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Sample records for lymphatic remodeling induced

  1. Lymphangiogenesis and Lymphatic Remodeling Induced by Filarial Parasites: Implications for Pathogenesis

    PubMed Central

    Bennuru, Sasisekhar; Nutman, Thomas B.

    2009-01-01

    Even in the absence of an adaptive immune system in murine models, lymphatic dilatation and dysfunction occur in filarial infections, although severe irreversible lymphedema and elephantiasis appears to require an intact adaptive immune response in human infections. To address how filarial parasites and their antigens influence the lymphatics directly, human lymphatic endothelial cells were exposed to filarial antigens, live parasites, or infected patient serum. Live filarial parasites or filarial antigens induced both significant LEC proliferation and differentiation into tube-like structures in vitro. Moreover, serum from patently infected (microfilaria positive) patients and those with longstanding chronic lymphatic obstruction induced significantly increased LEC proliferation compared to sera from uninfected individuals. Differentiation of LEC into tube-like networks was found to be associated with significantly increased levels of matrix metalloproteases and inhibition of their TIMP inhibitors (Tissue inhibitors of matrix metalloproteases). Comparison of global gene expression induced by live parasites in LEC to parasite-unexposed LEC demonstrated that filarial parasites altered the expression of those genes involved in cellular organization and development as well as those associated with junction adherence pathways that in turn decreased trans-endothelial transport as assessed by FITC-Dextran. The data suggest that filarial parasites directly induce lymphangiogenesis and lymphatic differentiation and provide insight into the mechanisms underlying the pathology seen in lymphatic filariasis. PMID:20011114

  2. The Lymphatic Endothelial mCLCA1 Antibody Induces Proliferation and Growth of Lymph Node Lymphatic Sinuses

    PubMed Central

    Jordan-Williams, Kimberly L.; Ramanujam, Neela; Farr, Andrew G.

    2016-01-01

    Lymphocyte- and leukocyte-mediated lymph node (LN) lymphatic sinus growth (lymphangiogenesis) is involved in immune responses and in diseases including cancer and arthritis. We previously discovered a 10.1.1 Ab that recognizes the lymphatic endothelial cell (LEC) surface protein mCLCA1, which is an interacting partner for LFA1 and Mac-1 that mediates lymphocyte adhesion to LECs. Here, we show that 10.1.1 Ab treatment specifically induces LEC proliferation, and influences migration and adhesion in vitro. Functional testing by injection of mice with 10.1.1 Ab but not control hamster Abs identified rapid induction of LN LEC proliferation and extensive lymphangiogenesis within 23 h. BrdU pulse-chase analysis demonstrated incorporation of proliferating LYVE-1-positive LEC into the growing medullary lymphatic sinuses. The 10.1.1 Ab-induced LN remodeling involved coordinate increases in LECs and also blood endothelial cells, fibroblastic reticular cells, and double negative stroma, as is observed during the LN response to inflammation. 10.1.1 Ab-induced lymphangiogenesis was restricted to LNs, as mCLCA1-expressing lymphatic vessels of the jejunum and dermis were unaffected by 23 h 10.1.1 Ab treatment. These findings demonstrate that 10.1.1 Ab rapidly and specifically induces proliferation and growth of LN lymphatic sinuses and stroma, suggesting a key role of mCLCA1 in coordinating LN remodeling during immune responses. PMID:27224029

  3. The Lymphatic Endothelial mCLCA1 Antibody Induces Proliferation and Growth of Lymph Node Lymphatic Sinuses.

    PubMed

    Jordan-Williams, Kimberly L; Ramanujam, Neela; Farr, Andrew G; Ruddell, Alanna

    2016-01-01

    Lymphocyte- and leukocyte-mediated lymph node (LN) lymphatic sinus growth (lymphangiogenesis) is involved in immune responses and in diseases including cancer and arthritis. We previously discovered a 10.1.1 Ab that recognizes the lymphatic endothelial cell (LEC) surface protein mCLCA1, which is an interacting partner for LFA1 and Mac-1 that mediates lymphocyte adhesion to LECs. Here, we show that 10.1.1 Ab treatment specifically induces LEC proliferation, and influences migration and adhesion in vitro. Functional testing by injection of mice with 10.1.1 Ab but not control hamster Abs identified rapid induction of LN LEC proliferation and extensive lymphangiogenesis within 23 h. BrdU pulse-chase analysis demonstrated incorporation of proliferating LYVE-1-positive LEC into the growing medullary lymphatic sinuses. The 10.1.1 Ab-induced LN remodeling involved coordinate increases in LECs and also blood endothelial cells, fibroblastic reticular cells, and double negative stroma, as is observed during the LN response to inflammation. 10.1.1 Ab-induced lymphangiogenesis was restricted to LNs, as mCLCA1-expressing lymphatic vessels of the jejunum and dermis were unaffected by 23 h 10.1.1 Ab treatment. These findings demonstrate that 10.1.1 Ab rapidly and specifically induces proliferation and growth of LN lymphatic sinuses and stroma, suggesting a key role of mCLCA1 in coordinating LN remodeling during immune responses. PMID:27224029

  4. Akt/Protein kinase B is required for lymphatic network formation, remodeling, and valve development.

    PubMed

    Zhou, Fei; Chang, Zai; Zhang, Luqing; Hong, Young-Kwon; Shen, Bin; Wang, Bo; Zhang, Fan; Lu, Guangming; Tvorogov, Denis; Alitalo, Kari; Hemmings, Brian A; Yang, Zhongzhou; He, Yulong

    2010-10-01

    Akt-mediated signaling plays an important role in blood vascular development. In this study, we investigated the role of Akt in lymphatic growth using Akt-deficient mice. First, we found that lymphangiogenesis occurred in Akt1(-/-), Akt2(-/-), and Akt3(-/-) mice. However, both the diameter and endothelial cell number of lymphatic capillaries were significantly less in Akt1(-/-) mice than in wild-type control mice, whereas there was only a slight change in Akt2(-/-) and Akt3(-/-) mice. Second, valves present in the small collecting lymphatics in the superficial dermal layer of the ear skin were rarely observed in Akt1(-/-) mice, although these valves could be detected in the large collecting lymphatics in the deep layer of the skin tissues. A fluorescence microlymphangiography assay showed that the skin lymphatic network in Akt1(-/-) mice was functional but abnormal as shown by fluorescein isothiocyanate-dextran draining. There was an uncharacteristic enlargement of collecting lymphatic vessels, and further analysis showed that smooth muscle cell coverage of collecting lymphatic vessels became much more sparse in Akt1-deficient mice than in wild-type control animals. Finally, we showed that lymphatic vessels were detected in compound Akt-null mice and that lymphangiogenesis could be induced by vascular endothelial growth factor-C delivered via adenoviral vectors in adult mice lacking Akt1. These results indicate that despite the compensatory roles of other Akt isoforms, Akt1 is more critically required during lymphatic development. PMID:20724596

  5. Electric current-induced lymphatic activation.

    PubMed

    Kajiya, Kentaro; Matsumoto-Okazaki, Yuko; Sawane, Mika; Fukada, Kaedeko; Takasugi, Yuya; Akai, Tomonori; Saito, Naoki; Mori, Yuichiro

    2014-12-01

    The lymphatic system in skin plays important roles in drainage of wastes and in the afferent phase of immune response. We previously showed that activation of vascular endothelial growth factor receptor (VEGFR), specifically the VEGFC/VEGFR-3 pathway, attenuates oedema and inflammation by promoting lymphangiogenesis, suggesting a protective role of lymphatic vessels against skin inflammation. However, it remains unknown how physical stimuli promote lymphatic function. Here, we show that lymphatic endothelial cells (LECs) are activated by direct-current (DC) electrical stimulation, which induced extension of actin filaments of LECs, increased calcium influx into LECs, and increased phosphorylation of p38 mitogen-activated protein kinase (MAPK). An inhibitor of focal adhesion kinase, which plays a role in cellular adhesion and motility, diminished the DC-induced extension of F-actin and abrogated p38 phosphorylation. Time-lapse imaging revealed that pulsed-DC stimulation promoted proliferation and migration of LECs. Overall, these results indicate that electro-stimulation activates lymphatic function by activating p38 MAPK. PMID:25308203

  6. Inhibition of VEGF-C modulates distal lymphatic remodeling and secondary metastasis.

    PubMed

    Gogineni, Alvin; Caunt, Maresa; Crow, Ailey; Lee, Chingwei V; Fuh, Germaine; van Bruggen, Nicholas; Ye, Weilan; Weimer, Robby M

    2013-01-01

    Tumor-associated lymphatics are postulated to provide a transit route for disseminating metastatic cells. This notion is supported by preclinical findings that inhibition of pro-lymphangiogenic signaling during tumor development reduces cell spread to sentinel lymph nodes (SLNs). However, it is unclear how lymphatics downstream of SLNs contribute to metastatic spread into distal organs, or if modulating distal lymph transport impacts disease progression. Utilizing murine models of metastasis, longitudinal in vivo imaging of lymph transport, and function blocking antibodies against two VEGF family members, we provide evidence that distal lymphatics undergo disease course-dependent up-regulation of lymph transport coincidental with structural remodeling. Inhibition of VEGF-C activity with antibodies against VEGF-C or NRP2 prevented these disease-associated changes. Furthermore, utilizing a novel model of adjuvant treatment, we demonstrate that antagonism of VEGF-C or NRP2 decreases post SLN metastasis. These data support a potential therapeutic strategy for inhibiting distant metastatic dissemination via targeting tumor-associated lymphatic remodeling. PMID:23874750

  7. Altered lymphatic function and architecture in salt-induced hypertension assessed by near-infrared fluorescence imaging

    NASA Astrophysics Data System (ADS)

    Kwon, Sunkuk; Agollah, Germaine D.; Chan, Wenyaw; Sevick-Muraca, Eva M.

    2012-08-01

    The lymphatic system plays an important role in maintaining the fluid homeostasis between the blood vascular and interstitial tissue compartment and there is recent evidence that its transport capabilities may regulate blood pressure in salt-induced hypertension. Yet, there is little known how the lymphatic contractile function and architecture responds to dietary salt-intake. Thus, we longitudinally characterized lymphatic contractile function and vessel remodeling noninvasively using dynamic near-infrared fluorescence imaging in animal models of salt-induced hypertension. The lymphatics of mice and rats were imaged following intradermal injection of indocyanine green to the ear tip or the base of the tail before and during two weeks of either a high salt diet (HSD) or normal chow. Our noninvasive imaging data demonstrated dilated lymphatic vessels in the skin of mice and rats on a HSD as compared to their baseline levels. In addition, our dynamic imaging results showed increased lymphatic contraction frequency in HSD-fed mice and rats. Lymphatic contractile function and vessel remodeling occurs in response to salt-induced hypertension suggesting a possible role for the lymphatics in the regulation of vascular blood pressure.

  8. NOK/STYK1 promotes the genesis and remodeling of blood and lymphatic vessels during tumor progression.

    PubMed

    Liu, Yue; Li, Tianqi; Hu, Dan; Zhang, Shuping

    2016-09-01

    Previous studies have indicated that the overexpression of NOK, also named STYK1, led to tumorigenesis and metastasis. Here, we provide evidence that increased expression of NOK/STYK1 caused marked alterations in the overall and inner structures of tumors and substantially facilitates the genesis and remodeling of the blood and lymphatic vessels during tumor progression. In particular, NOK-expressed HeLa stable cells (HeLa-K) significantly enhanced tumor growth and metastasis in xenografted nude mice. Hematoxylin and eosin (HE) staining demonstrated that the tumor tissues generated by HeLa-K cells were much more ichorous and had more interspaces than those generated by control HeLa cells (HeLa-C). The fluorescent areas stained with cluster of differentiation 31 (CD31), a marker protein for blood vessels, appeared to be in different patterns. The total blood vessels, especially the ring patterns, within the tumors of the HeLa-K group were highly enriched compared with those in the HeLa-C group. NOK-HA was demonstrated to be well colocalized with CD31 in the wall of the tubular structures within tumor tissues. Interestingly, antibody staining of the lymphatic vessel endothelial hyaluronan receptor (LYVE-1) further revealed the increase in ring (oratretic strip-like) lymphatic vessels in either the peritumoral or intratumoral areas in the HeLa-K group compared with the HeLa-C group. Consistently, the analysis of human cancerous tissue also showed that NOK was highly expressed in the walls of tubular structures. Thus, our results reveal a novel tumorigenic function of NOK to mediate the genesis and remodeling of blood and lymphatic vessels during tumor progression. PMID:27444381

  9. Dextran sulfate sodium-induced acute colitis impairs dermal lymphatic function in mice

    PubMed Central

    Agollah, Germaine D; Wu, Grace; Peng, Ho-Lan; Kwon, Sunkuk

    2015-01-01

    AIM: To investigate whether dermal lymphatic function and architecture are systemically altered in dextran sulfate sodium (DSS)-induced acute colitis. METHODS: Balb/c mice were administered 4% DSS in lieu of drinking water ad libitum for 7 d and monitored to assess disease activity including body weight, diarrhea severity, and fecal bleeding. Control mice received standard drinking water with no DSS. Changes in mesenteric lymphatics were assessed following oral administration of a fluorescently-labelled fatty acid analogue, while dermal lymphatic function and architecture was longitudinally characterized using dynamic near-infrared fluorescence (NIRF) imaging following intradermal injection of indocyanine green (ICG) at the base of the tail or to the dorsal aspect of the left paw prior to, 4, and 7 d after DSS administration. We also measured dye clearance rate after injection of Alexa680-bovine serum albumin (BSA). NIRF imaging data was analyzed to reveal lymphatic contractile activity after selecting fixed regions of interest (ROIs) of the same size in fluorescent lymphatic vessels on fluorescence images. The averaged fluorescence intensity within the ROI of each fluorescence image was plotted as a function of imaging time and the lymphatic contraction frequency was computed by assessing the number of fluorescent pulses arriving at a ROI. RESULTS: Mice treated with DSS developed acute inflammation with clinical symptoms of loss of body weight, loose feces/watery diarrhea, and fecal blood, all of which were aggravated as disease progressed to 7 d. Histological examination of colons of DSS-treated mice confirmed acute inflammation, characterized by segmental to complete loss of colonic mucosa with an associated chronic inflammatory cell infiltrate that extended into the deeper layers of the wall of the colon, compared to control mice. In situ intravital imaging revealed that mice with acute colitis showed significantly fewer fluorescent mesenteric lymphatic vessels

  10. Fstl1 Promotes Asthmatic Airway Remodeling by Inducing Oncostatin M.

    PubMed

    Miller, Marina; Beppu, Andrew; Rosenthal, Peter; Pham, Alexa; Das, Sudipta; Karta, Maya; Song, Dae Jin; Vuong, Christine; Doherty, Taylor; Croft, Michael; Zuraw, Bruce; Zhang, Xu; Gao, Xiang; Aceves, Seema; Chouiali, Fazila; Hamid, Qutayba; Broide, David H

    2015-10-15

    Chronic asthma is associated with airway remodeling and decline in lung function. In this article, we show that follistatin-like 1 (Fstl1), a mediator not previously associated with asthma, is highly expressed by macrophages in the lungs of humans with severe asthma. Chronic allergen-challenged Lys-Cre(tg) /Fstl1(Δ/Δ) mice in whom Fstl1 is inactivated in macrophages/myeloid cells had significantly reduced airway remodeling and reduced levels of oncostatin M (OSM), a cytokine previously not known to be regulated by Fstl1. The importance of the Fstl1 induction of OSM to airway remodeling was demonstrated in murine studies in which administration of Fstl1 induced airway remodeling and increased OSM, whereas administration of an anti-OSM Ab blocked the effect of Fstl1 on inducing airway remodeling, eosinophilic airway inflammation, and airway hyperresponsiveness, all cardinal features of asthma. Overall, these studies demonstrate that the Fstl1/OSM pathway may be a novel pathway to inhibit airway remodeling in severe human asthma. PMID:26355153

  11. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination

    PubMed Central

    Le, Caroline P.; Nowell, Cameron J.; Kim-Fuchs, Corina; Botteri, Edoardo; Hiller, Jonathan G.; Ismail, Hilmy; Pimentel, Matthew A.; Chai, Ming G.; Karnezis, Tara; Rotmensz, Nicole; Renne, Giuseppe; Gandini, Sara; Pouton, Colin W.; Ferrari, Davide; Möller, Andreas; Stacker, Steven A.; Sloan, Erica K.

    2016-01-01

    Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes. PMID:26925549

  12. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination.

    PubMed

    Le, Caroline P; Nowell, Cameron J; Kim-Fuchs, Corina; Botteri, Edoardo; Hiller, Jonathan G; Ismail, Hilmy; Pimentel, Matthew A; Chai, Ming G; Karnezis, Tara; Rotmensz, Nicole; Renne, Giuseppe; Gandini, Sara; Pouton, Colin W; Ferrari, Davide; Möller, Andreas; Stacker, Steven A; Sloan, Erica K

    2016-01-01

    Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes. PMID:26925549

  13. Pregnancy-induced remodeling of heart valves.

    PubMed

    Pierlot, Caitlin M; Moeller, Andrew D; Lee, J Michael; Wells, Sarah M

    2015-11-01

    Recent studies have demonstrated remodeling of aortic and mitral valves leaflets under the volume loading and cardiac expansion of pregnancy. Those valves' leaflets enlarge with altered collagen fiber architecture, content, and cross-linking and biphasic changes (decreases, then increases) in extensibility during gestation. This study extends our analyses to right-sided valves, with additional compositional measurements for all valves. Valve leaflets were harvested from nonpregnant heifers and pregnant cows. Leaflet structure was characterized by leaflet dimensions, and ECM composition was determined using standard biochemical assays. Histological studies assessed changes in cellular and ECM components. Leaflet mechanical properties were assessed using equibiaxial mechanical testing. Collagen thermal stability and cross-linking were assessed using denaturation and hydrothermal isometric tension tests. Pulmonary and tricuspid leaflet areas increased during pregnancy by 35 and 55%, respectively. Leaflet thickness increased by 20% only in the pulmonary valve and largely in the fibrosa (30% thickening). Collagen crimp length was reduced in both the tricuspid (61%) and pulmonary (42%) valves, with loss of crimped area in the pulmonary valve. Thermomechanics showed decreased collagen thermal stability with surprisingly maintained cross-link maturity. The pulmonary leaflet exhibited the biphasic change in extensibility seen in left side valves, whereas the tricuspid leaflet mechanics remained largely unchanged throughout pregnancy. The tricuspid valve exhibits a remodeling response during pregnancy that is significantly diminished from the other three valves. All valves of the heart remodel in pregnancy in a manner distinct from cardiac pathology, with much similarity valve to valve, but with interesting valve-specific responses in the aortic and tricuspid valves. PMID:26371175

  14. Downregulation of Lymphatic Vessel Formation Factors in PGF2α-induced Luteolysis in the Cow

    PubMed Central

    NITTA, Akane; SHIRASUNA, Koumei; NIBUNO, Sayo; BOLLWEIN, Heinrich; SHIMIZU, Takashi; MIYAMOTO, Akio

    2013-01-01

    Abstract Prostaglandin F2α (PGF2α) induces luteolysis in cows and causes infiltration of immune cells, which resembles inflammatory immune response. Since the general immune response is mediated by the lymphatic system, we hypothesized that luteolysis is associated with generation of an immune response that involves lymphatic vessels in the bovine corpus luteum (CL). The CL was obtained from Holstein cows at the mid-luteal phase (days 10–12, ovulation = day 0) by ovariectomy at various time points after PGF2α injection. Lymphatic endothelial cell (LyEC) marker, endothelial hyaluronan receptor 1 (LYVE1), levels decreased significantly 12 h after PGF2α injection. Podoplanin, another LyEC marker, decreased from 15 min after PGF2α injection. PGF2α also diminished mRNA expression of lymphangiogenic factors, such as vascular endothelial growth factor (VEGF) C, VEGFD and VEGF receptor 3 (VEGFR3). During PGF2α-induced luteolysis, the levels of mRNA expression of tumor necrosis factor α (TNFα; the major pro-inflammatory cytokine) and chemokine (C-X-C motif) ligand 1 (neutrophil chemokine) were increased. On the other hand, chemokine (C-C motif) ligand 21, which regulates outflow of immune cells from tissues via the lymphatic vessels during an immune response, was decreased. This study demonstrated that the lymphatic network in the CL is disrupted during luteolysis and suggests that during luteolysis, immune cells can induce a local immune response in the CL without using the lymphatic vessels. PMID:23524297

  15. CREB Selectively Controls Learning-Induced Structural Remodeling of Neurons

    ERIC Educational Resources Information Center

    Middei, Silvia; Spalloni, Alida; Longone, Patrizia; Pittenger, Christopher; O'Mara, Shane M.; Marie, Helene; Ammassari-Teule, Martine

    2012-01-01

    The modulation of synaptic strength associated with learning is post-synaptically regulated by changes in density and shape of dendritic spines. The transcription factor CREB (cAMP response element binding protein) is required for memory formation and in vitro dendritic spine rearrangements, but its role in learning-induced remodeling of neurons…

  16. Dynamical DNA accessibility induced by chromatin remodeling and protein binding

    NASA Astrophysics Data System (ADS)

    Montel, F.; Faivre-Moskalenko, C.; Castelnovo, M.

    2014-11-01

    Chromatin remodeling factors are enzymes being able to alter locally chromatin structure at the nucleosomal level and they actively participate in the regulation of gene expression. Using simple rules for individual nucleosome motion induced by a remodeling factor, we designed simulations of the remodeling of oligomeric chromatin, in order to address quantitatively collective effects in DNA accessibility upon nucleosome mobilization. Our results suggest that accessibility profiles are inhomogeneous thanks to borders effects like protein binding. Remarkably, we show that the accessibility lifetime of DNA sequence is roughly doubled in the vicinity of borders as compared to its value in bulk regions far from the borders. These results are quantitatively interpreted as resulting from the confined diffusion of a large nucleosome depleted region.

  17. Biomechanics of vascular mechanosensation and remodeling

    PubMed Central

    Baeyens, Nicolas; Schwartz, Martin A.

    2016-01-01

    Flowing blood exerts a frictional force, fluid shear stress (FSS), on the endothelial cells that line the blood and lymphatic vessels. The magnitude, pulsatility, and directional characteristics of FSS are constantly sensed by the endothelium. Sustained increases or decreases in FSS induce vessel remodeling to maintain proper perfusion of tissue. In this review, we discuss these mechanisms and their relevance to physiology and disease, and propose a model for how information from different mechanosensors might be integrated to govern remodeling. PMID:26715421

  18. Lymphatic vessel development: fluid flow and valve-forming cells.

    PubMed

    Kume, Tsutomu

    2015-08-01

    Hemodynamic forces regulate many aspects of blood vessel disease and development, including susceptibility to atherosclerosis and remodeling of primary blood vessels into a mature vascular network. Vessels of the lymphatic circulatory system are also subjected to fluid flow-associated forces, but the molecular and cellular mechanisms by which these forces regulate the formation and maintenance of lymphatic vessels remain largely uncharacterized. This issue of the JCI includes two articles that begin to address how fluid flow influences lymphatic vessel development and function. Sweet et al. demonstrate that lymph flow is essential for the remodeling of primary lymphatic vessels, for ensuring the proper distribution of smooth muscle cells (SMCs), and for the development and maturation of lymphatic valves. Kazenwadel et al. show that flow-induced lymphatic valve development is initiated by the upregulation of GATA2, which has been linked to lymphedema in patients with Emberger syndrome. Together, these observations and future studies inspired by these results have potential to lead to the development of strategies for the treatment of lymphatic disorders. PMID:26214518

  19. Obstruction-induced pulmonary vascular remodeling.

    PubMed

    Chow, Ming-Jay; Zou, Yu; He, Huamei; McGowan, Francis X; Zurakowski, David; Zhang, Yanhang

    2011-11-01

    Pulmonary obstruction occurs in many common forms of congenital heart disease. In this study, pulmonary artery (PA) banding is used as a model for pulmonary stenosis. Significant remodeling of the vascular bed occurs as a result of a prolonged narrowing of the PAs, and here we quantify the biophysical and molecular changes proximal and distal to the obstruction. Main and branch PAs are harvested from banded and sham rabbits and their mechanical properties are assessed using a biaxial tensile tester. Measurements defined as initial and stiff slopes are taken, assuming a linear region at the start and end of the J-shaped stress-strain curves, along with a transitional knee point. Collagen, elastin assays, Movat's pentachrome staining, and Doppler protocols are used to quantify biochemical, structural, and physiological differences. The banded main PAs have significantly greater initial slopes while banded branch PAs have lower initial slopes; however, this change in mechanical behavior cannot be explained by the assay results as the elastin content in both main and branch PAs is not significantly different. The stiff slopes of the banded main PAs are higher, which is attributed to the significantly greater amounts of insoluble collagen. Shifting of the knee points reveals a decreased toe region in the main PAs but an opposite trend in the branch PAs. The histology results show a loss of integrity of the media, increase in ground substance, and dispersion of collagen in the banded tissue samples. This indicates other structural changes could have led to the mechanical differences in banded and normal tissue. PMID:22168741

  20. Pentoxifylline Attenuates Cardiac Remodeling Induced by Tobacco Smoke Exposure

    PubMed Central

    Minicucci, Marcos; Oliveira, Fernando; Santos, Priscila; Polegato, Bertha; Roscani, Meliza; Fernandes, Ana Angelica; Lustosa, Beatriz; Paiva, Sergio; Zornoff, Leonardo; Azevedo, Paula

