian tick typhus: A rare case report

    PubMed Central

    Ijeri, Raghavendra; Beladiya, Gautam; Bhomaj, Sharad

    2016-01-01

    Tick typhus causes hemorrhagic lesions over the skin. Retina also shows hemorrhages and exudates. Many cases have been reported in western literature about this condition. To our best of knowledge, this is the first case report of tick typhus in India which was also associated with inflammatory choroidal neovascularization. PMID:27905346

  15. Long-Term Retinal PEDF Overexpression Prevents Neovascularization in a Murine Adult Model of Retinopathy

    PubMed Central

    Ribera, Albert; Bosch, Assumpcio; Ramos, David; Ruberte, Jesus; Bosch, Fatima

    2012-01-01

    Neovascularization associated with diabetic retinopathy (DR) and other ocular disorders is a leading cause of visual impairment and adult-onset blindness. Currently available treatments are merely palliative and offer temporary solutions. Here, we tested the efficacy of antiangiogenic gene transfer in an animal model that mimics the chronic progression of human DR. Adeno-associated viral (AAV) vectors of serotype 2 coding for antiangiogenic Pigment Epithelium Derived Factor (PEDF) were injected in the vitreous of a 1.5 month-old transgenic model of retinopathy that develops progressive neovascularization. A single intravitreal injection led to long-term production of PEDF and to a striking inhibition of intravitreal neovascularization, normalization of retinal capillary density, and prevention of retinal detachment. This was parallel to a reduction in the intraocular levels of Vascular Endothelial Growth Factor (VEGF). Normalization of VEGF was consistent with a downregulation of downstream effectors of angiogenesis, such as the activity of Matrix Metalloproteinases (MMP) 2 and 9 and the content of Connective Tissue Growth Factor (CTGF). These results demonstrate long-term efficacy of AAV-mediated PEDF overexpression in counteracting retinal neovascularization in a relevant animal model, and provides evidence towards the use of this strategy to treat angiogenesis in DR and other chronic proliferative retinal disorders. PMID:22911805

  16. Evaluation of 10 AMD Associated Polymorphisms as a Cause of Choroidal Neovascularization in Highly Myopic Eyes

    PubMed Central

    Anter, Jaouad; Bezunartea, Jaione; Hernandez-Sanchez, Maria; García-García, Laura; Alonso, Elena; Ruiz-Moreno, Jose María; Araiz-Iribarren, Javier; Fernandez-Robredo, Patricia; García-Layana, Alfredo

    2016-01-01

    Choroidal neovascularization (CNV) commonly occurs in age related macular degeneration and pathological myopia patients. In this study we conducted a case-control prospective study including 431 participants. The aim of this study was to determine the potential association between 10 single nucleotide polymorphisms (SNPs) located in 4 different genetic regions (CFI, COL8A1, LIPC, and APOE), and choroidal neovascularization in age-related macular degeneration and the development of choroidal neovascularization in highly myopic eyes of a Caucasian population. Univariate and multivariate logistic regression analysis adjusted for age, sex and hypertension was performed for each allele, genotype and haplotype frequency analysis. We found that in the univariate analysis that both single-nucleotide polymorphisms in COL8A1 gene (rs13095226 and rs669676) together with age, sex and hypertension were significantly associated with myopic CNV development in Spanish patients (p<0.05). After correcting for multiple testing none of the polymorphisms studied remained significantly associated with myopic CNV (p>0.05); however, analysis of the axial length between genotypes of rs13095226 revealed an important influence of COL8A1 in the development of CNV in high myopia. Furthermore we conducted a meta-analysis of COL8A1, CFI and LIPC genes SNPs (rs669676, rs10033900 and rs10468017) and found that only rs669676 of these SNPs were associated with high myopia neovascularization. PMID:27643879

  17. Reactive oxygen species regulate osteopontin expression in a murine model of postischemic neovascularization.

    PubMed

    Lyle, Alicia N; Joseph, Giji; Fan, Aaron E; Weiss, Daiana; Landázuri, Natalia; Taylor, W Robert

    2012-06-01

    Previous findings from our laboratory demonstrated that neovascularization was impaired in osteopontin (OPN) knockout animals. However, the mechanisms responsible for the regulation of OPN expression in the setting of ischemia remain undefined. Therefore, we sought to determine whether OPN is upregulated in response to ischemia and hypothesized that hydrogen peroxide (H(2)O(2)) is a critical component of the signaling mechanism by which OPN expression is upregulated in response to ischemia in vivo. To determine whether ischemic injury upregulates OPN, we used a murine model of hindlimb ischemia. Femoral artery ligation in C57BL/6 mice significantly increased OPN expression and H(2)O(2) production. Infusion of C57BL/6 mice with polyethylene glycol-catalase (10 000 U/kg per day) or the use of transgenic mice with smooth muscle cell-specific catalase overexpression blunted ischemia-induced OPN, suggesting ischemia-induced OPN expression is H(2)O(2)-dependent. Decreased H(2)O(2)-mediated OPN blunted reperfusion and collateral formation in vivo. In contrast, the overexpression of OPN using lentivirus restored neovascularization. Scavenging H(2)O(2) blocks ischemia-induced OPN expression, providing evidence that ischemia-induced OPN expression is H(2)O(2) dependent. Decreased OPN expression impaired neovascularization, whereas overexpression of OPN increased angiogenesis, supporting our hypothesis that OPN is a critical mediator of postischemic neovascularization and a potential novel therapeutic target for inducing new vessel growth.

  18. Ischemia-Reperfusion Induced Neovascularization in the Cerebral Cortex of the Ovine Fetus

    PubMed Central

    Virgintino, Daniela; Girolamo, Francesco; Rizzi, Marco; Ahmedli, Nigar; Sadowska, Grazyna B.; Stopa, Edward G.; Zhang, Jiyong; Stonestreet, Barbara S.

    2014-01-01

    Information is limited regarding the effects of injury on neovascularization in the immature brain. We investigated effects of ischemia on cerebral cortical neovascularization after exposure of fetuses to 30 minutes of cerebral ischemia and 48- (I/R-48) or 72- (I/R-72) hours of reperfusion or sham-control treatment (Non-I/R). Immunohistochemical and morphometric analyses of cerebral cortical sections included immunostaining for glial fibrillary acidic protein and collagen type IV (Coll IV), a molecular component of the vascular basal lamina, to determine the glial-vascular network in fetal brains, and Ki67 as a proliferation marker. Cerebral cortices from I/R-48 and I/R-72 fetuses exhibited general responses to ischemia, including reactive astrocyte morphology, which was not observed in Non-I/R fetuses. Cell bodies of reactive, proliferating astrocytes along with large end-feet surrounded walls of cerebral cortical microvessels in addition to the thick Coll IV-enriched basal lamina. Morphometric analysis of Non-I/R with I/R-48 and I/R-72 groups revealed increased Coll IV density in I/R-72 cerebral cortical microvessels (p < 0.01), which also frequently displayed a sprouting appearance, characterized by growing tip cells and activated pericytes. Increases in cerebral cortical basic fibroblast growth factor were associated with neovascularization. We conclude that increased neovascularization occurs within 72 hours after ischemia in fetal cerebral cortices. PMID:24806298

  19. Calpain inhibitors reduce retinal hypoxia in ischemic retinopathy by improving neovascular architecture and functional perfusion.

    PubMed

    Hoang, Mien V; Smith, Lois E H; Senger, Donald R

    2011-04-01

    In ischemic retinopathies, underlying hypoxia drives abnormal neovascularization that damages retina and causes blindness. The abnormal neovasculature is tortuous and leaky and fails to alleviate hypoxia, resulting in more pathological neovascularization and retinal damage. With an established model of ischemic retinopathy we found that calpain inhibitors, when administered in moderation, reduced architectural abnormalities, reduced vascular leakage, and most importantly reduced retinal hypoxia. Mechanistically, these calpain inhibitors improved stability and organization of the actin cytoskeleton in retinal endothelial cells undergoing capillary morphogenesis in vitro, and they similarly improved organization of actin cables within new blood vessels in vivo. Hypoxia induced calpain activity in retinal endothelial cells and severely disrupted the actin cytoskeleton, whereas calpain inhibitors preserved actin cables under hypoxic conditions. Collectively, these findings support the hypothesis that hyper-activation of calpains by hypoxia contributes to disruption of the retinal endothelial cell cytoskeleton, resulting in formation of neovessels that are defective both architecturally and functionally. Modest suppression of calpain activity with calpain inhibitors restores cytoskeletal architecture and promotes formation of a functional neovasculature, thereby reducing underlying hypoxia. In sharp contrast to "anti-angiogenesis" strategies that cannot restore normoxia and may aggravate hypoxia, the therapeutic strategy described here does not inhibit neovascularization. Instead, by improving the function of neovascularization to reduce underlying hypoxia, moderate calpain inhibition offers a method for alleviating retinal ischemia, thereby suggesting a new treatment paradigm based on improvement rather than inhibition of new blood vessel growth.

  20. Retinal Neovascularization Secondary to Proliferative Diabetic Retinopathy Characterized by Spectral Domain Optical Coherence Tomography

    PubMed Central

    Cho, Hyung; Alwassia, Ahmad A.; Regiatieri, Caio V.; Zhang, Jason Y.; Baumal, Caroline; Waheed, Nadia; Duker, Jay S.

    2014-01-01

    Purpose To characterize diabetic retinal neovascularization and accompanying retinal and vitreal morphological changes using high-resolution spectral domain optical coherence tomography (SD-OCT). Methods A cross-sectional retrospective analysis was performed on 16 eyes of 14 nonconsecutive subjects with proliferative diabetic retinopathy that were seen between August 2011 and December 2011 at the New England Eye Center, Boston, Massachusetts. Patients who had neovascularization of the disc (NVD), neovascularization elsewhere (NVE) and intraretinal microvascular abnormalities (IRMAs) were scanned using OCT scans directly over the region of the abnormal vessels. Results Characteristic changes of the retinal vasculature, retina and vitreous were seen in the 16 eyes with neovascularization. This study describes OCT characteristics of: 1) NVD; 2) NVE; 3) IRMA; 4) NV causing traction without retinal detachment; 5) NV causing traction with retinal detachment. The morphologic appearance of vitreous traction was found to be consistent with previous histological reports. Conclusions It is possible to image diabetic NV using SD-OCT and to visualize the spectrum of retinal, retinal vascular and vitreal changes seen through these areas of abnormal retinal vasculature. PMID:23400083

  1. Neovascularization in the pulmonary endothelium is regulated by the endosome: Rab4-mediated trafficking and p18-dependent signaling

    PubMed Central

    Braza, Julie; Duong, Huetran; Stark, Myranda; Harrington, Elizabeth O.

    2015-01-01

    Neovascularization, the formation of new blood vessels, requires multiple processes including vascular leak, migration, and adhesion. Endosomal proteins, such as Rabs, regulate trafficking of key signaling proteins involved in neovascularization. The novel endosome protein, p18, enhances vascular endothelial (VE)-cadherin recycling from early endosome to cell junction to improve pulmonary endothelial barrier function. Since endothelial barrier integrity is vital in neovascularization, we sought to elucidate the role for endosome proteins p18 and Rab4, Rab7, and Rab9 in the process of vessel formation within the pulmonary vasculature. Overexpression of wild-type p18 (p18wt), but not the nonendosomal-binding mutant (p18N39), significantly increased lung microvascular endothelial cell migration, adhesion, and both in vitro and in vivo tube formation. Chemical inhibition of mTOR or p38 attenuated the proneovascularization role of p18wt. Similar to the effect of p18wt, overexpression of prorecycling wild-type (Rab4WT) and endosome-anchored (Rab4Q67L) Rab4 enhanced neovascularization processes, whereas molecular inhibition of Rab4, by using the nonendosomal-binding mutant (Rab4S22N) attenuated VEGF-induced neovascularization. Unlike p18, Rab4-induced neovascularization was independent of mTOR or p38 inhibition but was dependent on p18 expression. This study shows for the first time that neovascularization within the pulmonary vasculature is dependent on the prorecycling endocytic proteins Rab4 and p18. PMID:26254426

  2. Diagnostic evaluation of type 2 (classic) choroidal neovascularization: optical coherence tomography, indocyanine green angiography, and fluorescein angiography.

    PubMed

    Sulzbacher, Florian; Kiss, Christopher; Munk, Marion; Deak, Gabor; Sacu, Stefan; Schmidt-Erfurth, Ursula

    2011-11-01

    To evaluate the diagnostic characteristics of type 2 (classic) choroidal neovascularizations secondary to age-related macular degeneration using spectral domain-optical coherence tomography (SD OCT), indocyanine green angiography (ICGA), and fluorescein angiography (FA). Observational case series. Institutional. Thirteen treatment-naïve eyes with type 2 choroidal neovascularization without an occult component. Greatest horizontal dimension, based on the anatomic features of the neovascular complex by SD OCT (Spectralis; Heidelberg Engineering), ICGA, and FA; retinal leakage area in late-phase FA and ICGA; and the area of retinal edema in SD OCT. For direct comparison, ICGA and FA images were overlaid manually on infrared plus SD OCT images using VirtualDub and Paint.NET software. Greatest horizontal dimension was measured using Image J software (National Institutes of Health). The mean greatest horizontal dimension of the neovascular complex and the retinal leakage area consistently were smaller on ICGA compared with the area of retinal edema on SD OCT. According to FA, the greatest horizontal dimension of early, well-demarcated hyperfluorescence was significantly smaller than the neovascular complex on SD OCT. In addition, the greatest horizontal dimension of the retinal leakage area in late-phase FA consistently was smaller than the area of retinal edema on SD OCT. In classic choroidal neovascularization, ICGA and FA seem to underestimate the extension of the neovascular complex and the associated retinal pathologic features compared with SD OCT imaging. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. The interface between glial progenitors and gliomas

    PubMed Central

    Canoll, Peter

    2009-01-01

    The mammalian brain and spinal cord contain heterogeneous populations of cycling, immature cells. These include cells with stem cell-like properties as well as progenitors in various stages of early glial differentiation. This latter population is distributed widely throughout gray and white matter and numerically represents an extremely large cell pool. In this review, we discuss the possibility that the glial progenitors that populate the adult CNS are one source of gliomas. Indeed, the marker phenotypes, morphologies, and migratory properties of cells in gliomas strongly resemble glial progenitors in many ways. We review briefly some salient features of normal glial development and then examine the similarities and differences between normal progenitors and cells in gliomas, focusing on the phenotypic plasticity of glial progenitors and the responses to growth factors in promoting proliferation and migration of normal and glioma cells, and discussing known mutational changes in gliomas in the context of how these might affect the proliferative and migratory behaviors of progenitors. Finally, we will discuss the “cancer stem cell” hypothesis in light of the possibility that glial progenitors can generate gliomas. PMID:18784926

  4. Prorenin receptor is critical for nephron progenitors

    PubMed Central

    Song, Renfang; Preston, Graeme; Kidd, Laura; Bushnell, Daniel; Sims-Lucas, Sunder; Bates, Carlton M.; Yosypiv, Ihor V.

    2016-01-01

    Deficient nephrogenesis is the major factor contributing to renal hypoplasia defined as abnormally small kidneys. Nephron induction during kidney development is driven by reciprocal interactions between progenitor cells of the cap mesenchyme (CM) and the ureteric bud (UB). The prorenin receptor (PRR) is a receptor for renin and prorenin, and an accessory subunit of the vacuolar proton pump H+-ATPase. Global loss of PRR is lethal in mice and PRR mutations are associated with a high blood pressure, left ventricular hypertrophy and X-linked mental retardation in humans. To circumvent lethality of the ubiquitous PRR mutation in mice and to determine the potential role of the PRR in nephrogenesis, we generated a mouse model with a conditional deletion of the PRR in Six2+ nephron progenitors and their epithelial derivatives (Six2PRR−/−). Targeted ablation of PRR in Six2+ nephron progenitors caused a marked decrease in the number of developing nephrons, small cystic kidneys and podocyte foot process effacement at birth, and early postnatal death. Reduced congenital nephron endowment resulted from premature depletion of nephron progenitor cell population due to impaired progenitor cell proliferation and loss of normal molecular inductive response to canonical Wnt/β-catenin signaling within the metanephric mesenchyme. At 2 months of age, heterozygous Six2PRR+/− mice exhibited focal glomerulosclerosis, decreased kidney function and massive proteinuria. Collectively, these findings demonstrate a cell-autonomous requirement for the PRR within nephron progenitors for progenitor maintenance, progression of nephrogenesis, normal kidney development and function. PMID:26658320

  5. Breaking barriers: insight into the pathogenesis of neovascular age-related macular degeneration

    PubMed Central

    Wang, Haibo; Wittchen, Erika S; Hartnett, M Elizabeth

    2011-01-01

    Neovascular age-related macular degeneration (AMD) is a leading cause of central visual acuity loss in a growing segment of the population, those over the age of 60 years. Treatment has improved over the last decade, with the availability of agents that inhibit the bioactivity of vascular endothelial growth factor (VEGF), but it is still limited, because of tachyphylaxis and potential risk and toxicity of anti-VEGF agents. The authors have sought to understand the mechanisms of choroidal endothelial cell (CEC) activation and transmigration of the retinal pigment epithelium (RPE) and of RPE barrier dysfunction, events preceding vision-threatening neovascular AMD. The authors developed physiologically relevant human RPE and CEC coculture and transmigration models that have been important in helping to understand causes of events in human neovascular AMD. The authors can control for interactions between these cells and can separately assess activation of signaling pathways in each cell type relevant during CEC transmigration. Using these models, it was found that VEGF, particularly the cell-associated VEGF splice variant VEGF189, accounts for about 40% of CEC transmigration across the RPE. This percentage is in the range of similar reports following clinical inhibition of VEGF in neovascular AMD. RPE VEGF189 working through CEC VEGF receptor 2 activates the small guanosine triphosphatase (GTPase) of the Rho family, Rac1, in CECs, which in turn facilitates CEC transmigration. Conversely, inhibition of Rac1 activity prevents CEC transmigration. Once activated, Rac1 aggregates with subunits of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, resulting in the generation of reactive oxygen species. Activated NADPH oxidase increases choroidal neovascularization in animal models of laser-induced injury. Rac1 is also downstream of the eotaxin-CCR3 pathway, another pathway important in human neovascular AMD. Studies also suggest that active Ras-related protein 1

  6. Honokiol inhibits pathological retinal neovascularization in oxygen-induced retinopathy mouse model

    SciTech Connect

    Vavilala, Divya Teja; O’Bryhim, Bliss E.; Ponnaluri, V.K. Chaithanya; White, R. Sid; Radel, Jeff; Symons, R.C. Andrew; Mukherji, Mridul

    2013-09-06

    Highlights: •Aberrant activation of HIF pathway is the underlying cause of ischemic neovascularization. •Honokiol has better therapeutic index as a HIF inhibitor than digoxin and doxorubicin. •Daily IP injection of honokiol in OIR mouse model reduced retinal neovascularization. •Honokiol also prevents vaso-obliteration, the characteristic feature of the OIR model. •Honokiol enhanced physiological revascularization of the retinal vascular plexuses. -- Abstract: Aberrant activation of the hypoxia inducible factor (HIF) pathway is the underlying cause of retinal neovascularization, one of the most common causes of blindness worldwide. The HIF pathway also plays critical roles during tumor angiogenesis and cancer stem cell transformation. We have recently shown that honokiol is a potent inhibitor of the HIF pathway in a number of cancer and retinal pigment epithelial cell lines. Here we evaluate the safety and efficacy of honokiol, digoxin, and doxorubicin, three recently identified HIF inhibitors from natural sources. Our studies show that honokiol has a better safety to efficacy profile as a HIF inhibitor than digoxin and doxorubicin. Further, we show for the first time that daily intraperitoneal injection of honokiol starting at postnatal day (P) 12 in an oxygen-induced retinopathy (OIR) mouse model significantly reduced retinal neovascularization at P17. Administration of honokiol also prevents the oxygen-induced central retinal vaso-obliteration, characteristic feature of the OIR model. Additionally, honokiol enhanced physiological revascularization of the retinal vascular plexuses. Since honokiol suppresses multiple pathways activated by HIF, in addition to the VEGF signaling, it may provide advantages over current treatments utilizing specific VEGF antagonists for ocular neovascular diseases and cancers.

  7. Anti-angiogenic effect of KR-31831 on corneal and choroidal neovascularization in rat models.

    PubMed

    Kim, In-Tae; Park, Hae-Young Lopilly; Choi, Jun-Sub; Joo, Choun-Ki

    2012-05-31

    We attempt to determine the effect and mechanism of KR-31831 in rat models of corneal neovascularization and choroidal neovascularization (CNV). Corneal neovascularization was induced by silver nitrate cauterization. Balanced salt solution (for control), KR-31831 (0.1 mg/mL), and bevacizumab (10 mg/mL) were applied topically with or without subsequent subconjunctival injection (10 μL). The degree of corneal neovascularization was compared among treatments. The effects of intravitreal (0.1 and 0.3 mg/mL) and intraperitoneal (25 mg/kg) of KR-31831, and intravitreal injection of bevacizumab (2.5 mg/mL) were compared in a laser-induced CNV model. FITC-dextran was used to observe the choroid vessels and to evaluate vessel leakage by fluorescence intensity. In the silver nitrate cauterized rat, topical KR-31831 (P = 0.008) or bevacizumab (P = 0.008) reduced effectively the area of corneal neovascularization compared to control on day 14. This was reduced further by additional subconjunctival injection of KR-31831 (P = 0.024) and bevacizumab (P = 0.016). After KR-31831 application, vascular endothelial growth factor (VEGF) receptor 2 and matrix metalloproteinase (MMP)-2 expression was decreased in the cornea. In the CNV model, intravitreal (0.3 mg/mL) and intraperitoneal KR-31831 inhibited significantly the CNV area (P = 0.008 and P = 0.008, respectively) and fluorescence leakage (P = 0.008 and P = 0.032, respectively). This effect was more significant compared to intravitreal bevacizumab in terms of the CNV area (P = 0.032 and P = 0.008, respectively) and fluorescence leakage (P = 0.016 and P = 0.008, respectively). The anti-angiogenic effect of KR-31831 was comparable in the cornea and more effective in the choroid compared to that of bevacizumab, and it may exert its effect by VEGF signaling and MMP-2.

  8. Cytochrome P450 monooxygenase lipid metabolites are significant second messengers in the resolution of choroidal neovascularization.

    PubMed

    Hasegawa, Eiichi; Inafuku, Saori; Mulki, Lama; Okunuki, Yoko; Yanai, Ryoji; Smith, Kaylee E; Kim, Clifford B; Klokman, Garrett; Bielenberg, Diane R; Puli, Narender; Falck, John R; Husain, Deeba; Miller, Joan W; Edin, Matthew L; Zeldin, Darryl C; Lee, Kin Sing Stephen; Hammock, Bruce D; Schunck, Wolf-Hagen; Connor, Kip M

    2017-09-05

    Age-related macular degeneration (AMD) is the most common cause of blindness for individuals age 50 and above in the developed world. Abnormal growth of choroidal blood vessels, or choroidal neovascularization (CNV), is a hallmark of the neovascular (wet) form of advanced AMD and leads to significant vision loss. A growing body of evidence supports a strong link between neovascular disease and inflammation. Metabolites of long-chain polyunsaturated fatty acids derived from the cytochrome P450 (CYP) monooxygenase pathway serve as vital second messengers that regulate a number of hormones and growth factors involved in inflammation and vascular function. Using transgenic mice with altered CYP lipid biosynthetic pathways in a mouse model of laser-induced CNV, we characterized the role of these lipid metabolites in regulating neovascular disease. We discovered that the CYP-derived lipid metabolites epoxydocosapentaenoic acids (EDPs) and epoxyeicosatetraenoic acids (EEQs) are vital in dampening CNV severity. Specifically, overexpression of the monooxygenase CYP2C8 or genetic ablation or inhibition of the soluble epoxide hydrolase (sEH) enzyme led to increased levels of EDP and EEQ with attenuated CNV development. In contrast, when we promoted the degradation of these CYP-derived metabolites by transgenic overexpression of sEH, the protective effect against CNV was lost. We found that these molecules work in part through their ability to regulate the expression of key leukocyte adhesion molecules, on both leukocytes and endothelial cells, thereby mediating leukocyte recruitment. These results suggest that CYP lipid signaling molecules and their regulators are potential therapeutic targets in neovascular diseases.

  9. Circulating monocytes and B-lymphocytes in neovascular age-related macular degeneration

    PubMed Central

    Hector, Sven Magnus; Sørensen, Torben Lykke

    2017-01-01

    Background Individuals with neovascular age-related macular degeneration (AMD) have altered number and distribution of retinal macrophages and show changes in circulating antibodies. We wanted to investigate the corresponding precursors, with subpopulations. We therefore measured monocyte and B-lymphocyte populations in individuals with neovascular AMD. Design This was an observational case–control study. Participants or samples A total of 31 individuals with neovascular AMD and 30 healthy age-matched controls were included. Methods Patients and controls were interviewed, and ophthalmological examination included visual acuity assessment using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, spectral domain optical coherence tomography (SD-OCT), slit-lamp examination and fundus photography. Moreover, venous blood was drawn and prepared for flow cytometry. Cells were gated and measured for surface markers. Main outcome measures Relative amounts of monocytes and B-lymphocytes with subsets, as well as selected surface markers, were measured. Results The two groups did not significantly differ in age, smoking history, body mass index, physical activity or C-reactive protein (CRP). Total monocytes (percentage of all leukocytes) were lower in the neovascular AMD group (median 5.5%) compared with the level in the control group (6.5%; P-value: 0.028). The percentage of intermediate monocytes positive for cluster of differentiation 11b (CD11b) was lower for AMD patients (99.4%) compared with 100% for the control group (P-value: 0.032). Conclusion We observed lower numbers of monocytes, which show a potentially impaired ability to migrate across the endothelial wall in patients with neovascular AMD. These subtle changes could potentially lead to an imbalance in the recruitment of macrophages into the retina during disease development. PMID:28176950

  10. VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting.

    PubMed

    Oladipupo, Sunday; Hu, Song; Kovalski, Joanna; Yao, Junjie; Santeford, Andrea; Sohn, Rebecca E; Shohet, Ralph; Maslov, Konstantin; Wang, Lihong V; Arbeit, Jeffrey M

    2011-08-09

    Although our understanding of the molecular regulation of adult neovascularization has advanced tremendously, vascular-targeted therapies for tissue ischemia remain suboptimal. The master regulatory transcription factors of the hypoxia-inducible factor (HIF) family are attractive therapeutic targets because they coordinately up-regulate multiple genes controlling neovascularization. Here, we used an inducible model of epithelial HIF-1 activation, the TetON-HIF-1 mouse, to test the requirement for VEGF in HIF-1 mediated neovascularization. TetON-HIF-1, K14-Cre, and VEGF(flox/flox) alleles were combined to create TetON-HIF-1:VEGF(Δ) mice to activate HIF-1 and its target genes in adult basal keratinocytes in the absence of concomitant VEGF. HIF-1 induction failed to produce neovascularization in TetON-HIF-1:VEGF(Δ) mice despite robust up-regulation of multiple proangiogenic HIF targets, including PlGF, adrenomedullin, angiogenin, and PAI-1. In contrast, endothelial sprouting was preserved, enhanced, and more persistent, consistent with marked reduction in Dll4-Notch-1 signaling. Optical-resolution photoacoustic microscopy, which provides noninvasive, label-free, high resolution, and wide-field vascular imaging, revealed the absence of both capillary expansion and arteriovenous remodeling in serially imaged individual TetON-HIF-1:VEGF(Δ) mice. Impaired TetON-HIF-1:VEGF(Δ) neovascularization could be partially rescued by 12-O-tetradecanoylphorbol-13-acetate skin treatment. These data suggest that therapeutic angiogenesis for ischemic cardiovascular disease may require treatment with both HIF-1 and VEGF.

  11. A Hypoxia-Responsive Glial Cell–Specific Gene Therapy Vector for Targeting Retinal Neovascularization

    PubMed Central

    Biswal, Manas R.; Prentice, Howard M.; Dorey, C. Kathleen; Blanks, Janet C.

    2014-01-01

    Purpose. Müller cells, the major glial cell in the retina, play a significant role in retinal neovascularization in response to tissue hypoxia. We previously designed and tested a vector using a hypoxia-responsive domain and a glial fibrillary acidic protein (GFAP) promoter to drive green fluorescent protein (GFP) expression in Müller cells in the murine model of oxygen-induced retinopathy (OIR). This study compares the efficacy of regulated and unregulated Müller cell delivery of endostatin in preventing neovascularization in the OIR model. Methods. Endostatin cDNA was cloned into plasmids with hypoxia-regulated GFAP or unregulated GFAP promoters, and packaged into self-complementary adeno-associated virus serotype 2 vectors (scAAV2). Before placement in hyperoxia on postnatal day (P)7, mice were given intravitreal injections of regulated or unregulated scAAV2, capsid, or PBS. Five days after return to room air, on P17, neovascular and avascular areas, as well as expression of the transgene and vascular endothelial growth factor (VEGF), were compared in OIR animals treated with a vector, capsid, or PBS. Results. The hypoxia-regulated, glial-specific, vector-expressing endostatin reduced neovascularization by 93% and reduced the central vaso-obliteration area by 90%, matching the results with the unregulated GFAP-Endo vector. Retinas treated with the regulated endostatin vector expressed substantial amounts of endostatin protein, and significantly reduced VEGF protein. Endostatin production from the regulated vector was undetectable in retinas with undamaged vasculature. Conclusions. These findings suggest that the hypoxia-regulated, glial cell–specific vector expressing endostatin may be useful for treatment of neovascularization in proliferative diabetic retinopathy. PMID:25377223

  12. OUTER RETINAL TUBULATION: Characteristics in Patients With Neovascular Age-Related Macular Degeneration.

    PubMed

    Iaculli, Cristiana; Barone, Antonio; Scudieri, Marilisa; Giovanna Palumbo, Maria; Delle Noci, Nicola

    2015-10-01

    To assess the incidence, characteristics, best-corrected visual acuity (BCVA), central macular thickness (CMT), and retinal sensitivity correlations in patients with and without outer retinal tubulation (ORT) affected by subfoveal choroidal neovascularization due to neovascular age-related macular degeneration. Prospective case series including 78 eyes of 78 consecutive patients with subfoveal choroidal neovascularization due to neovascular age-related macular degeneration. Baseline and follow-up visits included BCVA, intraocular pressure, ophthalmoscopic examination, CMT as measured by spectral domain optical coherence tomography, and retinal sensitivity tested with fundus-related perimetry (MP-1). Fluorescent angiography was performed at baseline. At the end of the follow-up period, the mean BCVA and CMT of patients with ORT were statistically different from those without ORT (BCVA: 0.61 ± 0.13 vs. 0.37 ± 1.59, P < 0.0001; CMT: 290 ± 26.7 vs. 215.2 ± 33.5 μm; P < 0.0001). Patients with ORT showed a decreased mean retinal sensitivity compared with patients without ORT (6.31 ± 2.5 dB vs. 9.89 ± 5.43 dB; P < 0.0001). The results of this study investigating the BCVA, CMT, and retinal sensitivity detected by MP-1 between patients with and without ORT in neovascular age-related macular degeneration suggest that these parameters are statistically different in patients with ORT; this may be due to the pathogenesis of ORT formation, secondary to retinal pigment epithelial tears or photoreceptor damage. MP-1 microperimeter is a noninvasive instrument that provides useful information to better characterize the functional aspect of ORT in patients with age-related macular degeneration.

  13. Progenitor's Signatures in Type Ia Supernova Remnants

    NASA Astrophysics Data System (ADS)

    Chiotellis, A.; Kosenko, D.; Schure, K. M.; Vink, J.

    2013-01-01

    The remnants of Type Ia supernovae (SNe Ia) can provide important clues about their progenitor histories. We discuss two well-observed supernova remnants (SNRs) that are believed to have resulted from SNe Ia, and use various tools to shed light on the possible progenitor histories. We find that Kepler's SNR is consistent with a symbiotic binary progenitor consisting of a white dwarf and an AGB star. Our hydrosimulations can reproduce the observed kinematic and morphological properties. For Tycho's remnant we use the characteristics of the X-ray spectrum and kinematics to show that the ejecta has likely interacted with dense circumstellar gas.

  14. A genetic analysis of neural progenitor differentiation.

    PubMed

    Geschwind, D H; Ou, J; Easterday, M C; Dougherty, J D; Jackson, R L; Chen, Z; Antoine, H; Terskikh, A; Weissman, I L; Nelson, S F; Kornblum, H I

    2001-02-01

    Genetic mechanisms regulating CNS progenitor function and differentiation are not well understood. We have used microarrays derived from a representational difference analysis (RDA) subtraction in a heterogeneous stem cell culture system to systematically study the gene expression patterns of CNS progenitors. This analysis identified both known and novel genes enriched in progenitor cultures. In situ hybridization in a subset of clones demonstrated that many of these genes were expressed preferentially in germinal zones, some showing distinct ventricular or subventricular zone labeling. Several genes were also enriched in hematopoietic stem cells, suggesting an overlap of gene expression in neural and hematopoietic progenitors. This combination of methods demonstrates the power of using custom microarrays derived from RDA-subtracted libraries for both gene discovery and gene expression analysis in the central nervous system.

  15. Circulating Vascular Progenitor Cells in Moyamoya Disease

    PubMed Central

    Kang, Hyun-Seung; Wang, Kyu-Chang

    2015-01-01

    Various approaches have been attempted in translational moyamoya disease research. One promising material for modeling and treating this disease is vascular progenitor cells, which can be acquired and expanded from patient peripheral blood. These cells may provide a novel experimental model and enable us to obtain insights regarding moyamoya disease pathogenesis. We briefly present the recent accomplishments in regard to the studies of vascular progenitor cells in moyamoya disease. PMID:26180610

  16. Ocular antisense oligonucleotide delivery by cationic nanoemulsion for improved treatment of ocular neovascularization: an in-vivo study in rats and mice.

    PubMed

    Hagigit, Tal; Abdulrazik, Muhammad; Valamanesh, Faty; Behar-Cohen, Francine; Benita, Simon

    2012-06-10

    The efficacy of an antisense oligonucleotide (ODN17) cationic nanoemulsion directed at VEGF-R2 to reduce neovascularization was evaluated using rat corneal neovascularization and retinopathy of prematurity (ROP) mouse models. Application of saline solution or scrambled ODN17 solution on eyes of rats led to the highest extent of corneal neovascularization. The groups treated with blank nanoemulsion or scrambled ODN17 nanoemulsion showed moderate inhibition in corneal neovascularization with no significant difference with the saline and scrambled ODN17 control solution groups, while the groups treated with ODN17 solution or Avastin® (positive ODN17 control) clearly elicited marked significant inhibition in corneal neovascularization confirming the results reported in the literature. The highest significant corneal neovascularization inhibition efficiency was noted in the groups treated with ODN17 nanoemulsion (topical and subconjunctivally). However, in the ROP mouse model, the ODN17 in PBS induced a 34% inhibition of retinal neovascularization when compared to the aqueous-vehicle-injected eyes. A significantly higher inhibition of vitreal neovascularization (64%) was observed in the group of eyes treated with ODN17 nanoemulsion. No difference in extent of neovascularization was observed between blank nanoemulsion, scrambled ODN17 nanoemulsion, vehicle or non-treated eyes. The overall results indicate that cationic nanoemulsion can be considered a promising potential ocular delivery system and an effective therapeutic tool of high clinical significance in the prevention and forthcoming treatment of ocular neovascular diseases. Copyright © 2011 Elsevier B.V. All rights reserved.

  17. Comparison of 2D reconstructions of surgically excised subfoveal choroidal neovascularization with fluorescein angiographic features: SST report No. 15.

    PubMed

    2006-02-01

    To compare topographic features of surgically excised subfoveal choroidal neovascularization with preoperative and postoperative fluorescein angiographic features from Submacular Surgery Trials (SST) patients, and to compare histological and angiographic features with preoperative and postoperative visual acuities (VAs). Patients enrolled in the SST Groups N, B, and H trials between October 1999 and September 2001 and assigned to the surgery arm had surgically removed choroidal neovascularization sent to the SST Pathology Center. Grossly intact specimens were sectioned serially for 2-dimensional reconstruction and were assigned to growth pattern groups based on topographic mapping of the location of cellular components relative to the retinal pigment epithelium (RPE): sub-RPE, subretinal, combined, or indeterminate. These features were compared with preoperative fluorescein angiographic features. The histological choroidal neovascularization growth pattern was compared with preoperative VAs. Two-dimensional reconstructions of surgically excised choroidal neovascularization could not be matched point for point to fluorescein angiographic features. Among the 52 specimens selected, the growth pattern could be determined by 2-dimensional reconstruction in 34 instances (65%), including 28 (80%) of 35 Group N specimens, 2 (40%) of 5 Group B specimens, and 4 (33%) of 12 Group H specimens. Among the choroidal neovascularization growth patterns that could be determined from specimens submitted, the majority of Group N specimens were combined, and the majority of Group H specimens were subretinal. In most instances for Group B specimens, the growth pattern was indeterminate. The postoperative abnormalities on fluorescein angiography were generally larger than measurements of excised specimens. The subretinal growth pattern was associated with the smallest decrease in 3-month postoperative average VA. Among the 52 specimens from the SST with adequate tissue to try to evaluate

  18. Interactions between endothelial progenitor cells (EPC) and titanium implant surfaces.

    PubMed

    Ziebart, Thomas; Schnell, Anne; Walter, Christian; Kämmerer, Peer W; Pabst, Andreas; Lehmann, Karl M; Ziebart, Johanna; Klein, Marc O; Al-Nawas, Bilal

    2013-01-01

    Endothelial cells play an important role in peri-implant angiogenesis during early bone formation. Therefore, interactions between endothelial progenitor cells (EPCs) and titanium dental implant surfaces are of crucial interest. The aim of our in vitro study was to investigate the reactions of EPCs in contact with different commercially available implant surfaces. EPCs from buffy coats were isolated by Ficoll density gradient separation. After cell differentiation, EPC were cultured for a period of 7 days on different titanium surfaces. The test surfaces varied in roughness and hydrophilicity: acid-etched (A), sand-blasted-blasted and acid-etched (SLA), hydrophilic A (modA), and hydrophilic SLA (modSLA). Plastic and fibronectin-coated plastic surfaces served as controls. Cell numbers and morphology were analyzed by confocal laser scanning microscopy. Secretion of vascular endothelial growth factor (VEGF)-A was measured by enzyme-linked immunosorbent assay and expressions of iNOS and eNOS were investigated by real-time polymerase chain reaction. Cell numbers were higher in the control groups compared to the cells of titanium surfaces. Initially, hydrophilic titanium surfaces (modA and modSLA) showed lower cell numbers than hydrophobic surfaces (A and SLA). After 7 days smoother surfaces (A and modA) showed increased cell numbers compared to rougher surfaces (SLA and modSLA). Cell morphology of A, modA, and control surfaces was characterized by a multitude of pseudopodia and planar cell soma architecture. SLA and modSLA promoted small and plump cell soma with little quantity of pseudopodia. The lowest VEGF level was measured on A, the highest on modSLA. The highest eNOS and iNOS expressions were found on modA surfaces. The results of this study demonstrate that biological behaviors of EPCs can be influenced by different surfaces. The modSLA surface promotes an undifferentiated phenotype of EPCs that has the ability to secrete growth factors in great quantities. In

  19. Defining response to anti-VEGF therapies in neovascular AMD.

    PubMed

    Amoaku, W M; Chakravarthy, U; Gale, R; Gavin, M; Ghanchi, F; Gibson, J; Harding, S; Johnston, R L; Kelly, S P; Kelly, S; Lotery, A; Mahmood, S; Menon, G; Sivaprasad, S; Talks, J; Tufail, A; Yang, Y

    2015-06-01

    The introduction of anti-vascular endothelial growth factor (anti-VEGF) has made significant impact on the reduction of the visual loss due to neovascular age-related macular degeneration (n-AMD). There are significant inter-individual differences in response to an anti-VEGF agent, made more complex by the availability of multiple anti-VEGF agents with different molecular configurations. The response to anti-VEGF therapy have been found to be dependent on a variety of factors including patient's age, lesion characteristics, lesion duration, baseline visual acuity (VA) and the presence of particular genotype risk alleles. Furthermore, a proportion of eyes with n-AMD show a decline in acuity or morphology, despite therapy or require very frequent re-treatment. There is currently no consensus as to how to classify optimal response, or lack of it, with these therapies. There is, in particular, confusion over terms such as 'responder status' after treatment for n-AMD, 'tachyphylaxis' and 'recalcitrant' n-AMD. This document aims to provide a consensus on definition/categorisation of the response of n-AMD to anti-VEGF therapies and on the time points at which response to treatment should be determined. Primary response is best determined at 1 month following the last initiation dose, while maintained treatment (secondary) response is determined any time after the 4th visit. In a particular eye, secondary responses do not mirror and cannot be predicted from that in the primary phase. Morphological and functional responses to anti-VEGF treatments, do not necessarily correlate, and may be dissociated in an individual eye. Furthermore, there is a ceiling effect that can negate the currently used functional metrics such as >5 letters improvement when the baseline VA is good (ETDRS>70 letters). It is therefore important to use a combination of both the parameters in determining the response.The following are proposed definitions: optimal (good) response is defined as when there

  20. Strategy to Prime the Host and Cells to Augment Therapeutic Efficacy of Progenitor Cells for Patients with Myocardial Infarction

    PubMed Central

    Kang, Jeehoon; Kim, Tae-Won; Hur, Jin; Kim, Hyo-Soo

    2016-01-01

    Cell therapy in myocardial infarction (MI) is an innovative strategy that is regarded as a rescue therapy to repair the damaged myocardium and to promote neovascularization for the ischemic border zone. Among several stem cell sources for this purpose, autologous progenitors from bone marrow or peripheral blood would be the most feasible and safest cell-source. Despite the theoretical benefit of cell therapy, this method is not widely adopted in the actual clinical practice due to its low therapeutic efficacy. Various methods have been used to augment the efficacy of cell therapy in MI, such as using different source of progenitors, genetic manipulation of cells, or priming of the cells or hosts (patients) with agents. Among these methods, the strategy to augment the therapeutic efficacy of the autologous peripheral blood mononuclear cells (PBMCs) by priming agents may be the most feasible and the safest method that can be applied directly to the clinic. In this review, we will discuss the current status and future directions of priming PBMCs or patients, as for cell therapy of MI. PMID:27933299

  1. Prorenin receptor is critical for nephron progenitors.

    PubMed

    Song, Renfang; Preston, Graeme; Kidd, Laura; Bushnell, Daniel; Sims-Lucas, Sunder; Bates, Carlton M; Yosypiv, Ihor V

    2016-01-15

    Deficient nephrogenesis is the major factor contributing to renal hypoplasia defined as abnormally small kidneys. Nephron induction during kidney development is driven by reciprocal interactions between progenitor cells of the cap mesenchyme (CM) and the ureteric bud (UB). The prorenin receptor (PRR) is a receptor for renin and prorenin, and an accessory subunit of the vacuolar proton pump H(+)-ATPase. Global loss of PRR is lethal in mice and PRR mutations are associated with a high blood pressure, left ventricular hypertrophy and X-linked mental retardation in humans. To circumvent lethality of the ubiquitous PRR mutation in mice and to determine the potential role of the PRR in nephrogenesis, we generated a mouse model with a conditional deletion of the PRR in Six2(+) nephron progenitors and their epithelial derivatives (Six2(PRR-/-)). Targeted ablation of PRR in Six2(+) nephron progenitors caused a marked decrease in the number of developing nephrons, small cystic kidneys and podocyte foot process effacement at birth, and early postnatal death. Reduced congenital nephron endowment resulted from premature depletion of nephron progenitor cell population due to impaired progenitor cell proliferation and loss of normal molecular inductive response to canonical Wnt/β-catenin signaling within the metanephric mesenchyme. At 2 months of age, heterozygous Six2(PRR+/-) mice exhibited focal glomerulosclerosis, decreased kidney function and massive proteinuria. Collectively, these findings demonstrate a cell-autonomous requirement for the PRR within nephron progenitors for progenitor maintenance, progression of nephrogenesis, normal kidney development and function. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Juxtapapillary neovascular membrane secondary to idiopathic intracranial hypertension treated with intravitreal bevacizumab: A case report.

    PubMed

    Hernández-Ortega, V; Soler-Sanchís, M I; Jiménez-Escribano, R M; Sanz-López, A M

    2016-05-01

    A 48 year-old woman with visual acuity loss in left eye (0.3). Funduscopic examination showed papillary oedema and neovascular membrane in the left eye. All neurological tests were normal, except the lumbar puncture with opening pressure of 35cmH2O, being diagnosed with idiopathic intracranial hypertension (IIH). After four doses of bevacizumab, the visual acuity of the left eye has not improved and is counting fingers. Pathogenesis of the juxtapapillary neovascular membrane associated with IIH is not well known. An effect was observed after the anti-VEGF treatment. In our case, there was no improvement after four doses of intravitreal bevacizumab. Copyright © 2016 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

  3. [Intravitreal ranibizumab in the treatment of subretinal neovascularization in a case of punctate inner choroidopathy].

    PubMed

    Jiménez, B; Pinilla, I; Cristóbal, J A; Mínguez, E; Pérez, D; Cruz, N; Peiro, C

    2014-03-01

    We report the case of a 28-year old woman suffering loss of visual acuity in her left eye, who presented an image suggestive of a subretinal neovascular membrane in her left eye, and bilateral retinal lesions compatible with punctate inner choroidopathy (PIC). She was treated with intravitreal ranibizumab obtaining excellent results. The differential diagnosis must be made between PIC and the rest of "white dot syndromes" and the presumed ocular histoplasmosis syndrome (POHS). Antiangiogenic drugs may be a good alternative for the treatment of such diseases when they develop a subretinal neovascular membrane. Copyright © 2011 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

  4. Neural Progenitors Adopt Specific Identities by Directly Repressing All Alternative Progenitor Transcriptional Programs.

    PubMed

    Kutejova, Eva; Sasai, Noriaki; Shah, Ankita; Gouti, Mina; Briscoe, James

    2016-03-21

    In the vertebrate neural tube, a morphogen-induced transcriptional network produces multiple molecularly distinct progenitor domains, each generating different neuronal subtypes. Using an in vitro differentiation system, we defined gene expression signatures of distinct progenitor populations and identified direct gene-regulatory inputs corresponding to locations of specific transcription factor binding. Combined with targeted perturbations of the network, this revealed a mechanism in which a progenitor identity is installed by active repression of the entire transcriptional programs of other neural progenitor fates. In the ventral neural tube, sonic hedgehog (Shh) signaling, together with broadly expressed transcriptional activators, concurrently activates the gene expression programs of several domains. The specific outcome is selected by repressive input provided by Shh-induced transcription factors that act as the key nodes in the network, enabling progenitors to adopt a single definitive identity from several initially permitted options. Together, the data suggest design principles relevant to many developing tissues.

  5. Suppression of T cell-induced osteoclast formation

    SciTech Connect

    Karieb, Sahar; Fox, Simon W.

    2013-07-12

    Highlights: •Genistein and coumestrol prevent activated T cell induced osteoclast formation. •Anti-TNF neutralising antibodies prevent the pro-osteoclastic effect of activated T cells. •Phytoestrogens inhibit T cell derived TNF alpha and inflammatory cytokine production. •Phytoestrogens have a broader range of anti-osteoclastic actions than other anti-resorptives. -- Abstract: Inhibition of T cell derived cytokine production could help suppress osteoclast differentiation in inflammatory skeletal disorders. Bisphosphonates are typically prescribed to prevent inflammatory bone loss but are not tolerated by all patients and are associated with an increased risk of osteonecrosis of the jaw. In light of this other anti-resorptives such as phytoestrogens are being considered. However the effect of phytoestrogens on T cell-induced osteoclast formation is unclear. The effect of genistein and coumestrol on activated T cell-induced osteoclastogenesis and cytokine production was therefore examined. Concentrations of genistein and coumestrol (10{sup −7} M) previously shown to directly inhibit osteoclast formation also suppressed the formation of TRAP positive osteoclast induced by con A activated T cells, which was dependent on inhibition of T cell derived TNF-α. While both reduced osteoclast formation their mechanism of action differed. The anti-osteoclastic effect of coumestrol was associated with a dual effect on con A induced T cell proliferation and activation; 10{sup −7} M coumestrol significantly reducing T cell number (0.36) and TNF-α (0.47), IL-1β (0.23) and IL-6 (0.35) expression, whereas genistein (10{sup −7} M) had no effect on T cell number but a more pronounced effect on T cell differentiation reducing expression of TNF-α (0.49), IL-1β (0.52), IL-6 (0.71) and RANKL (0.71). Phytoestrogens therefore prevent the pro-osteoclastic action of T cells suggesting they may have a role in the control of inflammatory bone loss.

  6. Inhibitory effect of Samul-tang on retinal neovascularization in oxygen-induced retinopathy.

    PubMed

    Lee, Yun Mi; Kim, Chan-Sik; Jo, Kyuhyung; Sohn, Eun Jin; Kim, Jin Sook; Kim, Junghyun

    2015-08-12

    Retinal neovascularization is a common cause of vision loss in proliferative diabetic retinopathy, retinopathy of prematurity and age-related macular degeneration. Samul-tang (SMT) is a widely used traditional herbal medicine in East Asia and is also known as Shimotsu-to in Japanese and Si-Wu decoction in Chinese. This study was designed to evaluate the inhibitory effect of SMT on retinal pathogenic angiogenesis in a mouse model of oxygen-induced retinopathy (OIR). The mice were exposed to a 75% concentration of oxygen for five days, starting on postnatal day 7 (P7-P12). The mice were then exposed to room air and were intraperitoneally injected with SMT (10 mg/kg or 50 mg/kg) once per day for five days (P12-P16). On P17, we measured retinal neovascularization and evaluated both the expression of angiogenesis-related proteins and changes in the gene expression level in the mRNA. SMT reduced the area of the central retina and reduced retinal neovascularization in OIR mice. The protein array revealed that SMT reduced the level of SDF-1 protein expression. Quantitative real-time PCR revealed that the HIF-1α, SDF-1, CXCR4 and VEGF mRNA levels in the retinas of OIR mice were elevated compared with those of normal control mice. However, SMT decreased the levels of HIF-1α, SDF-1, CXCR4 and VEGF mRNA in OIR mice. We are the first to elucidate that SMT inhibits the retinal pathogenic angiogenesis induced by ischemic retinopathy in OIR mice. SMT significantly inhibited retinal neovascularization by downregulating HIF-1α, SDF-1, CXCR4 and VEGF. Based on the results of our study, SMT could be a useful herbal medicine for treating ischemic retinopathy.

  7. Endogenous neurogenesis and neovascularization in the neocortex of the rat after focal cerebral ischemia.

    PubMed

    Shin, Hye Young; Kim, Jin Hyun; Phi, Ji Hoon; Park, Chul-Kee; Kim, Jung Eun; Kim, Jong-Hoon; Paek, Sun Ha; Wang, Kyu-Chang; Kim, Dong Gyu

    2008-02-01

    The present study was designed to examine whether endogenous neurogenesis and neovascularization occur in the neocortex of the ischemic rat brain after unilateral middle cerebral artery occlusion (MCAO). Sprague-Dawley rats were divided into six groups (n = 29): one control group (n = 4) and five groups composed of animals sacrificed at increasing times post-MCAO (2 days and 1, 2, 4, and 8 weeks; n = 5 per group). To determine the presence of neurogenesis and neovascularization in the ischemic brain, nestin, Tuj1, NeuN, GFAP, Tie2, RECA, and 5-bromo-2'-deoxyuridine (BrdU) were analyzed immunohistochemically. In addition, nestin, GFAP, and Tie2 expression was determined by Western blotting. Triple-labeling of nestin, BrdU, and laminin was performed to visualize the interaction between endogenous neurogenesis and neovascularization. The number of BrdU- and nestin-colabeled cells increased markedly in the neocortex and border zone of the ischemic area up to 1 week after MCAO and decreased thereafter. Western blot analysis revealed that the expression of nestin, Tie-2, and GFAP was amplified in the ipsilateral hemisphere 2 days after MCAO and peaked 1 week after MCAO, compared with that in the normal brain. After ischemic injury, nestin- and BrdU-colabeled cells were observed in the vicinity of the endothelial cells lining cerebral vessels in the ipsilateral neocortex of the ischemic brain. Endogenous neurogenesis and neovascularization were substantially activated and occurred in close proximity to one other in the ipsilateral neocortex of the ischemic rat brain. (c) 2007 Wiley-Liss, Inc.

  8. Investigating Neovascularization in Rat Decellularized Intestine: An In Vitro Platform for Studying Angiogenesis

    PubMed Central

    Dew, Lindsey; English, William R.; Chong, Chuh K.

    2016-01-01

    One of the main challenges currently faced by tissue engineers is the loss of tissues postimplantation due to delayed neovascularization. Several strategies are under investigation to create vascularized tissue, but none have yet overcome this problem. In this study, we produced a decellularized natural vascular scaffold from rat intestine to use as an in vitro platform for neovascularization studies for tissue-engineered constructs. Decellularization resulted in almost complete (97%) removal of nuclei and DNA, while collagen, glycosaminoglycan, and laminin content were preserved. Decellularization did, however, result in the loss of elastin and fibronectin. Some proangiogenic factors were retained, as fragments of decellularized intestine were able to stimulate angiogenesis in the chick chorioallantoic membrane assay. We demonstrated that decellularization left perfusable vascular channels intact, and these could be repopulated with human dermal microvascular endothelial cells. Optimization of reendothelialization of the vascular channels showed that this was improved by continuous perfusion of the vasculature and further improved by infusion of human dermal fibroblasts into the intestinal lumen, from where they invaded into the decellularized tissue. Finally we explored the ability of the perfused cells to form new vessels. In the absence of exogenous angiogenic stimuli, Dll4, a marker of endothelial capillary-tip cell activation during sprouting angiogenesis, was absent, indicating that the reformed vasculature was largely quiescent. However, after addition of vascular endothelial growth factor A, Dll4-positive endothelial cells could be detected, demonstrating that this engineered vascular construct maintained its capacity for neovascularization. In summary, we have demonstrated how a natural xenobiotic vasculature can be used as an in vitro model platform to study neovascularization and provide information on factors that are critical for efficient

  9. Identification of Chlamydia pneumoniae within human choroidal neovascular membranes secondary to age-related macular degeneration.

    PubMed

    Kalayoglu, Murat V; Bula, Deisy; Arroyo, Jorge; Gragoudas, Evangelos S; D'Amico, Donald; Miller, Joan W

    2005-11-01

    Age-related macular degeneration (AMD) is a leading cause of blindness in the United States, and increasing evidence suggests that it is an inflammatory disease. The prokaryotic obligate intracellular pathogen Chlamydia pneumoniae is emerging as a novel risk factor in cardiovascular disease, and recent sero-epidemiological data suggest that C. pneumoniae infection is also associated with AMD. In this study, we examined choroidal neovascular membrane (CNV) tissue from patients with neovascular AMD for the presence of C. pneumoniae and determined whether the pathogen can dysregulate the function of key cell types in ways that can cause neovascular AMD. Nine CNV removed from patients with neovascular AMD were examined for the presence of C. pneumoniae by immunohistochemistry (IHC) and polymerase chain reaction (PCR); in addition, we performed PCR on nine non-AMD eyes, and IHC on five non-AMD CNV, seven non-AMD eyes, and one internal limiting membrane specimen. Finally, human monocyte-derived macrophages and retinal pigment epithelial (RPE) cells were exposed to C. pneumoniae and assayed in vitro for the production of pro-angiogenic immunomodulators (VEGF, IL-8, and MCP-1). C. pneumoniae was detected in four of nine AMD CNV by IHC and two of nine AMD CNV by PCR, induced VEGF production by human macrophages, and increased production of IL-8 and MCP-1 by RPE cells. In contrast, none of the 22 non-AMD specimens showed evidence for C. pneumoniae. These data indicate that a pathogen capable of inducing chronic inflammation and pro-angiogenic cytokines can be detected in some AMD CNV, and suggest that infection may contribute to the pathogenesis of AMD.

  10. Investigating Neovascularization in Rat Decellularized Intestine: An In Vitro Platform for Studying Angiogenesis.

    PubMed

    Dew, Lindsey; English, William R; Chong, Chuh K; MacNeil, Sheila

    2016-12-01

    One of the main challenges currently faced by tissue engineers is the loss of tissues postimplantation due to delayed neovascularization. Several strategies are under investigation to create vascularized tissue, but none have yet overcome this problem. In this study, we produced a decellularized natural vascular scaffold from rat intestine to use as an in vitro platform for neovascularization studies for tissue-engineered constructs. Decellularization resulted in almost complete (97%) removal of nuclei and DNA, while collagen, glycosaminoglycan, and laminin content were preserved. Decellularization did, however, result in the loss of elastin and fibronectin. Some proangiogenic factors were retained, as fragments of decellularized intestine were able to stimulate angiogenesis in the chick chorioallantoic membrane assay. We demonstrated that decellularization left perfusable vascular channels intact, and these could be repopulated with human dermal microvascular endothelial cells. Optimization of reendothelialization of the vascular channels showed that this was improved by continuous perfusion of the vasculature and further improved by infusion of human dermal fibroblasts into the intestinal lumen, from where they invaded into the decellularized tissue. Finally we explored the ability of the perfused cells to form new vessels. In the absence of exogenous angiogenic stimuli, Dll4, a marker of endothelial capillary-tip cell activation during sprouting angiogenesis, was absent, indicating that the reformed vasculature was largely quiescent. However, after addition of vascular endothelial growth factor A, Dll4-positive endothelial cells could be detected, demonstrating that this engineered vascular construct maintained its capacity for neovascularization. In summary, we have demonstrated how a natural xenobiotic vasculature can be used as an in vitro model platform to study neovascularization and provide information on factors that are critical for efficient

  11. Characteristics of choroidal neovascularization in the complications of age-related macular degeneration prevention trial.

    PubMed

    Maguire, Maureen G; Alexander, Judith; Fine, Stuart L

    2008-09-01

    To describe the characteristics of incident choroidal neovascularization (CNV) in observed and treated eyes in the Complications of Age-related Macular Degeneration Prevention Trial (CAPT). Cross-sectional descriptive study within a multicenter, randomized clinical trial. Patients who developed CNV during CAPT follow-up. Inclusion criteria for CAPT specified bilateral large drusen (>or=10 drusen at least 125 micro), visual acuity >or=20/40 in each eye, and age >or=50. Exclusion criteria included CNV and geographic atrophy >1 Macular Photocoagulation Study (MPS) disc area or within 500 micro of the foveal center. One eye of each person was selected randomly for low-intensity laser treatment and the contralateral eye was observed. Fluorescein angiography was performed at baseline, annually for >or=5 years, and whenever there were symptoms of CNV. Trained readers at the CAPT Photograph Reading Center assessed color stereo photographs and angiogram negatives to identify CNV. Choroidal neovascularization was classified by type (predominantly classic CNV, minimally classic CNV, occult only CNV, or scar), location, and area. Visual acuity was measured by certified examiners. Symmetry of characteristics between eyes of bilaterally affected patients was examined. Choroidal neovascularization developed in 282 eyes of 225 patients. At the time of detection, 192 (68%) of the lesions were occult only, 153 (54%) were subfoveal, and 157 (56%) were or=20/40 in 123 (69%) of 179 eyes with visual acuity measured at the time of detection. Choroidal neovascularization developed in both eyes in 57 patients (25%) during CAPT follow-up. Lesions in eyes of bilaterally affected patients were no more similar to each other than affected eyes in 2 different patients. When patients are monitored closely, many CNV lesions can be detected outside of the fovea and when they are relatively small. Early detection may lead to improved long-term visual acuity.

  12. Type 1 Choroidal Neovascularization Lesion Size: Indocyanine Green Angiography Versus Optical Coherence Tomography Angiography.

    PubMed

    Costanzo, Eliana; Miere, Alexandra; Querques, Giuseppe; Capuano, Vittorio; Jung, Camille; Souied, Eric H

    2016-07-01

    To evaluate the size of type 1 choroidal neovascularization (CNV) in neovascular AMD by optical coherence tomography angiography (OCTA) and to compare with indocyanine green angiography (ICGA). Patients diagnosed type 1 CNV underwent multimodal imaging by fluorescein angiography (FA), ICGA, spectral-domain (SD)-OCT, and OCTA. Lesion size was measured both on OCTA at the choriocapillaris level with "select area" and "vessel area" functions, incorporated in AngioVue software and on ICGA at intermediate and late phases, by two masked independent readers. Nineteen eyes of 17 patients (mean age 80.6 ± 8.36) were included in the analysis. Mean visual acuity was 0.2 logMAR. All OCTA revealed a high flow neovascular network in the choriocapillaris segmentation. On OCTA, interclass correlation between readers 1 and 2 was 0.96 (95% confidence interval [CI] 0.94-0.99) for select area and 0.97 (95% CI 0.96-0.99) for vessel area. The difference between lesion size in OCTA versus ICGA was detected in all eyes and it was statistically significant for both readers (P < 0.05). Optical coherence tomography angiography provides both quantitative and qualitative information on type 1 CNV and appears as a new reproducible way to evaluate CNV area and vessels area. Type 1 CNV lesion size in the choriocapillaris segmentation of OCTA and ICGA intermediate and late phases revealed that the OCTA size is significantly smaller than the ICGA size. This supports the idea that OCTA could be considered for evaluation of the neovascular lesion and for evaluation of therapeutic responses.

  13. SOCIETAL COSTS ASSOCIATED WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION IN THE UNITED STATES.

    PubMed

    Brown, Melissa M; Brown, Gary C; Lieske, Heidi B; Tran, Irwin; Turpcu, Adam; Colman, Shoshana

    2016-02-01

    The purpose of this study was to use a cross-sectional prevalence-based health care economic survey to ascertain the annual, incremental, societal ophthalmic costs associated with neovascular age-related macular degeneration. Consecutive patients (n = 200) with neovascular age-related macular degeneration were studied. A Control Cohort included patients with good (20/20-20/25) vision, while Study Cohort vision levels included Subcohort 1: 20/30 to 20/50, Subcohort 2: 20/60 to 20/100, Subcohort 3: 20/200 to 20/400, and Subcohort 4: 20/800 to no light perception. An interviewer-administered, standardized, written survey assessed 1) direct ophthalmic medical, 2) direct nonophthalmic medical, 3) direct nonmedical, and 4) indirect medical costs accrued due solely to neovascular age-related macular degeneration. The mean annual societal cost for the Control Cohort was $6,116 and for the Study Cohort averaged $39,910 (P < 0.001). Study Subcohort 1 costs averaged $20,339, while Subcohort 4 costs averaged $82,984. Direct ophthalmic medical costs comprised 17.9% of Study Cohort societal ophthalmic costs, versus 74.1% of Control Cohort societal ophthalmic costs (P < 0.001) and 10.4% of 20/800 to no light perception subcohort costs. Direct nonmedical costs, primarily caregiver, comprised 67.1% of Study Cohort societal ophthalmic costs, versus 21.3% ($1,302/$6,116) of Control Cohort costs (P < 0.001) and 74.1% of 20/800 to no light perception subcohort costs. Total societal ophthalmic costs associated with neovascular age-related macular degeneration dramatically increase as vision in the better-seeing eye decreases.

  14. Gold nanoparticle enhancement of stereotactic radiosurgery for neovascular age-related macular degeneration

    NASA Astrophysics Data System (ADS)

    Ngwa, Wilfred; Makrigiorgos, G. Mike; Berbeco, Ross I.

    2012-10-01

    Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries for people over the age of 50. In this work, the dosimetric feasibility of using gold nanoparticles (AuNP) as radiosensitizers to enhance kilovoltage stereotactic radiosurgery for neovascular AMD is investigated. Microdosimetry calculations at the sub-cellular level were carried out to estimate the radiation dose enhancement to individual nuclei in neovascular AMD endothelial cells (nDEF) due to photon-induced photo-/Auger electrons from x-ray-irradiated AuNP. The nDEF represents the ratio of radiation doses to the endothelial cell nuclei with and without AuNP. The calculations were carried out for a range of feasible AuNP local concentrations using the clinically applicable 100 kVp x-ray beam parameters employed by a commercially available x-ray therapy system. The results revealed nDEF values of 1.30-3.26 for the investigated concentration range of 1-7 mg g-1, respectively. In comparison, for the same concentration range, nDEF values of 1.32-3.40, 1.31-3.33, 1.29-3.19, 1.28-3.12 were calculated for 80, 90, 110 and 120 kVp x-rays, respectively. Meanwhile, calculations as a function of distance from the AuNP showed that the dose enhancement, for 100 kVp, is markedly confined to the targeted neovascular AMD endothelial cells where AuNP are localized. These findings provide impetus for considering the application of AuNP to enhance therapeutic efficacy during stereotactic radiosurgery for neovascular AMD.

  15. Medicare costs for neovascular age-related macular degeneration, 1994-2007.

    PubMed

    Day, Shelley; Acquah, Kofi; Lee, Paul P; Mruthyunjaya, Prithvi; Sloan, Frank A

    2011-12-01

    To assess changes in Medicare payments for neovascular age-related macular degeneration (AMD) since introduction of anti-vascular endothelial growth factor (VEGF) therapies. Retrospective, longitudinal cohort study. Using the Medicare 5% sample, beneficiaries with new diagnoses of neovascular AMD in 1994 (N = 2497), 2000 (N = 3927), and 2006 (N = 6041) were identified using International Classification of Diseases (ICD-9-CM). The total first-year health care and eye care costs were calculated for each beneficiary. Propensity score matching was used to match individuals in the 2000 and 2006 cohorts with the 1994 cohort on age, sex, race, Charlson Comorbidity Index, and low vision/blindness. The number of beneficiaries newly diagnosed with neovascular AMD more than doubled between the 1994 and 2006 cohorts. Overall yearly Part B payments per beneficiary increased significantly from $3567 for the 1994 to $5991 for the 2006 cohort (P < .01) in constant 2008 dollars. Payments for eye care alone doubled from $1504 for the 1994 cohort to $3263 for the 2006 cohort (P < .01). Most of the increase in payments for eye care in 2006 reflected payments for anti-VEGF injections, which were $1609 over 1 year. Mean annual numbers of visits and imaging studies also increased significantly between the 1994 and 2006 cohort. Results were similar in the matched sample. The introduction of anti-VEGF intravitreal injections has offered remarkable clinical benefits for patients with neovascular AMD, but these benefits have come at the cost of an increased financial burden of providing care for these patients. Copyright © 2011 Elsevier Inc. All rights reserved.

  16. Overexpression of calmodulin in pancreatic beta cells induces diabetic nephropathy.

    PubMed

    Yuzawa, Yukio; Niki, Ichiro; Kosugi, Tomoki; Maruyama, Shoichi; Yoshida, Futoshi; Takeda, Motohiro; Tagawa, Yoshiaki; Kaneko, Yukiko; Kimura, Toshihide; Kato, Noritoshi; Yamamoto, Jyunichiro; Sato, Waichi; Nakagawa, Takahiko; Matsuo, Seiichi

    2008-09-01

    Recently, endothelial dysfunction induced by an uncoupling of vascular endothelial growth factor (VEGF) and nitric oxide has been implicated in the pathogenesis of diabetic nephropathy (DN). Investigating the pathogenesis of DN has been limited, however, because of the lack of animal models that mimic the human disease. In this report, pancreatic beta cell-specific calmodulin-overexpressing transgenic (CaMTg) mice, a potential new model of DN, are characterized with particular emphasis on VEGF and related molecules. CaMTg mice developed hyperglycemia at 3 wk and persistent proteinuria by 3 mo. Morphometric analysis showed considerable increases in the glomerular and mesangial areas with deposition of type IV collagen. Moreover, the pathologic hallmarks of human DN (mesangiolysis, Kimmelstiel-Wilson-like nodular lesions, exudative lesions, and hyalinosis of afferent and efferent arteries with neovascularization) were observed. In addition, increased VEGF expression was associated with an increased number of peritubular capillaries. Expression of endothelial nitric oxidase synthase was reduced and that of VEGF was markedly elevated in CaMTg mice kidney compared with nontransgenic mice. No differences in VEGF receptor-1 or VEGF receptor-2 expression were observed between CaMTg mice and nontransgenic kidneys. In summary, CaMTg mice develop most of the distinguishing lesions of human DN, and the elevated VEGF expression in the setting of diminished endothelial nitric oxide synthase expression may lead to endothelial proliferation and dysfunction. This model may prove useful in the study of the pathogenesis and treatment of DN.

  17. Alkali burn versus suture-induced corneal neovascularization in C57BL/6 mice: an overview of two common animal models of corneal neovascularization.

    PubMed

    Giacomini, Chiara; Ferrari, Giulio; Bignami, Fabio; Rama, Paolo

    2014-04-01

    The purpose of the present study was to quantify and compare corneal hem- and lymphangiogenesis between alkali burn and suture-induced corneal neovascularization (CNV) in two commonly used mouse strains. A retrospective analysis was performed on C57BL/6 and FVB neovascularized corneas. CNV was induced by surface caustication with NaOH or intrastromal placement of three 10.0 nylon sutures. Hemangiogenesis and lymphangiogenesis extent was calculated on whole mounted corneas by CD31 and LYVE1 immunofluorescence analysis. Blood vessel growth was similar between alkali burn and suture-induced CNV in C57BL/6 mice, and between C57BL/6 and FVB sutured strains. On the contrary, corneal lymphangiogenesis was more pronounced in the C57BL/6 sutured mice versus the alkali burn group, and in the FVB strain versus both C57BL/6 models. These results indicate that significant differences occur in lymphangiogenesis, but not hemangiogenesis, in the alkali burn and suture-induced models in C57BL/6 mice. Furthermore, lymphangiogenesis is more pronounced in the albino (FVB) strain after suture placement. We suggest that the suture model has a number of advantages and may be preferentially used to study corneal lymphangiogenesis. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Endoplasmic Reticulum Stress in Age-Related Macular Degeneration: Trigger for Neovascularization

    PubMed Central

    Salminen, Antero; Kauppinen, Anu; Hyttinen, Juha MT; Toropainen, Elisa; Kaarniranta, Kai

    2010-01-01

    Age-related macular degeneration (AMD) can be classified into two main categories: the atrophic, dry form and the exudative, wet form. The crucial difference between dry and wet AMD is the development of choroidal neovascularization in wet AMD. One fundamental cause of the neovascularization is the increased expression of VEGF (vascular endothelial growth factor) in retinal pigment epithelial cells. Progression of AMD is linked to augmentation of cellular stress, for example, oxidative stress, proteotoxic stress, inflammation and hypoxia. All these conditions can trigger stress in endoplasmic reticulum (ER), which maintains protein quality control in cells. ER stress induces the unfolded protein response (UPR) via IRE1 (inositol-requiring protein-1), PERK (protein kinase RNA-like ER kinase) and ATF6 (activating transcription factor-6) transducers. UPR signaling is a double-edged sword, that is, it can restore cellular homeostasis as far as possible, but ultimately may lead to chronic, overwhelming stress that can cause apoptotic cell death. Interestingly, ER stress is a well-known inducer of angiogenesis in cancer. Moreover, stress conditions associated with the progress of AMD can induce the expression of VEGF. We discuss the role of ER stress in the regulation of neovascularization and the conversion of dry AMD to its wet, detrimental counterpart. PMID:20683548

  19. Preliminary studies of the effects of vascular adhesion protein-1 inhibitors on experimental corneal neovascularization.

    PubMed

    Enzsöly, Anna; Dunkel, Petra; Récsán, Zsuzsa; Gyorffy, Hajnalka; Tóth, Jeanette; Marics, Gábor; Bori, Zoltán; Tóth, Miklós; Zelkó, Romána; Di Paolo, Maria Luisa; Mátyus, Péter; Németh, János

    2011-07-01

    Vascular adhesion protein-1 (VAP-1) controls the adhesion of lymphocytes to endothelial cells and is upregulated at sites of inflammation. Moreover, it expresses amine oxidase activity, due to the sequence identity with semicarbazide-sensitive amine oxidase. Recent studies indicate a significant role for VAP-1 in neovascularization, besides its contribution to inflammation. Pathological blood vessel development in severe ocular diseases (such as diabetes, age-related macula degeneration, trauma and infections) might lead to decreased visual acuity and finally to blindness, yet there is no clear consensus as to its appropriate treatment. In the present case study, the effects of two VAP-1 inhibitors on experimentally induced corneal neovascularization in rabbits were compared with the effects of a known inhibitor of angiogenesis, bevacizumab, an anti-vascular endothelial growth factor antibody. In accordance with recent literature data, the results of the preliminary study reported here indicate that the administration of VAP-1 inhibitors is a potentially valuable therapeutic option in the treatment of corneal neovascularization.

  20. Intrastromal Injection of Bevacizumab in the Management of Corneal Neovascularization: About 25 Eyes

    PubMed Central

    Ibtissam, Hajji; Mohammed, Baali; Hasna, Soummane; Abdeljalil, Moutaouakil

    2016-01-01

    Introduction. Corneal neovessels are a major risk factor for corneal graft rejection, due to the loss of the immune privilege. The purpose of this study is to evaluate the effectiveness of intrastromal injection of bevacizumab in the treatment of corneal neovascularization. Material and Methods. This is a prospective study that included 25 eyes of 22 patients with deep corneal neovessels, treated with intrastromal injections of bevacizumab. Results. The average age of patients was 31 years ranging from 16 to 44 years. The causes of neovascularization were dominated by herpetic keratitis (10 cases). The evolution was marked by complete regress of neovessels in 16 patients, partial regress in 6 cases, and reduced opacity and improved visual acuity in 5 patients. No side effects were noted. Discussion. Short-term results demonstrated the effectiveness of intrastromal injection of bevacizumab in the treatment of corneal neovessels. It may be an option or a complement to other useful treatments in stabilizing or improving vision. Conclusion. Bevacizumab is an effective additional treatment for the improvement of corneal transplants prognosis with preoperative corneal neovascularization. PMID:27610242

  1. Angiogenin expression in burn blister fluid: implications for its role in burn wound neovascularization.

    PubMed

    Pan, Shin-Chen; Wu, Li-Wha; Chen, Chung-Lin; Shieh, Shyh-Jou; Chiu, Haw-Yen

    2012-01-01

    Deep partial thickness burn (DPTB) wound fluids have a greater propensity for establishing neovascularization than did superficial partial thickness burn (SPTB) wound fluids in our previous study. To investigate the factors responsible for this activity, cytokine array and enzyme-linked immunosorbent assay were used to perform an expression analysis of angiogenic factors in burn fluid. Although present in approximately equal amounts in both SPTB and DPTB blister fluids from burn patients, angiogenin does appear to be involved in the ability of DPTB blister fluid to promote neovascularization in vitro and in vivo. Angiogenin alone was sufficient to induce endothelial differentiation of circulating angiogenic cells (CAC) without vascular endothelial growth factor A involvement. In addition, angiogenin was positively associated with CAC differentiation in the burn blister fluid. Blocking the effect of angiogenin in burn blister fluids resulted in a significant reduction of endothelial cell proliferation, CAC differentiation, and new blood vessels formation in vivo. Moreover, immunohistochemistry revealed that high angiogenin expression colocalizes with high vascularity in human burn wounds at day 7, further supporting our hypothesis that angiogenin is involved in burn wound neovascularization.

  2. Prospects for improving neovascularization of the ischemic heart: Lessons from development.

    PubMed

    Smart, Nicola

    2017-01-01

    Neovascularization of the ischemic myocardium postinfarction is necessary to restore blood flow to vulnerable cardiomyocytes and will be indispensable for prospective regenerative strategies, to perfuse newly formed myocardium. Therapeutic attempts to enhance new vessel formation have, to date, yielded modest clinical benefits, and innovative approaches are now needed. Intrinsic mechanisms are initiated by the heart in an attempt to rebuild injured vessels, but these are poorly understood. Insight into the underlying mechanisms may reveal targets for therapeutically augmenting this low-level neovascular response. Starting from a limited number of descriptive studies, this review summarizes what is known of coronary neovascularization and explores putative mechanisms and cellular sources which may endogenously contribute, or that may be pharmacologically triggered, to support vasculo- or angiogenesis. As injury responses in the adult frequently recapitulate embryological processes, a particular focus is placed on the developmental mechanisms of coronary vessel formation. An understanding of the cellular sources and the regulatory pathways used by the embryo may reveal novel targets for reactivating coronary vessel and myocardial regeneration.

  3. MACULAR ATROPHY AND MACULAR MORPHOLOGY IN AFLIBERCEPT-TREATED NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

    PubMed

    Kuroda, Yoshimasa; Yamashiro, Kenji; Ooto, Sotaro; Tamura, Hiroshi; Oishi, Akio; Nakanishi, Hideo; Miyata, Manabu; Hata, Masayuki; Takahashi, Ayako; Wakazono, Tomotaka; Yoshimura, Nagahisa; Tsujikawa, Akitaka

    2017-07-04

    To investigate the incidence and predictors of macular atrophy during treatment with aflibercept for neovascular age-related macular degeneration in Japanese patients. This study included patients with treatment-naive subfoveal neovascular age-related macular degeneration treated from December 2012 through January 2015. Patients were treated with bi-monthly aflibercept injections after 3 monthly loading injections for the first year. Diagnosis of retinal pigment epithelial atrophy was made based on color fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence. Baseline characteristics and morphological features were analyzed for their association with the development of macular atrophy. This study included 123 eyes that had no baseline macular atrophy and treated with aflibercept injections for 12 months. Thirteen eyes (10.6%) developed new macular atrophy at 12 months. Logistic regression analysis showed that the presence of intraretinal fluid and thinner subfoveal choroidal thickness at baseline were associated with the development of macular atrophy after aflibercept treatment. Macular atrophy developed in about 10% of eyes with neovascular age-related macular degeneration during 12 months of treatment with a fixed regimen of aflibercept. Intraretinal fluid and subfoveal choroidal thickness seem to be predictors for development of macular atrophy after anti-vascular endothelial growth factor (VEGF) therapy.