    2016-01-01

    Background Tobacco smoke exposure is an important risk factor for cardiac remodeling. Under this condition, inflammation, oxidative stress, energy metabolism abnormalities, apoptosis, and hypertrophy are present. Pentoxifylline has anti‑inflammatory, anti-apoptotic, anti-thrombotic and anti-proliferative properties. Objective The present study tested the hypothesis that pentoxifylline would attenuate cardiac remodeling induced by smoking. Methods Wistar rats were distributed in four groups: Control (C), Pentoxifylline (PX), Tobacco Smoke (TS), and PX-TS. After two months, echocardiography, invasive blood pressure measurement, biochemical, and histological studies were performed. The groups were compared by two-way ANOVA with a significance level of 5%. Results TS increased left atrium diameter and area, which was attenuated by PX. In the isolated heart study, TS lowered the positive derivate (+dp/dt), and this was attenuated by PX. The antioxidants enzyme superoxide dismutase and glutathione peroxidase were decreased in the TS group; PX recovered these activities. TS increased lactate dehydrogenase (LDH) and decreased 3-hydroxyacyl Coenzyme A dehydrogenases (OH-DHA) and citrate synthase (CS). PX attenuated LDH, 3-OH-DHA and CS alterations in TS-PX group. TS increased IL-10, ICAM-1, and caspase-3. PX did not influence these variables. Conclusion TS induced cardiac remodeling, associated with increased inflammation, oxidative stress, apoptosis, and changed energy metabolism. PX attenuated cardiac remodeling by reducing oxidative stress and improving cardiac bioenergetics, but did not act upon cardiac cytokines and apoptosis. PMID:27096523

  1. Oxazolone-Induced Contact Hypersensitivity Reduces Lymphatic Drainage but Enhances the Induction of Adaptive Immunity

    PubMed Central

    Aebischer, David; Willrodt, Ann-Helen; Halin, Cornelia

    2014-01-01

    Contact hypersensitivity (CHS) induced by topical application of haptens is a commonly used model to study dermal inflammatory responses in mice. Several recent studies have indicated that CHS-induced skin inflammation triggers lymphangiogenesis but may negatively impact the immune-function of lymphatic vessels, namely fluid drainage and dendritic cell (DC) migration to draining lymph nodes (dLNs). On the other hand, haptens have been shown to exert immune-stimulatory activity by inducing DC maturation. In this study we investigated how the presence of pre-established CHS-induced skin inflammation affects the induction of adaptive immunity in dLNs. Using a mouse model of oxazolone-induced skin inflammation we observed that lymphatic drainage was reduced and DC migration from skin to dLNs was partially compromised. At the same time, a significantly stronger adaptive immune response towards ovalbumin (OVA) was induced when immunization had occurred in CHS-inflamed skin as compared to uninflamed control skin. In fact, immunization with sterile OVA in CHS-inflamed skin evoked a delayed-type hypersensitivity (DTH) response comparable to the one induced by conventional immunization with OVA and adjuvant in uninflamed skin. Striking phenotypic and functional differences were observed when comparing DCs from LNs draining uninflamed or CHS-inflamed skin. DCs from LNs draining CHS-inflamed skin expressed higher levels of co-stimulatory molecules and MHC molecules, produced higher levels of the interleukin-12/23 p40 subunit (IL-12/23-p40) and more potently induced T cell activation in vitro. Immunization experiments revealed that blockade of IL-12/23-p40 during the priming phase partially reverted the CHS-induced enhancement of the adaptive immune response. Collectively, our findings indicate that CHS-induced skin inflammation generates an overall immune-stimulatory milieu, which outweighs the potentially suppressive effect of reduced lymphatic vessel function. PMID:24911791

  2. Focal myocardial infarction induces global remodeling of cardiac sympathetic innervation: neural remodeling in a spatial context

    PubMed Central

    Ajijola, Olujimi A.; Yagishita, Daigo; Patel, Krishan J.; Vaseghi, Marmar; Zhou, Wei; Yamakawa, Kentaro; So, Eileen; Lux, Robert L.; Mahajan, Aman

    2013-01-01

    Myocardial infarction (MI) induces neural and electrical remodeling at scar border zones. The impact of focal MI on global functional neural remodeling is not well understood. Sympathetic stimulation was performed in swine with anteroapical infarcts (MI; n = 9) and control swine (n = 9). A 56-electrode sock was placed over both ventricles to record electrograms at baseline and during left, right, and bilateral stellate ganglion stimulation. Activation recovery intervals (ARIs) were measured from electrograms. Global and regional ARI shortening, dispersion of repolarization, and activation propagation were assessed before and during sympathetic stimulation. At baseline, mean ARI was shorter in MI hearts than control hearts (365 ± 8 vs. 436 ± 9 ms, P < 0.0001), dispersion of repolarization was greater in MI versus control hearts (734 ± 123 vs. 362 ± 32 ms2, P = 0.02), and the infarcted region in MI hearts showed longer ARIs than noninfarcted regions (406 ± 14 vs. 365 ± 8 ms, P = 0.027). In control animals, percent ARI shortening was greater on anterior than posterior walls during right stellate ganglion stimulation (P = 0.0001), whereas left stellate ganglion stimulation showed the reverse (P = 0.0003). In infarcted animals, this pattern was completely lost. In 50% of the animals studied, sympathetic stimulation, compared with baseline, significantly altered the direction of activation propagation emanating from the intramyocardial scar during pacing. In conclusion, focal distal anterior MI alters regional and global pattern of sympathetic innervation, resulting in shorter ARIs in infarcted hearts, greater repolarization dispersion, and altered activation propagation. These conditions may underlie the mechanisms by which arrhythmias are initiated when sympathetic tone is enhanced. PMID:23893167

  3. Cocaine enhances HIV-1 gp120-induced lymphatic endothelial dysfunction in the lung

    PubMed Central

    Zhang, Xuefeng; Jiang, Susan; Yu, Jinlong; Kuzontkoski, Paula M; Groopman, Jerome E

    2015-01-01

    Pulmonary complications are common in both AIDS patients and cocaine users. We addressed the cellular and molecular mechanisms by which HIV and cocaine may partner to induce their deleterious effects. Using primary lung lymphatic endothelial cells (L-LECs), we examined how cocaine and HIV-1 gp120, alone and together, modulate signaling and functional properties of L-LECs. We found that brief cocaine exposure activated paxillin and induced cytoskeletal rearrangement, while sustained exposure increased fibronectin (FN) expression, decreased Robo4 expression, and enhanced the permeability of L-LEC monolayers. Moreover, incubating L-LECs with both cocaine and HIV-1 gp120 exacerbated hyperpermeability, significantly enhanced apoptosis, and further impaired in vitro wound healing as compared with cocaine alone. Our studies also suggested that the sigma-1 receptor (Sigma-1R) and the dopamine-4 receptor (D4R) are involved in cocaine-induced pathology in L-LECs. Seeking clinical correlation, we found that FN levels in sera and lung tissue of HIV+ donors were significantly elevated as compared to HIV− donors. Our in vitro data demonstrate that cocaine and HIV-1 gp120 induce dysfunction and damage of lung lymphatics, and suggest that cocaine use may exacerbate pulmonary edema and fibrosis associated with HIV infection. Continued exploration of the interplay between cocaine and HIV should assist the design of therapeutics to ameliorate HIV-induced pulmonary disorders within the drug using population. PMID:26311830

  4. Cocaine enhances HIV-1 gp120-induced lymphatic endothelial dysfunction in the lung.

    PubMed

    Zhang, Xuefeng; Jiang, Susan; Yu, Jinlong; Kuzontkoski, Paula M; Groopman, Jerome E

    2015-08-01

    Pulmonary complications are common in both AIDS patients and cocaine users. We addressed the cellular and molecular mechanisms by which HIV and cocaine may partner to induce their deleterious effects. Using primary lung lymphatic endothelial cells (L-LECs), we examined how cocaine and HIV-1 gp120, alone and together, modulate signaling and functional properties of L-LECs. We found that brief cocaine exposure activated paxillin and induced cytoskeletal rearrangement, while sustained exposure increased fibronectin (FN) expression, decreased Robo4 expression, and enhanced the permeability of L-LEC monolayers. Moreover, incubating L-LECs with both cocaine and HIV-1 gp120 exacerbated hyperpermeability, significantly enhanced apoptosis, and further impaired in vitro wound healing as compared with cocaine alone. Our studies also suggested that the sigma-1 receptor (Sigma-1R) and the dopamine-4 receptor (D4R) are involved in cocaine-induced pathology in L-LECs. Seeking clinical correlation, we found that FN levels in sera and lung tissue of HIV(+) donors were significantly elevated as compared to HIV(-) donors. Our in vitro data demonstrate that cocaine and HIV-1 gp120 induce dysfunction and damage of lung lymphatics, and suggest that cocaine use may exacerbate pulmonary edema and fibrosis associated with HIV infection. Continued exploration of the interplay between cocaine and HIV should assist the design of therapeutics to ameliorate HIV-induced pulmonary disorders within the drug using population. PMID:26311830

  5. Mechanisms of Acute Alcohol Intoxication-Induced Modulation of Cyclic Mobilization of [Ca2+] in Rat Mesenteric Lymphatic Vessels

    PubMed Central

    Kerut, Edmund K.; Breslin, Jerome W.; Molina, Patricia E.

    2015-01-01

    Abstract Background: We have demonstrated that acute alcohol intoxication (AAI) increases the magnitude of Ca2+ transients in pumping lymphatic vessels. We tested the contribution of extracellular Ca2+ via L-type Ca2+ channels and intracellular Ca2+ release from the sarcoplasmic reticulum (SR) to the AAI-induced increase in Ca2+ transients. Methods and Results: AAI was produced by intragastric administration of 30% alcohol to conscious, unrestrained rats; isovolumic administration of water served as the control. Mesenteric lymphatic vessels were isolated, cannulated, and loaded with Fura-2 AM to measure changes in intracellular Ca2+. Measurements were made at intraluminal pressures of 2, 6, and 10 cm H2O. L-type Ca2+ channels were blocked with nifedipine; IP-3 receptors were inhibited with xestospongin C; and SR Ca2+ release and Ca2+ pool (Ca2+ free APSS) were achieved using caffeine. Nifedipine reduced lymphatic Ca2+ transient magnitude in both AAI and control groups at all pressures tested, but reduced lymphatic contraction frequency only in the control group. Xestospongin C did not significantly change any of the Ca2+ parameters in either group; however, fractional shortening increased in the controls at low transmural pressure. RyR (ryanodine receptor) activation with caffeine resulted in a single contraction with a greater Ca2+ transient in lymphatics from AAI than those from controls. SR Ca2+ pool was also greater in lymphatics isolated from AAI- than from control animals. Conclusions: These data suggest that 1) L-type Ca2+ channels contribute to the AAI-induced increase in lymphatic Ca2+ transient, 2) blockage of IP-3 receptors could increase calcium sensitivity, and 3) AAI increases Ca2+ storage in the SR in lymphatic vessels. PMID:26056854

  6. Mechanisms of VIP-induced inhibition of the lymphatic vessel pump.

    PubMed

    von der Weid, Pierre-Yves; Rehal, Sonia; Dyrda, Peter; Lee, Stewart; Mathias, Ryan; Rahman, Mozibur; Roizes, Simon; Imtiaz, Mohammad S

    2012-06-01

    Lymphatic vessels serve as a route by which interstitial fluid, protein and other macromolecules are returned to the blood circulation and immune cells and antigens gain access to lymph nodes. Lymph flow is an active process promoted by rhythmical contraction-relaxation events occurring in the collecting lymphatic vessels. This lymphatic pumping is an intrinsic property of the lymphatic muscles in the vessel wall and consequent to action potentials. Compromised lymphatic pumping may affect lymph and immune cell transport, an action which could be particularly detrimental during inflammation. Importantly, many inflammatory mediators alter lymphatic pumping. Vasoactive intestinal peptide (VIP) is a neuro- and immuno-modulator thought to be released by nerve terminals and immune cells in close proximity to lymphatic vessels. We demonstrated the presence of the peptide in lymphatic vessels and in the lymph and examined the effects of VIP on mesenteric collecting lymphatic vessels of the guinea pig using pharmacological bioassays, intracellular microelectrode electrophysiology, immunofluorescence and quantitative real-time PCR. We showed that VIP alters lymphatic pumping by decreasing the frequency of lymphatic contractions and hyperpolarizing the lymphatic muscle membrane potential in a concentration-dependent manner. Our data further suggest that these effects are mainly mediated by stimulation of the VIP receptor VPAC2 located on the lymphatic muscle and the downstream involvement of protein kinase A (PKA) and ATP-sensitive K⁺ (KATP) channels. Inhibition of lymphatic pumping by VIP may compromise lymph drainage, oedema resolution and immune cell trafficking to the draining lymph nodes. PMID:22451438

  7. Rutaecarpine attenuates hypoxia-induced right ventricular remodeling in rats.

    PubMed

    Li, Wen-Qun; Li, Xiao-Hui; Du, Jie; Zhang, Wang; Li, Dai; Xiong, Xiao-Ming; Li, Yuan-Jian

    2016-07-01

    Rutaecarpine has been shown to exhibit wide pharmacological effects in the cardiovascular system via stimulation of calcitonin gene-related peptide (CGRP) release. In the present study, the effect of rutaecarpine on hypoxia-induced right ventricular (RV) remodeling and the underlying mechanisms were evaluated. RV remodeling was induced by hypoxia (10 % O2, 3 weeks) in rats. Rats were treated with rutaecarpine (20 or 40 mg/kg) by intragastric administration. Proliferation of cardiac fibroblasts was induced by TGF-β1 (5 ng/mL) and determined by MTS and EdU incorporation method. Cardiac fibroblasts were treated with exogenous CGRP (10 or 100 nM). The concentrations of CGRP and TGF-β1 in plasma were measured by ELISA. The expression of eIF3a, p27, α-SMA, collagen-I/III, ANP, and BNP were measured by real-time PCR or western blot. Hypoxia induced an increase of right ventricle systolic pressure (RVSP), ration of RV/LV+S, and RV/tibial length in rats, while cardiac hypertrophy, apoptosis, and fibrosis were detected. The expression of ANP, BNP, α-SMA, collagen-I, collagen-III, eIF3a, and TGF-β1 was up-regulated, and the expression of p27 was down-regulated in the right ventricle of hypoxia-treated rats. The plasma concentration of CGRP was decreased and TGF-β1 was increased in hypoxia-treated rats. All of these effects induced by hypoxia were attenuated by rutaecarpine in a dose-dependent manner. In cultured cardiac fibroblasts, TGF-β1 significantly promoted the proliferation and up-regulated the expression of α-SMA and collagen-I/III, while the expression of eIF3a was up-regulated and the expression of p27 was down-regulated. The effects of TGF-β1 were attenuated by CGRP. CGRP8-37, a selective CGRP receptor antagonist, abolished the effects of CGRP. Rutaecarpine attenuates hypoxia-induced RV remodeling via stimulation of CGRP release, and the effects of rutaecarpine involve the eIF3a/p27 pathway. PMID:27052575

  8. Thermally Induced Osteocyte Damage Initiates a Remodelling Signaling Cascade

    PubMed Central

    Dolan, Eimear B.; McNamara, Laoise M.

    2015-01-01

    Thermal elevations experienced by bone during orthopaedic procedures, such as cutting and drilling, exothermal reactions from bone cement, and thermal therapies such as tumor ablation, can result in thermal damage leading to death of native bone cells (osteocytes, osteoblasts, osteoclasts and mesenchymal stem cells). Osteocytes are believed to be the orchestrators of bone remodeling, which recruit nearby osteoclast and osteoblasts to control resorption and bone growth in response to mechanical stimuli and physical damage. However, whether heat-induced osteocyte damage can directly elicit bone remodelling has yet to be determined. This study establishes the link between osteocyte thermal damage and the remodeling cascade. We show that osteocytes directly exposed to thermal elevations (47°C for 1 minute) become significantly apoptotic and alter the expression of osteogenic genes (Opg and Cox2). The Rankl/Opg ratio is consistently down-regulated, at days 1, 3 and 7 in MLO-Y4s heat-treated to 47°C for 1 minute. Additionally, the pro-osteoblastogenic signaling marker Cox2 is significantly up-regulated in heat-treated MLO-Y4s by day 7. Furthermore, secreted factors from heat-treated MLO-Y4s administered to MSCs using a novel co-culture system are shown to activate pre-osteoblastic MSCs to increase production of the pro-osteoblastic differentiation marker, alkaline phosphatase (day 7, 14), and calcium deposition (day 21). Most interestingly, an initial pro-osteoclastogenic signaling response (increase Rankl and Rankl/Opg ratio at day 1) followed by later stage pro-osteoblastogenic signaling (down-regulation in Rankl and the Rankl/Opg ratio and an up-regulation in Opg and Cox2 by day 7) was observed in non-heat-treated MLO-Y4s in co-culture when these were exposed to the biochemicals produced by heat-treated MLO-Y4s. Taken together, these results elucidate the vital role of osteocytes in detecting and responding to thermal damage by means of thermally induced apoptosis

  9. Thermally induced osteocyte damage initiates a remodelling signaling cascade.

    PubMed

    Dolan, Eimear B; Haugh, Matthew G; Voisin, Muriel C; Tallon, David; McNamara, Laoise M

    2015-01-01

    Thermal elevations experienced by bone during orthopaedic procedures, such as cutting and drilling, exothermal reactions from bone cement, and thermal therapies such as tumor ablation, can result in thermal damage leading to death of native bone cells (osteocytes, osteoblasts, osteoclasts and mesenchymal stem cells). Osteocytes are believed to be the orchestrators of bone remodeling, which recruit nearby osteoclast and osteoblasts to control resorption and bone growth in response to mechanical stimuli and physical damage. However, whether heat-induced osteocyte damage can directly elicit bone remodelling has yet to be determined. This study establishes the link between osteocyte thermal damage and the remodeling cascade. We show that osteocytes directly exposed to thermal elevations (47°C for 1 minute) become significantly apoptotic and alter the expression of osteogenic genes (Opg and Cox2). The Rankl/Opg ratio is consistently down-regulated, at days 1, 3 and 7 in MLO-Y4s heat-treated to 47°C for 1 minute. Additionally, the pro-osteoblastogenic signaling marker Cox2 is significantly up-regulated in heat-treated MLO-Y4s by day 7. Furthermore, secreted factors from heat-treated MLO-Y4s administered to MSCs using a novel co-culture system are shown to activate pre-osteoblastic MSCs to increase production of the pro-osteoblastic differentiation marker, alkaline phosphatase (day 7, 14), and calcium deposition (day 21). Most interestingly, an initial pro-osteoclastogenic signaling response (increase Rankl and Rankl/Opg ratio at day 1) followed by later stage pro-osteoblastogenic signaling (down-regulation in Rankl and the Rankl/Opg ratio and an up-regulation in Opg and Cox2 by day 7) was observed in non-heat-treated MLO-Y4s in co-culture when these were exposed to the biochemicals produced by heat-treated MLO-Y4s. Taken together, these results elucidate the vital role of osteocytes in detecting and responding to thermal damage by means of thermally induced apoptosis

  10. Erythrocyte Stiffness during Morphological Remodeling Induced by Carbon Ion Radiation

    PubMed Central

    Zhang, Baoping; Liu, Bin; Zhang, Hong; Wang, Jizeng

    2014-01-01

    The adverse effect induced by carbon ion radiation (CIR) is still an unavoidable hazard to the treatment object. Thus, evaluation of its adverse effects on the body is a critical problem with respect to radiation therapy. We aimed to investigate the change between the configuration and mechanical properties of erythrocytes induced by radiation and found differences in both the configuration and the mechanical properties with involving in morphological remodeling process. Syrian hamsters were subjected to whole-body irradiation with carbon ion beams (1, 2, 4, and 6 Gy) or X-rays (2, 4, 6, and 12 Gy) for 3, 14 and 28 days. Erythrocytes in peripheral blood and bone marrow were collected for cytomorphological analysis. The mechanical properties of the erythrocytes were determined using atomic force microscopy, and the expression of the cytoskeletal protein spectrin-α1 was analyzed via western blotting. The results showed that dynamic changes were evident in erythrocytes exposed to different doses of carbon ion beams compared with X-rays and the control (0 Gy). The magnitude of impairment of the cell number and cellular morphology manifested the subtle variation according to the irradiation dose. In particular, the differences in the size, shape and mechanical properties of the erythrocytes were well exhibited. Furthermore, immunoblot data showed that the expression of the cytoskeletal protein spectrin-α1 was changed after irradiation, and there was a common pattern among its substantive characteristics in the irradiated group. Based on these findings, the present study concluded that CIR could induce a change in mechanical properties during morphological remodeling of erythrocytes. According to the unique characteristics of the biomechanical categories, we deduce that changes in cytomorphology and mechanical properties can be measured to evaluate the adverse effects generated by tumor radiotherapy. Additionally, for the first time, the current study provides a new

  11. Erythrocyte stiffness during morphological remodeling induced by carbon ion radiation.

    PubMed

    Zhang, Baoping; Liu, Bin; Zhang, Hong; Wang, Jizeng

    2014-01-01

    The adverse effect induced by carbon ion radiation (CIR) is still an unavoidable hazard to the treatment object. Thus, evaluation of its adverse effects on the body is a critical problem with respect to radiation therapy. We aimed to investigate the change between the configuration and mechanical properties of erythrocytes induced by radiation and found differences in both the configuration and the mechanical properties with involving in morphological remodeling process. Syrian hamsters were subjected to whole-body irradiation with carbon ion beams (1, 2, 4, and 6 Gy) or X-rays (2, 4, 6, and 12 Gy) for 3, 14 and 28 days. Erythrocytes in peripheral blood and bone marrow were collected for cytomorphological analysis. The mechanical properties of the erythrocytes were determined using atomic force microscopy, and the expression of the cytoskeletal protein spectrin-α1 was analyzed via western blotting. The results showed that dynamic changes were evident in erythrocytes exposed to different doses of carbon ion beams compared with X-rays and the control (0 Gy). The magnitude of impairment of the cell number and cellular morphology manifested the subtle variation according to the irradiation dose. In particular, the differences in the size, shape and mechanical properties of the erythrocytes were well exhibited. Furthermore, immunoblot data showed that the expression of the cytoskeletal protein spectrin-α1 was changed after irradiation, and there was a common pattern among its substantive characteristics in the irradiated group. Based on these findings, the present study concluded that CIR could induce a change in mechanical properties during morphological remodeling of erythrocytes. According to the unique characteristics of the biomechanical categories, we deduce that changes in cytomorphology and mechanical properties can be measured to evaluate the adverse effects generated by tumor radiotherapy. Additionally, for the first time, the current study provides a new

  12. b-FGF Induces Corneal Blood and Lymphatic Growth in a Spatially Distinct Pattern

    PubMed Central

    Hajrasouliha, Amir R.; Sadrai, Zahra; Chauhan, Sunil K.; Dana, Reza

    2013-01-01

    Purpose To study the spatial variances in ligand expression and angiogenic effect in response to the inflammatory response induced by b-FGF. Methods b-FGF micropellets (80ng) were implanted in the temporal side of the cornea of Balbc/c mice. On days 1, 3, and 7 blood (heme) and lymph-angiogenesis were observed by immunofluorescence staining of corneal flat mounts with LYVE-1 and CD31 to identify lymphatic and blood vessels, respectively. A second group of corneas were harvested for quantitative RT-PCR. Each cornea was divided in two different area defines as (i) pre-pellet area and (ii) opposite-pellet area. Expression of VEGF ligands were evaluated using Real-time PCR in each respective zone. Results Blood vessels grew into the cornea from the pre-pellet area while corneal lymphatic vessels grew from the opposite-pellet area toward the center of the cornea. VEGF-A was upregulated in the pre-pellet while VEGF-D expression was mostly observed in the opposite-pellet area. VEGF-C level increased simultaneously in both areas. Conclusion A single inducing factor, i.e., b-FGF, may simultaneously provoke heme-and lymph-angiogenesis in different locations of the cornea through differential expression of VEGF ligands. This distinctive spatial pattern should be considered while evaluating the corneal predilection for inflammation beyond that which is directly visible by slit lamp examination. PMID:22467003

  13. Nuclear translocation of phosphorylated STAT3 regulates VEGF-A-induced lymphatic endothelial cell migration and tube formation

    SciTech Connect

    Okazaki, Hideki; Tokumaru, Sho; Hanakawa, Yasushi; Shiraishi, Ken; Shirakata, Yuji; Dai, Xiuju; Yang, Lijun; Tohyama, Mikiko; Hashimoto, Koji; Sayama, Koji

    2011-09-02

    Highlights: {yields} VEGF-A enhanced lymphatic endothelial cell migration and increased tube formation. {yields} VEGF-A treated lymphatic endothelial cell showed activation of STAT3. {yields} Dominant-negative STAT3 inhibited VEGF-A-induced lymphatic endothelial cell migration and tube formation. -- Abstract: Vascular endothelial growth factor (VEGF) is an endothelial cell-specific growth factor that regulates endothelial functions, and signal transducers and activators of transcription (STATs) are known to be important during VEGF receptor signaling. The aim of this study was to determine whether STAT3 regulates VEGF-induced lymphatic endothelial cell (LEC) migration and tube formation. VEGF-A (33 ng/ml) enhanced LEC migration by 2-fold and increased tube length by 25% compared with the control, as analyzed using a Boyden chamber and Matrigel assay, respectively. Western blot analysis and immunostaining revealed that VEGF-A induced the nuclear translocation of phosphorylated STAT3 in LECs, and this translocation was blocked by the transfection of LECs with an adenovirus vector expressing a dominant-negative mutant of STAT3 (Ax-STAT3F). Transfection with Ax-STAT3F also almost completely inhibited VEGF-A-induced LEC migration and tube formation. These results indicate that STAT3 is essential for VEGF-A-induced LEC migration and tube formation and that STAT3 regulates LEC functions.

  14. Lymphatic Diseases

    MedlinePlus

    The lymphatic system is a network of tissues and organs. It is made up of Lymph - a fluid that contains ... They are part of the system, too. The lymphatic system clears away infection and keeps your body fluids ...

  15. Lymphatic obstruction

    MedlinePlus

    ... certain directions based on the structure of the lymphatic system. This helps the lymph fluid drain through the ... always appropriate or effective. Alternative Names Lymphedema Images Lymphatic system Yellow nail syndrome References Kurklinsky AK, Rooke TW. ...

  16. Acute versus chronic exercise-induced left-ventricular remodeling.

    PubMed

    Weiner, Rory B; Baggish, Aaron L

    2014-11-01

    Exercise-induced cardiac remodeling (EICR) is the process by which the heart adapts to the physiologic stress of exercise. Non-invasive cardiovascular imaging has led to advances in the understanding of EICR, with sport-specific changes in left-ventricular (LV) structure and function being described; however, the majority of data stem from cross-sectional and short-duration longitudinal studies. Due to the paucity of long-term longitudinal EICR studies, the time course of this process and any distinct differentiation between acute and chronic adaptations remain largely unexplored. In order to clarify the natural history of EICR, longer duration longitudinal study is required. Such work will determine whether exercise-induced changes in myocardial structure and function occur in discrete stages. Examination of prolonged exposures to exercise training will also be necessary to determine normative values across the age and training spectrums of athletic patients. This information will help to distinguish the boundary between physiology and pathology in athletic patients. PMID:25300444

  17. Osmotic stress-induced remodeling of the cortical cytoskeleton.

    PubMed

    Di Ciano, Caterina; Nie, Zilin; Szászi, Katalin; Lewis, Alison; Uruno, Takehito; Zhan, Xi; Rotstein, Ori D; Mak, Alan; Kapus, András

    2002-09-01

    Osmotic stress is known to affect the cytoskeleton; however, this adaptive response has remained poorly characterized, and the underlying signaling pathways are unexplored. Here we show that hypertonicity induces submembranous de novo F-actin assembly concomitant with the peripheral translocation and colocalization of cortactin and the actin-related protein 2/3 (Arp2/3) complex, which are key components of the actin nucleation machinery. Additionally, hyperosmolarity promotes the association of cortactin with Arp2/3 as revealed by coimmunoprecipitation. Using various truncation or phosphorylation-incompetent mutants, we show that cortactin translocation requires the Arp2/3- or the F-actin binding domain, but the process is independent of the shrinkage-induced tyrosine phosphorylation of cortactin. Looking for an alternative signaling mechanism, we found that hypertonicity stimulates Rac and Cdc42. This appears to be a key event in the osmotically triggered cytoskeletal reorganization, because 1) constitutively active small GTPases translocate cortactin, 2) Rac and cortactin colocalize at the periphery of hypertonically challenged cells, and 3) dominant-negative Rac and Cdc42 inhibit the hypertonicity-provoked cortactin and Arp3 translocation. The Rho family-dependent cytoskeleton remodeling may be an important osmoprotective response that reinforces the cell cortex. PMID:12176742

  18. CRSBP-1/LYVE-1 ligands disrupt lymphatic intercellular adhesion by inducing tyrosine phosphorylation and internalization of VE-cadherin

    PubMed Central

    Hou, Wei-Hsien; Liu, I-Hua; Tsai, Cheng C.; Johnson, Frank E.; Huang, Shuan Shian; Huang, Jung San

    2011-01-01

    Cell-surface retention sequence (CRS) binding protein (CRSBP-1) is a membrane glycoprotein identified by its ability to bind PDGF-BB and VEGF-A via their CRS motifs (clusters of basic amino acid residues). CRSBP-1 is identical to LYVE-1 and exhibits dual ligand (CRS-containing proteins and hyaluronic acid) binding activity, suggesting the importance of CRSBP-1 ligands in lymphatic function. Here, we show that CRSBP-1 ligands induce disruption of VE-cadherin-mediated intercellular adhesion and opening of intercellular junctions in lymphatic endothelial cell (LEC) monolayers as determined by immunofluorescence microscopy and Transwell permeability assay. This occurs by interaction with CRSBP-1 in the CRSBP-1–PDGFβR–β-catenin complex, resulting in tyrosine phosphorylation of the complex, dissociation of β-catenin and p120-catenin from VE-cadherin, and internalization of VE-cadherin. Pretreatment of LECs with a PDGFβR kinase inhibitor abolishes ligand-stimulated tyrosine phosphorylation of VE-cadherin, halts the ligand-induced disruption of VE-cadherin intercellular adhesion and blocks the ligand-induced opening of intercellular junctions. These CRSBP-1 ligands also induce opening of lymphatic intercellular junctions that respond to PDGFβR kinase inhibitor in wild-type mice (but not in Crsbp1-null mice) as evidenced by increased transit of injected FITC–dextran and induced edema fluid from the interstitial space into lymphatic vessels. These results disclose a novel mechanism involved in the opening of lymphatic intercellular junctions. PMID:21444752

  19. Inhibition of Rab prenylation by statins induces cellular glycosphingolipid remodeling.

    PubMed

    Binnington, Beth; Nguyen, Long; Kamani, Mustafa; Hossain, Delowar; Marks, David L; Budani, Monique; Lingwood, Clifford A

    2016-02-01

    Statins, which specifically inhibit HMG Co-A reductase, the rate-limiting step of cholesterol biosynthesis, are widely prescribed to reduce serum cholesterol and cardiac risk, but many other effects are seen. We now show an effect of these drugs to induce profound changes in the step-wise synthesis of glycosphingolipids (GSLs) in the Golgi. Glucosylceramide (GlcCer) was increased several-fold in all cell lines tested, demonstrating a widespread effect. Additionally, de novo or elevated lactotriaosylceramide (Lc3Cer; GlcNAcβ1-3Galβ1-4GlcCer) synthesis was observed in 70%. Western blot showed that GlcCer synthase (GCS) was elevated by statins, and GCS and Lc3Cer synthase (Lc3S) activities were increased; however, transcript was elevated for Lc3S only. Supplementation with the isoprenoid precursor, geranylgeranyl pyrophosphate (GGPP), a downstream product of HMG Co-A reductase, reversed statin-induced glycosyltransferase and GSL elevation. The Rab geranylgeranyl transferase inhibitor 3-PEHPC, but not specific inhibitors of farnesyl transferase, or geranylgeranyl transferase I, was sufficient to replicate statin-induced GlcCer and Lc3Cer synthesis, supporting a Rab prenylation-dependent mechanism. While total cholesterol was unaffected, the trans-Golgi network (TGN) cholesterol pool was dissipated and medial Golgi GCS partially relocated by statins. GSL-dependent vesicular retrograde transport of Verotoxin and cholera toxin to the Golgi/endoplasmic reticulum were blocked after statin or 3-PEHPC treatment, suggesting aberrant, prenylation-dependent vesicular traffic as a basis of glycosyltransferase increase and GSL remodeling. These in vitro studies indicate a previously unreported link between Rab prenylation and regulation of GCS activity and GlcCer metabolism. PMID:26405105

  20. Phosphorus starvation induces membrane remodeling and recycling in Emiliania huxleyi.

    PubMed

    Shemi, Adva; Schatz, Daniella; Fredricks, Helen F; Van Mooy, Benjamin A S; Porat, Ziv; Vardi, Assaf

    2016-08-01

    Nutrient availability is an important factor controlling phytoplankton productivity. Phytoplankton contribute c. 50% of the global photosynthesis and possess efficient acclimation mechanisms to cope with nutrient stress. We investigate the cellular response of the bloom-forming coccolithophore Emiliania huxleyi to phosphorus (P) scarcity, which is often a limiting factor in marine ecosystems. We combined mass spectrometry, fluorescence microscopy, transmission electron microscopy (TEM) and gene expression analyses in order to assess diverse cellular features in cells exposed to P limitation and recovery. Early starvation-induced substitution of phospholipids in the cells' membranes with galacto- and betaine lipids. Lipid remodeling was rapid and reversible upon P resupply. The PI3K inhibitor wortmannin reduced phospholipid substitution, suggesting a possible involvement of PI3K- signaling in this process. In addition, P limitation enhanced the formation and acidification of membrane vesicles in the cytoplasm. Intracellular vesicles may facilitate the recycling of cytoplasmic content, which is engulfed in the vesicles and delivered to the main vacuole. Long-term starvation was characterized by a profound increase in cell size and morphological alterations in cellular ultrastructure. This study provides cellular and molecular basis for future ecophysiological assessment of natural E. huxleyi populations in oligotrophic regions. PMID:27111716

  1. Hyperplasia, de novo lymphangiogenesis, and lymphatic regression in mice with tissue-specific, inducible overexpression of murine VEGF-D.

    PubMed

    Lammoglia, Gabriela M; Van Zandt, Carolynn E; Galvan, Daniel X; Orozco, Jose L; Dellinger, Michael T; Rutkowski, Joseph M

    2016-08-01

    Lymphatic vessels modulate tissue fluid balance and inflammation and provide a conduit for endocrine and lipid transport. The growth of new lymphatic vessels in the adult, lymphangiogenesis, is predominantly mediated through vascular endothelial growth factor receptor-3 (VEGFR-3) signaling. We took advantage of the unique binding of murine VEGF-D specifically to VEGFR-3 and generated mice capable of inducible, tissue-specific expression of murine VEGF-D under a tightly-controlled tetracycline response element (TRE) promoter to stimulate adult tissue lymphangiogenesis. With doxycycline-activated expression, TRE-VEGF-D mouse crossed to mice with tissue-specific promoters for the lung [Clara cell secretory protein-reverse tetracycline transactivator (rtTA)] developed pulmonary lymphangiectasia. In the kidney, (kidney-specific protein-rtTA × TRE-VEGF-D) mice exhibited rapid lymphatic hyperplasia on induction of VEGF-D expression. Crossed with adipocyte-specific adiponectin-rtTA mice [Adipo-VEGF-D (VD)], chronic VEGF-D overexpression was capable of inducing de novo lymphangiogenesis in white adipose tissue and a massive expansion of brown adipose tissue lymphatics. VEGF-D expression in white adipose tissue also increased macrophage infiltration and tissue fibrosis in the tissue. Expression did not, however, measurably affect peripheral fluid transport, the blood vasculature, or basal metabolic parameters. On removal of the doxycycline stimulus, VEGF-D expression returned to normal, and the expanded adipose tissue lymphatics regressed in Adipo-VD mice. The inducible TRE-VEGF-D mouse thus provides a novel murine platform to study the adult mechanisms and therapies of an array of disease- and tissue-specific models of lymphangiogenesis. PMID:27342876

  2. Mechanobiology of lymphatic contractions.

    PubMed

    Munn, Lance L

    2015-02-01

    The lymphatic system is responsible for controlling tissue fluid pressure by facilitating flow of lymph (i.e. the plasma and cells that enter the lymphatic system). Because lymph contains cells of the immune system, its transport is not only important for fluid homeostasis, but also immune function. Lymph drainage can occur via passive flow or active pumping, and much research has identified the key biochemical and mechanical factors that affect output. Although many studies and reviews have addressed how tissue properties and fluid mechanics (i.e. pressure gradients) affect lymph transport [1-3] there is less known about lymphatic mechanobiology. As opposed to passive mechanical properties, mechanobiology describes the active coupling of mechanical signals and biochemical pathways. Lymphatic vasomotion is the result of a fascinating system affected by mechanical forces exerted by the flowing lymph, including pressure-induced vessel stretch and flow-induced shear stresses. These forces can trigger or modulate biochemical pathways important for controlling the lymphatic contractions. Here, I review the current understanding of lymphatic vessel function, focusing on vessel mechanobiology, and summarize the prospects for a comprehensive understanding that integrates the mechanical and biomechanical control mechanisms in the lymphatic system. PMID:25636584

  3. Downregulation of β-Adrenoceptors in Isoproterenol-Induced Cardiac Remodeling through HuR

    PubMed Central

    Yin, Qian; Yang, Chengzhi; Wu, Jimin; Lu, Haiyan; Zheng, Xiaohui; Zhang, Youyi; Lv, Zhizhen; Zheng, Xiaopu; Li, Zijian

    2016-01-01

    β-adrenergic receptors (β-ARs) play an important role in cardiac remodeling, which is the key pathological process in various heart diseases and leads to heart failure. However, the regulation of β-AR expression in remodeling hearts is still unclear. This study aims to clarify the possible mechanisms underlying the regulation of β1- and β2-AR expression in cardiac remodeling. The rat model of cardiac remodeling was established by subcutaneous injection of isoproterenol(ISO) at the dose of 0.25 mg·kg−1·d−1 for 7days. We found that the expression of β1- and β2-ARs decreased in the remodeling heart. The mechanisms may include the inhibition of DNA transcription and the increase of mRNA degradation. cAMP-response element binding protein(CREB) is a well-known transcription factor of β-AR. However, the expression and activation of CREB was not changed in the remodeling heart. Further, human Antigen-R (HuR), a RNA binding protein, which binds to the 3'-untranslated region of the β-AR mRNA and promotes RNA degradation, was increased in the remodeling model. And in vitro, HuR deficiency reversed the reduction of β-AR mRNA induced by ISO. Therefore, the present findings indicate that HuR, but not CREB, is responsible for the reduction of β-AR expression in ISO induced cardiac remodeling. PMID:27035432

  4. Disruption of TGF-β signaling in smooth muscle cell prevents flow-induced vascular remodeling

    SciTech Connect

    Gao, Fu; Chambon, Pierre; Tellides, George; Kong, Wei; Zhang, Xiaoming; Li, Wei

    2014-11-07

    Highlights: • TGF-β signaling in SMC contributes to the flow-induced vascular remodeling. • Disruption of TGF-β signaling in SMC can prevent this process. • Targeting SM-specific Tgfbr2 could be a novel therapeutic strategy for vascular remodeling. - Abstract: Transforming growth factor-β (TGF-β) signaling has been prominently implicated in the pathogenesis of vascular remodeling, especially the initiation and progression of flow-induced vascular remodeling. Smooth muscle cells (SMCs) are the principal resident cells in arterial wall and are critical for arterial remodeling. However, the role of TGF-β signaling in SMC for flow-induced vascular remodeling remains unknown. Therefore, the goal of our study was to determine the effect of TGF-β pathway in SMC for vascular remodeling, by using a genetical smooth muscle-specific (SM-specific) TGF-β type II receptor (Tgfbr2) deletion mice model. Mice deficient in the expression of Tgfbr2 (MyhCre.Tgfbr2{sup f/f}) and their corresponding wild-type background mice (MyhCre.Tgfbr2{sup WT/WT}) underwent partial ligation of left common carotid artery for 1, 2, or 4 weeks. Then the carotid arteries were harvested and indicated that the disruption of Tgfbr2 in SMC provided prominent inhibition of vascular remodeling. And the thickening of carotid media, proliferation of SMC, infiltration of macrophage, and expression of matrix metalloproteinase (MMP) were all significantly attenuated in Tgfbr2 disruption mice. Our study demonstrated, for the first time, that the TGF-β signaling in SMC plays an essential role in flow-induced vascular remodeling and disruption can prevent this process.

  5. Lymphatic Vascular Response to Acute Inflammation

    PubMed Central

    Lachance, Pier-Anne; Hazen, Amy; Sevick-Muraca, Eva M.

    2013-01-01

    During acute inflammation, functioning lymphatics are believed to reduce edema and to provide a transiting route for immune cells, but the extent at which the dermal lymphatic remodeling impacts lymphatic transport or the factors regulating these changes remains unclear. Herein we quantify the increase in lymphatic endothelial cells (LECs) and examine the expression of pro-angiogenenic and lymphangiogenic factors during acute cutaneous hypersensitivity (CHS). We found that LECs actively proliferate during CHS but that this proliferation does not affect the lymphatic vessel density. Instead, lymphatic remodeling is accompanied by lymphatic vessel leakiness and lower ejection of lymph fluid, which is observed only in the proximal lymphatic vessel draining the inflamed area. LECs and the immune cells release growth factors and cytokines during inflammation, which impact the lymphatic microenvironment and function. We identified that FGF-2, PLGF-2, HGF, EGF, and KC/CXCL17 are differentially expressed within tissues during acute CHS, but both VEGF-C and VEGF-D levels do not significantly change. Our results indicate that VEGF-C and VEGF-D are not the only players and other factors may be responsible for the LECs proliferation and altered lymphatic function in acute CHS. PMID:24086691

  6. Acidic microenvironments induce lymphangiogenesis and IL-8 production via TRPV1 activation in human lymphatic endothelial cells.

    PubMed

    Nakanishi, Masako; Morita, Yoshihiro; Hata, Kenji; Muragaki, Yasuteru

    2016-07-15

    Local acidosis is one of the characteristic features of the cancer microenvironment. Many reports indicate that acidosis accelerates the proliferation and invasiveness of cancer cells. However, whether acidic conditions affect lymphatic metastasis is currently unknown. In the present study, we focused on the effects of acidosis on lymphatic endothelial cells (LECs) to assess the relationship between acidic microenvironments and lymph node metastasis. We demonstrated that normal human LECs express various acid receptors by immunohistochemistry and reverse transcriptase-polymerase chain reaction (PCR). Acidic stimulation with low pH medium induced morphological changes in LECs to a spindle shape, and significantly promoted cellular growth and tube formation. Moreover, real-time PCR revealed that acidic conditions increased the mRNA expression of interleukin (IL)-8. Acidic stimulation increased IL-8 production in LECs, whereas a selective transient receptor potential vanilloid subtype 1 (TRPV1) antagonist, 5'-iodoresiniferatoxin, decreased IL-8 production. IL-8 accelerated the proliferation of LECs, and inhibition of IL-8 diminished tube formation and cell migration. In addition, phosphorylation of nuclear factor (NF)-κB was induced by acidic conditions, and inhibition of NF-κB activation reduced acid-induced IL-8 expression. These results suggest that acidic microenvironments in tumors induce lymphangiogenesis via TRPV1 activation in LECs, which in turn may promote lymphatic metastasis. PMID:27312995

  7. TGF-β1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis.

    PubMed

    Pang, M-F; Georgoudaki, A-M; Lambut, L; Johansson, J; Tabor, V; Hagikura, K; Jin, Y; Jansson, M; Alexander, J S; Nelson, C M; Jakobsson, L; Betsholtz, C; Sund, M; Karlsson, M C I; Fuxe, J

    2016-02-11

    Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the lymphatic system and how they choose between lymphatic and blood vessels for migration. Here we report that mammary tumor cells undergoing epithelial-mesenchymal transition (EMT) in response to transforming growth factor-β (TGF-β1) become activated for targeted migration through the lymphatic system, similar to dendritic cells (DCs) during inflammation. EMT cells preferentially migrated toward lymphatic vessels compared with blood vessels, both in vivo and in 3D cultures. A mechanism of this targeted migration was traced to the capacity of TGF-β1 to promote CCR7/CCL21-mediated crosstalk between tumor cells and lymphatic endothelial cells. On one hand, TGF-β1 promoted CCR7 expression in EMT cells through p38 MAP kinase-mediated activation of the JunB transcription factor. Blockade of CCR7, or treatment with a p38 MAP kinase inhibitor, reduced lymphatic dissemination of EMT cells in syngeneic mice. On the other hand, TGF-β1 promoted CCL21 expression in lymphatic endothelial cells. CCL21 acted in a paracrine fashion to mediate chemotactic migration of EMT cells toward lymphatic endothelial cells. The results identify TGF-β1-induced EMT as a mechanism, which activates tumor cells for targeted, DC-like migration through the lymphatic system. Furthermore, it suggests that p38 MAP kinase inhibition may be a useful strategy to inhibit EMT and lymphogenic spread of tumor cells. PMID:25961925

  8. FOXC2 and FLT4 Gene Variants in Lymphatic Filariasis.

    PubMed

    Sheik, Yasmeen; Qureshi, Sameera Fatima; Mohhammed, Basheeruddin; Nallari, Pratibha

    2015-06-01

    Lymphatic filariasis is the leading cause of secondary lymphedema wherein lymph transport is impaired due to lymphatic damage. FLT4 signaling and transcription factors such as FOXC2 play an important role in this type of lymphangiogenesis process induced by filarial parasites. The present study aims to assess the association of FLT4 and FOXC2 genes in lymphatic development/remodeling in lymphatic filariasis. A total of 118 lymphatic filariasis patients and 100 non-endemic and 50 endemic healthy subjects were enrolled for the present study. Allele-specific PCR and PCR-RFLP were adopted for the genotyping, and screening of FLT4 and FOXC2 genes was carried out by PCR-SSCP, followed by in-silico and statistical analysis. A novel variation (G357A SNP) was identified on FOXC2 gene screening that may have an effect on codon usage frequency during translational process. In FLT4, A3123G mutation was found in 3.39% of the case subjects but the functional role of this mutation, along with subject's clinical presentations and patient's age, emphasize its pathogenic role in lymphedema development. Two of the subjects exhibit compound heterozygosity (A3123G FLT4 mutation and G357A SNP of FOXC2 gene). As these two genes share a common pathway, we hypothesise a synergistic interaction of these two SNPs in inhibiting the downstream signaling resulting in lymphedema progression. PMID:26091406

  9. Fucoidan Suppresses Hypoxia-Induced Lymphangiogenesis and Lymphatic Metastasis in Mouse Hepatocarcinoma

    PubMed Central

    Teng, Hongming; Yang, Yazong; Wei, Hengyun; Liu, Zundong; Liu, Zhichao; Ma, Yanhong; Gao, Zixiang; Hou, Lin; Zou, Xiangyang

    2015-01-01

    Metastasis, the greatest clinical challenge associated with cancer, is closely connected to multiple biological processes, including invasion and adhesion. The hypoxic environment in tumors is an important factor that causes tumor metastasis by activating HIF-1α. Fucoidan, extracted from brown algae, is a sulfated polysaccharide and, as a novel marine biological material, has been used to treat various disorders in China, Korea, Japan and other countries. In the present study, we demonstrated that fucoidan derived from Undaria pinnatifida sporophylls significantly inhibits the hypoxia-induced expression, nuclear translocation and activity of HIF-1α, the synthesis and secretion of VEGF-C and HGF, cell invasion and lymphatic metastasis in a mouse hepatocarcinoma Hca-F cell line. Fucoidan also suppressed lymphangiogenesis in vitro and in vivo. In addition, accompanied by a reduction in the HIF-1α nuclear translocation and activity, fucoidan significantly reduced the levels of p-PI3K, p-Akt, p-mTOR, p-ERK, NF-κB, MMP-2 and MMP-9, but increased TIMP-1 levels. These results indicate strongly that the anti-metastasis and anti-lymphangiogenesis activities of fucoidan are mediated by suppressing HIF-1α/VEGF-C, which attenuates the PI3K/Akt/mTOR signaling pathways. PMID:26047481

  10. Slug Is Increased in Vascular Remodeling and Induces a Smooth Muscle Cell Proliferative Phenotype

    PubMed Central

    Coll-Bonfill, Núria; Peinado, Victor I.; Pisano, María V.; Párrizas, Marcelina; Blanco, Isabel; Evers, Maurits; Engelmann, Julia C.; García-Lucio, Jessica; Tura-Ceide, Olga; Meister, Gunter

    2016-01-01

    Objective Previous studies have confirmed Slug as a key player in regulating phenotypic changes in several cell models, however, its role in smooth muscle cells (SMC) has never been assessed. The purpose of this study was to evaluate the expression of Slug during the phenotypic switch of SMC in vitro and throughout the development of vascular remodeling. Methods and Results Slug expression was decreased during both cell-to-cell contact and TGFβ1 induced SMC differentiation. Tumor necrosis factor-α (TNFα), a known inductor of a proliferative/dedifferentiated SMC phenotype, induces the expression of Slug in SMC. Slug knockdown blocked TNFα-induced SMC phenotypic change and significantly reduced both SMC proliferation and migration, while its overexpression blocked the TGFβ1-induced SMC differentiation and induced proliferation and migration. Genome-wide transcriptomic analysis showed that in SMC, Slug knockdown induced changes mainly in genes related to proliferation and migration, indicating that Slug controls these processes in SMC. Notably, Slug expression was significantly up-regulated in lungs of mice using a model of pulmonary hypertension-related vascular remodeling. Highly remodeled human pulmonary arteries also showed an increase of Slug expression compared to less remodeled arteries. Conclusions Slug emerges as a key transcription factor driving SMC towards a proliferative phenotype. The increased Slug expression observed in vivo in highly remodeled arteries of mice and human suggests a role of Slug in the pathogenesis of pulmonary vascular diseases. PMID:27441378

  11. Emphysema and Mechanical Stress-Induced Lung Remodeling

    PubMed Central

    Sato, Susumu; Parameswaran, Harikrishnan; Szabari, Margit V.; Takahashi, Ayuko; Bartolák-Suki, Erzsébet

    2013-01-01

    Transpulmonary pressure and the mechanical stresses of breathing modulate many essential cell functions in the lung via mechanotransduction. We review how mechanical factors could influence the pathogenesis of emphysema. Although the progression of emphysema has been linked to mechanical rupture, little is known about how these stresses alter lung remodeling. We present possible new directions and an integrated multiscale view that may prove useful in finding solutions for this disease. PMID:24186935

  12. A Computational Model for Simulating Spaceflight Induced Bone Remodeling

    NASA Technical Reports Server (NTRS)

    Pennline, James A.; Mulugeta, Lealem

    2014-01-01

    An overview of an initial development of a model of bone loss due to skeletal unloading in weight bearing sites is presented. The skeletal site chosen for the initial application of the model is the femoral neck region because hip fractures can be debilitating to the overall performance health of astronauts. The paper begins with the motivation for developing such a model of the time course of change in bone in order to understand the mechanism of bone demineralization experienced by astronauts in microgravity, to quantify the health risk, and to establish countermeasures. Following this, a general description of a mathematical formulation of the process of bone remodeling is discussed. Equations governing the rate of change of mineralized bone volume fraction and active osteoclast and osteoblast are illustrated. Some of the physiology of bone remodeling, the theory of how imbalance in remodeling can cause bone loss, and how the model attempts to capture this is discussed. The results of a preliminary validation analysis that was carried out are presented. The analysis compares a set of simulation results against bone loss data from control subjects who participated in two different bed rest studies. Finally, the paper concludes with outlining the current limitations and caveats of the model, and planned future work to enhance the state of the model.

  13. OCULAR LYMPHATICS: STATE-OF-THE-ART REVIEW

    PubMed Central

    Chen, L.