  4. The Application of OCTA in Assessment of Anti-VEGF Therapy for Idiopathic Choroidal Neovascularization

    PubMed Central

    Sun, Zihan; Dai, Hong

    2016-01-01

    Purpose. To assess the morphology of idiopathic choroidal neovascularization (ICNV) by optical coherence tomography angiography (OCTA) and determine the therapeutic effects of intravitreal antivascular endothelial growth factor (anti-VEGF). Method. Patients with naive ICNV were assessed by spectral domain optical coherence tomography (SD-OCT) and OCTA in this observational study. The timing of observation was before treatment, 1 day after treatment with intravitreal anti-VEGF injection, and 1 month after the treatment. The central retina thickness (CRT) on SD-OCT, selected CNV area, and flow area on OCTA were measured. Results. A total of 17 eyes from 17 patients with ICNV were included in this study. OCTA showed visible irregular choroidal neovascularization with “tree-in-bud” form on outer retinal layer. After treatment, as well as in the 1-day follow-up, CNV decreased in size from the periphery, and the vessel density was reduced. As shown on OCTA, the selected CNV area and flow area were significantly reduced compared to pretreatment. The rate of CNV vessel area changes was higher on OCTA than the changes in CRT on SD-OCT at 1-day and 1-month follow-up. Conclusion. Intravitreal injection of anti-VEGF is effective for idiopathic choroidal neovascularization, and the treatment outcomes are observable after 1 day. OCTA provides a useful approach for monitoring and evaluating the treatment of intravitreal anti-VEGF for CNV. PMID:27471600

  5. Honokiol inhibits pathological retinal neovascularization in oxygen-induced retinopathy mouse model.

    PubMed

    Vavilala, Divya Teja; O'Bryhim, Bliss E; Ponnaluri, V K Chaithanya; White, R Sid; Radel, Jeff; Symons, R C Andrew; Mukherji, Mridul

    2013-09-06

    Aberrant activation of the hypoxia inducible factor (HIF) pathway is the underlying cause of retinal neovascularization, one of the most common causes of blindness worldwide. The HIF pathway also plays critical roles during tumor angiogenesis and cancer stem cell transformation. We have recently shown that honokiol is a potent inhibitor of the HIF pathway in a number of cancer and retinal pigment epithelial cell lines. Here we evaluate the safety and efficacy of honokiol, digoxin, and doxorubicin, three recently identified HIF inhibitors from natural sources. Our studies show that honokiol has a better safety to efficacy profile as a HIF inhibitor than digoxin and doxorubicin. Further, we show for the first time that daily intraperitoneal injection of honokiol starting at postnatal day (P) 12 in an oxygen-induced retinopathy (OIR) mouse model significantly reduced retinal neovascularization at P17. Administration of honokiol also prevents the oxygen-induced central retinal vaso-obliteration, characteristic feature of the OIR model. Additionally, honokiol enhanced physiological revascularization of the retinal vascular plexuses. Since honokiol suppresses multiple pathways activated by HIF, in addition to the VEGF signaling, it may provide advantages over current treatments utilizing specific VEGF antagonists for ocular neovascular diseases and cancers. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. STAT3 activation in circulating monocytes contributes to neovascular age-related macular degeneration

    PubMed Central

    Chen, Mei; Lechner, Judith; Zhao, Jiawu; Toth, Levente; Hogg, Ruth; Silvestri, Giuliana; Kissenpfennig, Adrien; Chakravarthy, Usha; Xu, Heping

    2016-01-01

    Infiltrating macrophages are critically involved in pathogenic angiogenesis such as neovascular age-related macular degeneration (nAMD). Macrophages originate from circulating monocytes and three subtypes of monocyte exist in humans: classical (CD14+CD16-), non-classical (CD14-CD16+) and intermediate (CD14+CD16+) monocytes. The aim of this study was to investigate the role of circulating monocyte in neovascular age-related macular degeneration (nAMD). Flow cytometry analysis showed that the intermediate monocytes from nAMD patients expressed higher levels of CX3CR1 and HLA-DR compared to those from controls. Monocytes from nAMD patients expressed higher levels of phosphorylated Signal Transducer and Activator of Transcription 3 (pSTAT3), and produced higher amount of VEGF. In the mouse model of choroidal neovascularization (CNV), pSTAT3 expression was increased in the retina and RPE/choroid, and 49.24% of infiltrating macrophages express pSTAT3. Genetic deletion of the Suppressor of Cytokine Signalling 3 (SOCS3) in myeloid cells in the LysM-Cre+/-:SOCS3fl/fl mice resulted in spontaneous STAT3 activation and accelerated CNV formation. Inhibition of STAT3 activation using a small peptide LLL12 suppressed laser-induced CNV. Our results suggest that monocytes, in particular the intermediate subset of monocytes are activated in nAMD patients. STAT3 activation in circulating monocytes may contribute to the development of choroidal neovascularisation in AMD. PMID:27009107

  7. The development of an experimental model of subretinal neovascularization in disciform macular degeneration.

    PubMed Central

    Ryan, S J

    1979-01-01

    A reproducible model of subretinal neovascularization has been developed, an important first step in the study of disciform macular degeneration. The methodology and clinical description of subretinal neovascularization in the primate have been provided and histopathologic and electron microscopic correlations included. This model provides a most promising and useful mechanism for the evaluation of the many different factors and hypotheses that have been proposed for the genesis of the disciform response. In humans, it probably has more relevance to the traumatically induced disciform process, particularly that after laser therapy, than to the senile degenerative process. The purpose of this investigation is to develop the animal model by which many different theories regarding the pathogenesis of the disciform response can be tested. These initial studies relate to ischemia, hemorrhage, the inflammatory response, and position in relation to the center of the vascular-free zone as factors important in the development and evolution of subretinal neovascularization. Images FIGURE 1 FIGURE 2 A FIGURE 2 B FIGURE 2 C FIGURE 2 D FIGURE 3 A FIGURE 3 B FIGURE 3 C FIGURE 3 D FIGURE 3 E FIGURE 4 A FIGURE 4 B FIGURE 7 A FIGURE 7 B FIGURE 7 C FIGURE 7 D FIGURE 7 E FIGURE 7 F FIGURE 8 A FIGURE 8 B FIGURE 8 C FIGURE 8 D FIGURE 8 E FIGURE 8 F FIGURE 8 G FIGURE 9 A FIGURE 9 B FIGURE 9 C FIGURE 9 D FIGURE 10 A FIGURE 10 B FIGURE 10 C PMID:94717

  8. [Alternative splicing of vascular endothelial growth factor A and ocular neovascularization].

    PubMed

    Fan, Si-jun; He, Shou-zhi

    2011-04-01

    Ocular neovascularization is the primary cause of blindness in a wide range of ocular diseases. The vascular endothelial growth factor A (VEGF-A) is the key factor involved in ocular angiogenesis, which can cause eye diseases through the development of pathological angiogenesis and increase of vascular permeability. There are two families of VEGF-A isoforms formed by alternative splicing, the angiogenic VEGF-A family (VEGF(xxx)), known to contribute to ocular neovascularization, and the anti-angiogenic VEGF-A family (VEGF(xxx)b), which is found in normal ocular tissues but downregulated in human diabetic retinopathy. The first member of the VEGF(xxx)b family to be isolated was VEGF(165)b. It can significantly reduce preretinal neovascularization without inhibition of physiological intraretinal angiogenesis. As the studies on the VEGF(xxx)b family proceed more deeply, controlling the balance of VEGF(xxx) to VEGF(xxx)b isoforms may be therapeutically valuable in the treatment of angiogenic eye diseases such as diabetic retinopathy and age-related macular degeneration.

  9. CD200R signaling inhibits pro-angiogenic gene expression by macrophages and suppresses choroidal neovascularization

    PubMed Central

    Horie, Shintaro; Robbie, Scott J.; Liu, Jian; Wu, Wei-Kang; Ali, Robin R.; Bainbridge, James W.; Nicholson, Lindsay B.; Mochizuki, Manabu; Dick, Andrew D.; Copland, David A.

    2013-01-01

    Macrophages are rapidly conditioned by cognate and soluble signals to acquire phenotypes that deliver specific functions during inflammation, wound healing and angiogenesis. Whether inhibitory CD200R signaling regulates pro-angiogenic macrophage phenotypes with the potential to suppress ocular neovascularization is unknown. CD200R-deficient bone marrow derived macrophages (BMMΦ) were used to demonstrate that macrophages lacking this inhibitory receptor exhibit enhanced levels of Vegfa, Arg-1 and Il-1β when stimulated with PGE2 or RPE-conditioned (PGE2-enriched) media. Endothelial tube formation in HUVECs was increased when co-cultured with PGE2-conditioned CD200R−/− BMMΦ, and laser-induced choroidal neovascularization was enhanced in CD200R-deficient mice. In corroboration, signaling through CD200R results in the down-regulation of BMMΦ angiogenic and pro-inflammatory phenotypes. Translational potential of this pathway was investigated in the laser-induced model of choroidal neovascularization. Local delivery of a CD200R agonist mAb to target myeloid infiltrate alters macrophage phenotype and inhibits pro-angiogenic gene expression, which suppresses pathological angiogenesis and CNV development. PMID:24170042

  10. Combined intravitreal bevacizumab and photodynamic therapy for neovascular age-related macular degeneration.

    PubMed

    Ladewig, Markus S; Karl, Stefanie E; Hamelmann, Victoria; Helb, Hans-Martin; Scholl, Hendrik P N; Holz, Frank G; Eter, Nicole

    2008-01-01

    Our aim was to evaluate the short-term safety and efficacy of combined photodynamic therapy (PDT) with verteporfin and intravitreal bevacizumab in neovascular age-related macular degeneration (AMD). A prospective non-randomized interventional case series of 30 eyes of 30 patients with choroidal neovascularization (CNV) caused by AMD was studied. All patients were treated with PDT followed by an intravitreal injection of bevacizumab (1.5 mg) on the same day. Ophthalmic evaluations included determination of best-corrected visual acuity by using ETDRS charts. CNV lesion characteristics were determined by fluorescein angiography, and retinal morphology by optical coherence tomography. Review examinations were performed 1, 4, and 12 weeks following treatment. The median ETDRS letter scores increased by 3 letters after 4 weeks and 4.3 letters after 12 weeks. Median central retinal thickness decreased from the baseline by 145 microm (week 1), 205 microm (week 4), and 171 microm (week 12), respectively (P < 0.0001, for all comparisons). One patient experienced a transient moderate vision loss after 4 weeks post treatment. Leakage on fluorescein angiography was resolved in all patients at week 12. No significant ocular or systemic side-effects were observed. Short-term results suggest that a single PDT in combination with intravitreal bevacizumab is safe and associated with stabilization of visual acuity and decrease of intraretinal and subretinal fluid accumulation in the macula. Further evaluation of this treatment strategy for neovascular AMD appears warranted.

  11. Intermediate uveitis complicated by choroidal granuloma following subretinal neovascular membrane: case reports.

    PubMed

    Garcia, Carlos Alexandre de Amorim; Segundo, Paulo de Souza; Garcia Filho, Carlos Alexandre de Amorim; Garcia, Ana Cláudia Medeiros de Amorim

    2008-01-01

    Choroidal neovascularization is a very rare complication in intermediate uveitis. A 27-year-old female patient diagnosed with intermediate uveitis two years ago. She presented with 20/200 visual acuity, snowballs, snowbanks, and macular cystoid edema in the right eye observed by fluorescein and optical coherence tomography (OCT). Photocoagulation was performed in the inferior peripheral retina in both eyes. The patient refused to undergo the prescribed clinical treatment. She returned twelve months later presenting with count fingers visual acuity, dry retina and subretinal macular pigmented granuloma observed on OCT. A 15-year-old female patient with decreased visual acuity of 20/400 in the right eye for eight days. She presented with bilateral vasculitis and papilitis, in the right eye, hemorrhage and extramacular subretinal neovascular membrane were observed on fluorescein and OCT. She was treated with 40 mg prednisone and intravitreous injection of 1.25 mg bevacizumab. Five months later she presented with 20/50 visual acuity, and extramacular granuloma observed on OCT. The formation of subretinal granuloma in intermediate uveitis is a possibility when complicated by subretinal neovascular membrane.

  12. Management of Neovascular Age-related Macular Degeneration: A Review on Landmark Randomized Controlled Trials

    PubMed Central

    Agarwal, Aniruddha; Aggarwal, Kanika; Gupta, Vishali

    2016-01-01

    In the last decade, a number of prospective clinical trials with carefully designed study protocols have been conducted for the treatment of neovascular age-related macular degeneration (AMD). These landmark clinical trials such as ANCHOR and MARINA and, more recently, the Comparison of AMD Treatment Trials and VIEW studies have revolutionized the management of neovascular AMD. While AMD continues to remain a leading cause of severe visual loss worldwide, advances in pharmacotherapeutics have led to substantial improvements in the outcome of these patients. The introduction of anti-vascular endothelial growth factor agents has resulted in improvement of visual outcomes and has had a positive impact on the quality of life among elderly population. While the contemporary management of neovascular AMD has been successful in tremendously reducing the visual morbidity, the financial burden of therapy has increased exponentially. To overcome these challenges, newer pharmacologic agents are evaluated for their efficacy and safety in AMD. Ground-breaking advances in bench to bedside research have led to discovery of new pathways that appear to be viable targets for preventing visual loss in AMD. In this review, study designs and results of landmark clinical trials in AMD from the past decade have been summarized. PMID:26957836

  13. Retinal and choroidal neovascularization in a transgenic mouse model of sickle cell disease.

    PubMed Central

    Lutty, G. A.; McLeod, D. S.; Pachnis, A.; Costantini, F.; Fabry, M. E.; Nagel, R. L.

    1994-01-01

    A complication of sickle cell disease is proliferative retinopathy. We investigated the eyes from a transgenic mouse model of sickle cell disease (alpha H beta S[beta MDD] type) to determine if pathological changes occurred in their retinas and choroids. One retina from each animal was processed by flat-embedding adenosine diphosphatase-reacted retinas in glycol methacrylate. The fellow eye from each animal was embedded whole in glycol methacrylate for histopathological analysis of all ocular structures. Retinal vascular occlusions resulted in nonperfused areas of retina and arterio-venous anastomoses. Intra- and extraretinal neovascularization was observed adjacent to nonperfused areas. Retinal pigmented lesions were formed by the migration of retinal pigment epithelial cells into sensory retina, often ensheathing choroidal neovascularization. The incidence of this bilateral chorioretinopathy was 30% in animals older than 15 months of age. The ocular histopathological changes we observed in the mouse model mimicked many aspects of human proliferative sickle cell retinopathy. Furthermore, this is the first genetically derived animal model for chorio-retinal neovascularization. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:7519831

  14. Therapeutic Effects of Topical Netrin-4 Inhibits Corneal Neovascularization in Alkali-Burn Rats

    PubMed Central

    Han, Yun; Shao, Yi; Liu, Tingting; Qu, Yang-Luowa; Li, Wei; Liu, Zuguo

    2015-01-01

    Netrins are secreted molecules involved in axon guidance and angiogenesis. However, the role of netrins in the vasculature remains unclear. Netrin-4 and netrin-1 have been found to be either pro- or antiangiogenic factors. Previously, we found that netrin-1 acts as an anti-angiogenic factor in rats by inhibiting alkali burn-induced corneal neovascularization. Here, we further investigate the effects of netrin-4, another member of the same netrin family, on neovascularization in vitro and in vivo. We found that netrin-4 functions similarly as netrin-1 in angiogenesis. In vitro angiogenesis assay shows that netrin-4 affected human umbilical vein endothelial cell (HUVEC) tube formation, viability and proliferation, apoptosis, migration, and invasion in a dose-dependent manner. Netrin-4 was topically applied in vivo to alkali-burned rat corneas on day 0 (immediately after injury) and/or day 10 post-injury. Netrin-4 subsequently suppressed and reversed corneal neovascularization. Netrin-4 inhibited corneal epithelial and stromal cell apoptosis, inhibited vascular endothelial growth factor (VEGF), but promoted pigment epithelium-derived factor (PEDF) expression, decreased NK-KB p65 expression, and inhibits neutrophil and macrophage infiltration. These results indicate that netrin-4 shed new light on its potential roles in treatmenting for angiogenic diseases that affect the ocular surface, as well as other tissues. PMID:25853509

  15. Activin A in the Regulation of Corneal Neovascularization and Vascular Endothelial Growth Factor Expression

    PubMed Central

    Poulaki, Vassiliki; Mitsiades, Nicholas; Kruse, Friedrich E.; Radetzky, Sven; Iliaki, Eirini; Kirchhof, Bernd; Joussen, Antonia M.

    2004-01-01

    Activin A, a dimeric glycoprotein that belongs to the transforming growth factor-β superfamily, governs cellular differentiation in a wide variety of models and has been implicated in the regulation of angiogenesis. We examined the role of activin A and its downstream signaling pathway in a murine model of inflammatory corneal neovascularization induced by mechanical injury (debridement), and in vitro in corneal epithelial cells. Activin A expression increased steadily from day 2 until day 8 after mechanical debridement in vivo, paralleling vascular endothelial growth factor (VEGF) expression. Administration of recombinant activin A in mice increased the area of neovascularization, VEGF expression, and the kinase activities of p38 and p42/44 MAPKs after mechanical debridement. Systemic inhibition of activin A in vivo with a neutralizing antibody reduced the area of neovascularization, VEGF expression, and p38 and p42/44 MAPK activity, whereas administration of an isotype-matched control antibody had no effect. In vitro treatment with activin A increased VEGF secretion, as well as p38 and p42/44 MAPK activity in corneal epithelial cells, whereas concurrent administration of specific inhibitors of p38 or p42/44 MAPK abolished the stimulatory effect of activin A on VEGF production. We conclude that activin A stimulates inflammatory corneal angiogenesis by increasing VEGF levels through a p38 and p42/44 MAPK-dependent mechanism. PMID:15039217

  16. Ethyl pyruvate inhibits retinal pathogenic neovascularization by downregulating HMGB1 expression.

    PubMed

    Lee, Yun Mi; Kim, Junghyun; Jo, Kyuhyung; Shin, So Dam; Kim, Chan-Sik; Sohn, Eun Jin; Kim, Seon Gi; Kim, Jin Sook

    2013-01-01

    Retinal pathogenic angiogenesis in the eyes is a causative factor in retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. This study was designed to examine the pathogenic role of the high-mobility group box-1 (HMGB1) protein and the inhibitory effect of ethyl pyruvate (EP), a well-known antioxidant substance, in retinal pathogenic angiogenesis in mice with oxygen-induced retinopathy (OIR), one of the animal models of proliferative ischemic retinopathy. The OIR mouse model was used for our in vivo studies. The mice were exposed to 75% oxygen from postnatal day 7 (P7) to P11, after which the mice were brought to room air and intraperitoneally injected with EP (50 mg/kg, or 100 mg/kg) for five days. At P17, the mice were perfused with fluorescein isothiocyanate-dextran, and flat-mounted retinas were used to measure nonperfused and neovascular tufts. In OIR mice, an intraperitoneal injection of EP reduced the nonperfused retinal area in the treatment group and significantly reduced the retinal neovascular tufts. In addition, EP inhibited the overexpression of HMGB1 in the retinas of OIR mice. These data suggest that EP could serve as an innovative pharmaceutical agent to prevent retinal neovascularization through inhibiting HMGB1 expression.

  17. Management of Neovascular Age-related Macular Degeneration: A Review on Landmark Randomized Controlled Trials.

    PubMed

    Agarwal, Aniruddha; Aggarwal, Kanika; Gupta, Vishali

    2016-01-01

    In the last decade, a number of prospective clinical trials with carefully designed study protocols have been conducted for the treatment of neovascular age-related macular degeneration (AMD). These landmark clinical trials such as ANCHOR and MARINA and, more recently, the Comparison of AMD Treatment Trials and VIEW studies have revolutionized the management of neovascular AMD. While AMD continues to remain a leading cause of severe visual loss worldwide, advances in pharmacotherapeutics have led to substantial improvements in the outcome of these patients. The introduction of anti-vascular endothelial growth factor agents has resulted in improvement of visual outcomes and has had a positive impact on the quality of life among elderly population. While the contemporary management of neovascular AMD has been successful in tremendously reducing the visual morbidity, the financial burden of therapy has increased exponentially. To overcome these challenges, newer pharmacologic agents are evaluated for their efficacy and safety in AMD. Ground-breaking advances in bench to bedside research have led to discovery of new pathways that appear to be viable targets for preventing visual loss in AMD. In this review, study designs and results of landmark clinical trials in AMD from the past decade have been summarized.

  18. Tissue Engineering Functional Gastrointestinal Regions: The Importance of Stem and Progenitor Cells.

    PubMed

    Trecartin, Andrew; Grikscheit, Tracy

    2017-10-03

    The intestine shows extraordinary regenerative potential that might be harnessed to alleviate numerous morbid and lethal human diseases. The intestinal stem cells regenerate the epithelium every 5 days throughout an individual's lifetime. Understanding stem-cell signaling affords power to influence the niche environment for growing intestine. The manifold approaches to tissue engineering may be organized by variations of three basic components required for the transplantation and growth of stem/progenitor cells: (1) cell delivery materials or scaffolds; (2) donor cells including adult stem cells, induced pluripotent stem cells, and in vitro expansion of isolated or cocultured epithelial, smooth muscle, myofibroblasts, or nerve cells; and (3) environmental modulators or biopharmaceuticals. Tissue engineering has been applied to the regeneration of every major region of the gastrointestinal tract from esophagus to colon, with scientists around the world aiming to carry these techniques into human therapy. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

  19. Stem Cells and Progenitor Cells for Tissue-Engineered Solutions to Congenital Heart Defects

    PubMed Central

    Gao, Yang; Jacot, Jeffrey G

    2015-01-01

    Synthetic patches and fixed grafts currently used in the repair of congenital heart defects are nonliving, noncontractile, and not electrically responsive, leading to increased risk of complication, reoperation, and sudden cardiac death. Studies suggest that tissue-engineered patches made from living, functional cells could grow with the patient, facilitate healing, and help recover cardiac function. In this paper, we review the research into possible sources of cardiomyocytes and other cardiac cells, including embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, adipose-derived stem cells, umbilical cord blood cells, amniotic fluid-derived stem cells, and cardiac progenitor cells. Each cell source has advantages, but also has technical hurdles to overcome, including heterogeneity, functional maturity, immunogenicity, and pathogenicity. Additionally, biomaterials used as patch materials will need to attract and support desired cells and induce minimal immune responses. PMID:26379417

  20. Genetically modified endothelial progenitor cells in the therapy of cardiovascular disease and pulmonary hypertension.

    PubMed

    Lavoie, Jessie R; Stewart, Duncan J

    2012-05-01

    Since their initial discovery, endothelial progenitor cells (EPCs) have held tremendous promise for cell therapy for a variety of cardiovascular diseases including pulmonary hypertension. The clinical experience to date suggests that circulating or bone marrow mononuclear cells and EPCs can induce neovascularization, and enhance cardiac repair after myocardial function, as well as improvements in the hemodynamic and functional status of patients with idiopathic pulmonary arterial hypertension. Although these results are promising, the overall magnitude of the clinical benefits seen in these trials appear to be rather modest. Indeed, strong experimental evidence points towards a reduction in mobilization and impairment in function of EPCs in preclinical models and patients with cardiac disease or with cardiovascular risk factors such as advanced age, type I and II diabetes, hypercholesterolemia, coronary artery disease, as well as other conditions such as pulmonary hypertension. Genetic engineering of EPCs ex vivo, prior to transplantation, is a promising cell-enhancement strategy for restoring the angiogenic potential of autologous, patient-derived cells. This review provides an update of the experimental studies that have used gene-modified EPC therapy to treat ischemic cardiovascular disease and pulmonary hypertension.

  1. In vivo perfusion of human skin substitutes with microvessels formed by adult circulating endothelial progenitor cells.

    PubMed

    Kung, Elaine F; Wang, Feiya; Schechner, Jeffrey S

    2008-02-01

    At present, tissue-engineered human skin substitutes (HSSs) mainly function as temporary bioactive dressings due to inadequate perfusion. Failure to form functional vascular networks within the initial posttransplantation period compromises cell survival of the graft and its long-term viability in the wound bed. Our goal was to demonstrate that adult circulating endothelial progenitor cells (EPCs) seeded onto HSS can form functional microvessels capable of graft neovascularization and perfusion. Adult peripheral blood mononuclear cells (PBMCs) underwent CD34 selection and endothelial cell (EC) culture conditions. After in vitro expansion, flow cytometry verified EC phenotype before their incorporation into HSS. After 2 weeks in vivo, immunohistochemical analysis, immunofluorescent microscopy, and microfil polymer perfusion were performed. CD34+ PBMCs differentiated into EPC demonstrating characteristic EC morphology and expression of CD31, Tie-2, and E-selectin after TNFalpha-induction. Numerous human CD31 and Ulex europaeus agglutinin-1 (UEA-1) microvessels within the engineered grafts (HSS/EPCs) inosculated with recipient murine circulation. Limitation of murine CD31 immunoreactivity to HSS margins showed angiogenesis was attributable to human EPC at 2 weeks posttransplantation. Delivery of intravenous rhodamine-conjugated UEA-1 and microfil polymer to HSS/EPCs demonstrated enhanced perfusion by functional microvessels compared to HSS control without EPCs. We successfully engineered functional microvessels in HSS by incorporating adult circulating EPCs. This autologous EC source can form vascular conduits enabling perfusion and survival of human bioengineered tissues.

  2. Bone Marrow Stem/Progenitor Cells Attenuate the Inflammatory Milieu Following Substitution Urethroplasty

    PubMed Central

    Liu, Joceline S.; Bury, Matthew I.; Fuller, Natalie J.; Sturm, Renea M.; Ahmad, Nida; Sharma, Arun K.

    2016-01-01

    Substitution urethroplasty for the treatment of male stricture disease is often accompanied by subsequent tissue fibrosis and secondary stricture formation. Patients with pre-existing morbidities are often at increased risk of urethral stricture recurrence brought upon in-part by delayed vascularization accompanied by overactive inflammatory responses following surgery. Within the context of this study, we demonstrate the functional utility of a cell/scaffold composite graft comprised of human bone marrow-derived mesenchymal stem cells (MSC) combined with CD34+ hematopoietic stem/progenitor cells (HSPC) to modulate inflammation and wound healing in a rodent model of substitution urethroplasty. Composite grafts demonstrated potent anti-inflammatory effects with regards to tissue macrophage and neutrophil density following urethral tissue analyses. This was accompanied by a significant reduction in pro-inflammatory cytokines TNFα and IL-1β and further resulted in an earlier transition to tissue remodeling and maturation with a shift in collagen type III to I. Grafted animals demonstrated a progressive maturation and increase in vessel size compared to control animals. Overall, MSC/CD34+ HSPC composite grafts reduce inflammation, enhance an earlier transition to wound remodeling and maturation concurrently increasing neovascularization in the periurethral tissue. We demonstrate the feasibility and efficacy of a stem cell-seeded synthetic graft in a rodent substitution urethroplasty model. PMID:27762304

  3. Endothelial Progenitor Cells in Tumor Angiogenesis: Another Brick in the Wall

    PubMed Central

    Marçola, Marina; Rodrigues, Camila Eleuterio

    2015-01-01

    Until 15 years ago, vasculogenesis, the formation of new blood vessels from undifferentiated cells, was thought to occur only during embryonic development. The discovery of circulating cells that are able to promote vascular regeneration and repair—the so-called endothelial progenitor cells (EPCs)—changed that, and EPCs have since been studied extensively. It is already known that EPCs include many subtypes of cells that play a variety of roles in promoting vascular growth. Some EPCs are destined to differentiate into endothelial cells, whereas others are capable of promoting and sustaining angiogenesis through paracrine mechanisms. Vasculogenesis and angiogenesis might constitute complementary mechanisms for postnatal neovascularization, and EPCs could be at the core of this process. Although the formation of new blood vessels from preexisting vasculature plays a beneficial role in many physiological processes, such as wound healing, it also contributes to tumor growth and metastasis. However, many aspects of the role played by EPCs in tumor angiogenesis remain unclear. This review aims to address the main aspects of EPCs differentiation and certain characteristics of their main function, especially in tumor angiogenesis, as well as the potential clinical applications. PMID:26000021

  4. RNA-Seq for the identification of novel Mediator transcripts in endothelial progenitor cells.

    PubMed

    Rienzo, Monica; Costa, Valerio; Scarpato, Margherita; Schiano, Concetta; Casamassimi, Amelia; Grimaldi, Vincenzo; Ciccodicola, Alfredo; Napoli, Claudio

    2014-08-15

    Mediator (MED) complex is a multiprotein playing a key role in the eukaryotic transcription. Alteration of MED function may have enormous pathophysiological consequences and several MED genes have been implicated in human diseases. Here, we have combined computational and experimental approaches to identify and characterize, new transcripts generated by alternative splicing (AS) for all MED genes, through the analysis of our recently published RNA-Sequencing datasets of endothelial progenitor cells (EPCs). This combined strategy allowed us to identify novel transcripts for MED4, MED9, MED11, MED14, MED27 and CDK8 most of them generated by AS. All the newly identified transcripts, except MED11, are predicted to encode novel protein isoforms. The identification of novel MED variants could lead to the finding of other MED complexes with different functions depending on their subunit composition. Finally, the expression profile of all MED genes, together with an extensive gene expression analysis, may be useful to better classify the diverse subsets of cell populations that contribute to neovascularization. Copyright © 2014. Published by Elsevier B.V.

  5. Hypoxia-induced mediators of stem/progenitor cell trafficking are increased in children with hemangioma.

    PubMed

    Kleinman, Mark E; Greives, Matthew R; Churgin, Samara S; Blechman, Keith M; Chang, Eric I; Ceradini, Daniel J; Tepper, Oren M; Gurtner, Geoffrey C

    2007-12-01

    The mechanism of neovascularization during the proliferative phase of infantile hemangioma is poorly understood. It is known that circulating bone marrow-derived endothelial progenitor cells (EPCs) form new blood vessels in ischemic tissues using mediators regulated by the transcription factor, HIF-1alpha. Mobilization of EPCs is enhanced by VEGF-A, matrix metalloproteinase (MMP)-9, and estrogen, whereas homing is secondary to localized expression of stromal cell-derived factor-1alpha (SDF-1alpha). We examined whether these mediators of EPC trafficking are upregulated during the proliferation of infantile hemangioma. Surgical specimens and blood samples were obtained from children with proliferating hemangioma and age-matched controls (n=10, each group). VEGF-A and MMP-9 levels were measured in blood, and tissue sections were analyzed for SDF-1alpha, MMP-9, VEGF-A, and HIF-1alpha. The role of estrogen as a modulator of hemangioma endothelial cell growth was also investigated. We found that all these mediators of EPC trafficking are elevated in blood and specimens from children with proliferating infantile hemangioma. In vitro, the combination of hypoxia and estrogen demonstrated a synergistic effect on hemangioma endothelial cell proliferation. These findings demonstrate that proliferating hemangiomas express known mediators of vasculogenesis and suggest that this process may play a role in the initiation or progression of this disease.

  6. STELLAR BINARY COMPANIONS TO SUPERNOVA PROGENITORS

    SciTech Connect

    Kochanek, Christopher S.

    2009-12-20

    For typical models of binary statistics, 50%-80% of core-collapse supernova (ccSN) progenitors are members of a stellar binary at the time of the explosion. Independent of any consequences of mass transfer, this has observational consequences that can be used to study the binary properties of massive stars. In particular, the secondary companion to the progenitor of a Type Ib/c SN is frequently (approx50%) the more optically luminous star since the high effective temperatures of the stripped progenitors make it relatively easy for a lower luminosity, cooler secondary to emit more optical light. Secondaries to the lower mass progenitors of Type II SN will frequently produce excess blue emission relative to the spectral energy distribution of the red primary. Available data constrain the models weakly. Any detected secondaries also provide an independent lower bound on the progenitor mass and, for historical SN, show that it was not a Type Ia event. Bright ccSN secondaries have an unambiguous, post-explosion observational signature-strong, blueshifted, relatively broad absorption lines created by the developing SN remnant (SNR). These can be used to locate historical SN with bright secondaries, confirm that a source is a secondary, and, potentially, measure abundances of ccSN ejecta. Luminous, hot secondaries will re-ionize the SNR on timescales of 100-1000 yr that are faster than re-ionization by the reverse shock, creating peculiar H II regions due to the high metallicity and velocities of the ejecta.

  7. Safety and Tolerability Study of AAV2-sFLT01 in Patients With Neovascular Age-Related Macular Degeneration (AMD)

    ClinicalTrials.gov

    2016-10-20

    Macular Degeneration; Age-Related Maculopathies; Age-Related Maculopathy; Maculopathies, Age-Related; Maculopathy, Age-Related; Retinal Degeneration; Retinal Neovascularization; Gene Therapy; Therapy, Gene; Eye Diseases

  8. Quantitative optical coherence tomography angiography of choroidal neovascularization in age-related macular degeneration

    PubMed Central

    Jia, Yali; Bailey, Steven T.; Wilson, David J.; Tan, Ou; Klein, Michael L.; Flaxel, Christina J.; Potsaid, Benjamin; Liu, Jonathan J.; Lu, Chen D.; Kraus, Martin F.; Fujimoto, James G.; Huang, David

    2014-01-01

    Purpose To detect and quantify choroidal neovascularization (CNV) in age-related macular degeneration (AMD) patients using optical coherence tomography (OCT) angiography. Design Observational, cross-sectional study. Participants Five normal subjects and five neovascular AMD patients were included. Methods Five eyes with neovascular AMD and five normal age-matched controls were scanned by a high-speed (100,000 A-scans/sec) 1050 nm wavelength swept-source OCT. The macular angiography scan covered a 3×3 mm area and comprised 200×200×8 A-scans acquired in 3.5 sec. Flow was detected using the split-spectrum amplitude-decorrelation angiography (SSADA) algorithm. Motion artifacts were removed by three dimensional (3D) orthogonal registration and merging of 4 scans. The 3D angiography was segmented into 3 layers: inner retina (to show retinal vasculature), outer retina (to identify CNV), and choroid. En face maximum projection was used to obtain 2D angiograms from the 3 layers. CNV area and flow index were computed from the en face OCT angiogram of the outer retinal layer. Flow (decorrelation) and structural data were combined in composite color angiograms for both en face and cross-sectional views. Main Outcome Measurements CNV angiogram, CNV area, and CNV flow index. Results En face OCT angiograms of CNVs showed sizes and locations that were confirmed by fluorescein angiography. OCT angiography provided more distinct vascular network patterns that were less obscured by subretinal hemorrhage. The en face angiograms also showed areas of reduced choroidal flow adjacent to the CNV in all cases and significantly reduced retinal flow in one case. Cross-sectional angiograms were used to visualize CNV location relative to the retinal pigment epithelium and Bruch’s layer and classify type I and type II CNV. A feeder vessel could be identified in one case. Higher flow indexes were associated with larger CNV and type II CNV. Conclusions OCT angiography provides depth

  9. A value-based medicine analysis of ranibizumab for the treatment of subfoveal neovascular macular degeneration.

    PubMed

    Brown, Melissa M; Brown, Gary C; Brown, Heidi C; Peet, Jonathan

    2008-06-01

    To assess the conferred value and average cost-utility (cost-effectiveness) for intravitreal ranibizumab used to treat occult/minimally classic subfoveal choroidal neovascularization associated with age-related macular degeneration (AMD). Value-based medicine cost-utility analysis. MARINA (Minimally Classic/Occult Trial of the Anti-Vascular Endothelial Growth Factor Antibody Ranibizumab in the Treatment of Neovascular AMD) Study patients utilizing published primary data. Reference case, third-party insurer perspective, cost-utility analysis using 2006 United States dollars. Conferred value in the forms of (1) quality-adjusted life-years (QALYs) and (2) percent improvement in health-related quality of life. Cost-utility is expressed in terms of dollars expended per QALY gained. All outcomes are discounted at a 3% annual rate, as recommended by the Panel on Cost-effectiveness in Health and Medicine. Data are presented for the second-eye model, first-eye model, and combined model. Twenty-two intravitreal injections of 0.5 mg of ranibizumab administered over a 2-year period confer 1.039 QALYs, or a 15.8% improvement in quality of life for the 12-year period of the second-eye model reference case of occult/minimally classic age-related subfoveal choroidal neovascularization. The reference case treatment cost is $52652, and the cost-utility for the second-eye model is $50691/QALY. The quality-of-life gain from the first-eye model is 6.4% and the cost-utility is $123887, whereas the most clinically simulating combined model yields a quality-of-life gain of 10.4% and cost-utility of $74169. By conventional standards and the most commonly used second-eye and combined models, intravitreal ranibizumab administered for occult/minimally classic subfoveal choroidal neovascularization is a cost-effective therapy. Ranibizumab treatment confers considerably greater value than other neovascular macular degeneration pharmaceutical therapies that have been studied in randomized

  10. Are the Symptoms of Calcific Tendinitis Due to Neoinnervation and/or Neovascularization?

    PubMed

    Hackett, Lisa; Millar, Neal L; Lam, Patrick; Murrell, George A C

    2016-02-03

    Calcific tendinitis can be a substantial cause of pain and dysfunction in the shoulder, and the pathophysiology is unclear. Recent studies have shown a link among nerve ingrowth, neovascularization, and pain in tendinopathy. The aim of this study was to determine whether there is evidence of neoinnervation and/or neovascularization in calcific tendinitis lesions of the shoulder. At arthroscopy, ultrasound was used to identify calcium within the tendon. Samples were taken from the supraspinatus tendon adjacent to the calcific lesion (in the calcific tendinitis group, with ten patients), the torn supraspinatus tendon of patients undergoing rotator cuff repair (the rotator cuff tear group, with ten patients), and the subscapularis tendon of patients undergoing a stabilization surgical procedure (the control group, with ten patients). Biopsied tendon samples were evaluated immunohistochemically by quantifying the presence of macrophages (using CD68 and CD206), T cells (CD3), mast cells (mast cell tryptase), vascular endothelium (CD34), and peripheral nerve markers (PGP 9.5). There was a twofold to eightfold increase of nerve markers, neovascularization, macrophages, M2 macrophages, and mast cells in the calcific tendinitis group compared with the rotator cuff tear group (p < 0.001) and the control group (p < 0.001). Increased nerve counts positively correlated with more frequent extreme pain (r = 0.5, p < 0.01) and with increased neovascularization (r = 0.7, p < 0.01) and counts of CD68 macrophages (r = 0.8, p < 0.01), M2 macrophages (r = 0.6, p < 0.01), and mast cells (r = 0.7, p < 0.01). This is the first study to show a significant increase in neovascularization and neoinnervation in calcific tendinitis lesions of the shoulder along with an eightfold increase in mast cells and macrophages. The findings are consistent with the hypothesis that, in calcific tendinitis, the calcific material is inducing a vigorous inflammatory response within the tendon with formation

  11. Endothelial progenitor cells in cardiovascular diseases

    PubMed Central

    Lee, Poay Sian Sabrina; Poh, Kian Keong

    2014-01-01

    Endothelial dysfunction has been associated with the development of atherosclerosis and cardiovascular diseases. Adult endothelial progenitor cells (EPCs) are derived from hematopoietic stem cells and are capable of forming new blood vessels through a process of vasculogenesis. There are studies which report correlations between circulating EPCs and cardiovascular risk factors. There are also studies on how pharmacotherapies may influence levels of circulating EPCs. In this review, we discuss the potential role of endothelial progenitor cells as both diagnostic and prognostic biomarkers. In addition, we look at the interaction between cardiovascular pharmacotherapies and endothelial progenitor cells. We also discuss how EPCs can be used directly and indirectly as a therapeutic agent. Finally, we evaluate the challenges facing EPC research and how these may be overcome. PMID:25126384

  12. Transient nuclear Prospero induces neural progenitor quiescence.

    PubMed

    Lai, Sen-Lin; Doe, Chris Q

    2014-10-29

    Stem cells can self-renew, differentiate, or enter quiescence. Understanding how stem cells switch between these states is highly relevant for stem cell-based therapeutics. Drosophila neural progenitors (neuroblasts) have been an excellent model for studying self-renewal and differentiation, but quiescence remains poorly understood. In this study, we show that when neuroblasts enter quiescence, the differentiation factor Prospero is transiently detected in the neuroblast nucleus, followed by the establishment of a unique molecular profile lacking most progenitor and differentiation markers. The pulse of low level nuclear Prospero precedes entry into neuroblast quiescence even when the timing of quiescence is advanced or delayed by changing temporal identity factors. Furthermore, loss of Prospero prevents entry into quiescence, whereas a pulse of low level nuclear Prospero can drive proliferating larval neuroblasts into quiescence. We propose that Prospero levels distinguish three progenitor fates: absent for self-renewal, low for quiescence, and high for differentiation.

  13. Neuropeptides: developmental signals in placode progenitor formation.

    PubMed

    Lleras-Forero, Laura; Tambalo, Monica; Christophorou, Nicolas; Chambers, David; Houart, Corinne; Streit, Andrea

    2013-07-29

    Few families of signaling factors have been implicated in the control of development. Here, we identify the neuropeptides nociceptin and somatostatin, a neurotransmitter and neuroendocrine hormone, as a class of developmental signals in both chick and zebrafish. We show that signals from the anterior mesendoderm are required for the formation of anterior placode progenitors, with one of the signals being somatostatin. Somatostatin controls ectodermal expression of nociceptin, and both peptides regulate Pax6 in lens and olfactory progenitors. Consequently, loss of somatostatin and nociceptin signaling leads to severe reduction of lens formation. Our findings not only uncover these neuropeptides as developmental signals but also identify a long-sought-after mechanism that initiates Pax6 in placode progenitors and may explain the ancient evolutionary origin of neuropeptides, predating a complex nervous system.

  14. Effect of endothelial progenitor cells derived from human umbilical cord blood on oxygen-induced retinopathy in mice by intravitreal transplantation

    PubMed Central

    Wang, Dan; Zhang, Bo; Shi, Hui; Yang, Wei; Bi, Ming-Chao; Song, Xiang-Fu; Zhang, Chen; Cheng, Jian-Hui; Hao, Ji-Long; Song, E

    2016-01-01

    AIM To investigate the effect of endothelial progenitor cells (EPCs) labeled by carboxy fluorescein diacetate succinimidyl ester (CFSE) on murine oxygen-induced retinopathy (OIR) by intravitreal transplantation. METHODS After isolated from human umbilical cord blood mononuclear cells, EPCs were cultivated and then labeled with CFSE in vitro. C57BL/6J mice were placed to 75% hyperoxia chamber from P7 to P12 to establish OIR model. At P12, OIR mice were intravitreally injected with 1 µL suspension contained 2×105 EPCs (EPCs group) or isometric phosphate buffered saline (PBS group). The contralateral eye of each mice received no injection (OIR group). Evans blue angiography and frozen section were examined to track the labeled cells in OIR group at P15 and P19. Using retina paraffin sections and adenosinediphos phatase staining at P12 and P19, the effect of EPCs on OIR mice was evaluated quantitatively and qualitatively. RESULTS The retinas from EPCs group with less non-perfusion area and fewer peripheral tufts were observed at P19, comparing with that from PBS or OIR group. The retinopathy in EPCs group receded earlier with less non-ganglion cells and neovascular nuclei, together with relatively regular distribution. The counts of the neovascular nuclei at P19 were reduced by 44% or 45%, compared with those of OIR group or PBS group respectively. Three days after EPCs injection, a large number of EPCs appeared in the vitreous cavity and adhered to the retinal surface. While at one week, the cells gathered between the internal plexiform layer and the inner limiting membrane, and some EPCs appeared in retinal vessels. CONCLUSION EPCs transplantation can participate in the reparative procedure of the neovascularization in OIR. PMID:27990359

  15. THE AGES OF TYPE Ia SUPERNOVA PROGENITORS

    SciTech Connect

    Brandt, Timothy D.; Aubourg, Eric; Strauss, Michael A.; Tojeiro, Rita; Heavens, Alan; Jimenez, Raul

    2010-09-15

    Using light curves and host galaxy spectra of 101 Type Ia supernovae (SNe Ia) with redshift z {approx}< 0.3 from the Sloan Digital Sky Survey Supernova Survey (SDSS-SN), we derive the SN Ia rate as a function of progenitor age (the delay time distribution, DTD). We use the VESPA stellar population synthesis algorithm to analyze the SDSS spectra of all galaxies in the field searched by SDSS-SN, giving us a reference sample of 77,000 galaxies for our SN Ia hosts. Our method does not assume any a priori shape for the DTD and is therefore minimally parametric. We present the DTD in physical units for high-stretch (luminous, slow declining) and low-stretch (subluminous, fast declining) supernovae in three progenitor age bins. We find strong evidence of two progenitor channels: one that produces high-stretch SNe Ia {approx}<400 Myr after the birth of the progenitor system, and one that produces low-stretch SNe Ia with a delay {approx}>2.4 Gyr. We find that each channel contributes roughly half of the Type Ia rate in our reference sample. We also construct the average spectra of high-stretch and low-stretch SN Ia host galaxies, and find that the difference of these spectra looks like a main-sequence B star with nebular emission lines indicative of star formation. This supports our finding that there are two populations of SNe Ia, and indicates that the progenitors of high-stretch supernovae are at the least associated with very recent star formation in the last few tens of Myr. Our results provide valuable constraints for models of Type Ia progenitors and may help improve the calibration of SNe Ia as standard candles.

  16. COX-2 FROM THE INJURY MILIEU IS CRITICAL FOR THE INITIATION OF PERIOSTEAL PROGENITOR CELL MEDIATED BONE HEALING

    PubMed Central

    Xie, Chao; Ming, Xue; Wang, Qun; Schwarz, Edward M.; Guldberg, Robert E.; O’Keefe, Regis J.; Zhang, Xinping

    2009-01-01

    Although a critical role of COX-2 in bone repair has been established, the mechanism involved remains unclear. During early inflammatory phase of bone healing, COX-2 is produced by the surrounding inflammatory cells as well as bone/cartilage progenitors. Based on the temporal and spatial expression of COX-2 during the early phase of fracture healing, we hypothesize that COX-2 from both sources is critical for progenitor cell activation, proliferation and differentiation. To directly test this we utilized a murine femoral grafting model, in which live segmental grafts from the same strains were transplanted and donor versus host cell involvement in healing was assessed. Specifically, fresh femur cortical bone grafts of 4-mm in length from COX-2-/- (KO) mice were transplanted into wild type (WT) mice with the same sized segmental defect in femurs. Similarly, grafts from WT were transplanted into the defects in KO mice. As controls, transplantations between wild types, and transplantations between KO were also performed. Histologic analyses showed that WT-to-WT transplantation resulted in normal endochondral bone healing as evidenced by markedly induction of neovascularization and periosteal bone formation on donor graft. In contrast, transplantation of KO graft into KO host led to 96 % reduction of bone formation and near elimination of donor cell-initiated periosteal bone formation. Similarly, transplantation of WT graft into a KO host resulted in 87% reduction of bone formation (n=8, p>0.05), indicating that KO host impaired WT donor progenitor cell expansion and differentiation. When a KO graft was transplanted into WT host, KO donor periosteal cell-initiated endochondral bone formation was restored. Histomorphometric analyses demonstrated 10-fold increase in bone formation and 3-fold increase in cartilage formation compared to KO-to-KO transplantation (n=8, p<0.05), suggesting that COX-2 deficient donor cells were capable to differentiate and form bone when

  17. Bone marrow mesenchymal stromal cells induce nitric oxide synthase-dependent differentiation of CD11b+ cells that expedite hematopoietic recovery.

    PubMed

    Trento, Cristina; Marigo, Ilaria; Pievani, Alice; Galleu, Antonio; Dolcetti, Luigi; Wang, Chun-Yin; Serafini, Marta; Bronte, Vincenzo; Dazzi, Francesco

    2017-02-09

    Bone marrow microenvironment is fundamental for hematopoietic homeostasis. Numerous efforts have been made to reproduce or manipulate its activity to facilitate engraftment after hematopoietic stem cell transplantation but clinical results remain unconvincing. This probably reflects the complexity of the hematopoietic niche. Recent data have demonstrated the fundamental role of stromal and myeloid cells in regulating hematopoietic stem cell self-renewal and mobilization in the bone marrow. In this study we unveil a novel interaction by which bone marrow mesenchymal stromal cells induce the rapid differentiation of CD11b+ myeloid cells from bone marrow progenitors. Such an activity requires the expression of nitric oxide synthase-2. Importantly, the administration of these mesenchymal stromal cells-educated CD11b+ cells accelerates hematopoietic reconstitution in bone marrow transplant recipients. We conclude that the liaison between mesenchymal stromal cells and myeloid cells is fundamental in hematopoietic homeostasis and suggests that it can be harnessed in clinical transplantation.

  18. Perioperative iloprost and endothelial progenitor cells in uremic patients with severe limb ischemia undergoing peripheral revascularization.

    PubMed

    Coppolino, Giuseppe; Buemi, Antoine; Bolignano, Davide; Lacquaniti, Antonio; La Spada, Michele; Stilo, Francesco; De Caridi, Giovanni; Benedetto, Francesco; Loddo, Saverio; Buemi, Michele; Spinelli, Francesco

    2009-11-01

    The incidence of severe limb ischemia (SLI) is high among haemodialysis (HD) patients. Limb rescue rate after surgical revascularization is relatively poor compared with patients with normal renal function. Prostanoids are an interesting category as adjuvants to revascularization. New vessel growth develops not exclusively by proliferation of endothelial cells in vascular extremities but also by cells mobilized from the bone marrow (HSC), transformed into endothelial progenitor cells (EPC) contributing to both re-endothelialization and neovascularization. Basal number of HSC and EPC is significantly reduced in HD patients and correlated with a subsequent defective neovascularization. The aim of this study was to evaluate the effects of perioperative treatment with iloprost in uremic patients with acute ischemia of lower limbs, undergoing surgical revascularization, on endothelial progenitor cells, hypothesizing a possible biological mechanism induced by the prostanoids. A search was also made for vascular remodeling processes through the analysis of the concentrations of soluble adhesion molecules (i-CAM, v-CAM, e-selectin), biochemical markers of endothelial activation. Thirty HD patients with SLI undergoing peripheral revascularization were enrolled (15 were treated with iloprost and 15 with a placebo). Iloprost was administered as an intra-arterial bolus of 3000 ng over 1 to 3 min immediately after revascularization and in the same affected artery. Serum samples were taken before revascularization (T0), at 6 (T6) and 24 h (T24) after infusion to measure sICAM-1, sE-selectin, and sVCAM-1, and for quantification of HSC and EPC. Progenitors were identified by specific surface markers CD34+, CD133+ and VEGFR2+. Count was conducted using PROCOUNT performed in a TRUCOUNT tube and with a FACSort flow cytometer. Before revascularization, all patients showed a decreased number of HSC and EPC. After 6 h, HSC augmented significantly compared with T0 in both groups. The

  19. Heterochromatin Protein 1 Alpha (HP1α: CBX5) is a Key Regulator in Differentiation of Endothelial Progenitor Cells to Endothelial Cells.

    PubMed

    Maeng, Yong-Sun; Kwon, Ja Young; Kim, Eung Kweon; Kwon, Young-Guen

    2015-05-01

    As the ability to control the differentiation of endothelial stem/progenitor cells (EPCs) into vascular endothelial cell lineages could be useful for promoting neovascularization, it is important to obtain a deeper understanding of the epigenetic mechanisms that regulate EPC differentiation and neovascularization. Heterochromatin protein 1α (HP1α) is known to be involved in the epigenetic regulation of gene silencing. However, recent reports demonstrate that HP1α can also activate gene expression during cell differentiation. In this study, microarray analysis revealed that HP1α expression was induced during EPC differentiation and is associated with the expression of outgrowing endothelial cell (OEC)-specific protein markers. To explore the role of HP1α in the differentiation of EPCs to OECs, its expression was knocked-down or over-expressed in differentiating EPCs. Overexpression of HP1α promoted the differentiation and angiogenic activity of EPCs in vitro and in vivo, whereas knockdown of HP1α led to a defect in OEC migration, tube formation, and angiogenic sprouting activity. Gene expression profiling showed increased expression of angiogenic genes, including NOTCH1, cadherin-5, and angiopoietin-like-2, and decreased expression of progenitor cell marker genes, including CD133, CXCR4, and C-KIT, in HP1α-overexpressing EPCs. Also, increased HP1α at an early stage of EPC differentiation may regulate angiogenic gene transcription by interacting with chromatin that modifies epigenetic factors such as the methyl-CpG binding domain, Polycomb group ring finger 2, and DNA methyltransferases. Our findings demonstrate, for the first time, that HP1α plays an important role in the differentiation and angiogenic function of EPCs by regulating endothelial gene expression. Stem Cells 2015;33:1512-1522. © 2015 AlphaMed Press.

  20. Gene Therapy with Endogenous Inhibitors of Angiogenesis for Neovascular Age-Related Macular Degeneration: Beyond Anti-VEGF Therapy.

    PubMed

    Prea, Selwyn M; Chan, Elsa C; Dusting, Gregory J; Vingrys, Algis J; Bui, Bang V; Liu, Guei-Sheung

    2015-01-01

    Age-related macular degeneration (AMD) is the leading cause of substantial and irreversible vision loss amongst elderly populations in industrialized countries. The advanced neovascular (or "wet") form of the disease is responsible for severe and aggressive loss of central vision. Current treatments aim to seal off leaky blood vessels via laser therapy or to suppress vessel leakage and neovascular growth through intraocular injections of antibodies that target vascular endothelial growth factor (VEGF). However, the long-term success of anti-VEGF therapy can be hampered by limitations such as low or variable efficacy, high frequency of administration (usually monthly), potentially serious side effects, and, most importantly, loss of efficacy with prolonged treatment. Gene transfer of endogenous antiangiogenic proteins is an alternative approach that has the potential to provide long-term suppression of neovascularization and/or excessive vascular leakage in the eye. Preclinical studies of gene transfer in a large animal model have provided impressive preliminary results with a number of transgenes. In addition, a clinical trial in patients suffering from advanced neovascular AMD has provided proof-of-concept for successful gene transfer. In this mini review, we summarize current theories pertaining to the application of gene therapy for neovascular AMD and the potential benefits when used in conjunction with endogenous antiangiogenic proteins.

  1. Cyclic AMP Response Element Binding Protein Mediates Pathological Retinal Neovascularization via Modulating DLL4-NOTCH1 Signaling

    PubMed Central

    Singh, Nikhlesh K.; Kotla, Sivareddy; Kumar, Raj; Rao, Gadiparthi N.

    2015-01-01

    Retinal neovascularization is the most common cause of moderate to severe vision loss in all age groups. Despite the use of anti-VEGFA therapies, this complication continues to cause blindness, suggesting a role for additional molecules in retinal neovascularization. Besides VEGFA and VEGFB, hypoxia induced VEGFC expression robustly. Based on this finding, we tested the role of VEGFC in pathological retinal angiogenesis. VEGFC induced proliferation, migration, sprouting and tube formation of human retinal microvascular endothelial cells (HRMVECs) and these responses require CREB-mediated DLL4 expression and NOTCH1 activation. Furthermore, down regulation of VEGFC levels substantially reduced tip cell formation and retinal neovascularization in vivo. In addition, we observed that CREB via modulating the DLL4-NOTCH1 signaling mediates VEGFC-induced tip cell formation and retinal neovascularization. In regard to upstream mechanism, we found that down regulation of p38β levels inhibited hypoxia-induced CREB-DLL4-NOTCH1 activation, tip cell formation, sprouting and retinal neovascularization. Based on these findings, it may be suggested that VEGFC besides its role in the regulation of lymphangiogenesis also plays a role in pathological retinal angiogenesis and this effect depends on p38β and CREB-mediated activation of DLL4-NOTCH1 signaling. PMID:26870802

  2. PSGL-1–mediated activation of EphB4 increases the proangiogenic potential of endothelial progenitor cells

    PubMed Central

    Foubert, Philippe; Silvestre, Jean-Sébastien; Souttou, Boussad; Barateau, Véronique; Martin, Coralie; Ebrahimian, Téni G.; Leré-Déan, Carole; Contreres, Jean Olivier; Sulpice, Eric; Levy, Bernard I.; Plouët, Jean; Tobelem, Gérard; Le Ricousse-Roussanne, Sophie

    2007-01-01

    Endothelial progenitor cell (EPC) transplantation has beneficial effects for therapeutic neovascularization; however, only a small proportion of injected cells home to the lesion and incorporate into the neocapillaries. Consequently, this type of cell therapy requires substantial improvement to be of clinical value. Erythropoietin-producing human hepatocellular carcinoma (Eph) receptors and their ephrin ligands are key regulators of vascular development. We postulated that activation of the EphB4/ephrin-B2 system may enhance EPC proangiogenic potential. In this report, we demonstrate in a nude mouse model of hind limb ischemia that EphB4 activation with an ephrin-B2–Fc chimeric protein increases the angiogenic potential of human EPCs. This effect was abolished by EphB4 siRNA, confirming that it is mediated by EphB4. EphB4 activation enhanced P selectin glycoprotein ligand-1 (PSGL-1) expression and EPC adhesion. Inhibition of PSGL-1 by siRNA reversed the proangiogenic and adhesive effects of EphB4 activation. Moreover, neutralizing antibodies to E selectin and P selectin blocked ephrin-B2–Fc–stimulated EPC adhesion properties. Thus, activation of EphB4 enhances EPC proangiogenic capacity through induction of PSGL-1 expression and adhesion to E selectin and P selectin. Therefore, activation of EphB4 is an innovative and potentially valuable therapeutic strategy for improving the recruitment of EPCs to sites of neovascularization and thereby the efficiency of cell-based proangiogenic therapy. PMID:17510705

  3. Chronic Psychological Stress Accelerates Vascular Senescence and Impairs Ischemia-Induced Neovascularization: The Role of Dipeptidyl Peptidase-4/Glucagon-Like Peptide-1-Adiponectin Axis.

    PubMed

    Piao, Limei; Zhao, Guangxian; Zhu, Enbo; Inoue, Aiko; Shibata, Rei; Lei, Yanna; Hu, Lina; Yu, Chenglin; Yang, Guang; Wu, Hongxian; Xu, Wenhu; Okumura, Kenji; Ouchi, Noriyuki; Murohara, Toyoaki; Kuzuya, Masafumi; Cheng, Xian Wu

    2017-09-28

    Exposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular aging and regeneration. Given that dipeptidyl peptidase-4 (DPP4) regulates several intracellular signaling pathways associated with the glucagon-like peptide-1 (GLP-1) metabolism, we investigated the role of DPP4/GLP-1 axis in vascular senescence and ischemia-induced neovascularization in mice under chronic stress, with a special focus on adiponectin -mediated peroxisome proliferator activated receptor-γ/its co-activator 1α (PGC-1α) activation. Seven-week-old mice subjected to restraint stress for 4 weeks underwent ischemic surgery and were kept under immobilization stress conditions. Mice that underwent ischemic surgery alone served as controls. We demonstrated that stress impaired the recovery of the ischemic/normal blood-flow ratio throughout the follow-up period and capillary formation. On postoperative day 4, stressed mice showed the following: increased levels of plasma and ischemic muscle DPP4 and decreased levels of GLP-1 and adiponectin in plasma and phospho-AMP-activated protein kinase α (p-AMPKα), vascular endothelial growth factor, peroxisome proliferator activated receptor-γ, PGC-1α, and Sirt1 proteins and insulin receptor 1 and glucose transporter 4 genes in the ischemic tissues, vessels, and/or adipose tissues and numbers of circulating endothelial CD31(+)/c-Kit(+) progenitor cells. Chronic stress accelerated aortic senescence and impaired aortic endothelial sprouting. DPP4 inhibition and GLP-1 receptor activation improved these changes; these benefits were abrogated by adiponectin blocking and genetic depletion. These results indicate that the DPP4/GLP-1-adiponectin axis is a novel therapeutic target for the treatment of vascular aging and cardiovascular disease under chronic stress conditions. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  4. Single Degenerate Progenitors of Type Ia Supernovae

    NASA Astrophysics Data System (ADS)

    Bours, Madelon; Toonen, Silvia; Nelemans, Gijs

    2013-01-01

    There is a general agreement that Type Ia supernovae correspond to the thermonuclear runaway of a white dwarf (WD) in a compact binary. The details of these progenitor systems are still unclear. Using the population synthesis code SeBa and several assumption for the WD retention efficiency, we estimate the delay times and supernova rates for the single degenerate scenario.

  5. Direct Conversion of Fibroblasts to Megakaryocyte Progenitors.

    PubMed

    Pulecio, Julian; Alejo-Valle, Oriol; Capellera-Garcia, Sandra; Vitaloni, Marianna; Rio, Paula; Mejía-Ramírez, Eva; Caserta, Ilaria; Bueren, Juan A; Flygare, Johan; Raya, Angel

    2016-10-11

    Current sources of platelets for transfusion are insufficient and associated with risk of alloimmunization and blood-borne infection. These limitations could be addressed by the generation of autologous megakaryocytes (MKs) derived in vitro from somatic cells with the ability to engraft and differentiate in vivo. Here, we show that overexpression of a defined set of six transcription factors efficiently converts mouse and human fibroblasts into MK-like progenitors. The transdifferentiated cells are CD41(+), display polylobulated nuclei, have ploidies higher than 4N, form MK colonies, and give rise to platelets in vitro. Moreover, transplantation of MK-like murine progenitor cells into NSG mice results in successful engraftment and further maturation in vivo. Similar results are obtained using disease-corrected fibroblasts from Fanconi anemia patients. Our results combined demonstrate that functional MK progenitors with clinical potential can be obtained in vitro, circumventing the use of hematopoietic progenitors or pluripotent stem cells.

  6. The Progenitors of Type Ia Supernova

    NASA Astrophysics Data System (ADS)

    Tout, C. A.

    2005-08-01

    Type Ia supernovae are identified as exploding degenerate stars. Their luminosity is due to the radioactive decay of about a solar mass of 56Ni through 56Co to 56Fe. As such they are a major source of iron in the inter-stellar medium. Although it is generally accepted that a degenerate carbon/oxygen white dwarf explodes as it accretes material from a binary companion, the progenitors of type Ia supernovae have not been categorically identified. We discuss the various possible progenitors in detail and indicate theoretical and observational difficulties with each possibility. It may well be that the true nature of the progenitors has not yet even been conceived of. We look at why population synthesis fails to help distinguish and consider how the advent of population nucleosynthesis may change this. When used as universal standard candles SNe Ia are calibrated with the Phillips relation between absolute luminosity and light curve shape. This must therefore be valid at all redshifts and so both the absolute luminosity and the light curve decay must only depend on a single major property of the progenitors. We report on the latest understanding of this relation and find little to justify its universality beyond the local empirical evidence. A major effect on the absolute luminosities is the neutron to proton ratio at the time of the explosion because this determines the fraction of iron group elements made up of 56Ni.

  7. Targeting human oligodendrocyte progenitors for myelin repair.

    PubMed

    Dietz, Karen C; Polanco, Jessie J; Pol, Suyog U; Sim, Fraser J

    2016-09-01

    Oligodendrocyte development has been studied for several decades, and has served as a model system for both neurodevelopmental and stem/progenitor cell biology. Until recently, the vast majority of studies have been conducted in lower species, especially those focused on rodent development and remyelination. In humans, the process of myelination requires the generation of vastly more myelinating glia, occurring over a period of years rather than weeks. Furthermore, as evidenced by the presence of chronic demyelination in a variety of human neurologic diseases, it appears likely that the mechanisms that regulate development and become dysfunctional in disease may be, in key ways, divergent across species. Improvements in isolation techniques, applied to primary human neural and oligodendrocyte progenitors from both fetal and adult brain, as well as advancements in the derivation of defined progenitors from human pluripotent stem cells, have begun to reveal the extent of both species-conserved signaling pathways and potential key differences at cellular and molecular levels. In this article, we will review the commonalities and differences in myelin development between rodents and man, describing the approaches used to study human oligodendrocyte differentiation and myelination, as well as heterogeneity within targetable progenitor pools, and discuss the advances made in determining which conserved pathways may be both modeled in rodents and translate into viable therapeutic strategies to promote myelin repair.

  8. SUPERNOVA REMNANT PROGENITOR MASSES IN M31

    SciTech Connect

    Jennings, Zachary G.; Williams, Benjamin F.; Dalcanton, Julianne J.; Gilbert, Karoline M.; Fouesneau, Morgan; Weisz, Daniel R.; Murphy, Jeremiah W.; Dolphin, Andrew E. E-mail: adolphin@raytheon.com

    2012-12-10

    Using Hubble Space Telescope photometry, we age-date 59 supernova remnants (SNRs) in the spiral galaxy M31 and use these ages to estimate zero-age main-sequence masses (M{sub ZAMS}) for their progenitors. To accomplish this, we create color-magnitude diagrams (CMDs) and employ CMD fitting to measure the recent star formation history of the regions surrounding cataloged SNR sites. We identify any young coeval population that likely produced the progenitor star, then assign an age and uncertainty to that population. Application of stellar evolution models allows us to infer the M{sub ZAMS} from this age. Because our technique is not contingent on identification or precise location of the progenitor star, it can be applied to the location of any known SNRs. We identify significant young star formation around 53 of the 59 SNRs and assign progenitor masses to these, representing a factor of {approx}2 increase over currently measured progenitor masses. We consider the remaining six SNRs as either probable Type Ia candidates or the result of core-collapse progenitors that have escaped their birth sites. In general, the distribution of recovered progenitor masses is bottom-heavy, showing a paucity of the most massive stars. If we assume a single power-law distribution, dN/dM{proportional_to}M{sup {alpha}}, then we find a distribution that is steeper than a Salpeter initial mass function (IMF) ({alpha} = -2.35). In particular, we find values of {alpha} outside the range -2.7 {>=} {alpha} {>=} -4.4 to be inconsistent with our measured distribution at 95% confidence. If instead we assume a distribution that follows a Salpeter IMF up to some maximum mass, then we find that values of M{sub Max} > 26 are inconsistent with the measured distribution at 95% confidence. In either scenario, the data suggest that some fraction of massive stars may not explode. The result is preliminary and requires more SNRs and further analysis. In addition, we use our distribution to estimate a

  9. Inhibition of mouse alkali burn induced-corneal neovascularization by recombinant adenovirus encoding human vasohibin-1

    PubMed Central

    Xie, Zhao-lian; Xiao, Ou; Yang, Xiao-ru; Heng, Boon Chin; Sato, Yasufumi

    2010-01-01

    Purpose To evaluate the activity of recombinant adenovirus encoding human vasohibin-1 (Ad-Vasohibin-1) on mouse corneal neovasularization induced by alkali burn. Methods For the treatment group, 50 mice each received subconjunctival injection (5 μl) of 109 plaque forming units of replication-defective Ad-Vasohibin-1. Control group mice received the same dosage of blank adenoviral vector (AdNull). Five days after injection, corneal neovascularization (CNV) was induced by placing 2.5 μl of 0.1 M NaOH on the right cornea for 30 s. Subsequently, CNV was observed and photographed every 3 days for a total duration of 9 days after the alkali burn. The percentage of neovascularized area was measured and compared with the AdNull control. The expression of human vasohibin-1 protein was detected by immunohistochemistry and western blotting at 5, 8, and 14 days after injection. The mRNA expression levels of murine vascular endothelial growth factor (Vegf), VEGF receptor 1 and 2 (Vegfr1, Vegfr2), and vasohibin-1 (Vash1) were analyzed and compared by real time quantitative reverse-transcription polymerase chain reaction. Results The percentage of neovascularized area within the cornea was significantly reduced in mice treated with Ad-Vasohibin-1 compared to mice treated with AdNull at every time point after alkali-induced injury (7.11%±3.91% and 15.48%±1.79% of corneal area in the treatment and control groups, respectively, on day 3; 31.64%±4.71% and 43.93%±6.15% on day 6, and 45.02%±9.98% and 66.24%±7.17% on day 9, all p<0.001). Human vasohibin-1 protein was detected at the injection sites on day 3 after corneal burn and was highly expressed in the central subepithelial stroma and co-localized with neovascularized vessels within the alkali-treated cornea on day 6. On day 9, the peripheral cornea exhibited a similar staining pattern as the central cornea, but a more intense vasohibin-1 immunostaining signal was detected in the deep stroma. Some of the vasohibin-1 stain

  10. Retinal Pigment Epithelial Atrophy in Neovascular Age-Related Macular Degeneration After Ranibizumab Treatment.

    PubMed

    Kuroda, Yoshimasa; Yamashiro, Kenji; Tsujikawa, Akitaka; Ooto, Sotaro; Tamura, Hiroshi; Oishi, Akio; Nakanishi, Hideo; Miyake, Masahiro; Yoshikawa, Munemitsu; Yoshimura, Nagahisa

    2016-01-01

    To investigate the risk factors for development and progression of retinal pigment epithelial (RPE) atrophy during ranibizumab treatment for neovascular age-related macular degeneration (AMD) in Japanese patients. Retrospective interventional case series. This study included 195 eyes with treatment-naïve subfoveal neovascular AMD. All patients were treated with an as-needed regimen after 3 monthly ranibizumab treatments. Color fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence were evaluated for RPE atrophy diagnosis. Baseline characteristics and ARMS2 A69S and CFH I62V polymorphisms were analyzed for their association with development and progression of RPE atrophy. Ten of 195 eyes (5.1%) had RPE atrophy at baseline; 3 had typical AMD and 7 had polypoidal choroidal vasculopathy (PCV). Among 185 eyes without preexisting RPE atrophy at baseline, 7 (3.8%) developed RPE atrophy at 12 months and 10 (5.4%) during the mean follow-up of 26.7 months. The incidence of newly developed RPE atrophy was lower in PCV than in typical AMD (P = .036), while the progression of the RPE atrophy area was faster in typical AMD than in PCV (0.57 ± 0.35 and 0.31 ± 0.13 mm/year, respectively; P = .018). The ARMS2 A69S and CFH I62V polymorphisms were significantly associated with the baseline RPE atrophy (P = .014 and P = .009, respectively). The RPE atrophy developed in 5.4% of eyes with neovascular AMD during the 26.7 months of ranibizumab treatment. When compared with white individuals, RPE atrophy developed less frequently in Japanese patients, but the progression rate was similar. The subtype of AMD thus affects the development of RPE atrophy. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Preferential Hyperacuity Perimeter (PreView PHP) for detecting choroidal neovascularization study.

    PubMed

    Alster, Yair; Bressler, Neil M; Bressler, Susan B; Brimacombe, Judith A; Crompton, R Michael; Duh, Yi-Jing; Gabel, Veit-Peter; Heier, Jeffrey S; Ip, Michael S; Loewenstein, Anat; Packo, Kirk H; Stur, Michael; Toaff, Techiya

    2005-10-01

    To assess the ability of the Preferential Hyperacuity Perimeter (PreView PHP; Carl Zeiss Meditec, Dublin, CA) to detect recent-onset choroidal neovascularization (CNV) resulting from age-related macular degeneration (AMD) and to differentiate it from an intermediate stage of AMD. Prospective, comparative, concurrent, nonrandomized, multicenter study. Eligible participants' study eyes had a corrected visual acuity of 20/160 or better and either untreated CNV from AMD diagnosed within the last 60 days or an intermediate stage of AMD. After obtaining consent, visual acuity with habitual correction, masked PHP testing, stereoscopic color fundus photography, and fluorescein angiography were performed. Photographs and angiograms were evaluated by graders masked to diagnosis and PHP results. The reading center's diagnosis determined if the patient was categorized as having intermediate AMD or neovascular AMD. A successful study outcome was defined a priori as a sensitivity of at least 80% and a specificity of at least 80%. Of 185 patients who gave consent to be enrolled, 11 (6%) had PHP results judged to be unreliable. An additional 52 were not included because they did not meet all eligibility criteria. Of the remaining 122 patients, 57 had an intermediate stage of AMD and 65 had neovascular AMD. The sensitivity to detect newly diagnosed CNV using PHP testing was 82% (95% confidence interval [CI], 70%-90%). The specificity to differentiate newly diagnosed CNV from the intermediate stage of AMD using PHP testing was 88% (95% CI, 76%-95%). Preferential Hyperacuity Perimeter testing can detect recent-onset CNV resulting from AMD and can differentiate it from an intermediate stage of AMD with high sensitivity and specificity. These data suggest that monitoring with PHP should detect most cases of CNV of recent onset with few false-positive results at a stage when treatment usually would be beneficial. Thus, this monitoring should be considered in the management of the

  12. Inhibitory effect of sub-conjunctival tocilizumab on alkali burn induced corneal neovascularization in rats.

    PubMed

    Sari, Esin Sogutlu; Yazici, Alper; Aksit, Hasan; Yay, Arzu; Sahin, Gözde; Yildiz, Onur; Ermis, Sitki Samet; Seyrek, Kamil; Yalcin, Betul

    2015-01-01

    To evaluate the effects of sub-conjunctivally applied interleukin-6 receptor (IL-6R) antibody (tocilizumab) on alkali burn induced corneal neovascularization (CNV) in rats. Alkali burn induced corneal neovascularization was created in 24 right eyes of 24 rats. The rats were then randomized into 2 groups. Group 1 received sub-conjunctival injection of 4 mg/0.2 ml tocilizumab and Group 2 received sub-conjunctival injection of 0.2 ml normal saline at the 5th day of alkali burn. The corneal surface area invaded with neovascular vessels were calculated on photographs. The rats were sacrificed and the corneas were excised at the15th day. The corneal specimens were stained with hemotoxylin-eosin to evaluate tissue morphology and with Willebrand factor (vWF) to evaluate microvascular structures immunohistochemically. Vascular endothelial growth factor (VEGF) expression was analyzed by ELISA. The percent area of CNV was 26.9% in Group 1 and 56.5% in Group 2 (p < 0.001). The histological evaluation showed that the corneal structures were not visibly altered by sub-conjuntival tocilizumab injection. Group 1 showed significantly lower corneal inflammation score than Group 2 (p < 0.001). The number of vessels stained with vWF were significantly higher in Group 2 than Group 1 (15.23 and 5.46, respectively; p < 0.001). ELISA analyses showed that corneal VEGF levels were significantly lower in Group 1 compared to Group 2 (p = 0.013) CONCLUSION: The present data demonstrated first time the beneficial effects of sub-conjunctival tocilizumab on decreasing CNV in alkali burn model of the rat cornea. Further studies are warranted to confirm these findings for the clinical application.

  13. Phacoemulsification surgery in eyes with neovascular age-related macular degeneration.

    PubMed

    Grixti, Andre; Papavasileiou, Evangelia; Cortis, Dominic; Kumar, Balakrishna Vineeth; Prasad, Som

    2014-01-01

    Purpose. To evaluate the visual outcomes and effect of phacoemulsification surgery on the progression of neovascular age-related macular degeneration (AMD). Methods. Retrospective, noncomparative, and interventional case series. Thirty eyes from 29 subjects with neovascular AMD treated with intravitreal antivascular endothelial growth factor (VEGF) injections who underwent phacoemulsification and had a postsurgery follow-up of 6 months were included. LogMAR best corrected visual acuity (BCVA) was assessed preoperatively; 1 month, 3 months, and 6 months postoperatively; and finally at the last visit. The frequency of anti-VEGF therapy, calculated as the number of intravitreal injections per month, and central macular thickness (CMT) before and after cataract surgery were determined. Results. Median (range) logMAR BCVA was 0.69 (0.16 to 1.32) preoperatively; 0.55 (-0.04 to 1.32) at 1 month, 0.52 (-0.1 to 1.32) at 3 months, and 0.50 (0.0 to 1.32) at 6 months postoperatively; and 0.6 (0.0 to 1.4) at final visit (P = 0.0011). There was no difference in the frequency of anti-VEGF injections between the immediate 6 months before and after phacoemulsification, which was equal to 0.1667 injections per month (P = 0.6377). Median CMT measured 203  μ m preoperatively, which temporarily increased to 238  μ m at 1 month after surgery (P = 0.0093) and then spontaneously returned to baseline, measuring 212.5  μ m at 3 months postoperatively (P = 0.3811). Conclusion. Phacoemulsification surgery significantly improved vision in patients with neovascular AMD, with no increased need for anti-VEGF injections to keep the macula dry postoperatively.