    2015-01-01

    Research involving the lymphatic system has experienced an exponential progression during the past decade largely because of advancement of modern technology and discovery of several lymphatic specific molecules. The eye provides an excellent site for lymphatic studies due to its accessible location and the unique feature of tissue heterogeneity – while some tissues are lymphatic-rich, others are lymphatic-free or -inducible. This review provides an update on our current understanding of ocular lymphatics and possible associated eye diseases. PMID:19725271

  14. Pathway-related molecules of VEGFC/D-VEGFR3/NRP2 axis in tumor lymphangiogenesis and lymphatic metastasis.

    PubMed

    Wang, Jingwen; Huang, Yuhong; Zhang, Jun; Wei, Yuanyi; Mahoud, Salma; Bakheet, Ahmed Musa Hago; Wang, Li; Zhou, Shuting; Tang, Jianwu

    2016-10-01

    Precondition for tumor lymphatic metastasis is that tumor cells induce formation of original and newborn lymphatic vessels and invade surrounding lymphatic vessels in tumor stroma, while some pathway-related molecules play an important role in mechanisms associated with proliferation and migration of lymphatic endothelial cells (LECs) and tumor cells. In lymphangiogenesis and lymphatic metastasis, the pathway-related molecules of VEGFC/D-VEGFR3/NRP2 axis, such as Furin-like enzyme, CNTN1, Prox1, LYVE-1, Podoplanin, SOX18, SDF1 and CXCR4, are direct constitutors as a portion of VEGFC/D-VEGFR3/NRP2 axis, and their biological activities rely on this ligand-receptor system. These axis-related signal molecules could gradually produce waterfall-like cascading effects, mediate differentiation and maturation of LECs, remodel original and neonatal lymphatic vessels, as well as ultimately promote tumor cell chemotaxis, migration, invasion and metastasis to lymphoid tracts. This review summarizes the structure and function features of pathway-related molecules of VEGFC/D-VEGFR3/NRP2 axis, the expression changes of these molecules in different anatomic organs or histopathologic types or development stages of various tumors, the characteristics of transduction, implementation, integration of signal networks, the interactive effects on biological behaviors between tumor cells and lymphatic endothelial cells, and their molecular mechanisms and significances in tumor lymphangiogenesis and lymphatic metastasis. PMID:27527412

  15. Neutrophils rapidly transit inflamed lymphatic vessel endothelium via integrin-dependent proteolysis and lipoxin-induced junctional retraction.

    PubMed

    Rigby, David A; Ferguson, David J P; Johnson, Louise A; Jackson, David G

    2015-12-01

    Neutrophils are the first leukocyte population to be recruited from the circulation following tissue injury or infection, where they play key roles in host defense. However, recent evidence indicates recruited neutrophils can also enter lymph and shape adaptive immune responses downstream in draining lymph nodes. At present, the cellular mechanisms regulating neutrophil entry to lymphatic vessels and migration to lymph nodes are largely unknown. Here, we have investigated these events in an in vivo mouse Mycobacterium bovis bacillus Calmette-Guérin vaccination model, ex vivo mouse dermal explants, and in vitro Transwell system comprising monolayers of primary human dermal lymphatic endothelial cells. We demonstrate that neutrophils are reliant on endothelial activation for adhesion, initially via E-selectin and subsequently, by integrin-mediated binding to ICAM-1 and VCAM-1, combined with CXCL8-dependent chemotaxis. Moreover, we reveal that integrin-mediated neutrophil adhesion plays a pivotal role in subsequent transmigration by focusing the action of matrix metalloproteinases and the 15-lipoxygenase-1-derived chemorepellent 12(S)-hydroxyeicosatetraenoic acid at neutrophil:endothelial contact sites to induce transient endothelial junctional retraction and rapid, selective neutrophil trafficking. These findings reveal an unexpectedly intimate collaboration between neutrophils and the lymphatic vessel endothelium, in which these phagocytic leukocytes act as pathfinders for their own transit during inflammation. PMID:26216937

  16. Involvement of H1 and H2 receptors and soluble guanylate cyclase in histamine-induced relaxation of rat mesenteric collecting lymphatics

    PubMed Central

    Kurtz, Kristine H.; Moor, Andrea N.; Souza-Smith, Flavia M.; Breslin, Jerome W.

    2014-01-01

    Objective This study investigated the roles of the H1 and H2 histamine receptors, nitric oxide (NO) synthase, and soluble guanylate (sGC) cyclase in histamine-induced modulation of rat mesenteric collecting lymphatic pumping. Methods Isolated rat mesenteric collecting lymphatics were treated with 1–100 μM histamine. Histamine receptors were blocked with either the H1 antagonist mepyramine or the H2 antagonist cimetidine. The role of NO/sGC signaling was tested using the arginine analog L-NAME, the sGC inhibitor ODQ, and sodium nitroprusside (SNP) as a positive control. Results Histamine applied at 100 μM decreased tone and contraction frequency (CF) of isolated rat mesenteric collecting lymphatics. Pharmacologic blockade of either H1 or H2 histamine receptors significantly inhibited the response to histamine. Pretreatment with ODQ, but not L-NAME, completely inhibited the histamine-induced decrease in tone. ODQ pretreatment also significantly inhibited SNP-induced lymphatic relaxation. Conclusions H1 and H2 histamine receptors are both involved in histamine-induced relaxation of rat mesenteric collecting lymphatics. NO synthesis does not appear to contribute to the histamine-induced response. However, sGC is critical for the histamine-induced decrease in tone and contributes to the drop in CF. PMID:24702851

  17. Changes in pulmonary arterial wall mechanical properties and lumenal architecture with induced vascular remodeling

    NASA Astrophysics Data System (ADS)

    Molthen, Robert C.; Heinrich, Amy E.; Haworth, Steven T.; Dawson, Christopher A.

    2004-04-01

    To explore and quantify pulmonary arterial remodeling we used various methods including micro-CT, high-resolution 3-dimensional x-ray imaging, to examine the structure and function of intact pulmonary vessels in isolated rat lungs. The rat is commonly used as an animal model for studies of pulmonary hypertension (PH) and the accompanying vascular remodeling, where vascular remodeling has been defined primarily by changes in the vessel wall composition in response to hypertension inducing stimuli such as chronic hypoxic exposure (CHE) or monocrotaline (MCT) injection. Little information has been provided as to how such changes affect the vessel wall mechanical properties or the lumenal architecture of the pulmonary arterial system that actually account for the hemodynamic consequences of the remodeling. In addition, although the link between primary forms of pulmonary hypertension and inherited genetics is well established, the role that genetic coding plays in hemodynamics and vascular remodeling is not. Therefore, we are utilizing Fawn-Hooded (FH), Sprague-Dawley (SD) and Brown Norway (BN)rat strains along with unique imaging methods to parameterize both vessel distensibility and lumenal morphometry using a principal pulmonary arterial pathway analysis based on self-consistency. We have found for the hypoxia model, in addition to decreased body weight, increased hematocrit, increased right ventricular hypertrophy, the distensibility of the pulmonary arteries is shown to decrease significantly in the presence of remodeling.

  18. Lymphatic Filariasis

    MedlinePlus

    ... Search The CDC Cancel Submit Search The CDC Parasites - Lymphatic Filariasis Note: Javascript is disabled or is ... this? Submit Button Information For: Travelers Related Links Parasites A-Z Index Parasites Glossary Neglected Tropical Diseases ...

  19. Class A scavenger receptor deficiency augments angiotensin II-induced vascular remodeling.

    PubMed

    Qian, Lingling; Li, Xiaoyu; Fang, Ru; Wang, Zhuoyun; Xu, Yiming; Zhang, Hanwen; Bai, Hui; Yang, Qing; Zhu, Xudong; Ben, Jingjing; Xu, Yong; Chen, Qi

    2014-08-01

    Class A scavenger receptor (SR-A) is a multifunctional molecule that participates in macrophage-mediated inflammation. Here we evaluated the role of SR-A in angiotensin II (Ang II)-induced hypertensive vascular remodeling. Chronic infusion of Ang II leads to an increased systolic blood pressure both in SR-A knockout (SR-A(-/-)) and wild type (SR-A(+/+)) mice with no significant difference between these two groups. SR-A(-/-) hypertensive mice, however, exhibited a marked augmentation of arterial wall thickening and vascular cell proliferation compared with SR-A(+/+) hypertensive mice. M1 macrophage markers were increased whereas M2 macrophage markers were decreased in vascular tissues of SR-A(-/-) mice. Co-culture experiments revealed that more pro-inflammatory cytokines like TNF-α were produced by SR-A(-/-) peritoneal macrophages leading to a stronger proliferation of primary vascular smooth muscle cells in vitro. In addition, SR-A(-/-) macrophages were more prone to lipopolysaccharide-induced M1 differentiation while resisting interleukin-4-induced M2 differentiation. Importantly, transplantation of SR-A(-/-) bone marrow into SR-A(+/+) mice significantly augmented Ang II-induced vascular remodeling. These results show that SR-A is critical for Ang II-induced vascular remodeling by regulating macrophage polarization. Therefore, SR-A may be a useful therapeutic target for the intervention of hypertensive vascular remodeling. PMID:24875449

  20. Para-cresyl sulfate acutely impairs vascular reactivity and induces vascular remodeling.

    PubMed

    Gross, Priscilla; Massy, Ziad A; Henaut, Lucie; Boudot, Cédric; Cagnard, Joanna; March, Cécilia; Kamel, Saïd; Drueke, Tilman B; Six, Isabelle

    2015-12-01

    Chronic kidney disease (CKD) is characterized by vascular remodeling and the retention of uremic toxins, several of which are independently associated with the high cardiovascular mortality rate in CKD patients. Whether the association between these uremic toxins and cardiovascular mortality is due to induction of vascular dysfunction and resulting vascular remodeling remains to be determined. This study evaluates the effects of para-cresyl sulfate (PCS), a newly identified uremic toxin, on vascular function and remodeling. PCS acutely induced oxidative stress in both endothelial and vascular smooth muscle cells, with a maximal effect at 0.15 mM, corresponding to the mean "uremic" concentration found in dialysis patients. PCS significantly increased within 30 min phenylephrine-induced contraction of mouse thoracic aorta, through direct activation of rho-kinase, independently of oxidative stress induction, as demonstrated by the capacity of rho-kinase inhibitor Y-27632 to abolish this effect. After exposure of the aorta to PCS for 48 h, we observed inward eutrophic remodeling, a hallmark of uremic vasculopathy characterized by a reduction of the area of both lumen and media, with unchanged media/lumen ratio. In conclusion, elevated PCS concentrations such as those observed in CKD patients, by promoting both vascular dysfunction and vascular remodeling, may contribute to the development of hypertension and to cardiovascular mortality in CKD. PMID:25899466

  1. PHA-induced soluble factor(s) can activate B-cells from patients with chronic lymphatic leukaemia.

    PubMed Central

    Robert, K H

    1979-01-01

    Blood lymphocytes from eight patients with chronic lymphatic leukaemia (CLL) were stimulated by phytohaemagglutinin (PHA). The effect was defined as a pronounced increase of 3H-thymidine incorporation, and a concomitant blast transformation of a large portion of surface Ig-positive, E-rosette-forming (E-RFC) negative cells. E-RFC depletion reduced these effects to nearly background levels, and the pooled data strongly suggest that malignant B-lymphocytes in CLL are capable of responding to a PHA-induced T cell factor. A possible use for this factor in characterizing different subpopulations of CLL cells is discussed. PMID:315847

  2. Stress-induced remodeling of hippocampal CA3 pyramidal neurons.

    PubMed

    McEwen, Bruce S

    2016-08-15

    The discovery of steroid hormone receptors in brain regions that mediate virtually every aspect of brain function has broadened the definition of 'neuroendocrinology' to include the reciprocal communication between the brain and the body via hormonal and neural pathways. The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as determining the behavioral and physiological responses to the stressor. The adult and developing brain possess remarkable structural and functional plasticity in response to stress, including neurogenesis leading to neuronal replacement, dendritic remodeling, and synapse turnover. Stress causes an imbalance of neural circuitry subserving cognition, decision-making, anxiety and mood that can alter expression of those behaviors and behavioral states. The two Brain Research papers noted in this review played an important role in triggering these advances. This article is part of a Special Issue entitled SI:50th Anniversary Issue. PMID:26740399

  3. Morphogenesis of the lymphatic vasculature: A focus on new progenitors and cellular mechanisms important for constructing lymphatic vessels.

    PubMed

    Kazenwadel, Jan; Harvey, Natasha L

    2016-03-01

    Lymphatic vessels serve crucial roles in the regulation of tissue fluid homeostasis, dietary lipid absorption and immune cell trafficking. Defects in lymphatic vessel morphogenesis and function have been associated with lymphedema, obesity, hypertension and tumour metastasis. Morphogenetic events important for construction of the lymphatic vasculature during development include the specification and emergence of lymphatic endothelial progenitor cells, their differentiation and assembly into interconnected vessels and vascular remodeling, ultimately giving rise to a functional vascular network. Despite the embryonic origins of lymphatic endothelial progenitor cells being long debated, work performed over the last decade had overwhelmingly supported at least a great majority of progenitor cells arising from the venous vasculature. Here, we review the most recent advances in the field of lymphatic vessel morphogenesis, with a focus on studies that have identified novel sources of embryonic lymphatic endothelial progenitor cells, together with the cellular mechanisms by which lymphatic vessels are initially assembled. PMID:26228815

  4. Mechanical Stress Induces Remodeling of Vascular Networks in Growing Leaves

    PubMed Central

    Bar-Sinai, Yohai; Julien, Jean-Daniel; Sharon, Eran; Armon, Shahaf; Nakayama, Naomi; Adda-Bedia, Mokhtar; Boudaoud, Arezki

    2016-01-01

    Differentiation into well-defined patterns and tissue growth are recognized as key processes in organismal development. However, it is unclear whether patterns are passively, homogeneously dilated by growth or whether they remodel during tissue expansion. Leaf vascular networks are well-fitted to investigate this issue, since leaves are approximately two-dimensional and grow manyfold in size. Here we study experimentally and computationally how vein patterns affect growth. We first model the growing vasculature as a network of viscoelastic rods and consider its response to external mechanical stress. We use the so-called texture tensor to quantify the local network geometry and reveal that growth is heterogeneous, resembling non-affine deformations in composite materials. We then apply mechanical forces to growing leaves after veins have differentiated, which respond by anisotropic growth and reorientation of the network in the direction of external stress. External mechanical stress appears to make growth more homogeneous, in contrast with the model with viscoelastic rods. However, we reconcile the model with experimental data by incorporating randomness in rod thickness and a threshold in the rod growth law, making the rods viscoelastoplastic. Altogether, we show that the higher stiffness of veins leads to their reorientation along external forces, along with a reduction in growth heterogeneity. This process may lead to the reinforcement of leaves against mechanical stress. More generally, our work contributes to a framework whereby growth and patterns are coordinated through the differences in mechanical properties between cell types. PMID:27074136

  5. Corticosteroid-induced neural remodeling predicts behavioral vulnerability and resilience

    PubMed Central

    Gourley, Shannon L.; Swanson, Andrew M.; Koleske, Anthony J.

    2013-01-01

    Neurons in distinct brain regions remodel in response to postnatal stressor exposure, and structural plasticity may underlie stress-related modifications in behavioral outcomes. Given the persistence of stress-related diseases such as depression, a critical next step in identifying the contributions of neural structure to psychopathology will be to identify brain circuits and cell types that fail to recover from stressor exposure. We enumerated dendritic spines during and after chronic stress hormone exposure in hippocampal CA1, deep-layer prefrontal cortex, and the basal amygdala and also reconstructed dendritic arbors of CA1 pyramidal neurons. Corticosterone modified dendritic spine density in these regions, but with the exception of the orbitofrontal cortex, densities normalized with a recovery period. Dendritic retraction of hippocampal CA1 neurons and anhedonic-like insensitivity to a sucrose solution also persisted despite a recovery period. Using mice with reduced gene dosage of p190rhogap, a cytoskeletal regulatory protein localized to dendritic spines, we next isolated structural correlates of both behavioral vulnerability (spine elimination) and resilience (spine proliferation) to corticosterone within the orbital cortex. Our findings provide novel empirical support for the perspective that stress-related structural reorganization of certain neuron populations can persist despite a “recovery” period from stressor exposure, and that these modifications may lay a structural foundation for stressor vulnerability—or resiliency—across the lifespan. PMID:23407965

  6. Ectodomain Shedding of Lymphatic Vessel Endothelial Hyaluronan Receptor 1 (LYVE-1) Is Induced by Vascular Endothelial Growth Factor A (VEGF-A).

    PubMed

    Nishida-Fukuda, Hisayo; Araki, Ryoichi; Shudou, Masachika; Okazaki, Hidenori; Tomono, Yasuko; Nakayama, Hironao; Fukuda, Shinji; Sakaue, Tomohisa; Shirakata, Yuji; Sayama, Koji; Hashimoto, Koji; Detmar, Michael; Higashiyama, Shigeki; Hirakawa, Satoshi

    2016-05-13

    Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), a type I transmembrane glycoprotein, is known as one of the most specific lymphatic vessel markers in the skin. In this study, we found that the ectodomain of LYVE-1 undergoes proteolytic cleavage, and this process produces soluble LYVE-1. We further identified the cleavage site for ectodomain shedding and generated an uncleavable mutant of LYVE-1. In lymphatic endothelial cells, ectodomain shedding of LYVE-1 was induced by vascular endothelial growth factor (VEGF)-A, an important factor for angiogenesis and lymphangiogenesis under pathological conditions. VEGF-A-induced LYVE-1 ectodomain shedding was mediated via the extracellular signal-regulated kinase (ERK) and a disintegrin and metalloproteinase (ADAM) 17. Wild-type LYVE-1, but not uncleavable LYVE-1, promoted migration of lymphatic endothelial cells in response to VEGF-A. Immunostaining analyses in human psoriasis skin lesions and VEGF-A transgenic mouse skin suggested that the ectodomain shedding of LYVE-1 occurred in lymphatic vessels undergoing chronic inflammation. These results indicate that the ectodomain shedding of LYVE-1 might be involved in promoting pathological lymphangiogenesis. PMID:26966180

  7. Quantitative Imaging of Enzymatic Vitreolysis-Induced Fiber Remodeling

    PubMed Central

    Filas, Benjamen A.; Shah, Nihar S.; Zhang, Qianru; Shui, Ying-Bo; Lake, Spencer P.; Beebe, David C.

    2014-01-01

    Purpose. Collagen fiber remodeling in the vitreous body has been implicated in cases of vitreomacular traction, macular hole, and retinal detachment, and also may occur during pharmacologic vitreolysis. The purpose of this study was to evaluate quantitative polarized light imaging (QPLI) as a tool for studying fiber organization in the vitreous and near the vitreoretinal interface in control and enzymatically perturbed conditions. Methods. Fiber alignment was measured in anterior-posterior sections of bovine and porcine vitreous. Additional tests were performed on bovine lenses and nasal-temporal vitreous sections. Effects of proteoglycan degradation on collagen fiber alignment using trypsin and plasmin were assessed at the microstructural level using electron microscopy and at the global level using QPLI. Results. Control vitreous showed fiber organization patterns consistent with the literature across multiple-length scales, including the global anterior-posterior coursing of vitreous fibers, as well as local fibers parallel to the equatorial vitreoretinal interface and transverse to the posterior interface. Proteoglycan digestion with trypsin or plasmin significantly increased fiber alignment throughout the vitreous (P < 0.01). The largest changes (3×) occurred in the posterior vitreous where fibers are aligned transverse to the posterior vitreoretinal interface (P < 0.01). Conclusions. Proteoglycan loss due to enzymatic vitreolysis differentially increases fiber alignment at locations where tractions are most common. We hypothesize that a similar mechanism leads to retinal complications during age-related vitreous degeneration. Structural changes to the entire vitreous body (as opposed to the vitreoretinal interface alone) should be evaluated during preclinical testing of pharmacological vitreolysis candidates. PMID:25468895

  8. Effect of Brain-Derived Neurotrophic Factor Haploinsufficiency on Stress-Induced Remodeling of Hippocampal Neurons

    PubMed Central

    Magariños, A.M.; Li, C.J.; Toth, J. Gal; Bath, K.G.; Jing, D.; Lee, F.S.; McEwen, B.S.

    2010-01-01

    Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity-dependent manner, as a mediator of the stress-induced dendritic remodeling. The analysis of Golgi-impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF±) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF± mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF± mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling. PMID:20095008

  9. 20-HETE induces remodeling of renal resistance arteries independent of blood pressure elevation in hypertension.

    PubMed

    Ding, Yan; Wu, Cheng-Chia; Garcia, Victor; Dimitrova, Irina; Weidenhammer, Adam; Joseph, Gregory; Zhang, Frank; Manthati, Vijay L; Falck, John R; Capdevila, Jorge H; Schwartzman, Michal L

    2013-09-01

    20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P-450 (Cyp)-derived arachidonic acid metabolite that has been shown to increase smooth muscle contractions and proliferation, stimulate endothelial dysfunction and activation, and promote hypertension. We examined if 20-HETE contributes to microvascular remodeling in hypertension. In Sprague-Dawley rats, administration of the 20-HETE biosynthesis inhibitor HET0016 or the 20-HETE antagonist N-20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) prevented 5α-dihydrotestosterone (DHT)-induced increases in blood pressure as well as abrogated DHT-induced increases in the media-to-lumen ratio (M/L), media thickness, and collagen IV deposition in renal interlobar arteries. Reserpine prevented blood pressure elevation in DHT-treated rats but did not affect microvascular remodeling (M/L, media thickness, and collagen deposition); under these conditions, treatment with the 20-HETE antagonist attenuated microvascular remodeling, suggesting that 20-HETE contributes to DHT-induced vascular remodeling independent of blood pressure elevation. In Cyp4a14(-/-) mice, which display androgen-driven and 20-HETE-dependent hypertension, treatment with the 20-HETE antagonist abolished remodeling of renal resistance arteries measured as media thickness (24 ± 1 vs. 15 ± 1 μm) and M/L (0.29 ± 0.03 vs. 0.17 ± 0.01). Moreover, in Cyp4a12 transgenic mice in which the expression of Cyp4a12-20-HETE synthase is driven by a tetracycline-sensitive promoter, treatment with doxycycline resulted in blood pressure elevation (140 ± 4 vs. 92 ± 5 mmHg) and a significant increase in remodeling of renal resistance arteries (media thickness: 23 ± 1 vs. 16 ± 1 μm; M/L: 0.39 ± 0.04 vs. 0.23 ± 0.02); these increases were abrogated by cotreatment with 20-HEDE. This study demonstrated that 20-HETE is a key regulator of microvascular remodeling in hypertension; its effect is independent of blood pressure elevation and androgen levels. PMID

  10. 20-HETE induces remodeling of renal resistance arteries independent of blood pressure elevation in hypertension

    PubMed Central

    Ding, Yan; Wu, Cheng-Chia; Garcia, Victor; Dimitrova, Irina; Weidenhammer, Adam; Joseph, Gregory; Zhang, Frank; Manthati, Vijay L.; Falck, John R.; Capdevila, Jorge H.

    2013-01-01

    20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P-450 (Cyp)-derived arachidonic acid metabolite that has been shown to increase smooth muscle contractions and proliferation, stimulate endothelial dysfunction and activation, and promote hypertension. We examined if 20-HETE contributes to microvascular remodeling in hypertension. In Sprague-Dawley rats, administration of the 20-HETE biosynthesis inhibitor HET0016 or the 20-HETE antagonist N-20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) prevented 5α-dihydrotestosterone (DHT)-induced increases in blood pressure as well as abrogated DHT-induced increases in the media-to-lumen ratio (M/L), media thickness, and collagen IV deposition in renal interlobar arteries. Reserpine prevented blood pressure elevation in DHT-treated rats but did not affect microvascular remodeling (M/L, media thickness, and collagen deposition); under these conditions, treatment with the 20-HETE antagonist attenuated microvascular remodeling, suggesting that 20-HETE contributes to DHT-induced vascular remodeling independent of blood pressure elevation. In Cyp4a14−/− mice, which display androgen-driven and 20-HETE-dependent hypertension, treatment with the 20-HETE antagonist abolished remodeling of renal resistance arteries measured as media thickness (24 ± 1 vs. 15 ± 1 μm) and M/L (0.29 ± 0.03 vs. 0.17 ± 0.01). Moreover, in Cyp4a12 transgenic mice in which the expression of Cyp4a12–20-HETE synthase is driven by a tetracycline-sensitive promoter, treatment with doxycycline resulted in blood pressure elevation (140 ± 4 vs. 92 ± 5 mmHg) and a significant increase in remodeling of renal resistance arteries (media thickness: 23 ± 1 vs. 16 ± 1 μm; M/L: 0.39 ± 0.04 vs. 0.23 ± 0.02); these increases were abrogated by cotreatment with 20-HEDE. This study demonstrated that 20-HETE is a key regulator of microvascular remodeling in hypertension; its effect is independent of blood pressure elevation and androgen levels. PMID

  11. Membrane remodeling, an early event in benzo[alpha]pyrene-induced apoptosis

    SciTech Connect

    Tekpli, Xavier; Rissel, Mary; Huc, Laurence; Catheline, Daniel; Sergent, Odile; Rioux, Vincent; Legrand, Philippe; Holme, Jorn A.; Dimanche-Boitrel, Marie-Therese; Lagadic-Gossmann, Dominique

    2010-02-15

    Benzo[alpha]pyrene (B[alpha]P) often serves as a model for mutagenic and carcinogenic polycyclic aromatic hydrocarbons (PAHs). Our previous work suggested a role of membrane fluidity in B[alpha]P-induced apoptotic process. In this study, we report that B[alpha]P modifies the composition of cholesterol-rich microdomains (lipid rafts) in rat liver F258 epithelial cells. The cellular distribution of the ganglioside-GM1 was markedly changed following B[alpha]P exposure. B[alpha]P also modified fatty acid composition and decreased the cholesterol content of cholesterol-rich microdomains. B[alpha]P-induced depletion of cholesterol in lipid rafts was linked to a reduced expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase). Aryl hydrocarbon receptor (AhR) and B[alpha]P-related H{sub 2}O{sub 2} formation were involved in the reduced expression of HMG-CoA reductase and in the remodeling of membrane microdomains. The B[alpha]P-induced membrane remodeling resulted in an intracellular alkalinization observed during the early phase of apoptosis. In conclusion, B[alpha]P altered the composition of plasma membrane microstructures through AhR and H{sub 2}O{sub 2} dependent-regulation of lipid biosynthesis. In F258 cells, the B[alpha]P-induced membrane remodeling was identified as an early apoptotic event leading to an intracellular alkalinization.

  12. Aldosterone-Induced Vascular Remodeling and Endothelial Dysfunction Require Functional Angiotensin Type 1a Receptors.

    PubMed

    Briet, Marie; Barhoumi, Tlili; Mian, Muhammad Oneeb Rehman; Coelho, Suellen C; Ouerd, Sofiane; Rautureau, Yohann; Coffman, Thomas M; Paradis, Pierre; Schiffrin, Ernesto L

    2016-05-01

    We investigated the role of angiotensin type 1a receptors (AGTR1a) in vascular injury induced by aldosterone activation of mineralocorticoid receptors in Agtr1a(-/-) and wild-type (WT) mice infused with aldosterone for 14 days while receiving 1% NaCl in drinking water. Aldosterone increased systolic blood pressure (BP) by ≈30 mm Hg in WT mice and ≈50 mm Hg in Agtr1a(-/-) mice. Aldosterone induced aortic and small artery remodeling, impaired endothelium-dependent relaxation in WT mice, and enhanced fibronectin and collagen deposition and vascular inflammation. None of these vascular effects were observed in Agtr1a(-/-) mice. Aldosterone effects were prevented by the AGTR1 antagonist losartan in WT mice. In contrast to aldosterone, norepinephrine caused similar BP increase and mesenteric artery remodeling in WT and Agtr1a(-/-) mice. Agtr1a(-/-) mice infused with aldosterone did not increase sodium excretion in response to a sodium chloride challenge, suggesting that sodium retention could contribute to the exaggerated BP rise induced by aldosterone. Agtr1a(-/-) mice had decreased mesenteric artery expression of the calcium-activated potassium channel Kcnmb1, which may enhance myogenic tone and together with sodium retention, exacerbate BP responses to aldosterone/salt in Agtr1a(-/-) mice. We conclude that although aldosterone activation of mineralocorticoid receptors raises BP more in Agtr1a(-/-) mice, AGTR1a is required for mineralocorticoid receptor stimulation to induce vascular remodeling and inflammation and endothelial dysfunction. PMID:27045029

  13. Remodeling of the Mandibular Bone Induced by Overdentures Supported by Different Numbers of Implants.

    PubMed

    Li, Kai; Xin, Haitao; Zhao, Yanfang; Zhang, Zhiyuan; Wu, Yulu

    2016-05-01

    The objective of this study was to investigate the process of mandibular bone remodeling induced by implant-supported overdentures. computed tomography (CT) images were collected from edentulous patients to reconstruct the geometry of the mandibular bone and overdentures supported by implants. Based on the theory of strain energy density (SED), bone remodeling models were established using the user material subroutine (UMAT) in abaqus. The stress distribution in the mandible and bone density change was investigated to determine the effect of implant number on the remodeling of the mandibular bone. The results indicated that the areas where high Mises stress values were observed were mainly situated around the implants. The stress was concentrated in the distal neck region of the distal-most implants. With an increased number of implants, the biting force applied on the dentures was almost all taken up by implants. The stress and bone density in peri-implant bone increased. When the stress reached the threshold of remodeling, the bone density began to decrease. In the posterior mandible area, the stress was well distributed but increased with decreased implant numbers. Changes in bone density were not observed in this area. The computational results were consistent with the clinical data. The results demonstrate that the risk of bone resorption around the distal-most implants increases with increased numbers of implants and that the occlusal force applied to overdentures should be adjusted to be distributed more in the distal areas of the mandible. PMID:26963740

  14. Long Noncoding RNA-GAS5: A Novel Regulator of Hypertension-Induced Vascular Remodeling.

    PubMed

    Wang, Yang-Ning-Zhi; Shan, Kun; Yao, Mu-Di; Yao, Jin; Wang, Jia-Jian; Li, Xiang; Liu, Ban; Zhang, Yang-Yang; Ji, Yong; Jiang, Qin; Yan, Biao

    2016-09-01

    Vascular remodeling is an important pathological feature of hypertension, leading to increased vascular resistance and reduced compliance. Endothelial cell (EC) and vascular smooth muscle cell (VSMC) dysfunction is involved in vascular remodeling. Long noncoding RNAs are potential regulators of EC and VSMC function. Herein, we determined whether long noncoding RNA-growth arrest-specific 5 (GAS5) is involved in hypertension-related vascular remodeling. We revealed that GAS5 knockdown aggravated hypertension-induced microvascular dysfunction as shown by increased retinal neovascularization and capillary leakage. GAS5 regulated the remodeling of arteries, including caudal arteries, carotid arteries, renal arteries, and thoracic arteries. GAS5 was mainly expressed in ECs and VSMCs, and its expression was significantly downregulated in hypertension. GAS5 knockdown affected endothelial activation, endothelial proliferation, VSMC phenotypic conversion, and EC-VSMC communication in vivo and in vitro. Mechanistically, GAS5 regulated EC and VSMC function through β-catenin signaling. This study identified GAS5 as a critical regulator in hypertension and demonstrated the potential of gene therapy and drug development for treating hypertension. PMID:27432865

  15. Quantification of Protein-Induced Membrane Remodeling Kinetics In Vitro with Lipid Multilayer Gratings

    PubMed Central

    Lowry, Troy W.; Hariri, Hanaa; Prommapan, Plengchart; Kusi-Appiah, Aubrey; Vafai, Nicholas; Bienkiewicz, Ewa A.; Van Winkle, David H.; Stagg, Scott M.

    2016-01-01

    The dynamic self-organization of lipids in biological systems is a highly regulated process that enables the compartmentalization of living systems at micro- and nanoscopic scales. Consequently, quantitative methods for assaying the kinetics of supramolecular remodeling such as vesicle formation from planar lipid bilayers or multilayers are needed to understand cellular self-organization. Here, a new nanotechnology-based method for quantitative measurements of lipid–protein interactions is presented and its suitability for quantifying the membrane binding, inflation, and budding activity of the membrane-remodeling protein Sar1 is demonstrated. Lipid multilayer gratings are printed onto surfaces using nanointaglio and exposed to Sar1, resulting in the inflation of lipid multilayers into unilamellar structures, which can be observed in a label-free manner by monitoring the diffracted light. Local variations in lipid multilayer volume on the surface is used to vary substrate availability in a microarray format. A quantitative model is developed that allows quantification of binding affinity (KD) and kinetics (kon and koff). Importantly, this assay is uniquely capable of quantifying membrane remodeling. Upon Sar1-induced inflation of single bilayers from surface supported multilayers, the semicylindrical grating lines are observed to remodel into semispherical buds when a critical radius of curvature is reached. PMID:26649649

  16. ACF chromatin remodeling complex mediates stress–induced depressive–like behavior

    PubMed Central

    Sun, HaoSheng; Damez–Werno, Diane M.; Scobie, Kimberly N.; Shao, Ning–Yi; Dias, Caroline; Rabkin, Jacqui; Koo, Ja Wook; Korb, Erica; Bagot, Rosemary C.; Ahn, Francisca H.; Cahill, Michael E.; Labonté, Benoit; Mouzon, Ezekiell; Heller, Elizabeth A.; Cates, Hannah; Golden, Sam A; Gleason, Kelly; Russo, Scott J; Andrews, Simon; Neve, Rachael; Kennedy, Pamela J.; Maze, Ian; Dietz, David M.; Allis, C. David; Turecki, Gustavo; Varga–Weisz, Patrick; Tamminga, Carol; Shen, Li; Nestler, Eric J.

    2015-01-01

    Improved treatment for major depressive disorder (MDD) remains elusive due to limited understanding of its underlying biological mechanisms. Stress–induced maladaptive transcriptional regulation within limbic neural circuits likely contributes to the development of MDD, possibly through epigenetic factors that regulate chromatin structure. We establish that persistent upregulation of the ACF ATP–dependent chromatin remodeling complex, occurring in the nucleus accumbens of stress–susceptible mice and depressed humans, is necessary for stress–induced depressive–like behaviors. Altered ACF binding after chronic stress is correlated with altered nucleosome positioning, particularly around the transcription start sites of affected genes. These alterations in ACF binding and nucleosome positioning are associated with repressed expression of genes implicated in susceptibility to stress. Together, we identify the ACF chromatin remodeling complex as a critical component in the development of susceptibility to depression and in regulating stress–related behaviors. PMID:26390241

  17. Preclinical Lymphatic Imaging

    PubMed Central

    Zhang, Fan; Niu, Gang; Lu, Guangming; Chen, Xiaoyuan

    2011-01-01

    Non-invasive in vivo imaging of lymphatic vessels and lymphatic nodes is expected to fulfill the purpose of analyzing lymphatic vessels and their function, understanding molecular mechanisms of lymphangiogenesis and lymphatic spread of tumors, and utilizing lymphatic molecular markers as a prognostic or diagnostic indicator. In this review, we provide a comprehensive summary of in vivo imaging modalities for detecting lymphatic vessels, lymphatic drainage, lymphatic nodes, which include conventional lymphatic imaging techniques such as dyes and radionuclide scintigraphy as well as novel techniques for lymphatic imaging such as optical imaging, computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, positron emission tomography (PET) using lymphatic biomarkers, photoacoustic imaging and combinations of multiple modalities. The field of lymphatic imaging is ever evolving, and technological advances, combined with the development of new contrast agents, continue to improve the research of lymphatic vascular system in health and disease states as well as to improve the accuracy of diagnosis in the relevant diseases. PMID:20862613

  18. Axon membrane remodeling in the lead-induced demyelinating neuropathy of the rat.

    PubMed

    Coria, F; Berciano, M T; Berciano, J; Lafarga, M

    1984-01-23

    Single-teased fibers stained with the ferric ion-ferrocyanide method allowed us to study axonal remodeling in the lead-induced demyelinating neuropathy of the rat. Our findings, in agreement with recent physiological data, pointed to a transitory reorganization of the demyelinated axons to maintain impulse conduction until remyelination and formation of new cytochemically normal nodes had restored a secure saltatory conduction. PMID:6320964

  19. A Food-Derived Flavonoid Luteolin Protects against Angiotensin II-Induced Cardiac Remodeling

    PubMed Central

    Nakao, Tomoko; Yamaguchi, Toshihiro; Sumida, Tomokazu; Ikeda, Yuichi; Kumagai, Hidetoshi; Motozawa, Yoshihiro; Takahashi, Tsukasa; Imaizumi, Atsushi; Hashimoto, Tadashi; Nagai, Ryozo; Komuro, Issei

    2015-01-01

    Oxidative stress has been implicated in cardiac remodeling (cardiac fibrosis and hypertrophy), which impairs cardiac function and metabolism; therefore, it is anticipated antioxidative compounds will have protective properties against cardiac remodeling. Luteolin (3’,4’,5,7-tetrahydroxyflavone), a widely distributed flavonoid found in many herbal extracts including celery, green pepper, perilla leaves and seeds, and chamomile, is a known to be a potent antioxidant and was previously demonstrated to exert an antifibrotic effect in the lungs and the liver. In this study, we clearly demonstrate that oral pretreatment with the higher-luteolin diet (0.035% (wt/wt)) protected against cardiac fibrosis and hypertrophy as well as a hyperoxidative state in Ang II-infused rats. In cardiac tissue, increased gene expression levels of TGFβ1, CTGF, Nox2, Nox4, ANP, and BNP induced by Ang II were restored by oral pretreatment of this high-luteolin diet. In cultured rat cardiac fibroblasts, H2O2-induced TGFβ1 expression and the phosphorylation of JNK were suppressed by luteolin pretreatment. In conclusion, food-derived luteolin has protective actions against Ang II-induced cardiac remodeling, which could be mediated through attenuation of oxidative stress. PMID:26327560

  20. A Food-Derived Flavonoid Luteolin Protects against Angiotensin II-Induced Cardiac Remodeling.

    PubMed

    Nakayama, Atsuko; Morita, Hiroyuki; Nakao, Tomoko; Yamaguchi, Toshihiro; Sumida, Tomokazu; Ikeda, Yuichi; Kumagai, Hidetoshi; Motozawa, Yoshihiro; Takahashi, Tsukasa; Imaizumi, Atsushi; Hashimoto, Tadashi; Nagai, Ryozo; Komuro, Issei

    2015-01-01

    Oxidative stress has been implicated in cardiac remodeling (cardiac fibrosis and hypertrophy), which impairs cardiac function and metabolism; therefore, it is anticipated antioxidative compounds will have protective properties against cardiac remodeling. Luteolin (3',4',5,7-tetrahydroxyflavone), a widely distributed flavonoid found in many herbal extracts including celery, green pepper, perilla leaves and seeds, and chamomile, is a known to be a potent antioxidant and was previously demonstrated to exert an antifibrotic effect in the lungs and the liver. In this study, we clearly demonstrate that oral pretreatment with the higher-luteolin diet (0.035% (wt/wt)) protected against cardiac fibrosis and hypertrophy as well as a hyperoxidative state in Ang II-infused rats. In cardiac tissue, increased gene expression levels of TGFβ1, CTGF, Nox2, Nox4, ANP, and BNP induced by Ang II were restored by oral pretreatment of this high-luteolin diet. In cultured rat cardiac fibroblasts, H2O2-induced TGFβ1 expression and the phosphorylation of JNK were suppressed by luteolin pretreatment. In conclusion, food-derived luteolin has protective actions against Ang II-induced cardiac remodeling, which could be mediated through attenuation of oxidative stress. PMID:26327560

  1. Biophysics of α-synuclein induced membrane remodelling

    PubMed Central

    Shi, Zheng; Sachs, Jonathan; Rhoades, Elizabeth; Baumgart, Tobias

    2015-01-01

    α-synuclein is an intrinsically disordered protein whose aggregation is a hallmark of Parkinson’s disease. In neurons, α-synuclein is thought to play important roles in mediating both endo- and exocytosis of synaptic vesicles through interactions with either the lipid bilayer or other proteins. Upon membrane binding, the N-terminus of α-synuclein forms a helical structure and inserts into the hydrophobic region of the outer membrane leaflet. However, membrane structural changes induced by α-synuclein are still largely unclear. Here we report a substantial membrane area expansion induced by the binding of α-synuclein monomers. This measurement is accomplished by observing the increase of membrane area during the binding of α-synuclein to pipette-aspirated giant vesicles. The extent of membrane area expansion correlates linearly with the density of α-synuclein on the membrane, revealing a constant area increase induced by the binding per α-synuclein molecule. The area expansion per synuclein is found to exhibit a strong dependence on lipid composition, but is independent of membrane tension and vesicle size. Fragmentation or tubulation of the membrane follows the membrane expansion process. However, contrary to BAR domain proteins, no distinct tubulation-transition density can apparently be identified for α-synuclein, suggesting a more complex membrane curvature generation mechanism. Consideration of α-synuclein’s membrane binding free energy and biophysical properties of the lipid bilayer leads us to conclude that membrane expansion by α-synuclein results in thinning of the bilayer. These membrane thinning and tubulation effects may underlie α-synuclein’s role in mediating cell trafficking processes such as endo- and exocytosis. PMID:25665896

  2. Biophysics of α-synuclein induced membrane remodelling.

    PubMed

    Shi, Zheng; Sachs, Jonathan N; Rhoades, Elizabeth; Baumgart, Tobias

    2015-06-28

    α-Synuclein is an intrinsically disordered protein whose aggregation is a hallmark of Parkinson's disease. In neurons, α-synuclein is thought to play important roles in mediating both endo- and exocytosis of synaptic vesicles through interactions with either the lipid bilayer or other proteins. Upon membrane binding, the N-terminus of α-synuclein forms a helical structure and inserts into the hydrophobic region of the outer membrane leaflet. However, membrane structural changes induced by α-synuclein are still largely unclear. Here we report a substantial membrane area expansion induced by the binding of α-synuclein monomers. This measurement is accomplished by observing the increase of membrane area during the binding of α-synuclein to pipette-aspirated giant vesicles. The extent of membrane area expansion correlates linearly with the density of α-synuclein on the membrane, revealing a constant area increase induced by the binding per α-synuclein molecule. The area expansion per synuclein is found to exhibit a strong dependence on lipid composition, but is independent of membrane tension and vesicle size. Fragmentation or tubulation of the membrane follows the membrane expansion process. However, contrary to BAR domain proteins, no distinct tubulation-transition density can apparently be identified for α-synuclein, suggesting a more complex membrane curvature generation mechanism. Consideration of α-synuclein's membrane binding free energy and biophysical properties of the lipid bilayer leads us to conclude that membrane expansion by α-synuclein results in thinning of the bilayer. These membrane thinning and tubulation effects may underlie α-synuclein's role in mediating cell trafficking processes such as endo- and exocytosis. PMID:25665896

  3. Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

    PubMed Central

    Wicks, Shawna E.; Vandanmagsar, Bolormaa; Haynie, Kimberly R.; Fuller, Scott E.; Warfel, Jaycob D.; Stephens, Jacqueline M.; Wang, Miao; Han, Xianlin; Zhang, Jingying; Noland, Robert C.; Mynatt, Randall L.

    2015-01-01

    The correlations between intramyocellular lipid (IMCL), decreased fatty acid oxidation (FAO), and insulin resistance have led to the hypothesis that impaired FAO causes accumulation of lipotoxic intermediates that inhibit muscle insulin signaling. Using a skeletal muscle-specific carnitine palmitoyltransferase-1 KO model, we show that prolonged and severe mitochondrial FAO inhibition results in increased carbohydrate utilization, along with reduced physical activity; increased circulating nonesterified fatty acids; and increased IMCLs, diacylglycerols, and ceramides. Perhaps more importantly, inhibition of mitochondrial FAO also initiates a local, adaptive response in muscle that invokes mitochondrial biogenesis, compensatory peroxisomal fat oxidation, and amino acid catabolism. Loss of its major fuel source (lipid) induces an energy deprivation response in muscle coordinated by signaling through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity. PMID:26056297

  4. Simulated Microgravity and Recovery-Induced Remodeling of the Left and Right Ventricle

    PubMed Central

    Zhong, Guohui; Li, Yuheng; Li, Hongxing; Sun, Weijia; Cao, Dengchao; Li, Jianwei; Zhao, Dingsheng; Song, Jinping; Jin, Xiaoyan; Song, Hailin; Yuan, Xinxin; Wu, Xiaorui; Li, Qi; Xu, Qing; Kan, Guanghan; Cao, Hongqing; Ling, Shukuan; Li, Yingxian

    2016-01-01

    Physiological adaptations to microgravity involve alterations in cardiovascular systems. These adaptations result in cardiac remodeling and orthostatic hypotension. However, the response of the left ventricle (LV) and right ventricle (RV) following hindlimb unloading (HU) and hindlimb reloading (HR) is not clear and the underlying mechanism remains to be understood. In this study, three groups of mice were subjected to HU by tail suspension for 28 days. Following this, two groups were allowed to recover for 7 or 14 days. The control group was treated equally, with the exception of tail suspension. Echocardiography was performed to detect the structure and function changes of heart. Compared with the control, the HU group of mice showed reduced LV-EF (ejection fraction), and LV-FS (fractional shortening). However, mice that were allowed to recover for 7 days after HU (HR-7d) showed increased LVIDs (systolic LV internal diameter) and LV Vols (systolic LV volume). Mice that recovered for 14 days (HR-14d) returned to the normal state. In comparison, RV-EF and RV-FS didn't recover to the normal conditions till being reloaded for 14 days. Compared with the control, RVIDd (diastolic RV internal diameter), and RV Vold (diastolic RV volume) were reduced in HU group and recovered to the normal conditions in HR-7d and HR-14d groups, in which groups RVIDs (systolic RV internal diameter) and RV Vols (systolic RV volume) were increased. Histological analysis and cardiac remodeling gene expression results indicated that HU induces left and right ventricular remodeling. Western blot demonstrated that the phosphorylation of HDAC4 and ERK1/2 and the ratio of LC3-II / LC3-I, were increased following HU and recovered following HR in both LV and RV, and the phosphorylation of AMPK was inhibited in both LV and RV following HU, but only restored in LV following HR for 14 days. These results indicate that simulated microgravity leads to cardiac remodeling, and the remodeling changes can

  5. Rod photoreceptors protect from cone degeneration-induced retinal remodeling and restore visual responses in zebrafish

    PubMed Central

    Saade, Carole J.; Alvarez-Delfin, Karen; Fadool, James M.

    2013-01-01

    Humans are largely dependent upon cone-mediated vision. However, death or dysfunction of rods, the predominant photoreceptor subtype, results in secondary loss of cones, remodeling of retinal circuitry and blindness. The changes in circuitry may contribute to the vision deficit and undermine attempts at restoring sight. We exploit zebrafish larvae as a genetic model to specifically characterize changes associated with photoreceptor degenerations in a cone-dominated retina. Photoreceptors form synapses with two types of second order neurons, bipolar cells and horizontal cells. Using cell-specific reporter gene expression and immunolabeling for postsynaptic glutamate receptors, significant remodeling is observed following cone degeneration in the pde6cw59 larval retina but not rod degeneration in the Xops:mCFPq13 line. In adults, rods and cones are present in approximately equal numbers, and in pde6cw59 mutants glutamate receptor expression and synaptic structures in the outer plexiform layer are preserved, and visual responses are gained in these once-blind fish. We propose that the abundance of rods in the adult protects the retina from cone degeneration-induced remodeling. We test this hypothesis by genetically manipulating the number of rods in larvae. We show that an increased number and uniform distribution of rods in lor/tbx2bp22bbtl or six7 morpholino-injected larvae protect from pde6cw59-induced secondary changes. The observations that remodeling is a common consequence of photoreceptor death across species, and that in zebrafish a small number of surviving photoreceptors afford protection from degeneration-induced changes provides a model for systematic analysis of factors that slow or even prevent the secondary deteriorations associated with neural degenerative disease. PMID:23365220

  6. Lymphatic Anomalies Registry

    ClinicalTrials.gov

    2016-07-26

    Lymphatic Malformation; Generalized Lymphatic Anomaly (GLA); Central Conducting Lymphatic Anomaly; CLOVES Syndrome; Gorham-Stout Disease ("Disappearing Bone Disease"); Blue Rubber Bleb Nevus Syndrome; Kaposiform Lymphangiomatosis; Kaposiform Hemangioendothelioma/Tufted Angioma; Klippel-Trenaunay Syndrome; Lymphangiomatosis

  7. Somatic embryogenesis - Stress-induced remodeling of plant cell fate.

    PubMed

    Fehér, Attila

    2015-04-01

    Plants as sessile organisms have remarkable developmental plasticity ensuring heir continuous adaptation to the environment. An extreme example is somatic embryogenesis, the initiation of autonomous embryo development in somatic cells in response to exogenous and/or endogenous signals. In this review I briefly overview the various pathways that can lead to embryo development in plants in addition to the fertilization of the egg cell and highlight the importance of the interaction of stress- and hormone-regulated pathways during the induction of somatic embryogenesis. Somatic embryogenesis can be initiated in planta or in vitro, directly or indirectly, and the requirement for dedifferentiation as well as the way to achieve developmental totipotency in the various systems is discussed in light of our present knowledge. The initiation of all forms of the stress/hormone-induced in vitro as well as the genetically provoked in planta somatic embryogenesis requires extensive and coordinated genetic reprogramming that has to take place at the chromatin level, as the embryogenic program is under strong epigenetic repression in vegetative plant cells. Our present knowledge on chromatin-based mechanisms potentially involved in the somatic-to-embryogenic developmental transition is summarized emphasizing the potential role of the chromatin to integrate stress, hormonal, and developmental pathways leading to the activation of the embryogenic program. The role of stress-related chromatin reorganization in the genetic instability of in vitro cultures is also discussed. This article is part of a Special Issue entitled: Stress as a fundamental theme in cell plasticity. PMID:25038583

  8. Activation of AMPK Prevents Monocrotaline-Induced Extracellular Matrix Remodeling of Pulmonary Artery

    PubMed Central

    Li, Shaojun; Han, Dong; Zhang, Yonghong; Xie, Xinming; Ke, Rui; Zhu, Yanting; Liu, Lu; Song, Yang; Yang, Lan; Li, Manxiang

    2016-01-01

    Background The current study was performed to investigate the effect of adenosine monophosphate (AMP) – activated protein kinase (AMPK) activation on the extracellular matrix (ECM) remodeling of pulmonary arteries in pulmonary arterial hypertension (PAH) and to address its potential mechanisms. Material/Methods PAH was induced by a single intraperitoneal injection of monocrotaline (MCT) into Sprague-Dawley rats. Metformin (MET) was administered to activate AMPK. Immunoblotting was used to determine the phosphorylation and expression of AMPK and expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). Gelatin zymography was performed to determine the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9. Results Activation of AMPK by MET significantly reduced the right ventricle systolic pressure and the right ventricular hypertrophy in MCT-induced rat PAH model, and partially inhibited the ECM remodeling of pulmonary arteries. These effects were coupled with the decrease of MMP-2/9 activity and TIMP-1 expression. Conclusions This study suggests that activation of AMPK benefits PAH by inhibiting ECM remodeling of pulmonary arteries. Enhancing AMPK activity might have potential value in clinical treatment of PAH. PMID:26978596

  9. Axl, a receptor tyrosine kinase, mediates flow-induced vascular remodeling.

    PubMed

    Korshunov, Vyacheslav A; Mohan, Amy M; Georger, Mary A; Berk, Bradford C

    2006-06-01

    Intima-media thickening (IMT) in response to hemodynamic stress is a physiological process that requires coordinated signaling among endothelial, inflammatory, and vascular smooth muscle cells (VSMC). Axl, a receptor tyrosine kinase, whose ligand is Gas6, is highly induced in VSMC after carotid injury. Because Axl regulates cell migration, phagocytosis and apoptosis, we hypothesized that Axl would play a role in IMT. Vascular remodeling in mice deficient in Axl (Axl(-/-)) and wild-type littermates (Axl(+/+)) was induced by ligation of the left carotid artery (LCA) branches maintaining flow via the left occipital artery. Both genotypes had similar baseline hemodynamic parameters and carotid artery structure. Partial ligation altered blood flow equally in both genotypes: increased by 60% in the right carotid artery (RCA) and decreased by 80% in the LCA. There were no significant differences in RCA remodeling between genotypes. However, in the LCA Axl(-/-) developed significantly smaller intima+media compared with Axl(+/+) (31+/-4 versus 42+/-6x10(-6) microm3, respectively). Quantitative immunohistochemistry of Axl(-/-) LCA showed increased apoptosis compared with Axl(+/+) (5-fold). As expected, p-Akt was decreased in Axl(-/-), whereas there was no difference in Gas6 expression. Cell composition also changed significantly, with increases in CD45+ cells and decreases in VSMC, macrophages, and neutrophils in Axl(-/-) compared with Axl(+/+). These data demonstrate an important role for Axl in flow-dependent remodeling by regulating vascular apoptosis and vascular inflammation. PMID:16627783

  10. Protein-bound uremic toxins induce tissue remodeling by targeting the EGF receptor.

    PubMed

    Sun, Chiao-Yin; Young, Guang-Huar; Hsieh, Yu-Ting; Chen, Yau-Hung; Wu, Mai-Szu; Wu, Vin-Cent; Lee, Jia-Hung; Lee, Chin-Chan

    2015-02-01

    Indoxyl sulfate and p-cresol sulfate have been suggested to induce kidney tissue remodeling. This study aimed to clarify the molecular mechanisms underlying this tissue remodeling using cultured human proximal renal tubular cells and half-nephrectomized mice treated with indoxyl sulfate or p-cresol sulfate as study models. Molecular docking results suggested that indoxyl sulfate and p-cresol sulfate dock on a putative interdomain pocket of the extracellular EGF receptor. In vitro spectrophotometric analysis revealed that the presence of a synthetic EGF receptor peptide significantly decreased the spectrophotometric absorption of indoxyl sulfate and p-cresol sulfate. In cultured cells, indoxyl sulfate and p-cresol sulfate activated the EGF receptor and downstream signaling by enhancing receptor dimerization, and increased expression of matrix metalloproteinases 2 and 9 in an EGF receptor-dependent manner. Treatment of mice with indoxyl sulfate or p-cresol sulfate significantly activated the renal EGF receptor and increased the tubulointerstitial expression of matrix metalloproteinases 2 and 9. In conclusion, indoxyl sulfate and p-cresol sulfate may induce kidney tissue remodeling through direct binding and activation of the renal EGF receptor. PMID:25012179

  11. Antagonism of Stem Cell Factor/c-kit Signaling Attenuates Neonatal Chronic Hypoxia-Induced Pulmonary Vascular Remodeling

    PubMed Central

    Young, Karen C; Torres, Eneida; Hehre, Dorothy; Wu, Shu; Suguihara, Cleide; Hare, Joshua M.