  14. Phacoemulsification Surgery in Eyes with Neovascular Age-Related Macular Degeneration

    PubMed Central

    Papavasileiou, Evangelia; Kumar, Balakrishna Vineeth; Prasad, Som

    2014-01-01

    Purpose. To evaluate the visual outcomes and effect of phacoemulsification surgery on the progression of neovascular age-related macular degeneration (AMD). Methods. Retrospective, noncomparative, and interventional case series. Thirty eyes from 29 subjects with neovascular AMD treated with intravitreal antivascular endothelial growth factor (VEGF) injections who underwent phacoemulsification and had a postsurgery follow-up of 6 months were included. LogMAR best corrected visual acuity (BCVA) was assessed preoperatively; 1 month, 3 months, and 6 months postoperatively; and finally at the last visit. The frequency of anti-VEGF therapy, calculated as the number of intravitreal injections per month, and central macular thickness (CMT) before and after cataract surgery were determined. Results. Median (range) logMAR BCVA was 0.69 (0.16 to 1.32) preoperatively; 0.55 (−0.04 to 1.32) at 1 month, 0.52 (−0.1 to 1.32) at 3 months, and 0.50 (0.0 to 1.32) at 6 months postoperatively; and 0.6 (0.0 to 1.4) at final visit (P = 0.0011). There was no difference in the frequency of anti-VEGF injections between the immediate 6 months before and after phacoemulsification, which was equal to 0.1667 injections per month (P = 0.6377). Median CMT measured 203 μm preoperatively, which temporarily increased to 238 μm at 1 month after surgery (P = 0.0093) and then spontaneously returned to baseline, measuring 212.5 μm at 3 months postoperatively (P = 0.3811). Conclusion. Phacoemulsification surgery significantly improved vision in patients with neovascular AMD, with no increased need for anti-VEGF injections to keep the macula dry postoperatively. PMID:24719771

  15. Bevacizumab for neovascular age-related macular degeneration in Chinese patients in a clinical setting

    PubMed Central

    Ng, Danny Siu-Chun; Kwok, Alvin Kwan-Ho; Tong, Justin Man-Kit; Chan, Clement Wai-Nang; Li, Walton Wai-Tat

    2016-01-01

    AIM To determine the outcome of non-investigational treatment with intravitreal bevacizumab (IVB) in neovascular age-related macular degeneration (AMD) patients. METHODS Retrospective chart review of 81 eyes with neovascular AMD followed-up for at least 12mo and received 3-monthly loading IVB injections. Re-treat was based upon the individual clinician's judgment. Best-corrected visual acuity (BCVA) and optical coherence tomography measurements of central foveal thickness outcomes were evaluated at 12, 24mo. RESULTS Eighty-one eyes (of 75 patients) completed 12mo of follow-up and 44 eyes (of 41 patients) completed 24mo of follow-up. The mean baseline logMAR BCVA significantly improved from 0.94±0.69 to 0.85±0.68 at 12mo (P<0.001) and from 0.91±0.65 to 0.85±0.60 (P=0.004) at 24mo. The proportion of eyes that lost <15 logMAR letters at 12mo was 90.1% and at 24mo was 81.8%. IVB was effective in improving visual acuity in both treatment naïve and previous photodynamic therapy (PDT)-treated subgroups. Treatment naive patients required significantly fewer injections than patients with prior PDT. Multiple regression analysis identified that poorer baseline visual acuity was associated with greater improvement in visual acuity (P=0.015). CONCLUSION Fewer injections in clinical practice may result in suboptimal visual outcomes compared with clinical trials of IVB in neovascular AMD patients. Poor baseline visual acuity and prior PDT treatment may also improve vision after IVB. The safety and durability of effect was maintained at 24mo. PMID:27158614

  16. The efficacy of Alahmady ring implantation in the management of neovascular glaucoma

    PubMed Central

    Alsmman, Alahmady H; Radwan, Gamal; Elagouz, Mohammed; Mohammed, Usama Ali

    2017-01-01

    Purpose To evaluate the efficacy and safety of Alahmady ring implantation in the management of neovascular glaucoma. Methods A total of 15 eyes of 15 patients with intractable neovascular glaucoma with intraocular pressure (IOP) ≥28 mmHg not responding to medical treatment were retrospectively analyzed. All patients had poor visual acuity and underwent Alahmady ring implantation. The ring was designed from fenestrated silicon tube used in lacrimal surgeries and was implanted subsclerally after passing it through the anterior chamber. Patients were followed up for at least 24 months. Success in this study was defined based on IOP ≥8 mmHg and <21 mmHg, with not more than 1 glaucoma drug, and improvement of patient symptoms and signs with maximum use of beta blocker as antiglaucoma drug. Results A total of 15 eyes of 15 patients (9 males [60%] and 6 females [40%]) were analyzed in this study. The mean IOP before surgery was 38.6 mmHg (standard deviation [SD]: 6.98) and it was 14.05 mmHg (SD =7.57) after surgery. The follow-up range was 24–36 months. Success of silicon drainage device was defined as an IOP <21 mmHg on the last follow-up visit. Medications included only beta-blockers and topical steroids for those who were without severe complications or for those who were not in a condition to undergo a further glaucoma surgery. Conclusion Alahmady ring implantation proves to be a good surgical option for neovascular glaucoma; however, a longer follow-up period is recommended. PMID:28356708

  17. Progression of Retinal Pigment Epithelial Atrophy in Antiangiogenic Therapy of Neovascular Age-Related Macular Degeneration

    PubMed Central

    Schütze, Christopher; Wedl, Manuela; Baumann, Bernhard; Pircher, Michael; Hitzenberger, Christoph K.; Schmidt-Erfurth, Ursula

    2015-01-01

    Purpose To monitor retinal pigment epithelial (RPE) atrophy progression during antiangiogenic therapy of neovascular age-related macular degeneration (AMD) over 2 years using polarization-sensitive optical coherence tomography (OCT). Design Prospective interventional case series. Methods setting: Clinical practice. study population: Thirty patients (31 eyes) with treatment-naïve neovascular AMD. observation procedures: Standard intravitreal therapy (0.5 mg ranibizumab) was administered monthly during the first year and pro re nata (PRN; as-needed) during the second year. Spectral-domain (SD) OCT and polarization-sensitive OCT (selectively imaging the RPE) examinations were performed at baseline and at 1, 3, 6, 12, and 24 months using a standardized protocol. RPE-related changes were evaluated using a semi-automated polarization-sensitive OCT segmentation algorithm and correlated with SD OCT and fundus autofluorescence (FAF) findings. main outcome measures: RPE response, geographic atrophy (GA) progression. Results Atrophic RPE changes included RPE thinning, RPE porosity, focal RPE atrophy, and development of GA. Early RPE loss (ie, RPE porosity, focal atrophy) increased progressively during initial monthly treatment and remained stable during subsequent PRN-based therapy. GA developed in 61% of eyes at month 24. Mean GA area increased from 0.77 mm2 at 12 months to 1.10 mm2 (standard deviation = 1.09 mm2) at 24 months. Reactive accumulation of RPE-related material at the lesion borders increased until month 3 and subsequently decreased. Conclusions Progressive RPE atrophy and GA developed in the majority of eyes. RPE migration signifies certain RPE plasticity. Polarization-sensitive OCT specifically images RPE-related changes in neovascular AMD, contrary to conventional imaging methods. Polarization-sensitive OCT allows for precisely monitoring the sequence of RPE-related morphologic changes. PMID:25769245

  18. Rabbit retinal neovascularization induced by latex angiogenic-derived fraction: an experimental model.

    PubMed

    Sampaio, R B; Mendonca, R J; Simioni, A R; Costa, R A; Siqueira, R C; Correa, V M; Tedesco, A C; Haddad, A; Coutinho Netto, J; Jorge, R

    2010-01-01

    To create a retinal neovascularization experimental model using intravitreal injection of microspheres loaded with latex-derived angiogenic fraction. Thirty-two albino New Zealand rabbits, divided in 4 groups of 8 animals, were enrolled in this study. Rabbits in groups I, II, and III received one intravitreal injection of PLGA (L-lactide-co-glycolide) microspheres with 10, 30, and 50 microg of latex-derived angiogenic fraction into their right eyes, respectively, and group IV received 0.1 ml of microspheres without the angiogenic fraction. Weekly follow-up with ophthalmoscopy and fluorescein angiography was performed; the rabbits were sacrificed in the 4th week and their eyes processed for light microscopy. All eyes from group I demonstrated increased retinal vascular tortuosity, observed from 14 days after injection and maintained for 28 days, otherwise without new vessels detection. All group II eyes showed vascular changes similar to group I. Fifty percent of the eyes from group II rabbits developed retinal neovascularization 21 days after injection. All eyes from group III demonstrated significant vascular tortuosity and retinal new vessels 2 weeks after injection, progressing to fibrovascular proliferation and tractional retinal detachment. No vascular changes or retinal new vessels were observed in group IV eyes. Light microscopy confirmed the existence of new vessels previously seen on fluorescein angiography, in retinal sections adjacent to the optic disc, not observed in sections at the same area in the control group. Thirty- and 50-microg microspheres containing latex-derived angiogenic fraction injected into the vitreous cavity induced retinal neovascularization in rabbits.

  19. Visible-Light Optical Coherence Tomography Angiography for Monitoring Laser-Induced Choroidal Neovascularization in Mice

    PubMed Central

    Shah, Ronil S.; Soetikno, Brian T.; Yi, Ji; Liu, Wenzhong; Skondra, Dimitra; Zhang, Hao F.; Fawzi, Amani A.

    2016-01-01

    Purpose This study sought to determine the earliest time-point at which evidence of choroidal neovascularization (CNV) could be detected with visible-light optical coherence tomography angiography (vis-OCTA) in a mouse model of laser-induced CNV. Methods Visible light-OCTA was used to study laser-induced CNV at different time-points after laser injury to monitor CNV development and measure CNV lesion size. Measurements obtained from vis-OCTA angiograms were compared with histopathologic measurements from isolectin-stained choroidal flatmounts. Results Choroidal neovascularization area measurements between the vis-OCTA system and isolectin-stained choroidal flatmounts were significantly different in area for days 2 to 4 postlaser injury, and were not significantly different in area for days 5, 7, and 14. Choroidal neovascularization area measurements taken from the stained flatmounts were larger than their vis-OCTA counterparts for all time-points. Both modalities showed a similar trend of CNV size increasing from the day of laser injury until a peak of day 7 postlaser injury and subsequently decreasing by day 14. Conclusions The earliest vis-OCTA can detect the presence of aberrant vessels in a mouse laser-induced CNV model is 5 days after laser injury. Visible light-OCTA was able to visualize the maximum of the CNV network 7 days postlaser injury, in accordance with choroidal flatmount immunostaining. Visible light-OCTA is a reliable tool in both detecting the presence of CNV development, as well as accurately determining the size of the lesion in a mouse laser-induced CNV model. PMID:27409510

  20. Incidence and Clinical Features of Neovascularization of the Iris following Acute Central Retinal Artery Occlusion.

    PubMed

    Jung, Young Ho; Ahn, Seong Joon; Hong, Jeong-Ho; Park, Kyu Hyung; Han, Moon-Ku; Jung, Cheolkyu; Woo, Se Joon

    2016-10-01

    To investigate the incidence of neovascularization of the iris (NVI) and clinical features of patients with NVI following acute central retinal artery occlusion (CRAO). A retrospective review of 214 consecutive CRAO patients who visited one tertiary hospital between January 2009 and January 2015 was conducted. In total, 110 patients were eligible for this study after excluding patients with arteritic CRAO, a lack of follow-up, iatrogenic CRAO secondary to cosmetic filler injection, or NVI detected before CRAO attack. Fluorescein angiography (FA) was applied until retinal arterial reperfusion was achieved, typically within 1 to 3 months. The incidence of NVI was 10.9% (12 out of 110 patients). Neovascular glaucoma was found in seven patients (6.4%). The mean time to NVI diagnosis after CRAO events was 3.0 months (range, 1 week to 15 months). The cumulative incidence was 5.5% at 3 months, 7.3% at 6 months, and 10.9% at 15 months. Severely narrowed ipsilateral carotid arteries were observed in only three patients (27.3%). The other nine patients (75.0%) showed no predisposing conditions for NVI, such as proliferative diabetic retinopathy or central retinal vein occlusion. Reperfusion rate and prevalence of diabetes were significantly different between patients with NVI and patients without NVI (reperfusion: 0% [NVI] vs. 94.7% [no NVI], p < 0.001; diabetes: 50.0% [NVI] vs. 17.3% [no NVI], p = 0.017). CRAO may lead to NVI and neovascular glaucoma caused by chronic retinal ischemia from reperfusion failure. Our results indicate that follow-up fluorescein angiography is important to evaluate retinal artery reperfusion after acute CRAO events, and that prophylactic treatment such as panretinal photocoagulation should be considered if retinal arterial perfusion is not recovered.

  1. Dietary Compound Chrysin Inhibits Retinal Neovascularization with Abnormal Capillaries in db/db Mice

    PubMed Central

    Kang, Min-Kyung; Park, Sin-Hye; Kim, Yun-Ho; Lee, Eun-Jung; Antika, Lucia Dwi; Kim, Dong Yeon; Choi, Yean-Jung; Kang, Young-Hee

    2016-01-01

    Diabetic retinopathy (DR) develops in a significant proportion of patients with chronic diabetes, characterized by retinal macular edema and abnormal retinal vessel outgrowth leading to vision loss. Chrysin, a naturally-occurring flavonoid found in herb and honeycomb, has anti-inflammatory, antioxidant, and anti-cancer properties. This study sought to determine the protective effects of chrysin on retinal neovascularization with abnormal vessels and blood-retinal barrier (BRB) breakdown in 33 mM glucose-exposed human retinal endothelial cells and in db/db mouse eyes. High glucose caused retinal endothelial apoptotic injury, which was inhibited by submicromolar chrysin. This compound diminished the enhanced induction of HIF-1α, vascular endothelial growth factor (VEGF), and VEGF receptor-2 (VEGFR2) in high glucose-exposed retinal endothelial cells. Consistently, oral administration of 10 mg/kg chrysin reduced the induction of these proteins in db/db mouse eye tissues. In addition, chrysin restored the decrement of VE-cadherin and ZO-1 junction proteins and PECAM-1 in hyperglycemia-stimulated retinal endothelial cells and diabetic mouse retina, possibly maintaining tight cell-cell interactions of endothelial cells and pericytes. Anti-apoptotic chrysin reduced the up-regulation of Ang-1, Ang-2, and Tie-2 crucial to retinal capillary occlusion and BRB permeability. Furthermore, orally treating chrysin inhibited acellular capillary formation, neovascularization, and vascular leakage observed in diabetic retinas. These observations demonstrate, for the first time, that chrysin had a capability to encumber diabetes-associated retinal neovascularization with microvascular abnormalities and BRB breakdown. PMID:27918469

  2. Hierarchic micro-patterned porous scaffolds via electrochemical replica-deposition enhance neo-vascularization.

    PubMed

    Varoni, Elena Maria; Altomare, Lina; Cochis, Andrea; GhalayaniEsfahani, Arash; Cigada, Alberto; Rimondini, Lia; De Nardo, Luigi

    2016-04-21

    Neo-vascularization is a key factor in tissue regeneration within porous scaffolds. Here, we tested the hypothesis that micro-patterned scaffolds, with precisely-designed, open micro-channels, might help endothelial cells to produce intra-scaffold vascular networks. Three series of micro-patterned scaffolds were produced via electrochemical replica-deposition of chitosan and cross-linking. All had regularly-oriented micro-channels (ϕ 500 μm), which differed for the inter-channel spacing, at 600, 700, or 900 μm, respectively. Random-pore scaffolds, using the same technique, were taken as controls. Physical-mechanical characterization revealed high water uptake and favorable elastic mechanical behavior for all scaffolds, slightly reduced in the presence of cross-linking and enhanced with the 700 μm-spaced micro-pattern. At MTT assay, mouse endothelial cell viability was >90% at day 1, 3 and 7, confirmed by visual examination with scanning electron microscopy (SEM). Intra-scaffold cell density, at fluorescence analysis, was higher for the 600 μm-spaced and the 700 μm-spaced micro-patterns over the others. The 700 μm-spaced scaffold was selected for the in vivo testing, to be compared to the random-pore one. Neither type produced an inflammatory reaction; both showed excellent tissue ingrowth. Micro-patterned scaffolds enhanced neo-vascularization, demonstrated by immunofluorescent, semi-quantitative analyses. These findings support the use of micro-patterned porous scaffolds, with adequately spaced micro-channels, to promote neo-vascularization.

  3. PROGNOSTIC VALUE OF HYPERREFLECTIVE FOCI IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION TREATED WITH BEVACIZUMAB.

    PubMed

    Segal, Ori; Barayev, Edward; Nemet, Arie Y; Geffen, Noa; Vainer, Igor; Mimouni, Michael

    2016-11-01

    To study the prognostic value of optical coherence tomography hyperreflective foci (HF) in neovascular age-related macular degeneration. Charts of naive neovascular age-related macular degeneration eyes treated with intravitreal bevacizumab between January 2011 and January 2014 were reviewed, and optical coherence tomography was collected at baseline, 3 months, and 12 months. The presence, location (inner vs. outer retinal layers), and number (few = [0-10], moderate [11-20], many [>20]) of HF were graded. Overall, charts of 111 eyes were reviewed and 76 eyes of 73 patients fulfilled inclusion criteria. Baseline best-corrected visual acuity was lower in eyes with HF > 20 (P = 0.001), inner layer HF (P = 0.009), increased central retinal thickness (P < 0.001), and intraretinal fluid (P < 0.001). Baseline HF > 20 (P = 0.002), inner layer HF (P = 0.01), increased central retinal thickness (P < 0.001), and intraretinal fluid (P = 0.001) had worst best-corrected visual acuity at 12 months. Eyes with intraretinal fluid, HF > 20, and HF adjacent to intraretinal fluid demonstrated a greater reduction in central retinal thickness; only baseline HF > 20 remained significant in multivariate analysis (P < 0.001). Eyes with a reduction in HF (P = 0.02) and resolution of inner layer HF (P = 0.01) had a greater central retinal thickness reduction. Quantity and location of HF are of prognostic value in intravitreal bevacizumab-treated naive neovascular age-related macular degeneration. Increased awareness of specialists interpreting optical coherence tomography scans toward the number and location of HF is prudent.

  4. VEGF-Production by CCR2-Dependent Macrophages Contributes to Laser-Induced Choroidal Neovascularization

    PubMed Central

    Krause, Torsten A.; Alex, Anne F.; Engel, Daniel R.; Kurts, Christian; Eter, Nicole

    2014-01-01

    Age-related macular degeneration (AMD) is the most prevalent cause of blindness in the elderly, and its exsudative subtype critically depends on local production of vascular endothelial growth factor A (VEGF). Mononuclear phagocytes, such as macrophages and microglia cells, can produce VEGF. Their precursors, for example monocytes, can be recruited to sites of inflammation by the chemokine receptor CCR2, and this has been proposed to be important in AMD. To investigate the role of macrophages and CCR2 in AMD, we studied intracellular VEGF content in a laser-induced murine model of choroidal neovascularisation. To this end, we established a technique to quantify the VEGF content in cell subsets from the laser-treated retina and choroid separately. 3 days after laser, macrophage numbers and their VEGF content were substantially elevated in the choroid. Macrophage accumulation was CCR2-dependent, indicating recruitment from the circulation. In the retina, microglia cells were the main VEGF+ phagocyte type. A greater proportion of microglia cells contained VEGF after laser, and this was CCR2-independent. On day 6, VEGF-expressing macrophage numbers had already declined, whereas numbers of VEGF+ microglia cells remained increased. Other sources of VEGF detectable by flow cytometry included in dendritic cells and endothelial cells in both retina and choroid, and Müller cells/astrocytes in the retina. However, their VEGF content was not increased after laser. When we analyzed flatmounts of laser-treated eyes, CCR2-deficient mice showed reduced neovascular areas after 2 weeks, but this difference was not evident 3 weeks after laser. In summary, CCR2-dependent influx of macrophages causes a transient VEGF increase in the choroid. However, macrophages augmented choroidal neovascularization only initially, presumably because VEGF production by CCR2-independent eye cells prevailed at later time points. These findings identify macrophages as a relevant source of VEGF in laser

  5. VEGF-production by CCR2-dependent macrophages contributes to laser-induced choroidal neovascularization.

    PubMed

    Krause, Torsten A; Alex, Anne F; Engel, Daniel R; Kurts, Christian; Eter, Nicole

    2014-01-01

    Age-related macular degeneration (AMD) is the most prevalent cause of blindness in the elderly, and its exsudative subtype critically depends on local production of vascular endothelial growth factor A (VEGF). Mononuclear phagocytes, such as macrophages and microglia cells, can produce VEGF. Their precursors, for example monocytes, can be recruited to sites of inflammation by the chemokine receptor CCR2, and this has been proposed to be important in AMD. To investigate the role of macrophages and CCR2 in AMD, we studied intracellular VEGF content in a laser-induced murine model of choroidal neovascularisation. To this end, we established a technique to quantify the VEGF content in cell subsets from the laser-treated retina and choroid separately. 3 days after laser, macrophage numbers and their VEGF content were substantially elevated in the choroid. Macrophage accumulation was CCR2-dependent, indicating recruitment from the circulation. In the retina, microglia cells were the main VEGF+ phagocyte type. A greater proportion of microglia cells contained VEGF after laser, and this was CCR2-independent. On day 6, VEGF-expressing macrophage numbers had already declined, whereas numbers of VEGF+ microglia cells remained increased. Other sources of VEGF detectable by flow cytometry included in dendritic cells and endothelial cells in both retina and choroid, and Müller cells/astrocytes in the retina. However, their VEGF content was not increased after laser. When we analyzed flatmounts of laser-treated eyes, CCR2-deficient mice showed reduced neovascular areas after 2 weeks, but this difference was not evident 3 weeks after laser. In summary, CCR2-dependent influx of macrophages causes a transient VEGF increase in the choroid. However, macrophages augmented choroidal neovascularization only initially, presumably because VEGF production by CCR2-independent eye cells prevailed at later time points. These findings identify macrophages as a relevant source of VEGF in laser

  6. Deguelin inhibits retinal neovascularization by down-regulation of HIF-1α in oxygen-induced retinopathy

    PubMed Central

    Kim, J H; Kim, J H; Yu, Y S; Shin, J Y; Lee, H-Y; Kim, K-W

    2008-01-01

    Retinal neovascularization is the most common cause of blindness; Retinopathy of pre-maturity (ROP) for children and diabetic retinopa-thy for young age group. ROP still remains as the most serious cause of vision loss in children. We provided that deguelin significantly reduces retinal neovascularization in a mouse model of ROP. Deguelin never affected the transcriptional activity of hypoxia inducible factor (HIF)-1α, however, reduced HIF-1α expression, which led to the decrease of vascular endothelial growth factor expression. Deguelin effectively suppressed endothelial cell proliferation without cytotoxic effect under therapeutic concentration range. In addition, deguelin demonstrated no reduction or retardation in normal retinal development and no retinal toxicity. These data suggest deguelin is a potent inhibitor of retinal neovascularization and may be applied in the treatment of other vasoproliferative retinopathies. PMID:18208562

  7. Deguelin inhibits retinal neovascularization by down-regulation of HIF-1alpha in oxygen-induced retinopathy.

    PubMed

    Kim, J H; Kim, J H; Yu, Y S; Shin, J Y; Lee, H-Y; Kim, K-W

    2008-12-01

    Retinal neovascularization is the most common cause of blindness; Retinopathy of pre-maturity (ROP) for children and diabetic retinopathy for young age group. ROP still remains as the most serious cause of vision loss in children. We provided that deguelin significantly reduces retinal neovascularization in a mouse model of ROP. Deguelin never affected the transcriptional activity of hypoxia inducible factor (HIF)-1, however, reduced HIF-1 expression, which led to the decrease of vascular endothelial growth factor expression. Deguelin effectively suppressed endothelial cell proliferation without cytotoxic effect under therapeutic concentration range. In addition, deguelin demonstrated no reduction or retardation in normal retinal development and no retinal toxicity. These data suggest deguelin is a potent inhibitor of retinal neovascularization and may be applied in the treatment of other vasoproliferative retinopathies.

  8. Neovascularity in patellar tendinopathy and the response to eccentric training: a case report using Power Doppler ultrasound.

    PubMed

    McCreesh, Karen M; Riley, Sara J; Crotty, James M

    2013-12-01

    This report describes the case of an amateur soccer player with chronic patellar tendinopathy who underwent ultrasound imaging before and after engaging in an 8-week programme of eccentric exercise. On initial assessment, greyscale ultrasound imaging demonstrated tendon thickening and reduced echogenicity, while Power Doppler imaging demonstrated a large amount of neovascularity. After 8 weeks of an eccentric loading programme, the patient reported significantly improved symptoms and functional scores, while follow-up imaging demonstrated improvement in the echo appearance of the tendon and complete resolution of the neovascularity. The association between neovascularity and symptoms in tendinopathy research is conflicting, with a paucity of research in the area of patellar tendinopathy. While further research is needed to clarify the significance of greyscale and Power Doppler ultrasound changes in relation to symptoms in patellar tendinopathy, ultrasound imaging was shown to be a useful adjunct to diagnosis and outcome assessment in this case.

  9. Choroidal neovascularization secondary to ocular penetration during retrobulbar anesthesia and its treatment

    PubMed Central

    Dikci, Seyhan; Yılmaz, Turgut; Gök, Zarife Ekici; Demirel, Soner; Genç, Oğuzhan

    2017-01-01

    Retrobulbar anesthesia is still used before ocular surgery; however, it has various complications including ocular penetration. The penetration/perforation of the globe can cause complications such as endophthalmitis, retinal detachment, and scotoma. Choroidal neovascularization (CNV) is rarely seen, following choroidal rupture in penetrating eye injuries. Here, we present a patient who underwent a pars plana vitrectomy for vitreous hemorrhage secondary to ocular penetration during a retrobulbar injection for cataract surgery. This patient later developed CNV at the penetration site during follow-up. Physicians should remember that CNV can occur as an unusual late complication of ocular penetration during retrobulbar anesthesia.

  10. Identification of intraretinal neovascularization by high-speed indocyanine green angiography in idiopathic perifoveal telangiectasia.

    PubMed

    Soheilian, Masoud; Tavallali, Ali; Peyman, Gholam A

    2007-01-01

    Rapid advances in imaging technology have dramatically improved our understanding of the flow patterns of intraretinal circulation in normal and diseased states. To identify the angiographic features and flow pattern of retinal circulation in a patient with type 2 idiopathic perifoveal telangiectasia, dynamic simultaneous high-speed videoangiography using confocal scanning laser ophthalmoscopy was performed. This diagnostic tool provides enhanced anatomic resolution of retinal arterioles otherwise poorly defined by regular fluorescein and static indocyanine green angiography. High-speed indocyanine green angiography demonstrated dynamic flow abnormalities such as intraretinal neovascular complex and retino-retinal anastomosis in idiopathic perifoveal telangiectasia.

  11. Cost-effectiveness of bevacizumab and ranibizumab for newly diagnosed neovascular macular degeneration.

    PubMed

    Stein, Joshua D; Newman-Casey, Paula Anne; Mrinalini, Tavag; Lee, Paul P; Hutton, David W

    2014-04-01

    We sought to determine the most cost-effective treatment for patients with newly diagnosed neovascular macular degeneration: monthly or as-needed bevacizumab injections, or monthly or as-needed ranibizumab injections. Cost-effectiveness analysis. Hypothetical cohort of 80-year-old patients with newly diagnosed neovascular macular degeneration. Using a mathematical model with a 20-year time horizon, we compared the incremental cost-effectiveness of treating a hypothetical cohort of 80-year-old patients with newly diagnosed neovascular macular degeneration using monthly bevacizumab, as-needed bevacizumab, monthly ranibizumab, or as-needed ranibizumab. Data came from the Comparison of Age-related macular degeneration Treatment Trial (CATT), the Medicare Fee Schedule, and the medical literature. Costs, quality-adjusted life-years (QALYs), and incremental costs per QALY gained. Compared with as-needed bevacizumab, the incremental cost-effectiveness ratio of monthly bevacizumab is $24,2 357/QALY. Monthly ranibizumab gains an additional 0.02 QALYs versus monthly bevacizumab at an incremental cost-effectiveness ratio of >$10 million/QALY. As-needed ranibizumab was dominated by monthly bevacizumab, meaning it was more costly and less effective. In sensitivity analyses assuming a willingness to pay of $100,000/QALY, the annual risk of serious vascular events would have to be ≥2.5 times higher with bevacizumab than that observed in the CATT trial for as-needed ranibizumab to have an incremental cost-effectiveness ratio of <$100,000/QALY. In another sensitivity analysis, even if every patient receiving bevacizumab experienced declining vision by 1 category (e.g., from 20/25-20/40 to 20/50-20/80) after 2 years but every patient receiving ranibizumab retained their vision level, as-needed ranibizumab would have an incremental cost-effectiveness ratio of $97,340/QALY. Even after considering the potential for differences in risks of serious adverse events and therapeutic

  12. Cost-Effectiveness of Bevacizumab and Ranibizumab for Newly Diagnosed Neovascular Macular Degeneration

    PubMed Central

    Stein, Joshua D.; Newman-Casey, Paula Anne; Mrinalini, Tavag; Lee, Paul P.; Hutton, David W.

    2014-01-01

    Purpose To determine the most cost-effective treatment for patients with newly diagnosed neovascular macular degeneration: monthly or as-needed bevacizumab injections, or monthly or as-needed ranibizumab injections. Design Cost effectiveness analysis Participants Hypothetical cohort of 80-year-old patients with newly-diagnosed neovascular macular degeneration. Methods Using a mathematical model with a 20-year time horizon, we compared the incremental cost-effectiveness of treating a hypothetical cohort of 80-year-old patients with newly diagnosed neovascular macular degeneration using monthly bevacizumab, as-needed bevacizumab, monthly ranibizumab, or as-needed ranibizumab. Data came from the Comparison of Age-related macular degeneration Treatment Trial (CATT), the Medicare Fee Schedule, and the medical literature. Main Outcome Measures Costs, quality-adjusted life years (QALYs), and incremental costs per QALY gained. Results Compared with as-needed bevacizumab, the incremental cost-effectiveness ratio of monthly bevacizumab is $242 357/QALY. Monthly ranibizumab gains an additional 0.02 QALYs versus monthly bevacizumab at an incremental cost-effectiveness ratio of more than $10 million/QALY. As-needed ranibizumab was dominated by monthly bevacizumab, meaning it was more costly and less effective. In sensitivity analyses assuming a willingness to pay of $100 000/QALY, the annual risk of serious vascular events would have to be at least 2.5 times higher with bevacizumab than that observed in the CATT trial for as-needed ranibizumab to have an incremental cost-effectiveness ratio of <$100 000/QALY. In another sensitivity analysis, even if every patient receiving bevacizumab experienced declining vision by one category (e.g., from 20/25–20/40 to 20/50–20/80) after 2 years but every patient receiving ranibizumab retained their vision level, as-needed ranibizumab would have an incremental cost-effectiveness ratio of $97 340/QALY. Conclusion Even after considering

  13. Posterior capsule opacification and neovascularization treated with intravitreal bevacizumab and Nd:YAG capsulotomy

    PubMed Central

    Sánchez-Castro, Grimelda Yuriana; Hitos-Fájer, Alejandra; Mendoza-Schuster, Erick; Velez-Montoya, Raul; Velasco-Barona, Cecilio Francisco

    2008-01-01

    We reported a 75-year-old diabetic man, who developed opacification and neovascularization of the posterior capsule after extracapsular cataract extraction and posterior chamber intraocular lens implantation. The patient was treated with two injections of 2.5 mg of intravitreal bevacizumab. The treatment produced an important regression of the posterior capsular new vessels, allowing us to perform a successful Nd:YAG capsulotomy, clearing the visual axis and improving the visualization of the posterior pole. Even though, best corrected visual acuity was 20/200 due to diabetic macular edema. PMID:19668770

  14. Origin of hemopoietic stromal progenitor cells in chimeras

    SciTech Connect

    Chertkov, J.L.; Drize, N.J.; Gurevitch, O.A.; Samoylova, R.S.

    1985-12-01

    Intravenously injected bone marrow cells do not participate in the regeneration of hemopoietic stromal progenitors in irradiated mice, nor in the curetted parts of the recipient's marrow. The hemopoietic stromal progenitors in allogeneic chimeras are of recipient origin. The adherent cell layer (ACL) of long-term cultures of allogeneic chimera bone marrow contains only recipient hemopoietic stromal progenitors. However, in ectopic hemopoietic foci produced by marrow implantation under the renal capsule and repopulated by the recipient hemopoietic cells after irradiation and reconstitution by syngeneic hemopoietic cells, the stromal progenitors were of implant donor origin, as were stromal progenitors of the ACL in long-term cultures of hemopoietic cells from ectopic foci. Our results confirm that the stromal and hemopoietic progenitors differ in origin and that hemopoietic stromal progenitors are not transplantable by the intravenous route in mice.

  15. Clinical utilization of anti-VEGF agents and disease monitoring in neovascular age-related macular degeneration.

    PubMed

    Holekamp, Nancy M; Liu, Ying; Yeh, Wei-Shi; Chia, Yifeng; Kiss, Szilárd; Almony, Arghavan; Kowalski, Jonathan W

    2014-04-01

    To examine bevacizumab and ranibizumab utilization and disease monitoring patterns in patients with neovascular age-related macular degeneration (neovascular AMD) in clinical practice. Retrospective medical claims analysis. Patients receiving ≥1 ranibizumab or bevacizumab injection during the 12 months after initial neovascular AMD diagnosis were included. Annual bevacizumab and/or ranibizumab injection utilization was assessed by year of first injection cohorts: 2006 and 2007 (received either agent because of billing code overlap), 2008, 2009, and January-June 2010 (received each agent). Outcome measures were time to first injection relative to neovascular AMD diagnosis and mean numbers of intravitreal injections, ophthalmologist visits, and optical coherence tomography (OCT) and fluorescein angiography (FA) examinations in 12 months. In the 2006 and 2007 cohorts (n = 8767), mean annual numbers of bevacizumab or ranibizumab injections were 4.7 and 5.0, respectively. Over 92% of patients in all cohorts received first treatment within 3 months of neovascular AMD diagnosis. In the 2008-2010 cohorts (n = 10 259), mean annual number of injections remained low (bevacizumab: 4.6, 5.1, and 5.5; ranibizumab: 6.1, 6.6, and 6.9), as did mean numbers of ophthalmologist visits (bevacizumab only) and OCT examinations (both agents), but there was no such trend in FA examinations. Compared with treatment paradigms validated by clinical trials published at the time, in clinical practice, patients with neovascular AMD received fewer bevacizumab or ranibizumab injections and less-frequent monitoring from 2006 to mid-2011. Factors contributing to this lower injection frequency and visual outcomes associated with reduced utilization need to be researched. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Increased risk of Parkinson disease following a diagnosis of neovascular age-related macular degeneration: a retrospective cohort study.

    PubMed

    Chung, Shiu-Dong; Ho, Jau-Der; Hu, Chao-Chien; Lin, Herng-Ching; Sheu, Jau-Jiuan

    2014-02-01

    To investigate the risk for Parkinson disease during a 3-year follow-up period after a diagnosis of neovascular age-related macular degeneration (AMD) using a nationwide population-based dataset in Taiwan. A retrospective matched-cohort study. We identified 877subjects with neovascular AMD as the study cohort and randomly selected 8770 subjects for a comparison cohort. Each subject was individually followed for a 3-year period to identify those who subsequently developed Parkinson disease. Stratified Cox proportional hazard regressions were performed as a means of comparing the 3-year risk of subsequent Parkinson disease between the study and comparison cohorts. The incidence rate of Parkinson disease was 5.32 (95% confidence interval [CI]: 3.03-8.72) per 1000 person-years in patients with neovascular AMD and 2.09 (95% CI: 1.59-2.70) per 1000 person-years in comparison patients. The log-rank test indicated that subjects with neovascular AMD had a significantly lower 3-year Parkinson disease-free survival rate than comparison subjects (P < .001). After censoring cases in which patients died during the follow-up period and adjusting for monthly income, geographic region, hypertension, diabetes, hyperlipidemia, and coronary heart disease, the hazard ratio of Parkinson disease during the 3-year follow-up period for subjects with neovascular AMD was 2.57 (95% CI: 1.42-4.64) that of comparison subjects. In this study, subjects with neovascular AMD were found to be at a significant risk of Parkinson disease during a 3-year follow-up period after their diagnosis among Taiwanese Chinese. Further study is needed to confirm our findings and explore the underlying pathomechanism. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. A nationwide cohort study of cigarette smoking and risk of neovascular age-related macular degeneration in East Asian men.

    PubMed

    Rim, Tyler Hyungtaek; Cheng, Ching-Yu; Kim, Dong Wook; Kim, Sung Soo; Wong, Tien Y

    2017-10-01

    Few longitudinal studies have evaluated the relationship between cigarette smoking and risk of neovascular age-related macular degeneration (AMD) among Asian populations. This study aimed to prospectively evaluate the association between cigarette smoking and risk of neovascular AMD among Korean men. Men between the ages of 45 and 79 years included in the Korea National Health Insurance Service database from 2002 through 2013. We compared hazard ratios (HR) for neovascular AMD between 64 560 past/current and 64 560 never smokers by 1:1 propensity-matched analysis and 85 267 past/current and 72 347 never smokers by unmatched cohort and propensity-adjusted analysis. The risk of neovascular AMD among past/current smokers was 50% higher than that among never smokers (propensity-adjusted whole cohort analysis: HR, 1.48; 95% CI 1.22 to 1.79; propensity-matched analysis: HR, 1.50; 95% CI 1.22 to 1.84), with the risk more pronounced among current than past smokers (current vs past smokers: propensity-adjusted whole cohort analysis, HR, 1.66; 95% CI 1.35 to 2.04 vs HR, 1.15, 95% CI 0.87 to 1.52; propensity-matched analysis, HR, 1.65; 95% CI 1.32 to 2.05 vs HR, 1.21; 95% CI 0.90 to 1.63). Duration of smoking and daily cigarette consumption was associated with the incidence of neovascular AMD in a dose-dependent manner (p<0.001 for trend). Cigarette smoking is associated with a strong risk of neovascular AMD among Korean men. These data highlight the public health impact of smoking on blindness in Asia. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  18. Inhibitory effects of topical cyclosporine A 0.05% on immune-mediated corneal neovascularization in rabbits.

    PubMed

    Bucak, Yasin Yücel; Erdurmus, Mesut; Terzi, Elçin Hakan; Kükner, Aysel; Çelebi, Serdal

    2013-11-01

    We aimed to study the inhibitory effects of topical cyclosporine A (CsA) 0.05% on immune-mediated corneal neovascularization, and to compare its efficacy with those of dexamethasone 0.1% and bevacizumab 0.5%. Immune-mediated corneal neovascularization was created in 36 right eyes of 36 rabbits. The rabbits were then randomized into four groups. Group I received CsA 0.05%, Group II received dexamethasone 0.1%, Group III received bevacizumab 0.5%, and Group IV received isotonic saline twice a day for 14 days. The corneal surface covered with neovascular vessels was measured on the photographs. The rabbits were then sacrificed and the corneas excised. Paraffin-embedded sections were stained with hematoxylin-eosin and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. The means of percent area of corneal neovascularization in Group I, II, III, and IV were 24.4%, 5.9%, 37.1%, and 44.1%, respectively. The inhibitory effect of CsA 0.05% was found to be better than the effect found in the bevacizumab 0.5% and control groups (p = 0.03 and p = 0.02, respectively). CsA 0.05% was found to have significantly lesser inhibitory effects on corneal neovascularization than dexamethasone 0.1% (p < 0.001). Apoptotic cell density was higher in Group III and Group IV than in Group I and Group II. There was no difference between Group I and Group II in terms of apoptotic cell density (p = 0.7). Topical CsA 0.05% was shown to have an inhibitory effect on immune-mediated corneal neovascularization in rabbits.

  19. Inhibition of the Nuclear Receptor RORγ and Interleukin-17A Suppresses Neovascular Retinopathy: Involvement of Immunocompetent Microglia.

    PubMed

    Talia, Dean M; Deliyanti, Devy; Agrotis, Alex; Wilkinson-Berka, Jennifer L

    2016-06-01

    Although inhibitors of vascular endothelial growth factor (VEGF) provide benefit for the management of neovascular retinopathies, their use is limited to end-stage disease and some eyes are resistant. We hypothesized that retinoic acid-related orphan nuclear receptor γ (RORγ) and its downstream effector, interleukin (IL)-17A, upregulate VEGF and hence are important treatment targets for neovascular retinopathies. Utilizing a model of oxygen-induced retinopathy, confocal microscopy and flow cytometry, we identified that retinal immunocompetent cells, microglia, express IL-17A. This was confirmed in primary cultures of rat retinal microglia, where hypoxia increased IL-17A protein as well as IL-17A, RORγ, and tumor necrosis factor-α mRNA, which were reduced by the RORγ inhibitor, digoxin, and the RORα/RORγ inverse agonist, SR1001. By contrast, retinal macroglial Müller cells and ganglion cells, key sources of VEGF in oxygen-induced retinopathy, did not produce IL-17A when exposed to hypoxia and IL-1β. However, they expressed IL-17 receptors, and in response to IL-17A, secreted VEGF. This suggested that RORγ and IL-17A inhibition might attenuate neovascular retinopathy. Indeed, digoxin and SR1001 reduced retinal vaso-obliteration, neovascularization, and vascular leakage as well as VEGF and VEGF-related placental growth factor. Digoxin and SR1001 reduced microglial-derived IL-17A and Müller cell and ganglion cell damage. The importance of IL-17A in oxygen-induced retinopathy was confirmed by IL-17A neutralization reducing vasculopathy, VEGF, placental growth factor, tumor necrosis factor-α, microglial density and Müller cell, and ganglion cell injury. Our findings indicate that an RORγ/IL-17A axis influences VEGF production and neovascular retinopathy by mechanisms involving neuroglia. Inhibition of RORγ and IL-17A may have potential for the improved treatment of neovascular retinopathies. © 2016 American Heart Association, Inc.

  20. Galactic constraints on supernova progenitor models

    NASA Astrophysics Data System (ADS)

    Acharova, I. A.; Gibson, B. K.; Mishurov, Yu. N.; Kovtyukh, V. V.