    2015-01-01

    Background Accumulating evidence suggests that c-kit positive cells are present in the remodeled pulmonary vasculature bed of patients with pulmonary hypertension (PH). Whether stem cell factor (SCF)/ c-kit regulated pathways potentiate pulmonary vascular remodeling is unknown. Here, we tested the hypothesis that attenuated c-kit signaling would decrease chronic hypoxia-induced pulmonary vascular remodeling by decreasing pulmonary vascular cell mitogenesis. Methods Neonatal FVB/NJ mice treated with non-immune IgG (PL), or c-kit neutralizing antibody (ACK2) as well as c-kit mutant mice (WBB6F1- Kit W− v/ +) and their congenic controls, were exposed to normoxia (FiO2=0.21) or hypoxia (FiO2=0.12) for two weeks. Following this exposure, right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), pulmonary vascular cell proliferation and remodeling were evaluated. Results As compared to chronically hypoxic controls, c-kit mutant mice had decreased RVSP, RVH, pulmonary vascular remodeling and proliferation. Consistent with these findings, administration of ACK2 to neonatal mice with chronic hypoxia-induced PH decreased RVSP, RVH, pulmonary vascular cell proliferation and remodeling. This attenuation in PH was accompanied by decreased extracellular signal-regulated protein kinase (ERK) 1/2 activation. Conclusion SCF/c-kit signaling may potentiate chronic hypoxia-induced vascular remodeling by modulating ERK activation. Inhibition of c-kit activity may be a potential strategy to alleviate PH. PMID:26705118

  12. Pro-arrhythmogenic effects of atrial fibrillation-induced electrical remodelling: insights from the three-dimensional virtual human atria.

    PubMed

    Colman, Michael A; Aslanidi, Oleg V; Kharche, Sanjay; Boyett, Mark R; Garratt, Clifford; Hancox, Jules C; Zhang, Henggui

    2013-09-01

    Chronic atrial fibrillation (AF) is associated with structural and electrical remodelling in the atria, which are associated with a high recurrence of AF. Through biophysically detailed computer modelling, this study investigated mechanisms by which AF-induced electrical remodelling promotes and perpetuates AF. A family of Courtemanche-Ramirez-Nattel variant models of human atrial cell action potentials (APs), taking into account of intrinsic atrial electrophysiological properties, was modified to incorporate various experimental data sets on AF-induced changes of major ionic channel currents (ICaL, IKur, Ito, IK1, IKs, INaCa) and on intracellular Ca(2+) handling. The single cell models for control and AF-remodelled conditions were incorporated into multicellular three-dimensional (3D) atrial tissue models. Effects of the AF-induced electrical remodelling were quantified as the changes of AP profile, AP duration (APD) and its dispersion across the atria, and the vulnerability of atrial tissue to the initiation of re-entry. The dynamic behaviour of re-entrant excitation waves in the 3D models was characterised. In our simulations, AF-induced electrical remodelling abbreviated atrial APD non-uniformly across the atria; this resulted in relatively short APDs co-existing with marked regional differences in the APD at junctions of the crista terminalis/pectinate muscle, pulmonary veins/left atrium. As a result, the measured tissue vulnerability to re-entry initiation at these tissue junctions was increased. The AF-induced electrical remodelling also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained re-entry. Under the AF-remodelled condition, re-entrant scroll waves in the 3D model degenerated into persistent and erratic wavelets, leading to fibrillation. In conclusion, realistic 3D atrial tissue models indicate that AF-induced electrical remodelling produces regionally heterogeneous and shortened APD; these respectively facilitate

  13. Overload-Induced Skeletal Muscle Extracellular Matrix Remodeling And Myofiber Growth in Mice Lacking IL-6

    PubMed Central

    White, James P.; Reecy, James M.; Washington, Tyrone A.; Sato, Shuichi; Le, Michael E.; Davis, J. Mark; Wilson, L. Britt; Carson, James A.

    2011-01-01

    Aim Overloading healthy skeletal muscle produces myofiber hypertrophy and extracellular matrix remodeling, and these processes are thought to be interdependent for producing muscle growth. Inflammatory cytokine interleukin-6 (IL-6) gene expression is induced in overloaded skeletal muscle, and the loss of this IL-6 induction can attenuate the hypertrophic response to overload. Although the overload induction of IL-6 in skeletal muscle may be an important regulator of inflammatory processes and satellite cell proliferation, less is known about its role in the regulation of extracellular matrix remodeling. The purpose of the current study was to examine if overload-induced extracellular matrix remodeling, muscle growth, and associated gene expression were altered in mice that lack IL-6, when compared to wild-type mice. Methods Male C57/BL6 (WT) and C57/BL6 × IL-6-/- (IL-6-/-) mice (10 wks of age) were assigned to either a sham control or synergist ablation overload (OV) treatments for 3 or 21 days. Results Plantaris muscle mass increased 59% in WT and 116% in IL-6-/- mice after 21d OV. Myofiber CSA was also increased by 21d OV in both WT and IL-6-/- mice. Overload induced a 2-fold greater increase in the volume of non-contractile tissue in IL-6-/- muscle as compared to WT. Overload also induced a significantly greater accumulation of hydroxyproline and procollagen-1 mRNA in IL-6-/- muscle, when compared to WT muscle after 21d OV. TGF-β and IGF-1 mRNA expression were also induced to a greater extent in IL-6-/- muscle when compared to WT muscle after 21d OV. There was no effect of IL-6 loss on the induction of myogenin, and cyclin D1 mRNA expression after 3d OV. However, MyoD mRNA expression in 3d OV IL-6-/- muscle was attenuated when compared to WT overload mice. Conclusion IL-6 appears to be necessary for the normal regulation of extracellular matrix remodeling during overload-induced growth. PMID:19681796

  14. Functional brown adipose tissue limits cardiomyocyte injury and adverse remodeling in catecholamine-induced cardiomyopathy.

    PubMed

    Thoonen, Robrecht; Ernande, Laura; Cheng, Juan; Nagasaka, Yasuko; Yao, Vincent; Miranda-Bezerra, Alexandre; Chen, Chan; Chao, Wei; Panagia, Marcello; Sosnovik, David E; Puppala, Dheeraj; Armoundas, Antonis A; Hindle, Allyson; Bloch, Kenneth D; Buys, Emmanuel S; Scherrer-Crosbie, Marielle

    2015-07-01

    Brown adipose tissue (BAT) has well recognized thermogenic properties mediated by uncoupling protein 1 (UCP1); more recently, BAT has been demonstrated to modulate cardiovascular risk factors. To investigate whether BAT also affects myocardial injury and remodeling, UCP1-deficient (UCP1(-/-)) mice, which have dysfunctional BAT, were subjected to catecholamine-induced cardiomyopathy. At baseline, there were no differences in echocardiographic parameters, plasma cardiac troponin I (cTnI) or myocardial fibrosis between wild-type (WT) and UCP1(-/-) mice. Isoproterenol infusion increased cTnI and myocardial fibrosis and induced left ventricular (LV) hypertrophy in both WT and UCP1(-/-) mice. UCP1(-/-) mice also demonstrated exaggerated myocardial injury, fibrosis, and adverse remodeling, as well as decreased survival. Transplantation of WT BAT to UCP1(-/-) mice prevented the isoproterenol-induced cTnI increase and improved survival, whereas UCP1(-/-) BAT transplanted to either UCP1(-/-) or WT mice had no effect on cTnI release. After 3 days of isoproterenol treatment, phosphorylated AKT and ERK were lower in the LV's of UCP1(-/-) mice than in those of WT mice. Activation of BAT was also noted in a model of chronic ischemic cardiomyopathy, and was correlated to LV dysfunction. Deficiency in UCP1, and accompanying BAT dysfunction, increases cardiomyocyte injury and adverse LV remodeling, and decreases survival in a mouse model of catecholamine-induced cardiomyopathy. Myocardial injury and decreased survival are rescued by transplantation of functional BAT to UCP1(-/-) mice, suggesting a systemic cardioprotective role of functional BAT. BAT is also activated in chronic ischemic cardiomyopathy. PMID:25968336

  15. Stress-induced structural remodeling in hippocampus: Prevention by lithium treatment

    NASA Astrophysics Data System (ADS)

    Wood, Gwendolyn E.; Young, L. Trevor; Reagan, Lawrence P.; Chen, Biao; McEwen, Bruce S.

    2004-03-01

    Chronic restraint stress, psychosocial stress, as well as systemic or oral administration of the stress-hormone corticosterone induces a morphological reorganization in the rat hippocampus, in which adrenal steroids and excitatory amino acids mediate a reversible remodeling of apical dendrites on CA3 pyramidal cell neurons of the hippocampus. This stress-induced neuronal remodeling is accompanied also by behavioral changes, some of which can be prevented with selective antidepressant and anticonvulsive drug treatments. Lithium is an effective treatment for mood disorders and has neuroprotective effects, which may contribute to its therapeutic properties. Thus, we wanted to determine whether lithium treatment could prevent the effects of chronic stress on CA3 pyramidal cell neuroarchitecture and the associated molecular and behavioral measures. Chronic lithium treatment prevented the stress-induced decrease in dendritic length, as well as the stress-induced increase in glial glutamate transporter 1 (GLT-1) mRNA expression and the phosphorylation of cAMP-response element binding in the hippocampus. Lithium treatment, however, did not prevent stress effects on behavior in the open field or the plus-maze. These data demonstrate that chronic treatment with lithium can protect the hippocampus from potentially deleterious effects of chronic stress on glutamatergic activation, which may be relevant to its therapeutic efficacy in the treatment of major depressive disorder and bipolar disorder.

  16. Asiatic acid alleviates cardiovascular remodelling in rats with L-NAME-induced hypertension.

    PubMed

    Bunbupha, Sarawoot; Prachaney, Parichat; Kukongviriyapan, Upa; Kukongviriyapan, Veerapol; Welbat, Jariya Umka; Pakdeechote, Poungrat

    2015-11-01

    A previous study demonstrated the antihypertensive effect of asiatic acid. The current study investigates the effect of asiatic acid on cardiovascular remodelling and possible mechanisms involved in Nω -nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. Male Sprague-Dawley rats were treated with L-NAME (40 mg/kg per day) for 3 weeks in order to induce hypertension. Hypertensive rats were administered asiatic acid (20 mg/kg per day) or vehicle for a further 2 weeks. It was found that hypertensive rats showed high systolic blood pressure, left ventricular (LV) hypertrophy, increases in LV fibrosis, aortic wall thickness and aortic collagen deposition (P < 0.05). Moreover, decreased plasma nitrate and nitrite (NOx) and increased plasma tumor necrosis factor alpha (TNF-α) were observed in hypertensive rats (P < 0.05). This was consistent with downregulation of endothelial nitric oxide synthase (eNOS) expression and upregulation of inducible nitric oxide synthase (iNOS) expression in heart and aortic tissues (P < 0.05). Levels of malondialdehyde (MDA) in plasma, aortic and heart tissues were significantly increased in hypertensive rats (P < 0.05). Asiatic acid markedly reduced blood pressure, alleviated cardiovascular remodelling, and restored plasma NOx and TNF-α as well as eNOS/iNOS expression in heart and aortic tissues (P < 0.05). Additionally, there was a significant reduction of MDA levels in the tissues of treated hypertensive rats. In conclusion, this study demonstrates the therapeutic effects of asiatic acid on blood pressure and cardiovascular remodelling, which is possibly related to the restoration of eNOS/iNOS expression, and the resulting anti-inflammatory and antioxidant activities. PMID:26234646

  17. Adenosine triphosphate-induced photoreceptor death and retinal remodeling in rats

    PubMed Central

    Vessey, Kirstan A; Greferath, Ursula; Aplin, Felix P; Jobling, Andrew I; Phipps, Joanna A; Ho, Tracy; De Iongh, Robbert U; Fletcher, Erica L

    2014-01-01

    Many common causes of blindness involve the death of retinal photoreceptors, followed by progressive inner retinal cell remodeling. For an inducible model of retinal degeneration to be useful, it must recapitulate these changes. Intravitreal administration of adenosine triphosphate (ATP) has recently been found to induce acute photoreceptor death. The aim of this study was to characterize the chronic effects of ATP on retinal integrity. Five-week-old, dark agouti rats were administered 50 mM ATP into the vitreous of one eye and saline into the other. Vision was assessed using the electroretinogram and optokinetic response and retinal morphology investigated via histology. ATP caused significant loss of visual function within 1 day and loss of 50% of the photoreceptors within 1 week. At 3 months, 80% of photoreceptor nuclei were lost, and total photoreceptor loss occurred by 6 months. The degeneration and remodeling were similar to those found in heritable retinal dystrophies and age-related macular degeneration and included inner retinal neuronal loss, migration, and formation of new synapses; Müller cell gliosis, migration, and scarring; blood vessel loss; and retinal pigment epithelium migration. In addition, extreme degeneration and remodeling events, such as neuronal and glial migration outside the neural retina and proliferative changes in glial cells, were observed. These extreme changes were also observed in the 2-year-old P23H rhodopsin transgenic rat model of retinitis pigmentosa. This ATP-induced model of retinal degeneration may provide a valuable tool for developing pharmaceutical therapies or for testing electronic implants aimed at restoring vision. J. Comp. Neurol. 522:2928–2950, 2014. © 2014 Wiley Periodicals, Inc. PMID:24639102

  18. Structural Basis for Host Membrane Remodeling Induced by Protein 2B of Hepatitis A Virus

    PubMed Central

    Vives-Adrián, Laia; Garriga, Damià; Buxaderas, Mònica; Fraga, Joana; Pereira, Pedro José Barbosa

    2015-01-01

    ABSTRACT The complexity of viral RNA synthesis and the numerous participating factors require a mechanism to topologically coordinate and concentrate these multiple viral and cellular components, ensuring a concerted function. Similarly to all other positive-strand RNA viruses, picornaviruses induce rearrangements of host intracellular membranes to create structures that act as functional scaffolds for genome replication. The membrane-targeting proteins 2B and 2C, their precursor 2BC, and protein 3A appear to be primarily involved in membrane remodeling. Little is known about the structure of these proteins and the mechanisms by which they induce massive membrane remodeling. Here we report the crystal structure of the soluble region of hepatitis A virus (HAV) protein 2B, consisting of two domains: a C-terminal helical bundle preceded by an N-terminally curved five-stranded antiparallel β-sheet that displays striking structural similarity to the β-barrel domain of enteroviral 2A proteins. Moreover, the helicoidal arrangement of the protein molecules in the crystal provides a model for 2B-induced host membrane remodeling during HAV infection. IMPORTANCE No structural information is currently available for the 2B protein of any picornavirus despite it being involved in a critical process in viral factory formation: the rearrangement of host intracellular membranes. Here we present the structure of the soluble domain of the 2B protein of hepatitis A virus (HAV). Its arrangement, both in crystals and in solution under physiological conditions, can help to understand its function and sheds some light on the membrane rearrangement process, a putative target of future antiviral drugs. Moreover, this first structure of a picornaviral 2B protein also unveils a closer evolutionary relationship between the hepatovirus and enterovirus genera within the Picornaviridae family. PMID:25589659

  19. Regulation of Extracellular Matrix Remodeling Proteins by Osteoblasts in Titanium Nanoparticle-Induced Aseptic Loosening Model.

    PubMed

    Xie, Jing; Hou, Yanhua; Fu, Na; Cai, Xiaoxiao; Li, Guo; Peng, Qiang; Lin, Yunfeng

    2015-10-01

    Titanium (Ti)-wear particles, formed at the bone-implant interface, are responsible for aseptic loosening, which is a main cause of total joint replacement failure. There have been many studies on Ti particle-induced function changes in mono-cultured osteoblasts and synovial cells. However, little is known on extracellular matrix remodeling displayed by osteoblasts when in coexistence with Synovial cells. To further mimic the bone-implant interface environment, we firstly established a nanoscaled-Ti particle-induced aseptic loosening system by co-culturing osteoblasts and Synovial cells. We then explored the impact of the Synovial cells on Ti particle-engulfed osteoblasts in the mimicked flamed niche. The matrix metalloproteinases and lysyl oxidases expression levels, two protein families which are critical in osseointegration, were examined under induction by tumor necrosis factor-alpha. It was found that the co-culture between the osteoblasts and Synovial cells markedly increased the migration and proliferation of the osteoblasts, even in the Ti-particle engulfed osteoblasts. Importantly, the Ti-particle engulfed osteoblasts, induced by TNF-alpha after the co-culture, enhanced the release of the matrix metalloproteinases and reduced the expressions of lysyl oxidases. The regulation of extracellular matrix remodeling at the protein level was further assessed by investigations on gene expression of the matrix metalloproteinases and lysyl oxidases, which also suggested that the regulation started at the genetic level. Our research work has therefore revealed the critical role of multi cell-type interactions in the extracellular matrix remodeling within the peri-prosthetic tissues, which provides new insights on aseptic loosening and brings new clues about incomplete osseointegration between the implantation materials and their surrounding bones. PMID:26502645

  20. Tetrahydrocurcumin Protects against Cadmium-Induced Hypertension, Raised Arterial Stiffness and Vascular Remodeling in Mice

    PubMed Central

    Sangartit, Weerapon; Kukongviriyapan, Upa; Donpunha, Wanida; Pakdeechote, Poungrat; Kukongviriyapan, Veerapol; Surawattanawan, Praphassorn; Greenwald, Stephen E.

    2014-01-01

    Background Cadmium (Cd) is a nonessential heavy metal, causing oxidative damage to various tissues and associated with hypertension. Tetrahydrocurcumin (THU), a major metabolite of curcumin, has been demonstrated to be an antioxidant, anti-diabetic, anti-hypertensive and anti-inflammatory agent. In this study, we investigated the protective effect of THU against Cd-induced hypertension, raised arterial stiffness and vascular remodeling in mice. Methods Male ICR mice received CdCl2 (100 mg/l) via drinking water for 8 weeks. THU was administered intragastrically at dose of 50 or 100 mg/kg/day concurrently with Cd treatment. Results Administration of CdCl2 significantly increased arterial blood pressure, blunted vascular responses to vasoactive agents, increased aortic stiffness, and induced hypertrophic aortic wall remodeling by increasing number of smooth muscle cells and collagen deposition, decreasing elastin, and increasing matrix metalloproteinase (MMP)-2 and MMP-9 levels in the aortic medial wall. Supplementation with THU significantly decreased blood pressure, improved vascular responsiveness, and reversed the structural and mechanical alterations of the aortas, including collagen and elastin deposition. The reduction on the adverse response of Cd treatment was associated with upregulated eNOS and downregulated iNOS protein expressions, increased nitrate/nitrite level, alleviated oxidative stress and enhanced antioxidant glutathione. Moreover, THU also reduced the accumulation of Cd in the blood and tissues. Conclusions Our results suggest that THU ameliorates cadmium-induced hypertension, vascular dysfunction, and arterial stiffness in mice through enhancing NO bioavailability, attenuating oxidative stress, improving vascular remodeling and decreasing Cd accumulation in other tissues. THU has a beneficial effect in moderating the vascular alterations associated with Cd exposure. PMID:25502771

  1. Mechanical consequences of allergic induced remodeling on mice airway resistance and compressibility.

    PubMed

    Novali, Mauro; Shalaby, Karim H; Robichaud, Annette; Benedetti, Andrea; Fereydoonzad, Liah; McGovern, Toby K; Schuessler, Thomas F; Martin, James G

    2015-11-01

    The effect of remodeling on airway function is uncertain. It may affect airway compressibility during forced expirations differently than airflow resistance, providing a tool for its assessment. The aim of the current study was to compare the effects of acute and chronic antigen challenge on methacholine-induced bronchoconstriction assessed from resistance and maximal tidal expiratory flow. Balb/C mice were sensitized with ovalbumin (OVA) and challenged either daily for three days with intra-nasal OVA or daily for 5 days and three times a week for 5 subsequent weeks. Acute and chronic allergen challenge induced airway hyperresponsiveness (AHR) to methacholine. However the relationship between maximal tidal expiratory flow and resistance during methacholine challenge was different between the two conditions, suggesting that the determinants of AHR are not identical following acute and chronic allergen exposure. We conclude that the contrast of changes in maximal tidal expiratory flow and respiratory resistance during methacholine-induced bronchoconstriction may allow the detection of the mechanical consequences of airway remodeling. PMID:26213118

  2. Structural and functional remodeling of skeletal muscle microvasculature is induced by simulated microgravity

    NASA Technical Reports Server (NTRS)

    Delp, M. D.; Colleran, P. N.; Wilkerson, M. K.; McCurdy, M. R.; Muller-Delp, J.

    2000-01-01

    Hindlimb unloading of rats results in a diminished ability of skeletal muscle arterioles to constrict in vitro and elevate vascular resistance in vivo. The purpose of the present study was to determine whether alterations in the mechanical environment (i.e., reduced fluid pressure and blood flow) of the vasculature in hindlimb skeletal muscles from 2-wk hindlimb-unloaded (HU) rats induces a structural remodeling of arterial microvessels that may account for these observations. Transverse cross sections were used to determine media cross-sectional area (CSA), wall thickness, outer perimeter, number of media nuclei, and vessel luminal diameter of feed arteries and first-order (1A) arterioles from soleus and the superficial portion of gastrocnemius muscles. Endothelium-dependent dilation (ACh) was also determined. Media CSA of resistance arteries was diminished by hindlimb unloading as a result of decreased media thickness (gastrocnemius muscle) or reduced vessel diameter (soleus muscle). ACh-induced dilation was diminished by 2 wk of hindlimb unloading in soleus 1A arterioles, but not in gastrocnemius 1A arterioles. These results indicate that structural remodeling and functional adaptations of the arterial microvasculature occur in skeletal muscles of the HU rat; the data suggest that these alterations may be induced by reductions in transmural pressure (gastrocnemius muscle) and wall shear stress (soleus muscle).

  3. Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model

    PubMed Central

    Wang, Jessica Jen-Chu; Rau, Christoph; Avetisyan, Rozeta; Ren, Shuxun; Romay, Milagros C.; Gong, Ke Wei; Wang, Yibin; Lusis, Aldons J.

    2016-01-01

    We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced heart failure model in mice, which allowed control of confounding factors in an experimental setting. We characterized the changes in cardiac structure and function in response to chronic isoproterenol infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac structure and function, whether under normal or stress conditions, has a strong genetic component, with heritability estimates of left ventricular mass between 61% and 81%. Association analyses of cardiac remodeling traits, corrected for population structure, body size and heart rate, revealed 17 genome-wide significant loci, including several loci containing previously implicated genes. Cardiac tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation, and coding sequence variation analyses were performed to prioritize candidate genes and to generate hypotheses for downstream mechanistic studies. Using this approach, we have validated a novel gene, Myh14, as a negative regulator of ISO-induced left ventricular mass hypertrophy in an in vivo mouse model and demonstrated the up-regulation of immediate early gene Myc, fetal gene Nppb, and fibrosis gene Lgals3 in ISO-treated Myh14 deficient hearts compared to controls. PMID:27385019

  4. Laser-induced collagen remodeling and deposition within the basilar membrane of the mouse cochlea

    PubMed Central

    Wenzel, Gentiana I.; Anvari, Bahman; Mazhar, Amaan; Pikkula, Brian; Oghalai, John S.