    2013-09-01

    Aims: To estimate the mean masses of oxygen and iron ejected per each type of supernovae (SNe) event from observations of the elemental abundance patterns in the Galactic disk and constrain the relevant SNe progenitor models. Methods: We undertake a statistical analysis of the radial abundance distributions in the Galactic disk within a theoretical framework for Galactic chemical evolution which incorporates the influence of spiral arms. This framework has been shown to recover the non-linear behaviour in radial gradients, the mean masses of oxygen and iron ejected during SNe explosions to be estimated, and constraints to be placed on SNe progenitor models. Results: (i) The mean mass of oxygen ejected per core-collapse SNe (CC SNe) event (which are concentrated within spiral arms) is ~0.27 M⊙; (ii) the mean mass of iron ejected by tardy Type Ia SNe (SNeIa, whose progenitors are older/longer-lived stars with ages ≳100 Myr and up to several Gyr, which do not concentrate within spiral arms) is ~0.58 M⊙; (iii) the upper mass of iron ejected by prompt SNeIa (SNe whose progenitors are younger/shorter-lived stars with ages ≲100 Myr, which are concentrated within spiral arms) is ≤0.23 M⊙ per event; (iv) the corresponding mean mass of iron produced by CC SNe is ≤0.04 M⊙ per event; (v) short-lived SNe (core-collapse or prompt SNeIa) supply ~85% of the Galactic disk's iron. Conclusions: The inferred low mean mass of oxygen ejected per CC SNe event implies a low upper mass limit for the corresponding progenitors of ~23 M⊙, otherwise the Galactic disk would be overabundant in oxygen. This inference is the consequence of the non-linear dependence between the upper limit of the progenitor initial mass and the mean mass of oxygen ejected per CC SNe explosion. The low mean mass of iron ejected by prompt SNeIa, relative to the mass produced by tardy SNeIa (~2.5 times lower), prejudices the idea that both sub-populations of SNeIa have the same physical nature. We

  1. New therapy targeting differential androgen receptor signaling in prostate cancer stem/progenitor vs. non-stem/progenitor cells

    PubMed Central

    Lee, Soo Ok; Ma, Zhifang; Yeh, Chiuan-Ren; Luo, Jie; Lin, Tzu-Hua; Lai, Kuo-Pao; Yamashita, Shinichi; Liang, Liang; Tian, Jing; Li, Lei; Jiang, Qi; Huang, Chiung-Kuei; Niu, Yuanjie; Yeh, Shuyuan; Chang, Chawnshang

    2013-01-01

    The androgen deprivation therapy (ADT) to systematically suppress/reduce androgens binding to the androgen receptor (AR) has been the standard therapy for prostate cancer (PCa); yet, most of ADT eventually fails leading to the recurrence of castration resistant PCa. Here, we found that the PCa patients who received ADT had increased PCa stem/progenitor cell population. The addition of the anti-androgen, Casodex®, or AR-siRNA in various PCa cells led to increased stem/progenitor cells, whereas, in contrast, the addition of functional AR led to decreased stem/progenitor cell population but increased non-stem/progenitor cell population, suggesting that AR functions differentially in PCa stem/progenitor vs. non-stem/progenitor cells. Therefore, the current ADT might result in an undesired expansion of PCa stem/progenitor cell population, which explains why this therapy fails. Using various human PCa cell lines and three different mouse models, we concluded that targeting PCa non-stem/progenitor cells with AR degradation enhancer ASC-J9® and targeting PCa stem/progenitor cells with 5-azathioprine and γ-tocotrienol resulted in a significant suppression of the tumors at the castration resistant stage. This suggests that a combinational therapy that simultaneously targets both stem/progenitor and non-stem/progenitor cells will lead to better therapeutic efficacy and may become a new therapy to battle the PCa before and after castration resistant stages. PMID:22831834

  2. Sall1 in renal stromal progenitors non-cell autonomously restricts the excessive expansion of nephron progenitors.

    PubMed

    Ohmori, Tomoko; Tanigawa, Shunsuke; Kaku, Yusuke; Fujimura, Sayoko; Nishinakamura, Ryuichi

    2015-10-29

    The mammalian kidney develops from reciprocal interactions between the metanephric mesenchyme and ureteric bud, the former of which contains nephron progenitors. The third lineage, the stroma, fills up the interstitial space and is derived from distinct progenitors that express the transcription factor Foxd1. We showed previously that deletion of the nuclear factor Sall1 in nephron progenitors leads to their depletion in mice. However, Sall1 is expressed not only in nephron progenitors but also in stromal progenitors. Here we report that specific Sall1 deletion in stromal progenitors leads to aberrant expansion of nephron progenitors, which is in sharp contrast with a nephron progenitor-specific deletion. The mutant mice also exhibited cystic kidneys after birth and died before adulthood. We found that Decorin, which inhibits Bmp-mediated nephron differentiation, was upregulated in the mutant stroma. In contrast, the expression of Fat4, which restricts nephron progenitor expansion, was reduced mildly. Furthermore, the Sall1 protein binds to many stroma-related gene loci, including Decorin and Fat4. Thus, the expression of Sall1 in stromal progenitors restricts the excessive expansion of nephron progenitors in a non-cell autonomous manner, and Sall1-mediated regulation of Decorin and Fat4 might at least partially underlie the pathogenesis.

  3. Sall1 in renal stromal progenitors non-cell autonomously restricts the excessive expansion of nephron progenitors

    PubMed Central

    Ohmori, Tomoko; Tanigawa, Shunsuke; Kaku, Yusuke; Fujimura, Sayoko; Nishinakamura, Ryuichi

    2015-01-01

    The mammalian kidney develops from reciprocal interactions between the metanephric mesenchyme and ureteric bud, the former of which contains nephron progenitors. The third lineage, the stroma, fills up the interstitial space and is derived from distinct progenitors that express the transcription factor Foxd1. We showed previously that deletion of the nuclear factor Sall1 in nephron progenitors leads to their depletion in mice. However, Sall1 is expressed not only in nephron progenitors but also in stromal progenitors. Here we report that specific Sall1 deletion in stromal progenitors leads to aberrant expansion of nephron progenitors, which is in sharp contrast with a nephron progenitor-specific deletion. The mutant mice also exhibited cystic kidneys after birth and died before adulthood. We found that Decorin, which inhibits Bmp-mediated nephron differentiation, was upregulated in the mutant stroma. In contrast, the expression of Fat4, which restricts nephron progenitor expansion, was reduced mildly. Furthermore, the Sall1 protein binds to many stroma-related gene loci, including Decorin and Fat4. Thus, the expression of Sall1 in stromal progenitors restricts the excessive expansion of nephron progenitors in a non-cell autonomous manner, and Sall1-mediated regulation of Decorin and Fat4 might at least partially underlie the pathogenesis. PMID:26511275

  4. The potential benefits of nicaraven to protect against radiation-induced injury in hematopoietic stem/progenitor cells with relative low dose exposures.

    PubMed

    Ali, Haytham; Galal, Omima; Urata, Yoshishige; Goto, Shinji; Guo, Chang-Ying; Luo, Lan; Abdelrahim, Eman; Ono, Yusuke; Mostafa, Emtethal; Li, Tao-Sheng

    2014-09-26

    Nicaraven, a hydroxyl radical-specific scavenger has been demonstrated to attenuate radiation injury in hematopoietic stem cells with 5Gy γ-ray exposures. We explored the effect and related mechanisms of nicaraven for protecting radiation injury induced by sequential exposures to a relatively lower dose γ-ray. C57BL/6 mice were given nicaraven or placebo within 30min before exposure to 50mGy γ-ray daily for 30days in sequences (cumulative dose of 1.5Gy). Mice were victimized 24h after the last radiation exposure, and the number, function and oxidative stress of hematopoietic stem cells were quantitatively estimated. We also compared the gene expression in these purified stem cells from mice received nicaraven and placebo treatment. Nicaraven increased the number of c-kit(+) stem/progenitor cells in bone marrow and peripheral blood, with a recovery rate around 60-90% of age-matched non-irradiated healthy mice. The potency of colony forming from hematopoietic stem/progenitor cells as indicator of function was completely protected with nicaraven treatment. Furthermore, nicaraven treatment changed the expression of many genes associated to DNA repair, inflammatory response, and immunomodulation in c-kit(+) stem/progenitor cells. Nicaraven effectively protected against damages of hematopoietic stem/progenitor cells induced by sequential exposures to a relatively low dose radiation, via complex mechanisms. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Direct hepatic differentiation of mouse embryonic stem cells induced by valproic acid and cytokines

    PubMed Central

    Dong, Xue-Jun; Zhang, Guo-Rong; Zhou, Qing-Jun; Pan, Ruo-Lang; Chen, Ye; Xiang, Li-Xin; Shao, Jian-Zhong

    2009-01-01

    AIM: To develop a protocol for direct hepatic lineage differentiation from early developmental progenitors to a population of mature hepatocytes. METHODS: Hepatic progenitor cells and then mature hepatocytes from mouse embryonic stem (ES) cells were obtained in a sequential manner, induced by valproic acid (VPA) and cytokines (hepatocyte growth factor, epidermal growth factor and insulin). Morphological changes of the differentiated cells were examined by phase-contrast microscopy and electron microscopy. Reverse transcription polymerase chain reaction and immunocytochemical analyses were used to evaluate the gene expression profiles of the VPA-induced hepatic progenitors and the hepatic progenitor-derived hepatocytes. Glycogen storage, cytochrome P450 activity, transplantation assay, differentiation of bile duct-like structures and tumorigenic analyses were performed for the functional identification of the differentiated cells. Furthermore, FACS and electron microscopy were used for the analyses of cell cycle profile and apoptosis in VPA-induced hepatic differentiated cells. RESULTS: Based on the combination of VPA and cytokines, mouse ES cells differentiated into a uniform and homogeneous cell population of hepatic progenitor cells and then matured into functional hepatocytes. The progenitor population shared several characteristics with ES cells and hepatic stem/progenitor cells, and represented a novel progenitor cell between ES and hepatic oval cells in embryonic development. The differentiated hepatocytes from progenitor cells shared typical characteristics with mature hepatocytes, including the patterns of gene expression, immunological markers, in vitro hepatocyte functions and in vivo capacity to restore acute-damaged liver function. In addition, the differentiation of hepatic progenitor cells from ES cells was accompanied by significant cell cycle arrest and selective survival of differentiating cells towards hepatic lineages. CONCLUSION: Hepatic cells

  6. Noninvasive Imaging of Administered Progenitor Cells

    SciTech Connect

    Steven R Bergmann, M.D., Ph.D.

    2012-12-03

    The objective of this research grant was to develop an approach for labeling progenitor cells, specifically those that we had identified as being able to replace ischemic heart cells, so that the distribution could be followed non-invasively. In addition, the research was aimed at determining whether administration of progenitor cells resulted in improved myocardial perfusion and function. The efficiency and toxicity of radiolabeling of progenitor cells was to be evaluated. For the proposed clinical protocol, subjects with end-stage ischemic coronary artery disease were to undergo a screening cardiac positron emission tomography (PET) scan using N-13 ammonia to delineate myocardial perfusion and function. If they qualified based on their PET scan, they would undergo an in-hospital protocol whereby CD34+ cells were stimulated by the administration of granulocytes-colony stimulating factor (G-CSF). CD34+ cells would then be isolated by apharesis, and labeled with indium-111 oxine. Cells were to be re-infused and subjects were to undergo single photon emission computed tomography (SPECT) scanning to evaluate uptake and distribution of labeled progenitor cells. Three months after administration of progenitor cells, a cardiac PET scan was to be repeated to evaluate changes in myocardial perfusion and/or function. Indium oxine is a radiopharmaceutical for labeling of autologous lymphocytes. Indium-111 (In-111) decays by electron capture with a t{sub ½} of 67.2 hours (2.8 days). Indium forms a saturated complex that is neutral, lipid soluble, and permeates the cell membrane. Within the cell, the indium-oxyquinolone complex labels via indium intracellular chelation. Following leukocyte labeling, ~77% of the In-111 is incorporated in the cell pellet. The presence of red cells and /or plasma reduces the labeling efficacy. Therefore, the product needed to be washed to eliminate plasma proteins. This repeated washing can damage cells. The CD34 selected product was a 90

  7. Resident mesenchymal progenitors of articular cartilage.

    PubMed

    Candela, Maria Elena; Yasuhara, Rika; Iwamoto, Masahiro; Enomoto-Iwamoto, Motomi

    2014-10-01

    Articular cartilage has poor capacity of self-renewal and repair. Insufficient number and activity of resident mesenchymal (connective tissue) progenitors is likely one of the underlying reasons. Chondroprogenitors reside not only in the superficial zone of articular cartilage but also in other zones of articular cartilage and in the neighboring tissues, including perichondrium (groove of Ranvier), synovium and fat pad. These cells may respond to injury and contribute to articular cartilage healing. In addition, marrow stromal cells can migrate through subchondral bone when articular cartilage is damaged. We should develop drugs and methods that correctly stimulate resident progenitors for improvement of repair and inhibition of degenerative changes in articular cartilage. Copyright © 2014. Published by Elsevier B.V.

  8. Human progenitor cells for bone engineering applications.

    PubMed

    de Peppo, G M; Thomsen, P; Karlsson, C; Strehl, R; Lindahl, A; Hyllner, J

    2013-06-01

    In this report, the authors review the human skeleton and the increasing burden of bone deficiencies, the limitations encountered with the current treatments and the opportunities provided by the emerging field of cell-based bone engineering. Special emphasis is placed on different sources of human progenitor cells, as well as their pros and cons in relation to their utilization for the large-scale construction of functional bone-engineered substitutes for clinical applications. It is concluded that, human pluripotent stem cells represent a valuable source for the derivation of progenitor cells, which combine the advantages of both embryonic and adult stem cells, and indeed display high potential for the construction of functional substitutes for bone replacement therapies.

  9. Interneuron Progenitor Transplantation to Treat CNS Dysfunction

    PubMed Central

    Chohan, Muhammad O.; Moore, Holly

    2016-01-01

    Due to the inadequacy of endogenous repair mechanisms diseases of the nervous system remain a major challenge to scientists and clinicians. Stem cell based therapy is an exciting and viable strategy that has been shown to ameliorate or even reverse symptoms of CNS dysfunction in preclinical animal models. Of particular importance has been the use of GABAergic interneuron progenitors as a therapeutic strategy. Born in the neurogenic niches of the ventral telencephalon, interneuron progenitors retain their unique capacity to disperse, integrate and induce plasticity in adult host circuitries following transplantation. Here we discuss the potential of interneuron based transplantation strategies as it relates to CNS disease therapeutics. We also discuss mechanisms underlying their therapeutic efficacy and some of the challenges that face the field. PMID:27582692

  10. POPULATION SYNTHESIS AND GAMMA RAY BURST PROGENITORS

    SciTech Connect

    C. L. FREYER

    2000-12-11

    Population synthesis studies of binaries are always limited by a myriad of uncertainties from the poorly understood effects of binary mass transfer and common envelope evolution to the many uncertainties that still remain in stellar evolution. But the importance of these uncertainties depends both upon the objects being studied and the questions asked about these objects. Here I review the most critical uncertainties in the population synthesis of gamma-ray burst progenitors. With a better understanding of these uncertainties, binary population synthesis can become a powerful tool in understanding, and constraining, gamma-ray burst models. In turn, as gamma-ray bursts become more important as cosmological probes, binary population synthesis of gamma-ray burst progenitors becomes an important tool in cosmology.

  11. Bilateral choroidal neovascularization associated with optic nerve head drusen treated by antivascular endothelial growth factor therapy

    PubMed Central

    Delas, Barbara; Almudí, Lorena; Carreras, Anabel; Asaad, Mouafk

    2012-01-01

    Objective To report a good clinical outcome in a patient with bilateral choroidal neovascularization (CNV) associated with optic nerve head drusen (ONHD) treated with intravitreal ranibizumab injection. Methods A 12-year-old girl was referred for loss of right eye vision detected in a routine check-up. Best-corrected visual acuity (BCVA) was hand movements in the right eye and 0.9 in the left eye. Funduscopy revealed the presence of superficial and buried bilateral ONHD, which was confirmed by ultrasonography and computed tomography, and the study was completed with perimetry. The presence of bilateral CNV, active in the right eye, was observed and subsequently confirmed using fluorescein angiography and optical coherence tomography. Results Treatment with two consecutive injections of intravitreal ranibizumab resulted in inactivation of the neovascular membrane with subretinal fluid reabsorption and improved right eye BCVA. After 12 months’ follow-up, this was 20/60 and stable. Conclusion Although there are no published studies of safety in children, antiangiogenic therapy for CNV secondary to ONHD may be useful and safe. A search of the literature produced only one previously reported case of ONHD-associated CNV treated with antivascular endothelial growth factor alone. PMID:22368440

  12. Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization

    SciTech Connect

    Song, Yao; Baba, Tomohisa; Li, Ying-Yi; Furukawa, Kaoru; Tanabe, Yamato; Matsugo, Seiichi; Sasaki, Soichiro; Mukaida, Naofumi

    2015-03-06

    Patients with pancreatic ductal adenocarcinoma (PDAC) are frequently complicated with metastatic disease or locally advanced tumors, and consequently need chemotherapy. Gemcitabine is commonly used for PDAC treatment, but with limited efficacy. The capacity of gemcitabine to generate reactive oxygen species (ROS) in human pancreatic cancer cells, prompted us to examine its effects on the expression of pro-inflammatory cytokines and chemokines. We observed that gemcitabine enhanced selectively the expression of CXCL8 in human pancreatic cancer cells through ROS generation and NF-κB activation. In vitro blocking of CXCL8 failed to modulate gemcitabine-mediated inhibition of cell proliferation in human pancreatic cancer cells. Gemcitabine also enhanced CXCL8 expression in pancreatic cancer cells in xenografted tumor tissues. Moreover, anti-CXCL8 antibody treatment in vivo attenuated tumor formation as well as intra-tumoral vascularity in nude mice, which were transplanted with Miapaca-2 cells and treated with gemcitabine. Thus, gemcitabine-induced CXCL8 may counteract the drug through inducing neovascularization. - Highlights: • Gemcitabine induced CXCL8 expression in human pancreatic cancer cells. • CXCL8 expression required ROS generation and NF-κB activation. • CXCL8 did not affect in vitro proliferation of human pancreatic cancer cells. • CXCL8 in vivo counteracted gemcitabine by inducing neovascularization.

  13. Topographical distribution of retinal and optic disc neovascularization in early stages of proliferative diabetic retinopathy.

    PubMed

    Jansson, Ragnhild W; Frøystein, Torbjørn; Krohn, Jørgen

    2012-12-17

    We analyzed the topography of proliferative diabetic retinopathy (PDR), and visualized the distribution of neovascularization of the optic disc (NVD) and elsewhere in the retina (NVE). The study included 174 eyes of 106 patients with early PDR. Data on the size and location of 391 NVE and 73 NVD were converted into a database of two-dimensional retinal and optic disc charts. The geometric centers of the neovascular lesions were plotted into corresponding areas of the charts, and the topographic distributions of the NVE and NVD were visualized by merging the charts and displaying the number of overlapping lesions on color-coded contour maps. A total of 141 (36%) NVE was located in the temporal and 250 (64%) in the nasal hemisphere (P < 0.0001). The distribution of the NVD in the temporal and nasal half of the optic disc was 46 (63%) and 27 (37%), respectively (P = 0.03). NVE in type 1 diabetes were located significantly farther from the fovea and optic disc, and were more numerous and larger than in type 2 diabetes. The number and diameter of the NVE were also significantly higher when the time from the last examination to the appearance of PDR exceeded 12 months. The majority of NVE lesions are located inferonasal to the optic disc and along the superior vascular arcades, while NVD have a predilection for the upper temporal disc rim. More extensive PDR is found in patients with type 1 diabetes and those with examination intervals longer than one year.

  14. Visible light optical spectroscopy is sensitive to neovascularization in the dysplastic cervix.

    PubMed

    Chang, Vivide Tuan-Chyan; Bean, Sarah M; Cartwright, Peter S; Ramanujam, Nirmala

    2010-01-01

    Neovascularization in cervical intraepithelial neoplasia (CIN) is studied because it is the precursor to the third most common female cancer worldwide. Diffuse reflectance from 450-600 nm was collected from 46 patients (76 sites) undergoing colposcopy at Duke University Medical Center. Total hemoglobin, derived using an inverse Monte Carlo model, significantly increased in CIN 2+ (N=12) versus CIN 1 (N=16) and normal tissues (N=48) combined with P<0.004. Immunohistochemistry using monoclonal anti-CD34 was used to quantify microvessel density to validate the increased hemoglobin content. Biopsies from 51 sites were stained, and up to three hot spots per slide were selected for microvessel quantification by two observers. Similar to the optical study results, microvessel density was significantly increased in CIN 2+ (N=16) versus CIN 1 (N=21) and normal tissue (N=14) combined with P<0.007. Total vessel density, however, was not significantly associated with dysplastic grade. Hence, our quantitative optical spectroscopy system is primarily sensitive to dysplastic neovascularization immediately beneath the basement membrane, with minimal confounding from vascularity inherent in the normal stromal environment. This tool could have potential for in vivo applications in screening for cervical cancer, prognostics, and monitoring of antiangiogenic effects in chemoprevention therapies.

  15. Anti-angiogenic effect of bare titanium dioxide nanoparticles on pathologic neovascularization without unbearable toxicity.

    PubMed

    Jo, Dong Hyun; Kim, Jin Hyoung; Son, Jin Gyeong; Song, Nam Woong; Kim, Yong-Il; Yu, Young Suk; Lee, Tae Geol; Kim, Jeong Hun

    2014-07-01

    Local application requires fewer nanoparticles than systemic delivery to achieve effective concentration. In this study, we investigated the potential toxicity and efficacy of bare titanium dioxide (TiO2) nanoparticles by local administration into the eye. Mono-disperse, 20nm-size TiO2 nanoparticles did not affect the viability of retinal constituent cells within certain range of concentrations (~1.30μg/mL). Furthermore, local delivery of TiO2 nanoparticles did not induce any significant toxicity at the level of gene expression and histologic integrity in the retina of C57BL/6 mice. Interestingly, at the low concentration (130ng/mL) without definite toxicity, these nanoparticles suppressed in vitro angiogenesis processes and in vivo retinal neovascularization in oxygen-induced retinopathy mice when they are administered intravitreally. Taken together, our results demonstrate that even TiO2 nanoparticles can be safely utilized for the treatment of retinal diseases at the adequate concentration levels, especially through local administration. In this paper the local application of titanium dioxide is described as a local treatment for retinal diseases associated with neovascularization. While these nanoparticles have known systemic toxicity, this work demonstrates that when applied locally in a mouse model, they can be used without observable toxicity even in their native forms. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Lymphocytic Microparticles Modulate Angiogenic Properties of Macrophages in Laser-induced Choroidal Neovascularization

    PubMed Central

    Tahiri, Houda; Omri, Samy; Yang, Chun; Duhamel, François; Samarani, Suzanne; Ahmad, Ali; Vezina, Mark; Bussières, Martin; Vaucher, Elvire; Sapieha, Przemyslaw; Hickson, Gilles; Hammamji, Karim; Lapointe, Réjean; Rodier, Francis; Tremblay, Sophie; Royal, Isabelle; Cailhier, Jean-François; Chemtob, Sylvain; Hardy, Pierre

    2016-01-01

    Pathological choroidal neovascularization (CNV) is the common cause of vision loss in patients with age-related macular degeneration (AMD). Macrophages possess potential angiogenic function in CNV. We have demonstrated that human T lymphocyte-derived microparticles (LMPs) exert a potent antiangiogenic effect in several pathological neovascularization models. In this study, we investigated the alteration of proangiogenic properties of macrophages by LMPs treatment in vitro and in vivo models. LMPs regulated the expression of several angiogenesis-related factors in macrophages and consequently stimulated their antiangiogenic effects evidenced by the suppression of the proliferation of human retinal endothelial cells in co-culture experiments. The involvement of CD36 receptor in LMPs uptake by macrophages was demonstrated by in vitro assays and by immunostaining of choroidal flat mounts. In addition, ex vivo experiments showed that CD36 mediates the antiangiogenic effect of LMPs in murine and human choroidal explants. Furthermore, intravitreal injection of LMPs in the mouse model of laser-induced CNV significantly suppressed CNV in CD36 dependent manner. The results of this study suggested an ability of LMPs to alter the gene expression pattern of angiogenesis-related factors in macrophages, which provide important information for a new therapeutic approach for efficiently interfering with both vascular and extravascular components of CNV. PMID:27874077

  17. Expression of RAC2 in endothelial cells is required for the postnatal neovascular response

    PubMed Central

    De, Pradip; Peng, Qiong; Dmitry, T.; Li, Weiming; Yoder, Mervin C.; March, Keith L.; Durden, Donald L.

    2009-01-01

    Herein, we describe an obligate role for the hematopoietic specific GTPase, RAC2 in endothelial integrin signaling and the postnatal neovascularization response in vivo. Using a Rac2 knockout mouse model, we discovered that despite the presence of both RAC1 and RAC2 protein in endothelial cells, RAC2 is obligately required for the postnatal neovascular response and αvβ3/α4β1/α5β1 integrin-directed migration on vitronectin, H296 and CH271, fibronectin fragments, respectively. The molecular basis for RAC2 specificity was explored. A genetic analysis of Syk −/+ or Syk−/+; Rac2 −/+ mice revealed that SYK kinase is required for the integrin induced activation of RAC2. The analysis of endothelial cells from Rac2−/+ versus Syk−/+; Rac2−/+ mice provided genetic evidence that SYK-RAC2 signaling axis regulates integrin (avβ3, a4β1 and α5β1) dependent migration. Our results provide evidence that a specific region of the nonreceptor protein tyrosine kinase, SYK, the B linker region containing Y342 and Y346 is required for SYK’s regulation of RAC2 and integrin dependent migration. Moreover, the capacity of mice to vascularize the ischemic hindlimb following femoral artery ligation or matrigel plugs was markedly reduced in mice homozygous deficient for the Rac2 gene. These findings identify a novel signaling axis for the induction and potential modulation of postnatal angiogenesis. PMID:19123268

  18. Lymphocytic Microparticles Modulate Angiogenic Properties of Macrophages in Laser-induced Choroidal Neovascularization.

    PubMed

    Tahiri, Houda; Omri, Samy; Yang, Chun; Duhamel, François; Samarani, Suzanne; Ahmad, Ali; Vezina, Mark; Bussières, Martin; Vaucher, Elvire; Sapieha, Przemyslaw; Hickson, Gilles; Hammamji, Karim; Lapointe, Réjean; Rodier, Francis; Tremblay, Sophie; Royal, Isabelle; Cailhier, Jean-François; Chemtob, Sylvain; Hardy, Pierre

    2016-11-22

    Pathological choroidal neovascularization (CNV) is the common cause of vision loss in patients with age-related macular degeneration (AMD). Macrophages possess potential angiogenic function in CNV. We have demonstrated that human T lymphocyte-derived microparticles (LMPs) exert a potent antiangiogenic effect in several pathological neovascularization models. In this study, we investigated the alteration of proangiogenic properties of macrophages by LMPs treatment in vitro and in vivo models. LMPs regulated the expression of several angiogenesis-related factors in macrophages and consequently stimulated their antiangiogenic effects evidenced by the suppression of the proliferation of human retinal endothelial cells in co-culture experiments. The involvement of CD36 receptor in LMPs uptake by macrophages was demonstrated by in vitro assays and by immunostaining of choroidal flat mounts. In addition, ex vivo experiments showed that CD36 mediates the antiangiogenic effect of LMPs in murine and human choroidal explants. Furthermore, intravitreal injection of LMPs in the mouse model of laser-induced CNV significantly suppressed CNV in CD36 dependent manner. The results of this study suggested an ability of LMPs to alter the gene expression pattern of angiogenesis-related factors in macrophages, which provide important information for a new therapeutic approach for efficiently interfering with both vascular and extravascular components of CNV.

  19. Pulmonary Artery Adventitial Fibroblasts Cooperate with Vasa Vasorum Endothelial Cells to Regulate Vasa Vasorum Neovascularization

    PubMed Central

    Davie, Neil J.; Gerasimovskaya, Evgenia V.; Hofmeister, Stephen E.; Richman, Aaron P.; Jones, Peter L.; Reeves, John T.; Stenmark, Kurt R.

    2006-01-01

    The precise cellular and molecular mechanisms regulating adventitial vasa vasorum neovascularization, which occurs in the pulmonary arterial circulation in response to hypoxia, remain unknown. Here, using a technique to isolate and culture adventitial fibroblasts (AdvFBs) and vasa vasorum endothelial cells (VVECs) from the adventitia of pulmonary arteries, we report that hypoxia-activated pulmonary artery AdvFBs exhibited pro-angiogenic properties and influenced the angiogenic phenotype of VVEC, in a process of cell-cell communication involving endothelin-1 (ET-1). We demonstrated that AdvFBs, either via co-culture or conditioned media, stimulated VVEC proliferation and augmented the self-assembly and integrity of cord-like networks that formed when VVECs where cultured on Matrigel. In addition, hypoxia-activated AdvFBs produced ET-1, suggesting a paracrine role for this pro-angiogenic molecule in these processes. When co-cultured on Matrigel, AdvFBs and VVECs self-assembled into heterotypic cord-like networks, a process augmented by hypoxia but attenuated by either selective endothelin receptor antagonists or oligonucleotides targeting prepro-ET-1 mRNA. From these observations, we propose that hypoxia-activated AdvFBs exhibit pro-angiogenic properties and, as such, communicate with VVECs, in a process involving ET-1, to regulate vasa vasorum neovascularization occurring in the adventitia of pulmonary arteries in response to chronic hypoxia. PMID:16723696

  20. Gut microbiota influences pathological angiogenesis in obesity-driven choroidal neovascularization.

    PubMed

    Andriessen, Elisabeth Mma; Wilson, Ariel M; Mawambo, Gaelle; Dejda, Agnieszka; Miloudi, Khalil; Sennlaub, Florian; Sapieha, Przemyslaw

    2016-12-01

    Age-related macular degeneration in its neovascular form (NV AMD) is the leading cause of vision loss among adults above the age of 60. Epidemiological data suggest that in men, overall abdominal obesity is the second most important environmental risk factor after smoking for progression to late-stage NV AMD To date, the mechanisms that underscore this observation remain ill-defined. Given the impact of high-fat diets on gut microbiota, we investigated whether commensal microbes influence the evolution of AMD Using mouse models of NV AMD, microbiotal transplants, and other paradigms that modify the gut microbiome, we uncoupled weight gain from confounding factors and demonstrate that high-fat diets exacerbate choroidal neovascularization (CNV) by altering gut microbiota. Gut dysbiosis leads to heightened intestinal permeability and chronic low-grade inflammation characteristic of inflammaging with elevated production of IL-6, IL-1β, TNF-α, and VEGF-A that ultimately aggravate pathological angiogenesis. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

  1. Pulsed electromagnetic field improves postnatal neovascularization in response to hindlimb ischemia

    PubMed Central

    Li, Rui-Lin; Huang, Jing-Juan; Shi, Yi-Qin; Hu, An; Lu, Zhao-Yang; Weng, Liang; Wang, Shen-Qi; Han, Yi-Peng; Zhang, Lan; Hao, Chang-Ning; Duan, Jun-Li

    2015-01-01

    Pulsed electromagnetic fields (PEMF) have been shown to promote proliferation and regeneration in the damaged tissue. Here, we examined whether PEMF therapy improved postnatal neovascularization using murine model of hindlimb ischemia, and the underlying cellular/molecular mechanisms were further investigated. Hindlimb ischemia was induced by unilateral femoral artery resection using 6-8 week-old male C57BL6 mice. Then, mice were exposed to extracorporeal PEMF therapy (4 cycles, 8min/cycle, 30 ± 3 Hz, 5 mT) every day until day 14. Our data demonstrated that PEMF therapy significantly accelerated wound healing, decreased prevalence of gangrene and increased postnatal neovascularization. Moreover, the levels of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS) and Akt phosphorylation in ischemic muscles were markedly enhanced following PEMF therapy. In vitro, PEMF inhibited the process of hypoxia-induced apoptosis and augmented tube formation, migration and proliferative capacities of human umbilical vein endothelial cells (HUVECs). Additionally, PEMF exposure increased VEGF secretion, as well as the eNOS and Akt phosphorylation, and these benefits could be blocked by either phosphoinositide 3-kinase (PI3K) or eNOS inhibitor. In conclusion, our data indicated that PEMF therapy enhanced ischemia-mediated angiogenesis, through up-regulating VEGF expression and activating the PI3K-Akt-eNOS pathway. Therefore, PEMF should be a valuable treatment for the patients with critical limb ischemia. PMID:26045885

  2. Pulsed electromagnetic field improves postnatal neovascularization in response to hindlimb ischemia.

    PubMed

    Li, Rui-Lin; Huang, Jing-Juan; Shi, Yi-Qin; Hu, An; Lu, Zhao-Yang; Weng, Liang; Wang, Shen-Qi; Han, Yi-Peng; Zhang, Lan; Hao, Chang-Ning; Duan, Jun-Li

    2015-01-01

    Pulsed electromagnetic fields (PEMF) have been shown to promote proliferation and regeneration in the damaged tissue. Here, we examined whether PEMF therapy improved postnatal neovascularization using murine model of hindlimb ischemia, and the underlying cellular/molecular mechanisms were further investigated. Hindlimb ischemia was induced by unilateral femoral artery resection using 6-8 week-old male C57BL6 mice. Then, mice were exposed to extracorporeal PEMF therapy (4 cycles, 8min/cycle, 30 ± 3 Hz, 5 mT) every day until day 14. Our data demonstrated that PEMF therapy significantly accelerated wound healing, decreased prevalence of gangrene and increased postnatal neovascularization. Moreover, the levels of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS) and Akt phosphorylation in ischemic muscles were markedly enhanced following PEMF therapy. In vitro, PEMF inhibited the process of hypoxia-induced apoptosis and augmented tube formation, migration and proliferative capacities of human umbilical vein endothelial cells (HUVECs). Additionally, PEMF exposure increased VEGF secretion, as well as the eNOS and Akt phosphorylation, and these benefits could be blocked by either phosphoinositide 3-kinase (PI3K) or eNOS inhibitor. In conclusion, our data indicated that PEMF therapy enhanced ischemia-mediated angiogenesis, through up-regulating VEGF expression and activating the PI3K-Akt-eNOS pathway. Therefore, PEMF should be a valuable treatment for the patients with critical limb ischemia.

  3. Visible light optical spectroscopy is sensitive to neovascularization in the dysplastic cervix

    NASA Astrophysics Data System (ADS)

    Chang, Vivide Tuan-Chyan; Bean, Sarah M.; Cartwright, Peter S.; Ramanujam, Nirmala

    2010-09-01

    Neovascularization in cervical intraepithelial neoplasia (CIN) is studied because it is the precursor to the third most common female cancer worldwide. Diffuse reflectance from 450-600 nm was collected from 46 patients (76 sites) undergoing colposcopy at Duke University Medical Center. Total hemoglobin, derived using an inverse Monte Carlo model, significantly increased in CIN 2+ (N=12) versus CIN 1 (N=16) and normal tissues (N=48) combined with P<0.004. Immunohistochemistry using monoclonal anti-CD34 was used to quantify microvessel density to validate the increased hemoglobin content. Biopsies from 51 sites were stained, and up to three hot spots per slide were selected for microvessel quantification by two observers. Similar to the optical study results, microvessel density was significantly increased in CIN 2+ (N=16) versus CIN 1 (N=21) and normal tissue (N=14) combined with P<0.007. Total vessel density, however, was not significantly associated with dysplastic grade. Hence, our quantitative optical spectroscopy system is primarily sensitive to dysplastic neovascularization immediately beneath the basement membrane, with minimal confounding from vascularity inherent in the normal stromal environment. This tool could have potential for in vivo applications in screening for cervical cancer, prognostics, and monitoring of antiangiogenic effects in chemoprevention therapies.

  4. Mast cells, neovascularization, and microhemorrhages are associated with saccular intracranial artery aneurysm wall remodeling.

    PubMed

    Ollikainen, Eliisa; Tulamo, Riikka; Frösen, Juhana; Lehti, Satu; Honkanen, Petri; Hernesniemi, Juha; Niemelä, Mika; Kovanen, Petri T

    2014-09-01

    Chronic inflammation contributes to remodeling, degeneration, and rupture of saccular intracranial artery aneurysms. Mast cells are important proinflammatory and proangiogenic cells in chronic inflammatory vascular diseases. Here we studied mast cells and neovascularization in 36 intraoperatively resected aneurysms using histology and immunohistochemistry and analyzed the clinical characteristics of the aneurysms according to bleeding status (unruptured vs ruptured). Among the 36 aneurysms, 9 contained mast cells (tryptase-positive cells) and 15 contained neovessels (CD34- and CD31-positive capillarylike structures). The density of neovessels was significantly higher in aneurysm walls containing mast cells than in walls not containing them. In particular, wall areas with abundant mast cells and neovessels also contained iron deposits, indicating damage of newly formed endothelium with ensuing microhemorrhages. Walls with the highest neovessel density and the greatest iron deposition also showed evidence of degeneration. Finally, none of the mast cell-containing aneurysms showed an intact luminal endothelium. Thus, mast cells may adversely affect both neovascular and luminal endothelia. The novel association of mast cells with neovessels and injurious microhemorrhages, as well as with luminal endothelial erosion, suggests that mast cells contribute to remodeling and degeneration of saccular intracranial artery aneurysms.

  5. Collagen nerve conduits promote enhanced axonal regeneration, schwann cell association, and neovascularization compared to silicone conduits.

    PubMed

    Kemp, Stephen W P; Syed, Shahbaz; Walsh, Walsh; Zochodne, Douglas W; Midha, Rajiv

    2009-08-01

    Peripheral nerve regeneration within guidance conduits involves a critical association between regenerating axons, Schwann cells (SCs), and neovascularization. However, it is currently unknown if there is a greater association between these factors in nonpermeable versus semipermeable nerve guide conduits. We therefore examined this collaboration in both silicone- and collagen-based nerve conduits in both 5- and 10-mm-injury gaps in rat sciatic nerves. Results indicate that collagen conduits promoted enhanced axonal and SC regeneration and association when compared to silicone conduits in the shorter 5-mm-gap model. In addition, collagen tubes displayed enhanced neovascularization over silicone conduits, suggesting that these three factors are intimately related in successful peripheral nerve regeneration. At later time points (1- and 2-month analysis) in a 10-mm-gap model, collagen tubes displayed enhanced axonal regeneration, myelination, and vascularization when compared to silicone-based conduits. Results from these studies suggest that regenerating cables within collagen-based conduits are revascularized earlier and more completely, which in turn enhances peripheral nerve regeneration through these nerve guides as compared to silicone conduits.

  6. [Neovascularization in ocular tissues: mechanisms and role of proangiogenic and antiangiogenic factors].

    PubMed

    Nowak, Jerzy Z; Wiktorowska-Owczarek, Anna

    2004-01-01

    Blood vessel growth and stability are under precise control of an array of pro- and anti-angiogenic factors. Under physiological conditions, actions of particular regulatory factors, as well as their mutual interactions are harmonized and balanced. Disruption of the balance between these pro- and anti-angiogenic factors is characteristic of many vascular diseases, including those occurring within the eye. Functional dominancy of proangiogenic factors (e.g., vascular endothelial growth factor, VEGF) over antiangiogenic ones (e.g., pigment epithelium-derived growth factor, PEDF), which may occur under ischemic conditions, may initiate the process of retinal or choroidal neovascularization, representing a major threat to the eyesight. This article presents and discusses current ideas concerning molecular and cellular processes underlying aberrant growth on new blood vessels in ocular tissues, in relation to microvascular ocular complications associated mainly (but not only), with diabetes mellitus, age-related macular degeneration (AMD), and retinopathy of prematurity (ROP). This review also surveys latest achievements in the field of clinically more effective future therapeutic strategies, including gene therapy applicable to the neovascular eye diseases.