    2013-01-01

    The cochlea is the mammalian organ of hearing. Its predominant vibratory element, the basilar membrane, is tonotopically tuned, based on the spatial variation of its mass and stiffness. The constituent collagen fibers of the basilar membrane affect its stiffness. Laser irradiation can induce collagen remodeling and deposition in various tissues. We tested whether similar effects could be induced within the basilar membrane. Trypan blue was perfused into the scala tympani of anesthetized mice to stain the basilar membrane. We then irradiated the cochleas with a 694-nm pulsed ruby laser at 15 or 180 J /cm2. The mice were sacrificed 14 to 16 days later and collagen organization was studied. Polarization microscopy revealed that laser irradiation increased the birefringence within the basilar membrane in a dose-dependent manner. Electron microscopy demonstrated an increase in the density of collagen fibers and the deposition of new fibrils between collagen fibers after laser irradiation. As an assessment of hearing, auditory brainstem response (ABR) thresholds were found to increase moderately after 15 J/cm2 and substantially after 180 J /cm2. Our results demonstrate that collagen remodeling and new collagen deposition occurs within the basilar membrane after laser irradiation in a similar fashion to that found in other tissues. PMID:17477714

  5. Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model.

    PubMed

    Wang, Jessica Jen-Chu; Rau, Christoph; Avetisyan, Rozeta; Ren, Shuxun; Romay, Milagros C; Stolin, Gabriel; Gong, Ke Wei; Wang, Yibin; Lusis, Aldons J

    2016-07-01

    We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced heart failure model in mice, which allowed control of confounding factors in an experimental setting. We characterized the changes in cardiac structure and function in response to chronic isoproterenol infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac structure and function, whether under normal or stress conditions, has a strong genetic component, with heritability estimates of left ventricular mass between 61% and 81%. Association analyses of cardiac remodeling traits, corrected for population structure, body size and heart rate, revealed 17 genome-wide significant loci, including several loci containing previously implicated genes. Cardiac tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation, and coding sequence variation analyses were performed to prioritize candidate genes and to generate hypotheses for downstream mechanistic studies. Using this approach, we have validated a novel gene, Myh14, as a negative regulator of ISO-induced left ventricular mass hypertrophy in an in vivo mouse model and demonstrated the up-regulation of immediate early gene Myc, fetal gene Nppb, and fibrosis gene Lgals3 in ISO-treated Myh14 deficient hearts compared to controls. PMID:27385019

  6. Impaired Glutathione Redox System Paradoxically Suppresses Angiotensin II-Induced Vascular Remodeling

    PubMed Central

    Izawa, Kazuma; Okada, Motoi; Sumitomo, Kazuhiro; Nakagawa, Naoki; Aizawa, Yoshiaki; Kawabe, Junichi; Kikuchi, Kenjiro; Hasebe, Naoyuki

    2014-01-01

    Background Angiotensin II (AII) plays a central role in vascular remodeling via oxidative stress. However, the interaction between AII and reduced glutathione (GSH) redox status in cardiovascular remodeling remains unknown. Methods In vivo: The cuff-induced vascular injury model was applied to Sprague Dawley rats. Then we administered saline or a GSH inhibitor, buthionine sulfoximine (BSO, 30 mmol/L in drinking water) for a week, subsequently administered 4 more weeks by osmotic pump with saline or AII (200 ng/kg/minute) to the rats. In vitro: Incorporation of bromodeoxyuridine (BrdU) was measured to determine DNA synthesis in cultured rat vascular smooth muscle cells (VSMCs). Results BSO reduced whole blood GSH levels. Systolic blood pressure was increased up to 215±4 mmHg by AII at 4 weeks (p<0.01), which was not affected by BSO. Superoxide production in vascular wall was increased by AII and BSO alone, and was markedly enhanced by AII+BSO. The left ventricular weight to body weight ratio was significantly increased in AII and AII+BSO as compared to controls (2.52±0.08, 2.50±0.09 and 2.10±0.07 mg/g respectively, p<0.05). Surprisingly, the co-treatment of BSO totally abolished these morphological changes. Although the vascular circumferential wall stress was well compensated in AII, significantly increased in AII+BSO. The anti-single-stranded DNA staining revealed increasing apoptotic cells in the neointima of injured arteries in BSO groups. BrdU incorporation in cultured VSMCs with AII was increased dose-dependently. Furthermore it was totally abolished by BSO and was reversed by GSH monoethyl ester. Conclusions We demonstrated that a vast oxidative stress in impaired GSH redox system totally abolished AII-induced vascular, not cardiac remodeling via enhancement of apoptosis in the neointima and suppression of cell growth in the media. The drastic suppression of remodeling may result in fragile vasculature intolerable to mechanical stress by AII. PMID

  7. Diet-induced obesity promotes altered remodeling and exacerbated cardiac hypertrophy following pressure overload

    PubMed Central

    Holzem, Katherine M; Marmerstein, Joseph T; Madden, Eli J; Efimov, Igor R

    2015-01-01

    Heart failure (HF) is the end stage of cardiovascular disease, in which hypertrophic remodeling no longer meets cardiac output demand. Established animal models of HF have provided insights into disease pathogenesis. However, these models are developed on dissimilar metabolic backgrounds from humans – patients with HF are frequently overweight or obese, whereas animal models of HF are typically lean. Thus, we aimed to develop and investigate model for cardiac hypertrophy and failure that also recapitulates the cardiometabolic state of HF in humans. We subjected mice with established diet-induced obesity (DIO) to cardiac pressure overload provoked by transverse aortic constriction (TAC). Briefly, we fed WT male mice a normal chow or high-fat diet for 10 weeks prior to sham/TAC procedures and until surgical follow-up. We then analyzed cardiac hypertrophy, mechanical function, and electrophysiology at 5–6 weeks after surgery. In DIO mice with TAC, hypertrophy and systolic dysfunction were exacerbated relative to chow TAC animals, which showed minimal remodeling with our moderate constriction intensity. Normalized heart weight was 55.8% greater and fractional shortening was 30.9% less in DIO TAC compared with chow TAC hearts. However, electrophysiologic properties were surprisingly similar between DIO sham and TAC animals. To examine molecular pathways activated by DIO and TAC, we screened prohypertrophic signaling cascades, and the exacerbated remodeling was associated with early activation of the c-Jun-N-terminal kinase (JNK1/2) signaling pathway. Thus, DIO aggravates the progression of hypertrophy and HF caused by pressure overload, which is associated with JNK1/2 signaling, and cardiometabolic state can significantly modify HF pathogenesis. PMID:26290533

  8. Adolescent nicotine-induced dendrite remodeling in the nucleus accumbens is rapid, persistent, and D1-dopamine receptor dependent.

    PubMed

    Ehlinger, D G; Bergstrom, H C; Burke, J C; Fernandez, G M; McDonald, C G; Smith, R F

    2016-01-01

    Chronic nicotine exposure during adolescence induces dendritic remodeling of medium spiny neurons (MSNs) in the nucleus accumbens (NAcc) shell. While nicotine-induced dendritic remodeling has frequently been described as persistent, the trajectory of dendrite remodeling is unknown. Specifically, no study to date has characterized the structural plasticity of dendrites in the NAcc immediately following chronic nicotine, leaving open the possibility that dendrite remodeling emerges gradually over time. Further, the neuropharmacological mechanisms through which nicotine induces dendrite remodeling are not well understood. To address these questions, rats were co-administered chronic nicotine (0.5 mg/kg) and the D1-dopamine receptor (D1DR) antagonist SCH-23390 (0.05 mg/kg) subcutaneously every other day during adolescence. Brains were then processed for Golgi-Cox staining either 1 day or 21 days following drug exposure and dendrites from MSNs in the NAcc shell digitally reconstructed in 3D. Spine density was also measured at both time points. Our morphometric results show (1) the formation of new dendritic branches and spines 1 day following nicotine exposure, (2) new dendritic branches, but not spine density, remains relatively stable for at least 21 days, (3) the co-administration of SCH-23390 completely blocked nicotine-induced dendritic remodeling of MSNs at both early and late time points, suggesting the formation of new dendritic branches in response to nicotine is D1DR-dependent, and (4) SCH-23390 failed to block nicotine-induced increases in spine density. Overall this study provides new insight into how nicotine influences the normal trajectory of adolescent brain development and demonstrates a persistent form of nicotine-induced neuroplasticity in the NAcc shell that develops rapidly and is D1DR dependent. PMID:25257604

  9. Social stress in mice induces voiding dysfunction and bladder wall remodeling

    PubMed Central

    Chang, Andy; Butler, Stephan; Sliwoski, Joanna; Valentino, Rita; Canning, Douglas

    2009-01-01

    Several studies have anecdotally reported the occurrence of altered urinary voiding patterns in rodents exposed to social stress. A recent study characterized the urodynamic and central changes in a rat model of social defeat. Here, we describe a similar voiding phenotype induced in mice by social stress and in addition we describe potential molecular mechanisms underlying the resulting bladder wall remodeling. The mechanism leading to the altered voiding habits and underlying bladder phenotype may be relevant to the human syndrome of dysfunctional voiding which is thought to have a psychological component. To better characterize and investigate social stress-induced bladder wall hypertrophy, FVB mice (6 wk old) were randomized to either social stress or control manipulation. The stress involved repeated cycles of a 1-h direct exposure to a larger aggressive C57Bl6 breeder mouse followed by a 23-h period of barrier separation over 4 wk. Social stress resulted in altered urinary voiding patterns suggestive of urinary retention and increased bladder mass. In vivo cystometry revealed an increased volume at micturition with no change in the voiding pressure. Examination of these bladders revealed increased nuclear expression of the transcription factors MEF-2 and NFAT, as well as increased expression of the myosin heavy chain B isoform mRNA. BrdU uptake was increased within the urothelium and lamina propria layers in the social stress group. We conclude that social stress induces urinary retention that ultimately leads to shifts in transcription factors, alterations in myosin heavy chain isoform expression, and increases in DNA synthesis that mediate bladder wall remodeling. Social stress-induced bladder dysfunction in rodents may provide insight into the underlying mechanisms and potential treatment of dysfunctional voiding in humans. PMID:19587139

  10. GPER activation ameliorates aortic remodeling induced by salt-sensitive hypertension.

    PubMed

    Liu, Liu; Kashyap, Shreya; Murphy, Brennah; Hutson, Dillion D; Budish, Rebecca A; Trimmer, Emma H; Zimmerman, Margaret A; Trask, Aaron J; Miller, Kristin S; Chappell, Mark C; Lindsey, Sarah H

    2016-04-15

    The mRen2 female rat is an estrogen- and salt-sensitive model of hypertension that reflects the higher pressure and salt sensitivity associated with menopause. We previously showed that the G protein-coupled estrogen receptor (GPER) mediates estrogenic effects in this model. The current study hypothesized that GPER protects against vascular injury during salt loading. Intact mRen2 female rats were fed a normal (NS; 0.5% Na(+)) or high-salt diet (HS; 4% Na(+)) for 10 wk, which significantly increased systolic blood pressure (149 ± 5 vs. 224 ± 8 mmHg;P< 0.001). Treatment with the selective GPER agonist G-1 for 2 wk did not alter salt-sensitive hypertension (216 ± 4 mmHg;P> 0.05) or ex vivo vascular responses to angiotensin II or phenylephrine (P> 0.05). However, G-1 significantly attenuated salt-induced aortic remodeling assessed by media-to-lumen ratio (NS: 0.43; HS+veh: 0.89; HS+G-1: 0.61;P< 0.05). Aortic thickening was not accompanied by changes in collagen, elastin, or medial proliferation. However, HS induced increases in medial layer glycosaminoglycans (0.07 vs. 0.42 mm(2);P< 0.001) and lipid peroxidation (0.11 vs. 0.51 mm(2);P< 0.01), both of which were reduced by G-1 (0.20 mm(2)and 0.23 mm(2); both P< 0.05). We conclude that GPER's beneficial actions in the aorta of salt-loaded mRen2 females occur independently of changes in blood pressure and vasoreactivity. GPER-induced attenuation of aortic remodeling was associated with a reduction in oxidative stress and decreased accumulation of glycosaminoglycans. Endogenous activation of GPER may protect females from salt- and pressure-induced vascular damage. PMID:26873963

  11. Mechanism Investigation of the Improvement of Chang Run Tong on the Colonic Remodeling in Streptozotocin-Induced Diabetic Rats

    PubMed Central

    Sha, Hong; Zhao, Dong; Tong, Xiaolin; Zhao, Jingbo

    2016-01-01

    Previous study demonstrated that Chang Run Tong (CRT) could partly restore the colon remodeling in streptozotocin- (STZ-) induced diabetic rats. Here we investigated the mechanisms of such effects of CRT. Diabetes was induced by a single injection of 40 mg/kg of STZ. CRT was poured into the stomach by gastric lavage once daily for 60 days. The remodeling parameters were obtained from diabetic (DM), CRT treated diabetic (T1, 50 g/kg; T2, 25 g/kg), and normal (Con) rats. Expressions of advanced glycation end product (AGE), AGE receptor, transforming growth factor-β1 (TGF-β1), and TGF-β1 receptor in the colon wall were immunochemically detected and quantitatively analyzed. The association between the expressions of those proteins and the remodeling parameters was analyzed. The expressions of those proteins were significantly higher in different colon layers in the DM group (P < 0.05, P < 0.01) and highly correlated to the remodeling parameters. Furthermore, the expressions of those proteins were significantly decreased in the T1 group (P < 0.05, P < 0.01) but not in the T2 group (P > 0.05). The corrective effect on the expressions of those proteins is likely to be one molecular pathway for the improvement of CRT on the diabetes-induced colon remodeling. PMID:26839890

  12. BREAST CANCER-INDUCED BONE REMODELING, SKELETAL PAIN AND SPROUTING OF SENSORY NERVE FIBERS

    PubMed Central

    Bloom, Aaron P.; Jimenez-Andrade, Juan M.; Taylor, Reid N.; Castañeda-Corral, Gabriela; Kaczmarska, Magdalena J.; Freeman, Katie T.; Coughlin, Kathleen A.; Ghilardi, Joseph R.; Kuskowski, Michael A.; Mantyh, Patrick W.

    2011-01-01

    Breast cancer metastasis to bone is frequently accompanied by pain. What remains unclear is why this pain tends to become more severe and difficult to control with disease progression. Here we test the hypothesis that with disease progression sensory nerve fibers that innervate the breast cancer bearing bone undergo a pathological sprouting and reorganization, which in other non-malignant pathologies has been shown to generate and maintain chronic pain. Injection of human breast cancer cells (MDA-MB-231-BO) into the femoral intramedullary space of female athymic nude mice induces sprouting of calcitonin gene-related peptide (CGRP+) sensory nerve fibers. Nearly all CGRP+ nerve fibers that undergo sprouting also co-express tropomyosin receptor kinase A (TrkA+) and growth associated protein-43 (GAP43+). This ectopic sprouting occurs in periosteal sensory nerve fibers that are in close proximity to breast cancer cells, tumor-associated stromal cells and remodeled cortical bone. Therapeutic treatment with an antibody that sequesters nerve growth factor (NGF), administered when the pain and bone remodeling were first observed, blocks this ectopic sprouting and attenuates cancer pain. The present data suggest that the breast cancer cells and tumor-associated stromal cells express and release NGF, which drives bone pain and the pathological reorganization of nearby CGRP+ / TrkA+ / GAP43+ sensory nerve fibers. PMID:21497141

  13. Diabetes induces stromal remodelling and increase in chondroitin sulphate proteoglycans of the rat ventral prostate

    PubMed Central

    Ribeiro, Daniele Lisboa; Taboga, Sebastião Roberto; Góes, Rejane Maira

    2009-01-01

    Extracellular matrix (ECM) remodelling is an important process involved in prostate cancer progression. Alterations in ECM caused by diabetes in different tissues such as kidney is well described; however, it is poorly investigated in prostate. The aim of this study was to evaluate changes in ECM of rat prostate showing gland atrophy caused by diabetes and their implications in development of malignant lesions. Diabetes was induced in Wistar rats using alloxan (45 mg/kg bw). After 90 days of diabetes onset, animals were killed and ventral prostate was removed and prepared for light microscopy following immunoreaction for fibronectin, chondroitin sulphate and Picrossirius staining for collagen fibres. Proteoglycans (PG) were identified at transmission electron microscopy after fixation with Cuprolinic Blue. Diabetes led to a thickening of 25% in the acinar basement membrane accompanied by increase and disorganization of its proteoglycans (P1). Three additional populations of prostatic stromal PGs were identified: collagen fibril linked (P2) and interstitial (P3) and (P4) PGs. Diabetes increased P3 and mainly P4 which had higher dimension and accumulated around the smooth muscle cells. In addition, an increase in chondrotin sulphate (33%, mainly in sites where P4 were noted) and collagen (44%) was noted in diabetic rats, whereas fibronectin did not change. Atrophic changes observed in rat ventral prostate after diabetes are accompanied by stromal remodelation related to increase in collagen and chondroitin sulphate proteoglycans. Thus, diabetes can promote a stromal microenvironment rich in elements that could favour cell migration, proliferation and pathological process. PMID:19659898

  14. Inhalation exposure to ethylene induces eosinophilic rhinitis and nasal epithelial remodeling in Fischer 344 rats.

    PubMed

    Brandenberger, Christina; Hotchkiss, Jon A; Krieger, Shannon M; Pottenger, Lynn H; Harkema, Jack R

    2015-11-01

    This study investigated the time- and concentration-dependent effects of inhaled ethylene on eosinophilic rhinitis and nasal epithelial remodeling in Fisher 344 rats exposed to 0, 10, 50, 300, or 10,000 ppm ethylene, 6 h/day, 5 days/week for up to 4 weeks. Morphometric quantitation of eosinophilic inflammation and mucous cell metaplasia/hyperplasia (MCM) and nasal mucosal gene expression were evaluated at anatomic sites previously shown to undergo ethylene-induced epithelial remodeling. Serum levels of total IgE, IgG1 and IgG2a were measured to determine if ethylene exposure increased the expression of Th2-associated (IgE and IgG1) relative to Th1-associated (IgG2a) antibody isotypes. Rats exposed to 0 or 10,000 ppm for 1, 3, 5, 10, or 20 days were analyzed to assess the temporal pattern of ethylene-induced alterations in nasal epithelial cell proliferation, morphology and gene expression. Rats exposed to 0, 10, 50, 300, and 10,000 ppm ethylene for 20 days were analyzed to assess concentration-dependent effects on lesion development. Additional rats exposed 4 weeks to 0, 300, or 10,000 ppm ethylene were held for 13 weeks post-exposure to examine the persistence of ethylene-induced mucosal alterations. The data indicate that cell death and reparative cell proliferation were not a part of the pathogenesis of ethylene-induced nasal lesions. Enhanced gene expression of Th2 cytokines (e.g., IL-5, IL-13) and chitinase (YM1/2) in the nasal mucosa was much greater than that of Th1 cytokines (e.g., IFNγ) after ethylene exposure. A significant increase in MCM was measured after 5 days of exposure to 10,000 ppm ethylene and after 20 days of exposure 10 ppm ethylene. Ethylene-induced MCM was reversible after cessation of exposure. No increase in total serum IgE, IgG1 or IgG2a was measured in any ethylene-exposed group. These data do not support involvement of an immune-mediated allergic mechanism in the pathogenesis of ethylene-induced nasal lesions in rats. Repeated

  15. MicroRNA Expression Signature Is Altered in the Cardiac Remodeling Induced by High Fat Diets.

    PubMed

    Guedes, Elaine Castilho; França, Gustavo Starvaggi; Lino, Caroline Antunes; Koyama, Fernanda Christtanini; Moreira, Luana do Nascimento; Alexandre, Juliana Gomes; Barreto-Chaves, Maria Luiza M; Galante, Pedro Alexandre Favoretto; Diniz, Gabriela Placoná

    2016-08-01

    Recent studies have revealed the involvement of microRNAs (miRNAs) in the control of cardiac hypertrophy and myocardial function. In addition, several reports have demonstrated that high fat (HF) diet induces cardiac hypertrophy and remodeling. In the current study, we investigated the effect of diets containing different percentages of fat on the cardiac miRNA expression signature. To address this question, male C57Bl/6 mice were fed with a low fat (LF) diet or two HF diets, containing 45 kcal% fat (HF45%) and 60 kcal% fat (HF60%) for 10 and 20 weeks. HF60% diet promoted an increase on body weight, fasting glycemia, insulin, leptin, total cholesterol, triglycerides, and induced glucose intolerance. HF feeding promoted cardiac remodeling, as evidenced by increased cardiomyocyte transverse diameter and interstitial fibrosis. RNA sequencing analysis demonstrated that HF feeding induced distinct miRNA expression patterns in the heart. HF45% diet for 10 and 20 weeks changed the abundance of 64 and 26 miRNAs in the heart, respectively. On the other hand, HF60% diet for 10 and 20 weeks altered the abundance of 27 and 88 miRNAs in the heart, respectively. Bioinformatics analysis indicated that insulin signaling pathway was overrepresented in response to HF diet. An inverse correlation was observed between cardiac levels of GLUT4 and miRNA-29c. Similarly, we found an inverse correlation between expression of GSK3β and the expression of miRNA-21a-3p, miRNA-29c-3p, miRNA-144-3p, and miRNA-195a-3p. In addition, miRNA-1 overexpression prevented cardiomyocyte hypertrophy. Taken together, our results revealed differentially expressed miRNA signatures in the heart in response to different HF diets. J. Cell. Physiol. 231: 1771-1783, 2016. © 2015 Wiley Periodicals, Inc. PMID:26638879

  16. Effect of Lysyl Oxidase Inhibition on Angiotensin II-Induced Arterial Hypertension, Remodeling, and Stiffness

    PubMed Central

    Eberson, Lance S.; Sanchez, Pablo A.; Majeed, Beenish A.; Tawinwung, Supannikar; Secomb, Timothy W.; Larson, Douglas F.

    2015-01-01

    It is well accepted that angiotensin II (Ang II) induces altered vascular stiffness through responses including both structural and material remodeling. Concurrent with remodeling is the induction of the enzyme lysyl oxidase (LOX) through which ECM proteins are cross-linked. The study objective was to determine the effect of LOX mediated cross-linking on vascular mechanical properties. Three-month old mice were chronically treated with Ang II with or without the LOX blocker, β -aminopropionitrile (BAPN), for 14 days. Pulse wave velocity (PWV) from Doppler measurements of the aortic flow wave was used to quantify in vivo vascular stiffness in terms of an effective Young’s modulus. The increase in effective Young’s modulus with Ang II administration was abolished with the addition of BAPN, suggesting that the material properties are a major controlling element in vascular stiffness. BAPN inhibited the Ang II induced collagen cross-link formation by 2-fold and PWV by 44% (P<0.05). Consistent with this observation, morphometric analysis showed that BAPN did not affect the Ang II mediated increase in medial thickness but significantly reduced the adventitial thickness. Since the hypertensive state contributes to the measured in vivo PWV stiffness, we removed the Ang II infusion pumps on Day 14 and achieved normal arterial blood pressures. With pump removal we observed a decrease of the PWV in the Ang II group to 25% above that of the control values (P=0.002), with a complete return to control values in the Ang II plus BAPN group. In conclusion, we have shown that the increase in vascular stiffness with 14 day Ang II administration results from a combination of hypertension-induced wall strain, adventitial wall thickening and Ang II mediated LOX ECM cross-linking, which is a major material source of vascular stiffening, and that the increased PWV was significantly inhibited with co-administration of BAPN. PMID:25875748

  17. PPAR-pan activation induces hepatic oxidative stress and lipidomic remodelling.

    PubMed

    Ament, Zsuzsanna; West, James A; Stanley, Elizabeth; Ashmore, Tom; Roberts, Lee D; Wright, Jayne; Nicholls, Andrew W; Griffin, Julian L

    2016-06-01

    The peroxisome proliferator-activated receptors (PPARs) are ligand activated nuclear receptors that regulate cellular homoeostasis and metabolism. PPARs control the expression of genes involved in fatty-acid and lipid metabolism. Despite evidence showing beneficial effects of their activation in the treatment of metabolic diseases, particularly dyslipidaemias and type 2 diabetes, PPAR agonists have also been associated with a variety of side effects and adverse pathological changes. Agonists have been developed that simultaneously activate the three PPAR receptors (PPARα, γ and δ) in the hope that the beneficial effects can be harnessed while avoiding some of the negative side effects. In this study, the hepatic effects of a discontinued PPAR-pan agonist (a triple agonist of PPAR-α, -γ, and -δ), was investigated after dietary treatment of male Sprague-Dawley (SD) rats. The agonist induced liver enlargement in conjunction with metabolomic and lipidomic remodelling. Increased concentrations of several metabolites related to processes of oxidation, such as oxo-methionine, methyl-cytosine and adenosyl-methionine indicated increased stress and immune status. These changes are reflected in lipidomic changes, and increased energy demands as determined by free fatty acid (decreased 18:3 n-3, 20:5 n-3 and increased ratios of n-6/n-3 fatty acids) triacylglycerol, phospholipid (decreased and increased bulk changes respectively) and eicosanoid content (increases in PGB2 and 15-deoxy PGJ2). We conclude that the investigated PPAR agonist, GW625019, induces liver enlargement, accompanied by lipidomic remodelling, oxidative stress and increases in several pro-inflammatory eicosanoids. This suggests that such pathways should be monitored in the drug development process and also outline how PPAR agonists induce liver proliferation. PMID:26654758

  18. Tie1 is required for lymphatic valve and collecting vessel development

    PubMed Central

    Qu, Xianghu; Zhou, Bin; Baldwin, H. Scott

    2015-01-01

    Tie1 is a receptor tyrosine kinase with broad expression in embryonic endothelium. Reduction of Tie1 levels in mouse embryos with a hypomorphic Tie1 allele resulted in abnormal lymphatic patterning and architecture, decreased lymphatic draining efficiency, and ultimately, embryonic demise. Here we report that Tie1 is present uniformly throughout the lymphatics and from late embryonic/early postnatal stages, becomes more restricted to lymphatic valve regions. To investigate later events of lymphatic development, we employed Cre-loxP recombination utilizing a floxed Tie1 allele and an Nfatc1Cre line, to provide loxP excision predominantly in lymphatic endothelium and developing valves. Interestingly, unlike the early prenatal defects previously described by ubiquitous endothelial deletion, excision of Tie1 with Nfatc1Cre resulted in abnormal lymphatic defects in postnatal mice and was characterized by agenesis of lymphatic valves and a deficiency of collecting lymphatic vessels. Attenuation of Tie1 signaling in lymphatic endothelium prevented initiation of lymphatic valve specification by Prox1 high expression lymphatic endothelial cells that is associated with the onset of turbulent flow in the lymphatic circulation. Our findings reveal a fundamental role for Tie signaling during lymphatic vessel remodeling and valve morphogenesis and implicate it as a candidate gene involved in primary lymphedema. PMID:25576926

  19. Lymphatic endothelial lineage assemblage during corneal lymphangiogenesis.

    PubMed

    Connor, Alicia L; Kelley, Philip M; Tempero, Richard M

    2016-03-01

    Postnatal inflammatory lymphangiogenesis presumably requires precise regulatory processes to properly assemble proliferating lymphatic endothelial cells (LECs). The specific mechanisms that regulate the assembly of LECs during new lymphatic vessel synthesis are unclear. Dynamic endothelial shuffling and rearrangement has been proposed as a mechanism of blood vessel growth. We developed genetic lineage-tracing strategies using an inductive transgenic technology to track the fate of entire tandem dimer tomato-positive (tdT) lymphatic vessels or small, in some cases clonal, populations of LECs. We coupled this platform with a suture-induced mouse model of corneal lymphangiogenesis and used different analytic microscopy techniques including serial live imaging to study the spatial properties of proliferating tdT(+) LEC progenies. LEC precursors and their progeny expanded from the corneal limbal lymphatic vessel and were assembled contiguously to comprise a subunit within a new lymphatic vessel. VE-cadherin blockade induced morphologic abnormalities in newly synthesized lymphatic vessels, but did not disrupt the tdT(+) lymphatic endothelial lineage assembly. Analysis of this static and dynamic data based largely on direct in vivo observations supports a model of lymphatic endothelial lineage assemblage during corneal inflammatory lymphangiogenesis. PMID:26658452

  20. Lymphatic endothelial lineage assemblage during corneal lymphangiogenesis

    PubMed Central

    Connor, Alicia L.; Kelley, Philip M.; Tempero, Richard M.