  7. Analysis of Scleral Feeder Vessel in Myopic Choroidal Neovascularization Using Optical Coherence Tomography Angiography

    PubMed Central

    Louzada, Ricardo Noguera; Ferrara, Daniela; Novais, Eduardo Amorim; Moult, Eric; Cole, Emily; Lane, Mark; Fujimoto, James; Duker, Jay S.; Baumal, Caroline R.

    2017-01-01

    To describe the appearance of a scleral-derived feeder vessel in a highly myopic eye with secondary choroidal neovascularization (CNV) as visualized on both en face high-speed swept-source (SS) optical coherence tomography angiography (OCTA) prototype, and a commercially available spectral-domain (SD) OCTA, with the corresponding en face and cross-sectional structural OCT images. In this case report, a 60-year-old white male presented with high myopia and secondary CNV in the right eye, previously treated with anti-vascular endothelial growth factor, and was imaged on both SD-OCT and SS-OCT. The neovascular complex could be visualized on both devices. Structural en face SS-OCT images demonstrated a large choroidalscleral feeder vessel that was not visualized with SD-OCT. The authors concluded that structural en face SS-OCT better visualizes scleral feeder vessel compared to SD-OCT due to the longer wavelength (~1,050 nm) with increased choroidal penetration and decreased sensitivity roll-off in the SS-OCT system. PMID:27759864

  8. JNK inhibition reduces apoptosis and neovascularization in a murine model of age-related macular degeneration

    PubMed Central

    Du, Hongjun; Sun, Xufang; Guma, Monica; Luo, Jing; Ouyang, Hong; Zhang, Xiaohui; Zeng, Jing; Quach, John; Nguyen, Duy H.; Shaw, Peter X.; Karin, Michael; Zhang, Kang

    2013-01-01

    Age-related macular degeneration (AMD) is the leading cause of registered blindness among the elderly and affects over 30 million people worldwide. It is well established that oxidative stress, inflammation, and apoptosis play critical roles in pathogenesis of AMD. In advanced wet AMD, although, most of the severe vision loss is due to bleeding and exudation of choroidal neovascularization (CNV), and it is well known that vascular endothelial growth factor (VEGF) plays a pivotal role in the growth of the abnormal blood vessels. VEGF suppression therapy improves visual acuity in AMD patients. However, there are unresolved issues, including safety and cost. Here we show that mice lacking c-Jun N-terminal kinase 1 (JNK1) exhibit decreased inflammation, reduced CNV, lower levels of choroidal VEGF, and impaired choroidal macrophage recruitment in a murine model of wet AMD (laser-induced CNV). Interestingly, we also detected a substantial reduction in choroidal apoptosis of JNK1-deficient mice. Intravitreal injection of a pan-caspase inhibitor reduced neovascularization in the laser-induced CNV model, suggesting that apoptosis plays a role in laser-induced pathological angiogenesis. Intravitreal injection of a specific JNK inhibitor decreased choroidal VEGF expression and reduced pathological CNV. These results suggest that JNK1 plays a key role in linking oxidative stress, inflammation, macrophage recruitment apoptosis, and VEGF production in wet AMD and pharmacological JNK inhibition offers a unique and alternative avenue for prevention and treatment of AMD. PMID:23341606

  9. BMP9/ALK1 inhibits neovascularization in mouse models of age-related macular degeneration

    PubMed Central

    Ntumba, Kalonji; Akla, Naoufal; Oh, S. Paul; Eichmann, Anne; Larrivée, Bruno

    2016-01-01

    Age-related macular degeneration (AMD) is the leading cause of blindness in aging populations of industrialized countries. The drawbacks of inhibitors of vascular endothelial growth factor (VEGFs) currently used for the treatment of AMD, which include resistance and potential serious side-effects, require the identification of new therapeutic targets to modulate angiogenesis. BMP9 signaling through the endothelial Alk1 serine-threonine kinase receptor modulates the response of endothelial cells to VEGF and promotes vessel quiescence and maturation during development. Here, we show that BMP9/Alk1 signaling inhibits neovessel formation in mouse models of pathological ocular angiogenesis relevant to AMD. Activating Alk1 signaling in laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR) inhibited neovascularization and reduced the volume of vascular lesions. Alk1 signaling was also found to interfere with VEGF signaling in endothelial cells whereas BMP9 potentiated the inhibitory effects of VEGFR2 signaling blockade, both in OIR and laser-induced CNV. Together, our data show that targeting BMP9/Alk1 efficiently prevents the growth of neovessels in AMD models and introduce a new approach to improve conventional anti-VEGF therapies. PMID:27517154

  10. Inhibition of Choroidal Neovascularization by Intravenous Injection of Adenoviral Vectors Expressing Secretable Endostatin

    PubMed Central

    Mori, Keisuke; Ando, Akira; Gehlbach, Peter; Nesbitt, David; Takahashi, Kyoichi; Goldsteen, Donna; Penn, Michael; Chen, Cheauyan T.; Mori, Keiko; Melia, Michele; Phipps, Sandrina; Moffat, Diana; Brazzell, Kim; Liau, Gene; Dixon, Katharine H.; Campochiaro, Peter A.

    2001-01-01

    Endostatin is a cleavage product of collagen XVIII that inhibits tumor angiogenesis and growth. Interferon α2a blocks tumor angiogenesis and causes regression of hemangiomas, but has no effect on choroidal neovascularization (CNV). Therefore, inhibitors of tumor angiogenesis do not necessarily inhibit ocular neovascularization. In this study, we used an intravenous injection of adenoviral vectors containing a sig-mEndo transgene consisting of murine immunoglobulin κ-chain leader sequence coupled to sequence coding for murine endostatin to investigate the effect of high serum levels of endostatin on CNV in mice. Mice injected with a construct in which sig-mEndo expression was driven by the Rous sarcoma virus promoter had moderately high serum levels of endostatin and significantly smaller CNV lesions at sites of laser-induced rupture of Bruch’s membrane than mice injected with null vector. Mice injected with a construct in which sig-mEndo was driven by the simian cytomegalovirus promoter had ∼10-fold higher endostatin serum levels and had nearly complete prevention of CNV. There was a strong inverse correlation between endostatin serum level and area of CNV. This study provides proof of principle that gene therapy to increase levels of endostatin can prevent the development of CNV and may provide a new treatment for the leading cause of severe loss of vision in patients with age-related macular degeneration. PMID:11438478

  11. The Anti-angiogenic Effect of Chlorogenic Acid on Choroidal Neovascularization

    PubMed Central

    Kim, Cinoo; Yu, Hyeong Gon

    2010-01-01

    Purpose To evaluate the inhibitory effect of chlorogenic acid on laser-induced choroidal neovascularization (CNV) in a rat model. Methods Intraperitoneal injection of chlorogenic acid (10 mg/kg) was inititated one day prior to laser photocoagulation and continued for eight days. Eyes were removed 14 days after laser photocoagulation. Fluorescein angiography was employed at seven and 14 days to assess the CNV lesions, and histological examination was performed. Quantification of CNV size and leakage were performed both in histological sections and fluorescein angiography in order to compare the inhibitory effects of chlorogenic acid on CNV with the results of the control. Results Histological analysis showed no significant difference in CNV size between the treated and control groups. However, CNV leakage on fluorescein angiography had significantly decreased in the chlorogenic acid-treated group at 14 days after laser photocoagulation compared with that of the control group. In addition, CNV size on fluorescein angiography had significantly decreased in the treated group at seven and 14 days. Conclusions These results suggest that chlorogenic acid has anti-angiogenic effects on CNV and may be useful as an inhibitor in the treatment or prevention of neovascular age-related macular degeneration. PMID:20532143

  12. [Subtenonial application of triamcinolone in neovascular form of senile macular degeneration].

    PubMed

    Loncarek, Karmen; Brajac, Ines; Stalekar, Hrvoje

    2007-09-01

    The aim of this prospective study was to investigate the effectiveness of sub-tenon application of triamcinolone for neovascular age-related macular degeneration. The study included 38 eyes (26 patients; 14 women and 12 men, aged 63 to 82 years) with newly diagnosed subfoveal neovascular age-related macular degeneration. Each eye received sub-tenon injection of 0.5 mL suspension of triamcinolone-acetonide (20 mg of active substance). Follow up period was 12 months. After initial application, the injections were repeated on individual case, none to five times. Elevated intraocular pressure occurred in five patients (seven eyes) and was treated with topical antiglaucomatous therapy. Transient ptosis of upper eyelid occurred in one case and completely recovered in two days. The mean visual acuity was 0.13 +/- 0.17 on the beginning of the study and 0.22 +/- 0.22 at the end of the study. Visual acuity improved in 15/38 (39%) eyes, remained unchanged in 10/38 (26%) eyes, and worsened in 13/38 (35%) eyes. Improvement by three or more lines on Snellen optotype occurred in two cases. Comparing our results to those from other authors, sub-tenon application of triamcinolone did not prove as effective as when applied intravitreally, but is substantially less expensive and easier to perform.

  13. Schwann cells induce cancer cell dispersion and invasion

    PubMed Central

    Deborde, Sylvie; Lyubchik, Anna; Zhou, Yi; He, Shizhi; McNamara, William F.; Chernichenko, Natalya; Lee, Sei-Young; Barajas, Fernando; Chen, Chun-Hao; Bakst, Richard L.; Vakiani, Efsevia; He, Shuangba; Hall, Alan; Wong, Richard J.

    2016-01-01

    Nerves enable cancer progression, as cancers have been shown to extend along nerves through the process of perineural invasion, which carries a poor prognosis. Furthermore, the innervation of some cancers promotes growth and metastases. It remains unclear, however, how nerves mechanistically contribute to cancer progression. Here, we demonstrated that Schwann cells promote cancer invasion through direct cancer cell contact. Histological evaluation of murine and human cancer specimens with perineural invasion uncovered a subpopulation of Schwann cells that associates with cancer cells. Coculture of cancer cells with dorsal root ganglion extracts revealed that Schwann cells direct cancer cells to migrate toward nerves and promote invasion in a contact-dependent manner. Upon contact, Schwann cells induced the formation of cancer cell protrusions in their direction and intercalated between the cancer cells, leading to cancer cell dispersion. The formation of these processes was dependent on Schwann cell expression of neural cell adhesion molecule 1 (NCAM1) and ultimately promoted perineural invasion. Moreover, NCAM1-deficient mice showed decreased neural invasion and less paralysis. Such Schwann cell behavior reflects normal Schwann cell programs that are typically activated in nerve repair but are instead exploited by cancer cells to promote perineural invasion and cancer progression. PMID:26999607

  14. Schwann cells induce cancer cell dispersion and invasion.

    PubMed

    Deborde, Sylvie; Omelchenko, Tatiana; Lyubchik, Anna; Zhou, Yi; He, Shizhi; McNamara, William F; Chernichenko, Natalya; Lee, Sei-Young; Barajas, Fernando; Chen, Chun-Hao; Bakst, Richard L; Vakiani, Efsevia; He, Shuangba; Hall, Alan; Wong, Richard J

    2016-04-01

    Nerves enable cancer progression, as cancers have been shown to extend along nerves through the process of perineural invasion, which carries a poor prognosis. Furthermore, the innervation of some cancers promotes growth and metastases. It remains unclear, however, how nerves mechanistically contribute to cancer progression. Here, we demonstrated that Schwann cells promote cancer invasion through direct cancer cell contact. Histological evaluation of murine and human cancer specimens with perineural invasion uncovered a subpopulation of Schwann cells that associates with cancer cells. Coculture of cancer cells with dorsal root ganglion extracts revealed that Schwann cells direct cancer cells to migrate toward nerves and promote invasion in a contact-dependent manner. Upon contact, Schwann cells induced the formation of cancer cell protrusions in their direction and intercalated between the cancer cells, leading to cancer cell dispersion. The formation of these processes was dependent on Schwann cell expression of neural cell adhesion molecule 1 (NCAM1) and ultimately promoted perineural invasion. Moreover, NCAM1-deficient mice showed decreased neural invasion and less paralysis. Such Schwann cell behavior reflects normal Schwann cell programs that are typically activated in nerve repair but are instead exploited by cancer cells to promote perineural invasion and cancer progression.

  15. Chondrogenic Progenitor Cells Respond to Cartilage Injury

    PubMed Central

    Choe, Hyeonghun; Zheng, Hongjun; Yu, Yin; Jang, Keewoong; Walter, Morgan W.; Lehman, Abigail D.; Ding, Lei; Buckwalter, Joseph A.; Martin, James A.

    2014-01-01

    Objective Hypocellularity resulting from chondrocyte death in the aftermath of mechanical injury is thought to contribute to posttraumatic osteoarthritis. However, we observed that nonviable areas in cartilage injured by blunt impact were repopulated within 7–14 days by cells that appeared to migrate from the surrounding matrix. The aim of this study was to assess our hypothesis that the migrating cell population included chondrogenic progenitor cells that were drawn to injured cartilage by alarmins. Methods Osteochondral explants obtained from mature cattle were injured by blunt impact or scratching, resulting in localized chondrocyte death. Injured sites were serially imaged by confocal microscopy, and migrating cells were evaluated for chondrogenic progenitor characteristics. Chemotaxis assays were used to measure the responses to chemokines, injury-conditioned medium, dead cell debris, and high mobility group box chromosomal protein 1 (HMGB-1). Results Migrating cells were highly clonogenic and multipotent and expressed markers associated with chondrogenic progenitor cells. Compared with chondrocytes, these cells overexpressed genes involved in proliferation and migration and underexpressed cartilage matrix genes. They were more active than chondrocytes in chemotaxis assays and responded to cell lysates, conditioned medium, and HMGB-1. Glycyrrhizin, a chelator of HMGB-1 and a blocking antibody to receptor for advanced glycation end products (RAGE), inhibited responses to cell debris and conditioned medium and reduced the numbers of migrating cells on injured explants. Conclusion Injuries that caused chondrocyte death stimulated the emergence and homing of chondrogenic progenitor cells, in part via HMGB-1 release and RAGE-mediated chemotaxis. Their repopulation of the matrix could promote the repair of chondral damage that might otherwise contribute to progressive cartilage loss. PMID:22777600

  16. Endothelial progenitor cell biology in ankylosing spondylitis.

    PubMed

    Verma, Inderjeet; Syngle, Ashit; Krishan, Pawan

    2015-03-01

    Endothelial progenitor cells (EPCs) are unique populations which have reparative potential in overcoming endothelial damage and reducing cardiovascular risk. Patients with ankylosing spondylitis (AS) have increased risk of cardiovascular morbidity and mortality. The aim of this study was to investigate the endothelial progenitor cell population in AS patients and its potential relationships with disease variables. Endothelial progenitor cells were measured in peripheral blood samples from 20 AS and 20 healthy controls by flow cytometry on the basis of CD34 and CD133 expression. Disease activity was evaluated by using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Functional ability was monitored by using Bath Ankylosing Spondylitis Functional Index (BASFI). EPCs were depleted in AS patients as compared to healthy controls (CD34(+) /CD133(+) : 0.027 ± 0.010% vs. 0.044 ± 0.011%, P < 0.001). EPC depletions were significantly associated with disease duration (r = -0.52, P = 0.01), BASDAI (r = -0.45, P = 0.04) and C-reactive protein (r = -0.5, P = 0.01). This is the first study to demonstrate endothelial progenitor cell depletion in AS patients. EPC depletions inversely correlate with disease duration, disease activity and inflammation, suggesting the pivotal role of inflammation in depletion of EPCs. EPC would possibly also serve as a therapeutic target for preventing cardiovascular disease in AS. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  17. EVOLUTION OF PROGENITORS FOR ELECTRON CAPTURE SUPERNOVAE

    SciTech Connect

    Takahashi, Koh; Umeda, Hideyuki; Yoshida, Takashi E-mail: umeda@astron.s.u-tokyo.ac.jp

    2013-07-01

    We provide progenitor models for electron capture supernovae (ECSNe) with detailed evolutionary calculation. We include minor electron capture nuclei using a large nuclear reaction network with updated reaction rates. For electron capture, the Coulomb correction of rates is treated and the contribution from neutron-rich isotopes is taken into account in each nuclear statistical equilibrium (NSE) composition. We calculate the evolution of the most massive super asymptotic giant branch stars and show that these stars undergo off-center carbon burning and form ONe cores at the center. These cores become heavier up to the critical mass of 1.367 M{sub Sun} and keep contracting even after the initiation of O+Ne deflagration. Inclusion of minor electron capture nuclei causes convective URCA cooling during the contraction phase, but the effect on the progenitor evolution is small. On the other hand, electron capture by neutron-rich isotopes in the NSE region has a more significant effect. We discuss the uniqueness of the critical core mass for ECSNe and the effect of wind mass loss on the plausibility of our models for ECSN progenitors.

  18. Endothelial Progenitors: A Consensus Statement on Nomenclature.

    PubMed

    Medina, Reinhold J; Barber, Chad L; Sabatier, Florence; Dignat-George, Francoise; Melero-Martin, Juan M; Khosrotehrani, Kiarash; Ohneda, Osamu; Randi, Anna M; Chan, Jerry K Y; Yamaguchi, Teruhide; Van Hinsbergh, Victor W M; Yoder, Mervin C; Stitt, Alan W

    2017-03-10

    Endothelial progenitor cell (EPC) nomenclature remains ambiguous and there is a general lack of concordance in the stem cell field with many distinct cell subtypes continually grouped under the term "EPC." It would be highly advantageous to agree standards to confirm an endothelial progenitor phenotype and this should include detailed immunophenotyping, potency assays, and clear separation from hematopoietic angiogenic cells which are not endothelial progenitors. In this review, we seek to discourage the indiscriminate use of "EPCs," and instead propose precise terminology based on defining cellular phenotype and function. Endothelial colony forming cells and myeloid angiogenic cells are examples of two distinct and well-defined cell types that have been considered EPCs because they both promote vascular repair, albeit by completely different mechanisms of action. It is acknowledged that scientific nomenclature should be a dynamic process driven by technological and conceptual advances; ergo the ongoing "EPC" nomenclature ought not to be permanent and should become more precise in the light of strong scientific evidence. This is especially important as these cells become recognized for their role in vascular repair in health and disease; and, in some cases, progress toward use in cell therapy. © Stem Cells Translational Medicine 2017.

  19. Transient nuclear Prospero induces neural progenitor quiescence

    PubMed Central

    Lai, Sen-Lin; Doe, Chris Q

    2014-01-01

    Stem cells can self-renew, differentiate, or enter quiescence. Understanding how stem cells switch between these states is highly relevant for stem cell-based therapeutics. Drosophila neural progenitors (neuroblasts) have been an excellent model for studying self-renewal and differentiation, but quiescence remains poorly understood. In this study, we show that when neuroblasts enter quiescence, the differentiation factor Prospero is transiently detected in the neuroblast nucleus, followed by the establishment of a unique molecular profile lacking most progenitor and differentiation markers. The pulse of low level nuclear Prospero precedes entry into neuroblast quiescence even when the timing of quiescence is advanced or delayed by changing temporal identity factors. Furthermore, loss of Prospero prevents entry into quiescence, whereas a pulse of low level nuclear Prospero can drive proliferating larval neuroblasts into quiescence. We propose that Prospero levels distinguish three progenitor fates: absent for self-renewal, low for quiescence, and high for differentiation. DOI: http://dx.doi.org/10.7554/eLife.03363.001 PMID:25354199

  20. Incident choroidal neovascularization in fellow eyes of patients with unilateral subfoveal choroidal neovascularization secondary to age-related macular degeneration: SST report No. 20 from the Submacular Surgery Trials Research Group.

    PubMed

    Solomon, Sharon D; Jefferys, Joan L; Hawkins, Barbara S; Bressler, Neil M

    2007-10-01

    To describe incident choroidal neovascular lesions in fellow eyes of participants in the Submacular Surgery Trials who had age-related macular degeneration (AMD). Review of baseline fluorescein angiograms confirmed the absence of neovascular AMD in fellow eyes of 364 participants at risk. Subjects were eligible for a minimum of 2 years of follow-up with angiograms of eyes at risk reevaluated to estimate incidence rates of choroidal neovascularization (CNV) and to characterize these lesions. Incidence of CNV during follow-up, characteristics of the incident lesion (composition, size, and location), and visual acuity at the time of incidence. Incident lesions were confirmed in 98 fellow eyes of participants, yielding 2- and 4-year cumulative incidence rates of 22% and 37%. Incident lesions were predominantly CNV in 87 fellow eyes (90%), extrafoveal in 29 fellow eyes (30%), and juxtafoveal in 9 fellow eyes (9%). Occult without classic CNV lesions were found in 64 eyes (67%), minimally classic CNV and predominantly classic CNV lesions in 12 eyes (13%) each, and predominantly blood lesions in 4 eyes (4%). Nearly two-thirds of all incident lesions were 3 disc areas or smaller in size. Median visual acuity decreased from 20/25 at baseline to 20/250 at the 4-year follow-up in fellow eyes with incident CNV. CONCLUSIONS AND APPLICATION TO CLINICAL PRACTICE: Frequent angiographic follow-up of fellow eyes at risk for CNV may lead to earlier detection and treatment of neovascular AMD and better visual acuity outcomes.

  1. Adrenomedullary progenitor cells: Isolation and characterization of a multi-potent progenitor cell population.

    PubMed

    Vukicevic, Vladimir; Rubin de Celis, Maria Fernandez; Pellegata, Natalia S; Bornstein, Stefan R; Androutsellis-Theotokis, Andreas; Ehrhart-Bornstein, Monika

    2015-06-15

    The adrenal is a highly plastic organ with the ability to adjust to physiological needs by adapting hormone production but also by generating and regenerating both adrenocortical and adrenomedullary tissue. It is now apparent that many adult tissues maintain stem and progenitor cells that contribute to their maintenance and adaptation. Research from the last years has proven the existence of stem and progenitor cells also in the adult adrenal medulla throughout life. These cells maintain some neural crest properties and have the potential to differentiate to the endocrine and neural lineages. In this article, we discuss the evidence for the existence of adrenomedullary multi potent progenitor cells, their isolation and characterization, their differentiation potential as well as their clinical potential in transplantation therapies but also in pathophysiology.

  2. SEMIAUTOMATED QUANTITATIVE APPROACH TO CHARACTERIZE TREATMENT RESPONSE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Real-World Study.

    PubMed

    Roberts, Philipp K; Nesper, Peter L; Gill, Manjot K; Fawzi, Amani A

    2017-08-01

    To perform a quantitative study of the vascular microstructure in actively treated choroidal neovascularization by optical coherence tomographic angiography. Patients undergoing individualized anti-vascular endothelial growth factor therapy of minimum 12 months duration were included in this cross-sectional observational study and imaged using optical coherence tomographic angiography. En face optical coherence tomographic angiography images were analyzed for quantitative features, such as junction density, vessel length, and lacunarity using validated software (Angiotool). Patients were divided into 2 groups depending on their individualized treatment interval: "good responders, treated less frequently than 6 weeks" versus "poor responders, treated every 6 weeks or more frequently." Nonparametric testing was used to assess differences between these groups. Twenty-five eyes of 23 consecutive patients with a median 58-month history of choroidal neovascularization, treated by median of 34 anti-vascular endothelial growth factor injections, were included in the analysis. There was no significant difference between any of the microvascular choroidal neovascularization features between the 2 groups (P > 0.05). The semiautomated vessel segmentation software provides an objective and quantitative approach for choroidal neovascularization characterization. The consistently nonsignificant outcomes between the groups may provide evidence to support the "normalization hypothesis." This would suggest that regardless of treatment interval, individualized therapy in these eyes established vessel stability.

  3. Conditional HIF-1 induction produces multistage neovascularization with stage-specific sensitivity to VEGFR inhibitors and myeloid cell independence.

    PubMed

    Oladipupo, Sunday S; Hu, Song; Santeford, Andrea C; Yao, Junjie; Kovalski, Joanna R; Shohet, Ralph V; Maslov, Konstantin; Wang, Lihong V; Arbeit, Jeffrey M

    2011-04-14

    Neovascularization is a crucial component of tumor growth and ischemia. Although prior work primarily used disease models, delineation of neovascularization in the absence of disease can reveal intrinsic mechanisms of microvessel regulation amenable to manipulation in illness. We created a conditional model of epithelial HIF-1 induction in adult mice (TetON-HIF-1 mice). Longitudinal photoacoustic microscopy (L-PAM) was coincidentally developed for noninvasive, label-free serial imaging of red blood cell-perfused vasculature in the same mouse for weeks to months. TetON-HIF-1 mice evidenced 3 stages of neovascularization: development, maintenance, and transgene-dependent regression. Regression occurred despite extensive and tight pericyte coverage. L-PAM mapped microvascular architecture and quantified volumetric changes in neocapillary morphogenesis, arteriovenous remodeling, and microvessel regression. Developmental stage endothelial proliferation down-regulation was associated with a DNA damage checkpoint consisting of p53, p21, and endothelial γ-H2AX induction. The neovasculature was temporally responsive to VEGFR2 immuno-blockade, with the developmental stage sensitive, and the maintenance stage resistant, to DC101 treatment. L-PAM analysis also pinpointed microvessels ablated or resistant to VEGFR2 immuno-blockade. HIF-1-recruited myeloid cells did not mediate VEGFR2 inhibitor resistance. Thus, HIF-1 neovascularization in the absence of disease is self-regulated via cell autonomous endothelial checkpoints, and resistant to angiogenesis inhibitors independent of myeloid cells.

  4. Regulation of the nascent brain vascular network by neural progenitors.

    PubMed

    Santhosh, Devi; Huang, Zhen

    2015-11-01

    Neural progenitors are central players in the development of the brain neural circuitry. They not only produce the diverse neuronal and glial cell types in the brain, but also guide their migration in this process. Recent evidence indicates that neural progenitors also play a critical role in the development of the brain vascular network. At an early stage, neural progenitors have been found to facilitate the ingression of blood vessels from outside the neural tube, through VEGF and canonical Wnt signaling. Subsequently, neural progenitors directly communicate with endothelial cells to stabilize nascent brain vessels, in part through down-regulating Wnt pathway activity. Furthermore, neural progenitors promote nascent brain vessel integrity, through integrin αvβ8-dependent TGFβ signaling. In this review, we will discuss the evidence for, as well as questions that remain, regarding these novel roles of neural progenitors and the underlying mechanisms in their regulation of the nascent brain vascular network.

  5. A Proinflammatory Function of Toll-Like Receptor 2 in the Retinal Pigment Epithelium as a Novel Target for Reducing Choroidal Neovascularization in Age-Related Macular Degeneration.

    PubMed

    Feng, Lili; Ju, Meihua; Lee, Kei Ying V; Mackey, Ashley; Evangelista, Mariasilvia; Iwata, Daiju; Adamson, Peter; Lashkari, Kameran; Foxton, Richard; Shima, David; Ng, Yin Shan

    2017-10-01

    Current treatments for choroidal neovascularization, a major cause of blindness for patients with age-related macular degeneration, treat symptoms but not the underlying causes of the disease. Inflammation has been strongly implicated in the pathogenesis of choroidal neovascularization. We examined the inflammatory role of Toll-like receptor 2 (TLR2) in age-related macular degeneration. TLR2 was robustly expressed by the retinal pigment epithelium in mouse and human eyes, both normal and with macular degeneration/choroidal neovascularization. Nuclear localization of NF-κB, a major downstream target of TLR2 signaling, was detected in the retinal pigment epithelium of human eyes, particularly in eyes with advanced stages of age-related macular degeneration. TLR2 antagonism effectively suppressed initiation and growth of spontaneous choroidal neovascularization in a mouse model, and the combination of anti-TLR2 and antivascular endothelial growth factor receptor 2 yielded an additive therapeutic effect on both area and number of spontaneous choroidal neovascularization lesions. Finally, in primary human fetal retinal pigment epithelium cells, ligand binding to TLR2 induced robust expression of proinflammatory cytokines, and end products of lipid oxidation had a synergistic effect on TLR2 activation. Our data illustrate a functional role for TLR2 in the pathogenesis of choroidal neovascularization, likely by promoting inflammation of the retinal pigment epithelium, and validate TLR2 as a novel therapeutic target for reducing choroidal neovascularization. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  6. Early endothelial progenitor cells in bone marrow are a biomarker of cell therapy success in patients with critical limb ischemia.

    PubMed

    Smadja, David M; Duong-van-Huyen, Jean-Paul; Dal Cortivo, Liliane; Blanchard, Anne; Bruneval, Patrick; Emmerich, Joseph; Gaussem, Pascale

    2012-02-01

    Endothelial progenitor cells (EPC) have been proposed for autologous angiogenic therapy. The objectives of this study were to quantify EPC in the peripheral blood and bone marrow mononuclear cells (BM-MNC) of patients with critical limb ischemia that had received BM-MNC as a cell therapy product, and to study the putative relationship between the presence of EPC and the process of neovascularization in toe or transmetatarsal amputation specimens. Early and late endothelial progenitor cells (CFU-EC and ECFC) were cultivated and quantified according to published methods in peripheral blood and BM-MNC from patients with critical limb ischemia (CLI; n = 11) enrolled in the OPTIPEC trial ( http://clinicaltrials.gov/ct2/show/NCT00377897 ) to receive BM-MNC as a cell therapy product. Eight out of the 11 patients had undergone amputations. Three of the patients displayed a neoangiogenic process that was associated with a higher number of CFU-EC in BM-MNC, while CD3+ , CFU-GM and CD34+ in BM-MNC, and EPC in peripheral blood, did not correlate with the appearance of newly formed vessels. As expected, circulating CFU-EC and ECFC counts were significantly lower in CLI patients compared with age-matched controls. In patients with critical limb ischemia, EPC in peripheral blood were decreased compared with healthy individuals. However, in BM-MNC we found that relative numbers of CFU-EC could be used as an indicator to discriminate patients with neoangiogenic processes. These results need to be confirmed in a randomized study.

  7. Transfusion Support for ABO-Incompatible Progenitor Cell Transplantation

    PubMed Central

    Kopko, Patricia M.

    2016-01-01

    Summary ABO-incompatible transplants comprise up to 50% of allogeneic progenitor cell transplants. Major, minor and bidirectional ABO-incompatible transplants each have unique complications that can occur, including hemolysis at the time of progenitor cell infusion, hemolysis during donor engraftment, passenger lymphocyte syndrome, delayed red blood cell engraftment, and pure red cell aplasia. Appropriate transfusion support during the different phases of the allogeneic progenitor cell transplant process is an important part of ABO-incompatible transplantation. PMID:27022318

  8. Modulating putative endothelial progenitor cells for the treatment of endothelial dysfunction and cardiovascular complications in diabetes.

    PubMed

    Wils, Julien; Favre, Julie; Bellien, Jérémy

    2017-02-01

    Diabetes induces a decrease in the number and function of different pro-angiogenic cell types generically designated as putative endothelial progenitor cells (EPC), which encompasses cells from myeloid origin that act in a paracrine fashion to promote angiogenesis and putative "true" EPC that contribute to endothelial replacement. This not only compromises neovasculogenesis in ischemic tissues but also impairs, at an early stage, the reendotheliziation process at sites of injury, contributing to the development of endothelial dysfunction and cardiovascular complications. Hyperglycemia, insulin resistance and dyslipidemia promote putative EPC dysregulation by affecting the SDF-1/CXCR-4 and NO pathways and the p53/SIRT1/p66Shc axis that contribute to their mobilization, migration, homing and vasculogenic properties. To optimize the clinical management of patients with hypoglycemic agents, statins and renin-angiotensin system inhibitors, which display pleiotropic effects on putative EPC, is a first step to improve their number and angiogenic potential but specific strategies are needed. Among them, mobilizing therapies based on G-CSF, erythropoietin or CXCR-4 antagonism have been developed to increase putative EPC number to treat ischemic diseases with or without prior cell isolation and transplantation. Growth factors, genetic and pharmacological strategies are also evaluated to improve ex vivo cultured EPC function before transplantation. Moreover, pharmacological agents increasing in vivo the bioavailability of NO and other endothelial factors demonstrated beneficial effects on neovascularization in diabetic ischemic models but their effects on endothelial dysfunction remain poorly evaluated. More experiments are warranted to develop orally available drugs and specific agents targeting p66Shc to reverse putative EPC dysfunction in the expected goal of preventing endothelial dysfunction and diabetic cardiovascular complications. Copyright © 2016. Published by

  9. The atheroma plaque secretome stimulates the mobilization of endothelial progenitor cells ex vivo.

    PubMed

    Vega, Francisco M; Gautier, Violette; Fernandez-Ponce, Cecilia M; Extremera, M J; Altelaar, A F M; Millan, Jaime; Tellez, Juan C; Hernandez-Campos, Jose A; Conejero, Rosario; Bolivar, Jorge; Pardal, Ricardo; Garcia-Cózar, Francisco J; Aguado, Enrique; Heck, Albert J R; Duran-Ruiz, Mª Carmen

    2017-04-01

    Endothelial progenitor cells (EPCs) constitute a promising alternative in cardiovascular regenerative medicine due to their assigned role in angiogenesis and vascular repair. In response to injury, EPCs promote vascular remodeling by replacement of damaged endothelial cells and/or by secreting angiogenic factors over the damaged tissue. Nevertheless, such mechanisms need to be further characterized. In the current approach we have evaluated the initial response of early EPCs (eEPCs) from healthy individuals after direct contact with the factors released by carotid arteries complicated with atherosclerotic plaques (AP), in order to understand the mechanisms underlying the neovascularization and remodeling properties assigned to these cells. Herein, we found that the AP secretome stimulated eEPCs proliferation and mobilization ex vivo, and such increase was accompanied by augmented permeability, cell contraction and also an increase of cell-cell adhesion in association with raised vinculin levels. Furthermore, a comparative mass spectrometry analysis of control versus stimulated eEPCs revealed a differential expression of proteins in the AP treated cells, mostly involved in cell migration, proliferation and vascular remodeling. Some of these protein changes were also detected in the eEPCs isolated from atherosclerotic patients compared to eEPCs from healthy donors. We have shown, for the first time, that the AP released factors activate eEPCs ex vivo by inducing their mobilization together with the expression of vasculogenic related markers. The present approach could be taken as a ex vivo model to study the initial activation of vascular cells in atherosclerosis and also to evaluate strategies looking to potentiate the mobilization of EPCs prior to clinical applications.

  10. Tissue engineering of bladder using vascular endothelial growth factor gene-modified endothelial progenitor cells.

    PubMed

    Chen, Bai-Song; Xie, Hua; Zhang, Sheng-Li; Geng, Hong-Quan; Zhou, Jun-Mei; Pan, Jun; Chen, Fang

    2011-12-01

    This study assessed the use of vascular endothelial growth factor (VEGF) gene-modified endothelial progenitor cells (EPCs) seeded onto bladder acellular matrix grafts (BAMGs), to enhance the blood supply in tissue-engineered bladders in a porcine model. Autologous porcine peripheral EPCs were isolated, cultured, expanded, characterized, and modified with the VEGF gene using an adenovirus vector. The expression of VEGF was examined using reverse transcriptase polymerase chain reaction (RT-PCR) and an enzyme-linked immunosorbent assay (ELISA). VEGF gene modified EPCs were seeded onto BAMG and cultured for 3 days before implantation into pigs for bladder tissue engineering. A partial bladder cystectomy was performed in 12 pigs. The experimental group (6 pigs) received VEGF gene-modified EPC-seeded BAMG. The control group (6 pigs) received BAMG without seeded EPCs. The resulting tissue-engineered bladders were subject to a general and histological analysis. Microvessel density (MVD) was assessed using immunohistochemistry. The ex vivo transfection efficiency of EPCs was greater than 60%-70% when concentrated adenovirus was used. The genetically modified cells expressed both VEGF and green fluorescent protein (GFP). Scanning electron microscopy (SEM) and Masson's trichrome staining of cross sections of the cultured cells seeded to BAMG showed cell attachment and proliferation on the surface of the BAMG. Histological examination revealed bladder regeneration in a time-dependent fashion. Significant increases in MVD were observed in the experimental group, in comparison with the control group. VEGF-modified EPCs significantly enhanced neovascularization, compared with BAMG alone. These results indicate that EPCs, combined with VEGF gene therapy, may be a suitable approach for increasing blood supply in the tissue engineering of bladders. Thus, a useful strategy to achieve a tissue-engineered bladder is indicated.

  11. Significance and therapeutic implications of endothelial progenitor cells in angiogenic-mediated tumour metastasis.

    PubMed

    Flamini, Valentina; Jiang, Wen G; Lane, Jane; Cui, Yu-Xin

    2016-04-01

    Cancer conveys profound social and economic consequences throughout the world. Metastasis is responsible for approximately 90% of cancer-associated mortality and, when it occurs, cancer becomes almost incurable. During metastatic dissemination, cancer cells pass through a series of complex steps including the establishment of tumour-associated angiogenesis. The human endothelial progenitor cells (hEPCs) are a cell population derived from the bone marrow which are required for endothelial tubulogenesis and neovascularization. They also express abundant inflammatory cytokines and paracrine angiogenic factors. Clinically hEPCs are highly correlated with relapse, disease progression, metastasis and treatment response in malignancies such as breast cancer, ovarian cancer and non-small-cell lung carcinoma. It has become evident that the hEPCs are involved in the angiogenesis-required progression and metastasis of tumours. However, it is not clear in what way the signalling pathways, controlling the normal cellular function of human BM-derived EPCs, are hijacked by aggressive tumour cells to facilitate tumour metastasis. In addition, the actual roles of hEPCs in tumour angiogenesis-mediated metastasis are not well characterised. In this paper we reviewed the clinical relevance of the hEPCs with cancer diagnosis, progression and prognosis. We further summarised the effects of tumour microenvironment on the hEPCs and underlying mechanisms. We also hypothesized the roles of altered hEPCs in tumour angiogenesis and metastasis. We hope this review may enhance our understanding of the interaction between hEPCs and tumour cells thus aiding the development of cellular-targeted anti-tumour therapies.

  12. VEGF165b, an endogenous C-terminal splice variant of VEGF, inhibits retinal neovascularization in mice.

    PubMed

    Konopatskaya, O; Churchill, A J; Harper, S J; Bates, David O; Gardiner, T A

    2006-05-26

    Hypoxia driven ocular angiogenesis occurs in a range of ischemic retinopathies including proliferative diabetic retinopathy and retinopathy of prematurity. These conditions are initiated and sustained by hypoxia dependent vascular endothelial growth factor (VEGF) expression in the eye. There are two families of VEGF isoforms formed by differential splicing, the pro-angiogenic VEGF family, known to contribute to ocular neovascularization, and the anti-angiogenic VEGF family, which are downregulated in diabetic retinopathy in humans. The first member of the VEGF family to be isolated was VEGF165b. To determine whether VEGF165b could inhibit hypoxia driven angiogenesis in the eye, the oxygen induced retinopathy mouse model of ocular neovascularization was used. 1 ng of recombinant human VEGF165b peptide was injected intraocularly upon return to normoxia after 5 days exposure to 95% oxygen, and neovascularization assessed. VEGF165b significantly inhibited the percentage area of retinal neovascularization from 23+/-3% to 12+/-3.3%, and significantly increased normal vascular areas from 62+/-4% to 74+/-4%. The percentage area of residual ischemic retina was not affected. These results show that a single injection of VEGF165b can significantly reduce preretinal neovascularization without inhibition of physiological intraretinal angiogenesis. Controlling the balance of VEGF(xxx) to VEGF(xxx) isoforms may therefore be therapeutically valuable in the treatment of proliferative eye diseases such as diabetic retinopathy and age related macular degeneration. The regulation of splicing between these two families of isoforms may provide a novel therapeutic strategy for proliferative eye disease.

  13. Estimated cases of blindness and visual impairment from neovascular age-related macular degeneration avoided in Australia by ranibizumab treatment.

    PubMed

    Mitchell, Paul; Bressler, Neil; Doan, Quan V; Dolan, Chantal; Ferreira, Alberto; Osborne, Aaron; Rochtchina, Elena; Danese, Mark; Colman, Shoshana; Wong, Tien Y

    2014-01-01

    Intravitreal injections of anti-vascular endothelial growth factor agents, such as ranibizumab, have significantly improved the management of neovascular age-related macular degeneration. This study used patient-level simulation modelling to estimate the number of individuals in Australia who would have been likely to avoid legal blindness or visual impairment due to neovascular age-related macular degeneration over a 2-year period as a result of intravitreal ranibizumab injections. The modelling approach used existing data for the incidence of neovascular age-related macular degeneration in Australia and outcomes from ranibizumab trials. Blindness and visual impairment were defined as visual acuity in the better-seeing eye of worse than 6/60 or 6/12, respectively. In 2010, 14,634 individuals in Australia were estimated to develop neovascular age-related macular degeneration who would be eligible for ranibizumab therapy. Without treatment, 2246 individuals would become legally blind over 2 years. Monthly 0.5 mg intravitreal ranibizumab would reduce incident blindness by 72% (95% simulation interval, 70-74%). Ranibizumab given as needed would reduce incident blindness by 68% (64-71%). Without treatment, 4846 individuals would become visually impaired over 2 years; this proportion would be reduced by 37% (34-39%) with monthly intravitreal ranibizumab, and by 28% (23-33%) with ranibizumab given as needed. These data suggest that intravitreal injections of ranibizumab, given either monthly or as needed, can substantially lower the number of cases of blindness and visual impairment over 2 years after the diagnosis of neovascular age-related macular degeneration.

  14. Aflibercept: a review of its use in the treatment of choroidal neovascularization due to age-related macular degeneration

    PubMed Central

    Balaratnasingam, Chandrakumar; Dhrami-Gavazi, Elona; McCann, Jesse T; Ghadiali, Quraish; Freund, K Bailey

    2015-01-01

    Choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) is an important cause of visual morbidity globally. Modern treatment strategies for neovascular AMD achieve regression of CNV by suppressing the activity of key growth factors that mediate angiogenesis. Vascular endothelial growth factor (VEGF) has been the major target of neovascular AMD therapy for almost two decades, and there have been several intravitreally-administered agents that have enabled anatomical restitution and improvement in visual function with continual dosing. Aflibercept (EYLEA®), initially named VEGF Trap-eye, is the most recent anti-VEGF agent to be granted US Food and Drug Administration approval for the treatment of neovascular AMD. Biologic advantages of aflibercept include its greater binding affinity for VEGF, a longer intravitreal half-life relative to other anti-VEGF agents, and the capacity to antagonize growth factors other than VEGF. This paper provides an up-to-date summary of the molecular mechanisms mediating CNV. The structural, pharmacodynamic, and pharmacokinetic advantages of aflibercept are also reviewed to rationalize the utility of this agent for treating CNV. Results of landmark clinical investigations, including VIEW 1 and 2 trials, and other important studies are then summarized and used to illustrate the efficacy of aflibercept for managing treatment-naïve CNV, recalcitrant CNV, and CNV due to polypoidal choroidal vasculopathy. Safety profile, patient tolerability, and quality of life measures related to aflibercept are also provided. The evidence provided in this paper suggests aflibercept to be a promising agent that can be used to reduce the treatment burden of neovascular AMD. PMID:26719668

  15. Platelet-derived microparticles augment the adhesion and neovascularization capacities of circulating angiogenic cells obtained from atherosclerotic patients.

    PubMed

    Ohtsuka, Masanori; Sasaki, Ken-ichiro; Ueno, Takafumi; Seki, Ritsuko; Nakayoshi, Takaharu; Koiwaya, Hiroshi; Toyama, Yasuyuki; Yokoyama, Shinji; Mitsutake, Yoshiaki; Chibana, Hidetoshi; Itaya, Naoki; Okamura, Takashi; Imaizumi, Tsutomu

    2013-04-01

    The neovascularization-related capacities of circulating angiogenic cells (CACs) are impaired in atherosclerotic patients, which may explain the unsatisfactory effects of therapeutic angiogenesis with atherosclerotic patient-derived CACs. Platelet-derived microparticles (PMPs) were reported to augment the re-endothelialization capacity of CACs. Accordingly, we investigated whether PMPs could augment the neovascularization-related capacities of atherosclerotic patient-derived CACs in vitro and in vivo and if so, the associated mechanisms. We isolated mononuclear cells and PMPs from atherosclerotic patient-derived peripheral blood and generated PMP-pretreated CACs (PMP-CACs) by co-culture of the mononuclear cells and PMPs. Although the migration capacity of PMP-CACs was similar to that of CACs, the adhesion capacity of PMP-CACs was greater. PMPs released RANTES into the culture medium, and the receptors were similarly expressed on the surfaces of CACs and PMP-CACs. Intravenous injection of PMP-CACs to rats with hindlimb ischemia augmented neovascularization of the ischemic limbs more than the injection of CACs. The number of PMP-CACs incorporated into the capillaries of the ischemic limbs was greater than that of incorporated CACs. The augmented adhesion and neovascularization capacities by PMP-CACs were canceled out by a RANTES neutralizing antibody. PMP-secreted RANTES may play a role in the augmenting adhesion and neovascularization capacities of CACs. Injection of PMP-CACs may be a new strategy to augment the effects of therapeutic angiogenesis for limb ischemia in atherosclerotic patients. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  16. Aflibercept: a review of its use in the treatment of choroidal neovascularization due to age-related macular degeneration.

    PubMed

    Balaratnasingam, Chandrakumar; Dhrami-Gavazi, Elona; McCann, Jesse T; Ghadiali, Quraish; Freund, K Bailey

    2015-01-01

    Choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) is an important cause of visual morbidity globally. Modern treatment strategies for neovascular AMD achieve regression of CNV by suppressing the activity of key growth factors that mediate angiogenesis. Vascular endothelial growth factor (VEGF) has been the major target of neovascular AMD therapy for almost two decades, and there have been several intravitreally-administered agents that have enabled anatomical restitution and improvement in visual function with continual dosing. Aflibercept (EYLEA(®)), initially named VEGF Trap-eye, is the most recent anti-VEGF agent to be granted US Food and Drug Administration approval for the treatment of neovascular AMD. Biologic advantages of aflibercept include its greater binding affinity for VEGF, a longer intravitreal half-life relative to other anti-VEGF agents, and the capacity to antagonize growth factors other than VEGF. This paper provides an up-to-date summary of the molecular mechanisms mediating CNV. The structural, pharmacodynamic, and pharmacokinetic advantages of aflibercept are also reviewed to rationalize the utility of this agent for treating CNV. Results of landmark clinical investigations, including VIEW 1 and 2 trials, and other important studies are then summarized and used to illustrate the efficacy of aflibercept for managing treatment-naïve CNV, recalcitrant CNV, and CNV due to polypoidal choroidal vasculopathy. Safety profile, patient tolerability, and quality of life measures related to aflibercept are also provided. The evidence provided in this paper suggests aflibercept to be a promising agent that can be used to reduce the treatment burden of neovascular AMD.

  17. Comparative study of tacrolimus and bevacizumab on corneal neovascularization in rabbits.

    PubMed

    Park, Jin-Heung; Joo, Choun-Ki; Chung, Sung Kun

    2015-04-01

    To compare the antiangiogenic effects of tacrolimus and bevacizumab on corneal neovascularization (CNV) in rabbits. Neovascularization was induced in 32 eyes of 16 rabbits by placing a suture in the corneal stroma. Seven days after suture placement, all rabbits were divided into 4 groups and were treated subconjunctivally with bevacizumab (AVA_sub) 0.05 mL (5 mg/0.05 mL), tacrolimus (TAC_sub) 0.05 mL (0.25 mg/0.05 mL), balanced salt solution (0.05 mL was subconjunctivally injected in 1 eye of each rabbit and applied by eye drops in the other eyes, control group), and tacrolimus eye drops (TAC_drop) (5 mg/5 mL applied 4 times daily). Digital photographs were obtained and surface area of CNV was measured 7 days after subconjunctival injections. Corneal specimens were analyzed histopathologically and were used to measure the concentration of vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin-1 beta (IL-1β), and monocyte chemoattractant protein 1 mRNA by reverse transcription polymerase chain reaction. In digital photographs, the neovascularized area was decreased in all treatment groups (AVA_sub, 0.58; TAC_sub, 0.60; TAC_drop, 0.68) compared with the control group (balanced salt solution, 0.81). Histological examination showed markedly regressed new vessels in treatment groups, and immunohistochemical staining revealed weakly stained anti-VEGF and anti-F4/80 antibodies in treatment groups. In semiquantitative reverse transcription polymerase chain reaction, concentration of VEGF (AVA_sub, 0.24; TAC_drop, 0.18), TNF-α (AVA_sub, 0.19; TAC_sub, 0.24; TAC_drop 0.15), and IL-1β (AVA_sub, 0.19; TAC_sub, 0.33; TAC_drop, 0.18) mRNA were significantly lower in treatment groups than in the control group (VEGF, 0.47; TNF-α, 0.44; IL-1β, 0.87) (P < 0.05). Topical and subconjunctival tacrolimus application may be useful in reducing CNV and have comparable effects to subconjunctival bevacizumab injection.

  18. Neuroprotectin D1 Attenuates Laser-induced Choroidal Neovascularization in Mouse

    PubMed Central

    Sheets, Kristopher G.; Zhou, Yongdong; Ertel, Monica K.; Knott, Eric J.; Regan, Cornelius E.; Elison, Jasmine R.; Gordon, William C.; Gjorstrup, Per

    2010-01-01

    Purpose To examine the effects of neuroprotectin D1 (NPD1), a stereospecific derivative of docosahexaenoic acid, on choroidal neovascularization (CNV) in a laser-induced mouse model. Specifically, this was assessed by clinically grading laser-induced lesions, measuring leakage area, and volumetrically quantifying vascular endothelial cell proliferation. Methods C57Bl/6 mice were treated with vehicle control or NPD1, and choroidal neovascularization was induced by laser rupture of Bruch's membrane; treatment was administered throughout the first week of recovery. One and two weeks after CNV induction, fundus fluorescein angiography was performed. Angiograms were clinically graded to assess leakage severity, while leakage area was measured by image analysis of angiograms. Proliferation of vascular endothelial cells was evaluated volumetrically by three-dimensional laser confocal immunofluorescent microscopy of cytoskeletal, nuclear, and endothelial cell markers. Results At seven days after CNV induction, NPD1-treated mice had 60% fewer clinically relevant lesions than controls, dropping to 80% fewer by 14 days. NPD1 mice exhibited 25% smaller leakage area than controls at 7 days and 44% smaller area at 14 days. Volumetric immunofluorescence revealed 46% less vascular endothelial cell volume in 7-day NPD1-treated mice than in 7-day controls, and by 14 days NPD1 treatment was 68% lower than controls. Furthermore, comparison of 7- and 14-day volumes of NPD1-treated mice revealed a 50% reduction at 14 days. Conclusions NPD1 significantly inhibits choroidal neovascularization. There are at least two possible mechanisms that could explain the neuroprotective action of NPD1. Ultimately, nuclear factor-κB could be inhibited with a reduction in cyclooxygenase-2 (COX-2) to reduce vascular endothelial growth factor (VEGF) expression, and/or activation of the resolution phase of the inflammatory response/survival pathways could be upregulated. Moreover, NPD1 continues to be

  19. Aryl hydrocarbon receptor knock-out exacerbates choroidal neovascularization via multiple pathogenic pathways

    PubMed Central

    Choudhary, Mayur; Kazmin, Dmitri; Hu, Peng; Thomas, Russell S; McDonnell, Donald P; Malek, Goldis

    2015-01-01

    The aryl hydrocarbon receptor (AhR) is a heterodimeric transcriptional regulator with pleiotropic functions in xenobiotic metabolism and detoxification, vascular development and cancer. Herein, we report a previously undescribed role for the AhR signalling pathway in the pathogenesis of the wet, neovascular subtype of age-related macular degeneration (AMD), the leading cause of vision loss in the elderly in the Western world. Comparative analysis of gene expression profiles of aged AhR−/− and wild-type (wt) mice, using high-throughput RNA sequencing, revealed differential modulation of genes belonging to several AMD-related pathogenic pathways, including inflammation, angiogenesis and extracellular matrix regulation. To investigate AhR regulation of these pathways in wet AMD, we experimentally induced choroidal neovascular lesions in AhR−/− mice and found that they measured significantly larger in area and volume compared to age-matched wt mice. Furthermore, these lesions displayed a higher number of ionized calcium-binding adaptor molecule 1-positive (Iba1+) microglial cells and a greater amount of collagen type IV deposition, events also seen in human wet AMD pathology specimens. Consistent with our in vivo observations, AhR knock-down was sufficient to increase choroidal endothelial cell migration and tube formation in vitro. Moreover, AhR knock-down caused an increase in collagen type IV production and secretion in both retinal pigment epithelial (RPE) and choroidal endothelial cell cultures, increased expression of angiogenic and inflammatory molecules, including vascular endothelial growth factor A (VEGFA) and chemokine (C–C motif) ligand 2 (CCL2) in RPE cells, and increased expression of secreted phosphoprotein 1 (SPP1) and transforming growth factor-β1 (TGFβ1) in choroidal endothelial cells. Collectively, our findings identify AhR as a regulator of multiple pathogenic pathways in experimentally induced choroidal neovascularization, findings that

  20. Rap1 GTPase Activation and Barrier Enhancement in RPE Inhibits Choroidal Neovascularization In Vivo

    PubMed Central

    McCloskey, Manabu; Wang, Haibo; Quilliam, Lawrence A.; Chrzanowska-Wodnicka, Magdalena; Hartnett, M. Elizabeth

    2013-01-01

    Loss of barrier integrity precedes the development of pathologies such as metastasis, inflammatory disorders, and blood-retinal barrier breakdown present in neovascular age-related macular degeneration. Rap1 GTPase is involved in regulating both endothelial and epithelial cell junctions; the specific role of Rap1A vs. Rap1B isoforms is less clear. Compromise of retinal pigment epithelium barrier function is a contributing factor to the development of AMD. We utilized shRNA of Rap1 isoforms in cultured human retinal pigment epithelial cells, along with knockout mouse models to test the role of Rap1 on promoting RPE barrier properties, with emphasis on the dynamic junctional regulation that is triggered when the adhesion between cells is challenged. In vitro, Rap1A shRNA reduced steady-state barrier integrity, whereas Rap1B shRNA affected dynamic junctional responses. In a laser-induced choroidal neovascularization (CNV) model of macular degeneration, Rap1b−/− mice exhibited larger CNV volumes compared to wild-type or Rap1a−/−. In vivo, intravitreal injection of a cAMP analog (8CPT-2′-O-Me-cAMP) that is a known Rap1 activator significantly reduced laser-induced CNV volume, which correlated with the inhibition of CEC transmigration across 8CPT-2′O-Me-cAMP-treated RPE monolayers in vitro. Rap1 activation by 8CPT-2′-O-Me-cAMP treatment increased recruitment of junctional proteins and F-actin to cell-cell contacts, increasing both the linearity of junctions in vitro and in cells surrounding laser-induced lesions in vivo. We conclude that in vitro, Rap1A may be important for steady state barrier integrity, while Rap1B is involved more in dynamic junctional responses such as resistance to junctional disassembly induced by EGTA and reassembly of cell junctions following disruption. Furthermore, activation of Rap1 in vivo inhibited development of choroidal neovascular lesions in a laser-injury model. Our data suggest that targeting Rap1 isoforms in vivo with 8

  1. Retinal Inhibition of CCR3 Induces Retinal Cell Death in a Murine Model of Choroidal Neovascularization

    PubMed Central

    Wang, Haibo; Han, Xiaokun; Gambhir, Deeksha; Becker, Silke; Kunz, Eric; Liu, Angelina Jingtong; Hartnett, M. Elizabeth

    2016-01-01

    Inhibition of chemokine C-C motif receptor 3 (CCR3) signaling has been considered as treatment for neovascular age-related macular degeneration (AMD). However, CCR3 is expressed in neural retina from aged human donor eyes. Therefore, broad CCR3 inhibition may be harmful to the retina. We assessed the effects of CCR3 inhibition on retina and choroidal endothelial cells (CECs) that develop into choroidal neovascularization (CNV). In adult murine eyes, CCR3 colocalized with glutamine-synthetase labeled Műller cells. In a murine laser-induced CNV model, CCR3 immunolocalized not only to lectin-stained cells in CNV lesions but also to the retina. Compared to non-lasered controls, CCR3 mRNA was significantly increased in laser-treated retina. An intravitreal injection of a CCR3 inhibitor (CCR3i) significantly reduced CNV compared to DMSO or PBS controls. Both CCR3i and a neutralizing antibody to CCR3 increased TUNEL+ retinal cells overlying CNV, compared to controls. There was no difference in cleaved caspase-3 in laser-induced CNV lesions or in overlying retina between CCR3i- or control-treated eyes. Following CCR3i, apoptotic inducible factor (AIF) was significantly increased and anti-apoptotic factor BCL2 decreased in the retina; there were no differences in retinal vascular endothelial growth factor (VEGF). In cultured human Műller cells exposed to eotaxin (CCL11) and VEGF, CCR3i significantly increased TUNEL+ cells and AIF but decreased BCL2 and brain derived neurotrophic factor, without affecting caspase-3 activity or VEGF. CCR3i significantly decreased AIF in RPE/choroids and immunostaining of phosphorylated VEGF receptor 2 (p-VEGFR2) in CNV with a trend toward reduced VEGF. In cultured CECs treated with CCL11 and/or VEGF, CCR3i decreased p-VEGFR2 and increased BCL2 without increasing TUNEL+ cells and AIF. These findings suggest that inhibition of retinal CCR3 causes retinal cell death and that targeted inhibition of CCR3 in CECs may be a safer if CCR3 inhibition

  2. Retinal Inhibition of CCR3 Induces Retinal Cell Death in a Murine Model of Choroidal Neovascularization.

    PubMed

    Wang, Haibo; Han, Xiaokun; Gambhir, Deeksha; Becker, Silke; Kunz, Eric; Liu, Angelina Jingtong; Hartnett, M Elizabeth

    2016-01-01

    Inhibition of chemokine C-C motif receptor 3 (CCR3) signaling has been considered as treatment for neovascular age-related macular degeneration (AMD). However, CCR3 is expressed in neural retina from aged human donor eyes. Therefore, broad CCR3 inhibition may be harmful to the retina. We assessed the effects of CCR3 inhibition on retina and choroidal endothelial cells (CECs) that develop into choroidal neovascularization (CNV). In adult murine eyes, CCR3 colocalized with glutamine-synthetase labeled Műller cells. In a murine laser-induced CNV model, CCR3 immunolocalized not only to lectin-stained cells in CNV lesions but also to the retina. Compared to non-lasered controls, CCR3 mRNA was significantly increased in laser-treated retina. An intravitreal injection of a CCR3 inhibitor (CCR3i) significantly reduced CNV compared to DMSO or PBS controls. Both CCR3i and a neutralizing antibody to CCR3 increased TUNEL+ retinal cells overlying CNV, compared to controls. There was no difference in cleaved caspase-3 in laser-induced CNV lesions or in overlying retina between CCR3i- or control-treated eyes. Following CCR3i, apoptotic inducible factor (AIF) was significantly increased and anti-apoptotic factor BCL2 decreased in the retina; there were no differences in retinal vascular endothelial growth factor (VEGF). In cultured human Műller cells exposed to eotaxin (CCL11) and VEGF, CCR3i significantly increased TUNEL+ cells and AIF but decreased BCL2 and brain derived neurotrophic factor, without affecting caspase-3 activity or VEGF. CCR3i significantly decreased AIF in RPE/choroids and immunostaining of phosphorylated VEGF receptor 2 (p-VEGFR2) in CNV with a trend toward reduced VEGF. In cultured CECs treated with CCL11 and/or VEGF, CCR3i decreased p-VEGFR2 and increased BCL2 without increasing TUNEL+ cells and AIF. These findings suggest that inhibition of retinal CCR3 causes retinal cell death and that targeted inhibition of CCR3 in CECs may be a safer if CCR3 inhibition

  3. Six-year outcomes in neovascular age-related macular degeneration with ranibizumab

    PubMed Central

    Jacob, Julie; Brié, Heidi; Leys, Anita; Levecq, Laurent; Mergaerts, Filip; Denhaerynck, Kris; Vancayzeele, Stefaan; Van Craeyveld, Eline; Abraham, Ivo; MacDonald, Karen

    2017-01-01

    AIM To evaluate the outcomes of ≥6y ranibizumab therapy in neovascular age-related macular degeneration (AMD). METHODS HELIX was a retrospective, observational effectiveness study using medical records of patients treated in three clinics in Belgium. Patients had neovascular AMD and were initially treated with intravitreal ranibizumab (0.5 mg) between November 1, 2007 and October 31, 2008, had ≥6y of data available, and were treated on an ongoing, as-needed basis. Outcomes included best-corrected visual acuity (BCVA) and central retinal thickness (CRT). RESULTS The sample consisted of 88 eyes from 69 patients. Mean age was 76.4±6.5y, most patients were female (62.3%). Most eyes (62.5%) were treatment-naive, 33 previously treated eyes had received predominantly other anti-vascular endothelial growth factor agents and verteporfin. Mean baseline BCVA was 57.4±12.7 ETDRS letters and CRT was 291.5±86.1 μm. On average, patients received 20.6±11.9 ranibizumab injections over the ≥6y. Intervals between injections were on average 12.7±16.1wk. Mean change in BCVA from baseline to last observation for the sample was less than one letter (-0.9±17.3 letters), with an average loss of -3.2±15.6 letters in previously treated eyes versus a gain of 0.6±18.4 letters in treatment-naïve eyes. When considering a loss of <15 letters over 6y as stabilization of disease, 75.9% of all eyes showed a positive (improvement or stabilization) outcome. Mean change in CRT from baseline to last observation for the sample was -26.9±148.4 μm with the greatest reduction observed in treatment-naive eyes. CONCLUSION This retrospective study of 69 neovascular AMD patients treated for ≥6y with ranibizumab demonstrates long-term visual stabilization. In light of the natural evolution of the disease, these data confirm that ranibizumab is effective long-term under real-world conditions of heterogeneity of patients, clinicians, and centers. PMID:28149782

  4. Aryl hydrocarbon receptor knock-out exacerbates choroidal neovascularization via multiple pathogenic pathways.

    PubMed

    Choudhary, Mayur; Kazmin, Dmitri; Hu, Peng; Thomas, Russell S; McDonnell, Donald P; Malek, Goldis

    2015-01-01

    The aryl hydrocarbon receptor (AhR) is a heterodimeric transcriptional regulator with pleiotropic functions in xenobiotic metabolism and detoxification, vascular development and cancer. Herein, we report a previously undescribed role for the AhR signalling pathway in the pathogenesis of the wet, neovascular subtype of age-related macular degeneration (AMD), the leading cause of vision loss in the elderly in the Western world. Comparative analysis of gene expression profiles of aged AhR(-/-) and wild-type (wt) mice, using high-throughput RNA sequencing, revealed differential modulation of genes belonging to several AMD-related pathogenic pathways, including inflammation, angiogenesis and extracellular matrix regulation. To investigate AhR regulation of these pathways in wet AMD, we experimentally induced choroidal neovascular lesions in AhR(-/-) mice and found that they measured significantly larger in area and volume compared to age-matched wt mice. Furthermore, these lesions displayed a higher number of ionized calcium-binding adaptor molecule 1-positive (Iba1(+) ) microglial cells and a greater amount of collagen type IV deposition, events also seen in human wet AMD pathology specimens. Consistent with our in vivo observations, AhR knock-down was sufficient to increase choroidal endothelial cell migration and tube formation in vitro. Moreover, AhR knock-down caused an increase in collagen type IV production and secretion in both retinal pigment epithelial (RPE) and choroidal endothelial cell cultures, increased expression of angiogenic and inflammatory molecules, including vascular endothelial growth factor A (VEGFA) and chemokine (C-C motif) ligand 2 (CCL2) in RPE cells, and increased expression of secreted phosphoprotein 1 (SPP1) and transforming growth factor-β1 (TGFβ1) in choroidal endothelial cells. Collectively, our findings identify AhR as a regulator of multiple pathogenic pathways in experimentally induced choroidal neovascularization, findings that

  5. Nutritional regulation of stem and progenitor cells in Drosophila

    PubMed Central

    Shim, Jiwon; Gururaja-Rao, Shubha; Banerjee, Utpal

    2013-01-01

    Stem cells and their progenitors are maintained within a microenvironment, termed the niche, through local cell-cell communication. Systemic signals originating outside the niche also affect stem cell and progenitor behavior. This review summarizes studies that pertain to nutritional effects on stem and progenitor cell maintenance and proliferation in Drosophila. Multiple tissue types are discussed that utilize the insulin-related signaling pathway to convey nutritional information either directly to these progenitors or via other cell types within the niche. The concept of systemic control of these cell types is not limited to Drosophila and may be functional in vertebrate systems, including mammals. PMID:24255094

  6. CD133+ Renal Progenitor Cells Contribute to Tumor Angiogenesis

    PubMed Central

    Bruno, Stefania; Bussolati, Benedetta; Grange, Cristina; Collino, Federica; Efrem Graziano, Manuela; Ferrando, Ugo; Camussi, Giovanni

    2006-01-01

    In the present study, we tested the hypothesis that resident progenitor cells may contribute to tumor vascularization and growth. CD133+ cells were isolated from 30 human renal carcinomas and characterized as renal resident progenitor cells on the basis of the expression of renal embryonic and mesenchymal stem cell markers. CD133+ progenitors differentiated into endothelial and epithelial cells as the normal CD133+ counterpart present in renal tissue. In the presence of tumor-derived growth factors, these cells were committed to differentiate into endothelial cells able to form vessels in vivo in SCID mice. Undifferentiated CD133+ progenitors were unable to form tumors when transplanted alone in SCID mice. When co-transplanted with renal carcinoma cells, CD133+ progenitors significantly enhanced tumor development and growth. This effect was not attributable to the tumorigenic nature of CD133+ progenitor cells because the same results were obtained with CD133+ cells from normal kidney. CD133+ progenitors contributed to tumor vascularization as the majority of neoformed vessels present within the transplanted tumors were of human origin and derived from the co-transplanted CD133+ progenitors. In conclusion, these results indicate the presence of a renal progenitor cell population in renal carcinomas that may differentiate in endothelial cells and favor vascularization and tumor growth. PMID:17148683

  7. Defining human dendritic cell progenitors by multiparametric flow cytometry

    PubMed Central

    Breton, Gaëlle; Lee, Jaeyop; Liu, Kang; Nussenzweig, Michel C

    2015-01-01

    Human dendritic cells (DCs) develop from progressively restricted bone marrow (BM) progenitors: these progenitor cells include granulocyte, monocyte and DC progenitor (GMDP) cells; monocyte and DC progenitor (MDP) cells; and common DC progenitor (CDP) and DC precursor (pre-DC) cells. These four DC progenitors can be defined on the basis of the expression of surface markers such as CD34 and hematopoietin receptors. In this protocol, we describe five multiparametric flow cytometry panels that can be used as a tool (i) to simultaneously detect or phenotype the four DC progenitors, (ii) to isolate DC progenitors to enable in vitro differentiation or (iii) to assess the in vitro differentiation and proliferation of DC progenitors. The entire procedure from isolation of cells to flow cytometry can be completed in 3–7 h. This protocol provides optimized antibody panels, as well as gating strategies, for immunostaining of BM and cord blood specimens to study human DC hematopoiesis in health, disease and vaccine settings. PMID:26292072

  8. Progenitor Cells in Proximal Airway Epithelial Development and Regeneration

    PubMed Central

    Lynch, Thomas J.; Engelhardt, John F.

    2015-01-01

    Multiple distinct epithelial domains are found throughout the airway that are distinguishable by location, structure, function, and cell-type composition. Several progenitor cell populations in the proximal airway have been identified to reside in confined microenvironmental niches including the submucosal glands (SMGs), which are embedded in the tracheal connective tissue between the surface epithelium and cartilage, and basal cells that reside within the surface airway epithelium (SAE). Current research suggests that regulatory pathways that coordinate development of the proximal airway and establishment of progenitor cell niches may overlap with pathways that control progenitor cell responses during airway regeneration following injury. SMGs have been shown to harbor epithelial progenitor cells, and this niche is dysregulated in diseases such as cystic fibrosis. However, mechanisms that regulate progenitor cell proliferation and maintenance within this glandular niche are not completely understood. Here we discuss glandular progenitor cells during development and regeneration of the proximal airway and compare properties of glandular progenitors to those of basal cell progenitors in the SAE. Further investigation into glandular progenitor cell control will provide a direction for interrogating therapeutic interventions to correct aberrant conditions affecting the SMGs in diseases such as cystic fibrosis, chronic bronchitis, and asthma. PMID:24818588

  9. Exosomes Derived from Human Endothelial Progenitor Cells Accelerate Cutaneous Wound Healing by Promoting Angiogenesis Through Erk1/2 Signaling

    PubMed Central

    Zhang, Jieyuan; Chen, Chunyuan; Hu, Bin; Niu, Xin; Liu, Xiaolin; Zhang, Guowei; Zhang, Changqing; Li, Qing; Wang, Yang

    2016-01-01

    Chronic skin wounds represent one of the most common and disabling complications of diabetes. Endothelial progenitor cells (EPCs) are precursors of endothelial cells and can enhance diabetic wound repair by facilitating neovascularization. Recent studies indicate that the transplanted cells exert therapeutic effects primarily via a paracrine mechanism and exosomes are an important paracrine factor that can be directly used as therapeutic agents for regenerative medicine. However, application of exosomes in diabetic wound repair has been rarely reported. In this study, we demonstrated that the exosomes derived from human umbilical cord blood-derived EPCs (EPC-Exos) possessed robust pro-angiogenic and wound healing effects in streptozotocin-induced diabetic rats. By using a series of in vitro functional assays, we found that EPC-Exos could be incorporated into endothelial cells and significantly enhance endothelial cells' proliferation, migration, and angiogenic tubule formation. Moreover, microarray analyses indicated that exosomes treatment markedly altered the expression of a class of genes involved in Erk1/2 signaling pathway. It was further confirmed with functional study that this signaling process was the critical mediator during the exosomes-induced angiogenic responses of endothelial cells. Therefore, EPC-Exos are able to stimulate angiogenic activities of endothelial cells by activating Erk1/2 signaling, which finally facilitates cutaneous wound repair and regeneration. PMID:27994512

  10. The matrix protein CCN1 (CYR61) promotes proliferation, migration and tube formation of endothelial progenitor cells

    SciTech Connect

    Yu Yang; Gao Yu; Wang, Hong; Huang Lan Qin Jun; Guo Ruiwei; Song Mingbao; Yu Shiyong; Chen Jianfei; Cui Bin; Gao Pan

    2008-10-15

    Neovascularization and re-endothelialization relies on circulating endothelial progenitor cells (EPCs), but their recruitment and angiogenic roles are subjected to regulation by the vascular microenvironment, which remains largely unknown. The present study was designed to investigate the effects of mature ECs and matrix protein CCN1 on the properties of EPCs. In a coculture system, effects of ECs on proliferation, migration and participation in tube-like formation of EPCs were evaluated, and functional assays were employed to identify the exact role of CCN1 in EPCs vitality and function. We demonstrated that ECs, as an indispensable part of the cellular milieu, significantly promoted the proliferation, migration and tube formation activities of EPCs, and more importantly, CCN1 was potentially involved in such effects of ECs. Expression of CCN1 in EPCs was significantly increased by serum, VEGF, ECs-cocultivation and ECs conditioned medium. Moreover, Ad-CCN1-mediated overexpression of CCN1 directly enhanced migration and tube formation of EPCs, whereas silencing of endogenous CCN1 in EPCs inhibits cell functions. Furthermore, CCN1 induced the expressions of chemokines and growth factors, such as MCP-1 and VEGF, suggesting a complex interaction between those proangiogenic factors. Our data suggest that matrix protein CCN1 may play an important role in microenvironment-mediated biological properties of EPCs.

  11. The matrix protein CCN1 (CYR61) promotes proliferation, migration and tube formation of endothelial progenitor cells.

    PubMed

    Yu, Yang; Gao, Yu; Wang, Hong; Huang, Lan; Qin, Jun; Guo, Ruiwei; Song, Mingbao; Yu, Shiyong; Chen, Jianfei; Cui, Bin; Gao, Pan

    2008-10-15

    Neovascularization and re-endothelialization relies on circulating endothelial progenitor cells (EPCs), but their recruitment and angiogenic roles are subjected to regulation by the vascular microenvironment, which remains largely unknown. The present study was designed to investigate the effects of mature ECs and matrix protein CCN1 on the properties of EPCs. In a coculture system, effects of ECs on proliferation, migration and participation in tube-like formation of EPCs were evaluated, and functional assays were employed to identify the exact role of CCN1 in EPCs vitality and function. We demonstrated that ECs, as an indispensable part of the cellular milieu, significantly promoted the proliferation, migration and tube formation activities of EPCs, and more importantly, CCN1 was potentially involved in such effects of ECs. Expression of CCN1 in EPCs was significantly increased by serum, VEGF, ECs-cocultivation and ECs conditioned medium. Moreover, Ad-CCN1-mediated overexpression of CCN1 directly enhanced migration and tube formation of EPCs, whereas silencing of endogenous CCN1 in EPCs inhibits cell functions. Furthermore, CCN1 induced the expressions of chemokines and growth factors, such as MCP-1 and VEGF, suggesting a complex interaction between those proangiogenic factors. Our data suggest that matrix protein CCN1 may play an important role in microenvironment-mediated biological properties of EPCs.

  12. Glucagon-like Peptide-1 improves proliferation and differentiation of endothelial progenitor cells via upregulating VEGF generation

    PubMed Central

    Xie, Xiao-Yun; Mo, Zhao-Hui; Chen, Ke; He, Hong-Hui; Xie, Yan-Hong

    2011-01-01

    Summary Background Glucagon-like peptide-1(GLP-1), released from enteroendocrine cells of the intestine, exerted cardiovascular protective effect. Circulating endothelial progenitor cells (EPCs) play an important role in maintaining endothelial integrity regulating neovascularization and reendothelialization after endothelial injury. Vascular endothelial growth factor (VEGF) is an important cytokine in the process of EPCs vascular differentiation and proliferation. Material/Methods This study was designed to investigate the association between VEGF changes and the proliferation/differentiation function of EPCs in the presence of GLP-1. Results We demonstrated that GLP-1 markedly enhanced the EPCs proliferation and expression of EC-specific markers, and simultaneously upregulated VEGF secretion in EPCs. Exogenous VEGF augmented EPCs proliferation/differentiation abilities in a dose-dependent manner. However, all of the beneficial effects of GLP-1 were suppressed by anti-VEGFmAb or the KDR-specific tyrosine kinase inhibitor SU1498. Conclusions These findings suggest that GLP-1 improves VEGF generation, which contributed to improvement of EPCs biological function, partly by tyrosine kinase KDR. VEGF is a necessary intermediate, mediating the effects of GLP-1 on EPCs. These changes offer a novel explanation that upregulation EPCs bioactivities may be one of the mechanisms of GLP-1 cardiovascular protective effect. PMID:21278683

  13. Bone Marrow Stress Decreases Osteogenic Progenitors.

    PubMed

    Ng, Adeline H; Baht, Gurpreet S; Alman, Benjamin A; Grynpas, Marc D

    2015-11-01

    Age-related bone loss may be a result of declining levels of stem cells in the bone marrow. Using the Col2.3Δtk (DTK) transgenic mouse, osteoblast depletion was used as a source of marrow stress in order to investigate the effects of aging on osteogenic progenitors which reside in the marrow space. Five-month-old DTK mice were treated with one or two cycles of ganciclovir to conditionally ablate differentiated osteoblasts, whereas controls were saline-treated. Treatment cycles were two weeks in length followed by four weeks of recovery. All animals were sacrificed at 8 months of age; bone marrow stromal cells (BMSCs) were harvested for cell culture and whole bones were excised for bone quality assessment. Colony-forming unit (CFU) assays were conducted to investigate the osteogenic potential of BMSC in vitro, and RNA was extracted to assess the expression of osteoblastic genes. Bone quality assessments included bone histomorphometry, TRAP staining, microcomputed tomography, and biomechanical testing. Osteoblast depletion decreased CFU-F (fibroblast), CFU-ALP (alkaline phosphatase), and CFU-VK (von Kossa) counts and BMSC osteogenic capacity in cell culture. Ex vivo, there were no differences in bone mineral density of vertebrae or femurs between treatment groups. Histology showed a decrease in bone volume and bone connectivity with repeated osteoblast depletion; however, this was accompanied by an increase in bone formation rate. There were no notable differences in osteoclast parameters or observed bone marrow adiposity. We have developed a model that uses bone marrow stress to mimic age-related decrease in osteogenic progenitors. Our data suggest that the number of healthy BMSCs and their osteogenic potential decline with repeated osteoblast depletion. However, activity of the remaining osteoblasts increases to compensate for this loss in progenitor osteogenic potential.

  14. Ethanol induces cytostasis of cortical basal progenitors.

    PubMed

    Riar, Amanjot Kaur; Narasimhan, Madhusudhanan; Rathinam, Mary Latha; Henderson, George I; Mahimainathan, Lenin

    2016-01-19

    Developing brain is a major target for alcohol's actions and neurological/functional abnormalities include microencephaly, reduced frontal cortex, mental retardation and attention-deficits. Previous studies have shown that ethanol altered the lateral ventricular neuroepithelial cell proliferation. However, the effect of ethanol on subventricular basal progenitors which generate majority of the cortical layers is not known. We utilized spontaneously immortalized rat brain neuroblasts obtained from cultures of 18-day-old fetal rat cerebral cortices using in vitro ethanol exposures and an in utero binge model. In the in vitro acute model, cells were exposed to 86 mM ethanol for 8, 12 and 24 h. The second in vitro model comprised of chronic intermittent ethanol (CIE) exposure which consisted of 14 h of ethanol treatment followed by 10 h of withdrawal with three repetitions. E18 neuroblasts expressing Tbr2 representing immature basal progenitors displayed significant reduction of proliferation in response to ethanol in both the models. The decreased proliferation was accompanied by absence of apoptosis or autophagy as illustrated by FACS analysis and expression of apoptotic and autophagic markers. The BrdU incorporation assay indicated that ethanol enhanced the accumulation of cells at G1 with reduced cell number in S phase. In addition, the ethanol-inhibited basal neuroblasts proliferation was connected to decrease in cyclin D1 and Rb phosphorylation indicating cell cycle arrest. Further, in utero ethanol exposure in pregnant rats during E15-E18 significantly decreased Tbr2 and cyclin D1 positive cell number in cerebral cortex of embryos as assessed by cell sorting analysis by flow cytometry. Altogether, the current findings demonstrate that ethanol impacts the expansion of basal progenitors by inducing cytostasis t