    2015-01-01

    Post natal inflammatory lymphangiogenesis presumably requires precise regulatory processes to properly assemble proliferating lymphatic endothelial cells (LECs). The specific mechanisms that regulate the assembly of LECs during new lymphatic vessel synthesis are unclear. Dynamic endothelial shuffling and rearrangement has been proposed as a mechanism of blood vessel growth. We developed genetic lineage tracing strategies using an inductive transgenic technology to track the fate of entire tandem dimer tomato positive (tdT) lymphatic vessels or small, in some cases clonal, populations of LECs. We coupled this platform with a suture induced mouse model of corneal lymphangiogenesis and used different analytic microscopy techniques including serial live imaging to study the spatial properties of proliferating tdT+ LEC progenies. LEC precursors and their progeny expanded from the corneal limbal lymphatic vessel and were assembled contiguously to comprise a subunit within a new lymphatic vessel. VE-cadherin blockade induced morphologic abnormalities in newly synthesized lymphatic vessels, but did not disrupt the tdT+ lymphatic endothelial lineage assembly. Analysis of this static and dynamic data based largely on direct in vivo observations supports a model of lymphatic endothelial lineage assemblage during corneal inflammatory lymphangiogenesis. PMID:26658452

  1. MiR-155 Knockout in Fibroblasts Improves Cardiac Remodeling by Targeting Tumor Protein p53-Inducible Nuclear Protein 1.

    PubMed

    He, Wangwei; Huang, He; Xie, Qiang; Wang, Zhiqiang; Fan, Yang; Kong, Bin; Huang, Dan; Xiao, Yali

    2016-07-01

    Cardiac remodeling caused by acute myocardial infarction (AMI) represents a major challenge for heart failure research. MiR-155 has been identified as a key mediator of cardiac inflammation and hypertrophy. In this study, we investigate the role of miR-155 in cardiac remodeling induced by AMI. We demonstrate that miR-155 expressed in cardiac fibroblasts is a potent contributor to cardiac remodeling. We reveal that in vivo, miR-155 knockout improves left ventricular function, reduces infarct size, and attenuates collagen deposition, whereas overexpression of miR-155 produces the opposite effects. MiR-155 knockout also inhibits cardiac fibroblast proliferation and differentiation into myofibroblasts. In addition, downregulation of tumor protein p53-inducible nuclear protein 1 (TP53INP1) by small interfering RNA reverses the effects of miR-155 knockout on cardiac fibroblasts. Our data reveal that knockout of miR-155 in cardiac fibroblasts improves cardiac remodeling by targeting TP53INP1, which may be a novel treatment strategy for cardiac remodeling. PMID:26589288

  2. Rapid Lymphatic Dissemination of Encapsulated Group A Streptococci via Lymphatic Vessel Endothelial Receptor-1 Interaction

    PubMed Central

    Johnson, Louise A.; Holder, Kayla A.; Reglinski, Mark; Wing, Peter A. C.; Rigby, David; Jackson, David G.; Sriskandan, Shiranee

    2015-01-01

    The host lymphatic network represents an important conduit for pathogen dissemination. Indeed, the lethal human pathogen group A streptococcus has a predilection to induce pathology in the lymphatic system and draining lymph nodes, however the underlying basis and subsequent consequences for disease outcome are currently unknown. Here we report that the hyaluronan capsule of group A streptococci is a crucial virulence determinant for lymphatic tropism in vivo, and further, we identify the lymphatic vessel endothelial receptor-1 as the critical host receptor for capsular hyaluronan in the lymphatic system. Interference with this interaction in vivo impeded bacterial dissemination to local draining lymph nodes and, in the case of a hyper-encapsulated M18 strain, redirected streptococcal entry into the blood circulation, suggesting a pivotal role in the manifestation of streptococcal infections. Our results reveal a novel function for bacterial capsular polysaccharide in directing lymphatic tropism, with potential implications for disease pathology. PMID:26352587

  3. Lymphatics and the breast

    MedlinePlus Videos and Cool Tools

    ... a very worrisome role in the spread of breast cancer. Components of the lymphatic system called lymph ... extensive network of lymphatic vessels in every woman’s breast tissue, which is important in regulating the local ...

  4. AID-induced remodeling of immunoglobulin genes and B cell fate

    PubMed Central

    Laffleur, Brice; Denis-Lagache, Nicolas; Péron, Sophie; Sirac, Christophe; Moreau, Jeanne; Cogné, Michel

    2014-01-01

    Survival and phenotype of normal and malignant B lymphocytes are critically dependent on constitutive signals by the B cell receptor (BCR) for antigen. In addition, either antigen ligation of the BCR or various mitogenic stimuli result in B cell activation and induction of activation-induced deaminase (AID). AID activity can in turn mediate somatic hypermutation (SHM) of immunoglobulin (Ig) V regions and also deeply remodel the Ig heavy chain locus through class switch recombination (CSR) or locus suicide recombination (LSR). In addition to changes linked to affinity for antigen, modifying the class/isotype (i.e. the structure and function) of the BCR or suddenly deleting BCR expression also modulates the fate of antigen-experienced B cells. PMID:24851241

  5. Back to the future: transgenerational transmission of xenobiotic-induced epigenetic remodeling

    PubMed Central

    Jiménez-Chillarón, Josep C; Nijland, Mark J; Ascensão, António A; Sardão, Vilma A; Magalhães, José; Hitchler, Michael J; Domann, Frederick E; Oliveira, Paulo J

    2015-01-01

    Epigenetics, or regulation of gene expression independent of DNA sequence, is the missing link between genotype and phenotype. Epigenetic memory, mediated by histone and DNA modifications, is controlled by a set of specialized enzymes, metabolite availability, and signaling pathways. A mostly unstudied subject is how sub-toxic exposure to several xenobiotics during specific developmental stages can alter the epigenome and contribute to the development of disease phenotypes later in life. Furthermore, it has been shown that exposure to low-dose xenobiotics can also result in further epigenetic remodeling in the germ line and contribute to increase disease risk in the next generation (multigenerational and transgenerational effects). We here offer a perspective on current but still incomplete knowledge of xenobiotic-induced epigenetic alterations, and their possible transgenerational transmission. We also propose several molecular mechanisms by which the epigenetic landscape may be altered by environmental xenobiotics and hypothesize how diet and physical activity may counteract epigenetic alterations. PMID:25774863

  6. Titin, a Central Mediator for Hypertrophic Signaling, Exercise-Induced Mechanosignaling and Skeletal Muscle Remodeling

    PubMed Central

    Krüger, Martina; Kötter, Sebastian

    2016-01-01

    Titin is a giant scaffold protein with multiple functions in striated muscle physiology. Due to the elastic I-band domains and the filament-like integration in the half-sarcomere titin is an important factor for sarcomere assembly and serves as an adaptable molecular spring that determines myofilament distensibility. Protein-interactions e.g., with muscle ankyrin repeat proteins or muscle LIM-protein link titin to hypertrophic signaling and via p62 and Muscle Ring Finger proteins to mechanisms that control protein quality control. This review summarizes our current knowledge on titin as a central node for exercise-induced mechanosignaling and remodeling and further highlights the pathophysiological implications. PMID:26973541

  7. Titin, a Central Mediator for Hypertrophic Signaling, Exercise-Induced Mechanosignaling and Skeletal Muscle Remodeling.

    PubMed

    Krüger, Martina; Kötter, Sebastian

    2016-01-01

    Titin is a giant scaffold protein with multiple functions in striated muscle physiology. Due to the elastic I-band domains and the filament-like integration in the half-sarcomere titin is an important factor for sarcomere assembly and serves as an adaptable molecular spring that determines myofilament distensibility. Protein-interactions e.g., with muscle ankyrin repeat proteins or muscle LIM-protein link titin to hypertrophic signaling and via p62 and Muscle Ring Finger proteins to mechanisms that control protein quality control. This review summarizes our current knowledge on titin as a central node for exercise-induced mechanosignaling and remodeling and further highlights the pathophysiological implications. PMID:26973541

  8. The orphan nuclear receptor Nur77 inhibits low shear stress-induced carotid artery remodeling in mice

    PubMed Central

    YU, YING; CAI, ZHAOHUA; CUI, MINGLI; NIE, PENG; SUN, ZHE; SUN, SHIQUN; CHU, SHICHUN; WANG, XIAOLEI; HU, LIUHUA; YI, JING; SHEN, LINGHONG; HE, BEN

    2015-01-01

    Shear stress, particularly low and oscillatory shear stress, plays a critical pathophysiological role in vascular remodeling-related cardiovascular diseases. Growing evidence suggests that the orphan nuclear receptor Nur77 [also known as TR3 or nuclear receptor subfamily 4, group A, member 1 (NR4A1)] is expressed in diseased human vascular tissue and plays an important role in vascular physiology and pathology. In the present study, we used a mouse model of flow-dependent remodeling by partial ligation of the left common carotid artery (LCCA) to define the exact role of Nur77 in vascular remodeling induced by low shear stress. Following vascular remodeling, Nur77 was highly expressed in neointimal vascular smooth muscle cells (VSMCs) in the ligated carotid arteries. The reactive oxygen species (ROS) levels were elevated in the remodeled arteries in vivo and in primary rat VSMCs in vitro following stimulation with platelet-derived growth factor (PDGF). Further in vitro experiments revealed that Nur77 expression was rapidly increased in the VSMCs following stimulation with PDGF and H2O2, whereas treatment with N-acetyl cysteine (NAC, a ROS scavenger) reversed the increase in the protein level of Nur77 induced by H2O2. Moreover, Nur77 overexpression markedly inhibited the proliferation and migration of VSMCs, induced by PDGF. Finally, to determine the in vivo role of Nur77 in low shear stress-induced vascular remodeling, wild-type (WT) and Nur77-deficient mice were subjected to partial ligation of the LCCA. Four weeks following surgery, in the LCCAs of the Nur77-deficient mice, a significant increase in the intima-media area and carotid intima-media thickness was noted, as well as more severe elastin disruption and collagen deposition compared to the WT mice. Immunofluorescence staining revealed an increase in VSMC proliferation [determined by the expression of proliferating cell nuclear antigen (PCNA)] and matrix metalloproteinase 9 (MMP-9) production in the Nur77

  9. Drinking Citrus Fruit Juice Inhibits Vascular Remodeling in Cuff-Induced Vascular Injury Mouse Model

    PubMed Central

    Ohnishi, Arika; Asayama, Rie; Mogi, Masaki; Nakaoka, Hirotomo; Kan-no, Harumi; Tsukuda, Kana; Chisaka, Toshiyuki; Wang, Xiao-Li; Bai, Hui-Yu; Shan, Bao-Shuai; Kukida, Masayoshi; Iwanami, Jun; Horiuchi, Masatsugu

    2015-01-01

    Citrus fruits are thought to have inhibitory effects on oxidative stress, thereby attenuating the onset and progression of cancer and cardiovascular disease; however, there are few reports assessing their effect on vascular remodeling. Here, we investigated the effect of drinking the juice of two different citrus fruits on vascular neointima formation using a cuff-induced vascular injury mouse model. Male C57BL6 mice were divided into five groups as follows: 1) Control (water) (C), 2) 10% Citrus unshiu (CU) juice (CU10), 3) 40% CU juice (CU40), 4) 10% Citrus iyo (CI) juice (CI10), and 5) 40% CI juice (CI40). After drinking them for 2 weeks from 8 weeks of age, cuff injury was induced by polyethylene cuff placement around the femoral artery. Neointima formation was significantly attenuated in CU40, CI10 and CI40 compared with C; however, no remarkable preventive effect was observed in CU10. The increases in levels of various inflammatory markers including cytokines such as monocyte chemotactic protein-1, interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α in response to vascular injury did not differ significantly between C, CU10 and CI10. The increases in cell proliferation and superoxide anion production were markedly attenuated in CI10, but not in CU10 compared with C. The increase in phosphorylated ERK expression was markedly attenuated both in CU10 and CI10 without significant difference between CU10 and CI10. Accumulation of immune cells did not differ between CU10 and CI10. These results indicate that drinking citrus fruit juice attenuates vascular remodeling partly via a reduction of oxidative stress. Interestingly, the preventive efficacy on neointima formation was stronger in CI than in CU at least in part due to more prominent inhibitory effects on oxidative stress by CI. PMID:25692290

  10. Drinking citrus fruit juice inhibits vascular remodeling in cuff-induced vascular injury mouse model.

    PubMed

    Ohnishi, Arika; Asayama, Rie; Mogi, Masaki; Nakaoka, Hirotomo; Kan-No, Harumi; Tsukuda, Kana; Chisaka, Toshiyuki; Wang, Xiao-Li; Bai, Hui-Yu; Shan, Bao-Shuai; Kukida, Masayoshi; Iwanami, Jun; Horiuchi, Masatsugu

    2015-01-01

    Citrus fruits are thought to have inhibitory effects on oxidative stress, thereby attenuating the onset and progression of cancer and cardiovascular disease; however, there are few reports assessing their effect on vascular remodeling. Here, we investigated the effect of drinking the juice of two different citrus fruits on vascular neointima formation using a cuff-induced vascular injury mouse model. Male C57BL6 mice were divided into five groups as follows: 1) Control (water) (C), 2) 10% Citrus unshiu (CU) juice (CU10), 3) 40% CU juice (CU40), 4) 10% Citrus iyo (CI) juice (CI10), and 5) 40% CI juice (CI40). After drinking them for 2 weeks from 8 weeks of age, cuff injury was induced by polyethylene cuff placement around the femoral artery. Neointima formation was significantly attenuated in CU40, CI10 and CI40 compared with C; however, no remarkable preventive effect was observed in CU10. The increases in levels of various inflammatory markers including cytokines such as monocyte chemotactic protein-1, interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α in response to vascular injury did not differ significantly between C, CU10 and CI10. The increases in cell proliferation and superoxide anion production were markedly attenuated in CI10, but not in CU10 compared with C. The increase in phosphorylated ERK expression was markedly attenuated both in CU10 and CI10 without significant difference between CU10 and CI10. Accumulation of immune cells did not differ between CU10 and CI10. These results indicate that drinking citrus fruit juice attenuates vascular remodeling partly via a reduction of oxidative stress. Interestingly, the preventive efficacy on neointima formation was stronger in CI than in CU at least in part due to more prominent inhibitory effects on oxidative stress by CI. PMID:25692290

  11. Immunology of lymphatic filariasis

    PubMed Central

    Babu, Subash; Nutman, Thomas B.

    2013-01-01

    The immune responses to filarial parasites encompass a complex network of innate and adaptive cells whose interaction with the parasite underlies a spectrum of clinical manifestations. The predominant immunological feature of lymphatic filariasis is an antigen - specific Th2 response and an expansion of IL-10 producing CD4+ T cells that is accompanied by a muted Th1 response. This antigen specific T cell hypo-responsiveness appears to be crucial for the maintenance of the sustained, long-standing infection often with high parasite densities. While the correlates of protective immunity to lymphatic filariasis are still incompletely understood, primarily due to the lack of suitable animal models to study susceptibility, it is clear that T cells and to a certain extent B cells are required for protective immunity. Host immune responses, especially CD4+ T cell responses clearly play a role in mediating pathological manifestations of LF, including lymphedema, hydrocele and elephantiasis. The main underlying defect in the development of clinical pathology appears to be a failure to induce T cell hypo-responsiveness in the face of antigenic stimulation. Finally, another intriguing feature of filarial infections is their propensity to induce bystander effects on a variety of immune responses, including responses to vaccinations, allergens and to other infectious agents. The complexity of the immune response to filarial infection therefore provides an important gateway to understanding the regulation of immune responses to chronic infections, in general. PMID:24134686

  12. Hydrogen sulfide mitigates homocysteine mediated pathological remodeling by inducing miR-133a in cardiomyocytes

    PubMed Central

    Kesherwani, Varun; Nandi, Shyam S.; Sharawat, Surender K.; Shahshahan, Hamid R.; Mishra, Paras K.

    2015-01-01

    An elevated level of homocysteine called hyperhomocysteinemia (HHcy) is associated with pathological cardiac remodeling. Hydrogen sulfide (H2S) acts as a cardioprotective gas, however the mechanism by which H2S mitigates homocysteine mediated pathological remodeling in cardiomyocytes is unclear. We hypothesized that H2S ameliorates HHcy mediated hypertrophy by inducing cardioprotective miR-133a in cardiomyocytes. To test the hypothesis, HL1 cardiomyocytes were treated with: 1) plain medium (control, CT), 2) 100μM of homocysteine (Hcy), 3) Hcy with 30μM of H2S (Hcy+H2S), and 4) H2S for 24 hour. The levels of hypertrophy markers: c-fos, atrial natriuretic peptide (ANP), and beta-myosin heavy chain (β-MHC), miR-133a and its transcriptional inducer myosin enhancer factor- 2c (MEF2C) were determined by Western blotting, RT-qPCR, and immunofluorescence. The activity of MEF2C was assessed by co-immunoprecipitation of MEF2C with histone deacetylase -1(HDAC1). Our results show that H2S ameliorates homocysteine mediated up regulation of c-fos, ANP and β-MHC, and down regulation of MEF2C and miR-133a. HHcy induces the binding of MEF2C with HDAC1, whereas H2S releases MEF2C from MEF2C-HDAC1 complex causing activation of MEF2C. These findings elicit that HHcy induces cardiac hypertrophy by promoting MEF2C-HDAC1 complex formation that inactivates MEF2C causing suppression of anti-hypertrophy miR-133a in cardiomyocytes. H2S mitigates hypertrophy by inducing miR-133a through activation of MEF2C in HHcy cardiomyocytes. To our knowledge this is a novel mechanism of H2S mediated activation of MEF2C and induction of miR-133a and inhibition of hypertrophy in HHcy cardiomyocytes. PMID:25763715

  13. Epac1 and Epac2 are differentially involved in inflammatory and remodeling processes induced by cigarette smoke

    PubMed Central

    Oldenburger, Anouk; Timens, Wim; Bos, Sophie; Smit, Marieke; Smrcka, Alan V.; Laurent, Anne-Coline; Cao, Junjun; Hylkema, Machteld; Meurs, Herman; Maarsingh, Harm; Lezoualc'h, Frank; Schmidt, Martina

    2014-01-01

    Cigarette smoke (CS) induces inflammatory responses characterized by increase of immune cells and cytokine release. Remodeling processes, such as mucus hypersecretion and extracellular matrix protein production, are also directly or indirectly induced by CS. Recently, we showed that activation of the exchange protein directly activated by cAMP (Epac) attenuates CS extract-induced interleukin (IL)-8 release from cultured airway smooth muscle cells. Using an acute, short-term model of CS exposure, we now studied the role of Epac1, Epac2, and the Epac effector phospholipase-Cε (PLCε) in airway inflammation and remodeling in vivo. Compared to wild-type mice exposed to CS, the number of total inflammatory cells, macrophages, and neutrophils and total IL-6 release was lower in Epac2−/− mice, which was also the case for neutrophils and IL-6 in PLCε−/− mice. Taken together, Epac2, acting partly via PLCε, but not Epac1, enhances CS-induced airway inflammation in vivo. In total lung homogenates of Epac1−/− mice, MUC5AC and matrix remodeling parameters (transforming growth factor-β1, collagen I, and fibronectin) were increased at baseline. Our findings suggest that Epac1 primarily is capable of inhibiting remodeling processes, whereas Epac2 primarily increases inflammatory processes in vivo.—Oldenburger, A., Timens, W., Bos, S., Smit, M., Smrcka, A. V., Laurent, A.-C., Cao, J., Hylkema, M., Meurs, H., Maarsingh, H., Lezoualc'h, F., and Schmidt, M. Epac1 and Epac2 are differentially involved in inflammatory and remodeling processes induced by cigarette smoke. PMID:25103224

  14. Lymphatic vessels regulate immune microenvironments in human and murine melanoma.

    PubMed

    Lund, Amanda W; Wagner, Marek; Fankhauser, Manuel; Steinskog, Eli S; Broggi, Maria A; Spranger, Stefani; Gajewski, Thomas F; Alitalo, Kari; Eikesdal, Hans P; Wiig, Helge; Swartz, Melody A

    2016-09-01

    Lymphatic remodeling in tumor microenvironments correlates with progression and metastasis, and local lymphatic vessels play complex and poorly understood roles in tumor immunity. Tumor lymphangiogenesis is associated with increased immune suppression, yet lymphatic vessels are required for fluid drainage and immune cell trafficking to lymph nodes, where adaptive immune responses are mounted. Here, we examined the contribution of lymphatic drainage to tumor inflammation and immunity using a mouse model that lacks dermal lymphatic vessels (K14-VEGFR3-Ig mice). Melanomas implanted in these mice grew robustly, but exhibited drastically reduced cytokine expression and leukocyte infiltration compared with those implanted in control animals. In the absence of local immune suppression, transferred cytotoxic T cells more effectively controlled tumors in K14-VEGFR3-Ig mice than in control mice. Furthermore, gene expression analysis of human melanoma samples revealed that patient immune parameters are markedly stratified by levels of lymphatic markers. This work suggests that the establishment of tumor-associated inflammation and immunity critically depends on lymphatic vessel remodeling and drainage. Moreover, these results have implications for immunotherapies, the efficacies of which are regulated by the tumor immune microenvironment. PMID:27525437

  15. Nanoscale analysis of caspofungin-induced cell surface remodelling in Candida albicans

    NASA Astrophysics Data System (ADS)

    El-Kirat-Chatel, Sofiane; Beaussart, Audrey; Alsteens, David; Jackson, Desmond N.; Lipke, Peter N.; Dufrêne, Yves F.

    2013-01-01

    The advent of fungal pathogens that are resistant to the classic repertoire of antifungal drugs has increased the need for new therapeutic agents. A prominent example of such a novel compound is caspofungin, known to alter cell wall biogenesis by inhibiting β-1,3-d-glucan synthesis. Although much progress has been made in understanding the mechanism of action of caspofungin, little is known about its influence on the biophysical properties of the fungal cells. Here, we use atomic force microscopy (AFM) to demonstrate that caspofungin induces major remodelling of the cell surface properties of Candida albicans. Caspofungin causes major morphological and structural alterations of the cells, which correlate with a decrease of the cell wall mechanical strength. Moreover, we find that the drug induces the massive exposure of the cell adhesion protein Als1 on the cell surface and leads to increased cell surface hydrophobicity, two features that trigger cell aggregation. This behaviour is not observed in yeast species lacking Als1, demonstrating the key role that the protein plays in determining the aggregation phenotype of C. albicans. The results show that AFM opens up new avenues for understanding the molecular bases of microbe-drug interactions and for developing new therapeutic agents.The advent of fungal pathogens that are resistant to the classic repertoire of antifungal drugs has increased the need for new therapeutic agents. A prominent example of such a novel compound is caspofungin, known to alter cell wall biogenesis by inhibiting β-1,3-d-glucan synthesis. Although much progress has been made in understanding the mechanism of action of caspofungin, little is known about its influence on the biophysical properties of the fungal cells. Here, we use atomic force microscopy (AFM) to demonstrate that caspofungin induces major remodelling of the cell surface properties of Candida albicans. Caspofungin causes major morphological and structural alterations of the

  16. Anti-Siglec-F Antibody Reduces Allergen-Induced Eosinophilic Inflammation and Airway Remodeling1

    PubMed Central

    Song, Dae Jin; Cho, Jae Youn; Lee, Sang Yeub; Miller, Marina; Rosenthal, Peter; Soroosh, Pejman; Croft, Michael; Zhang, Mai; Varki, Ajit; Broide, David H.

    2009-01-01

    Siglec-F is a sialic acid-binding Ig superfamily receptor that is highly expressed on eosinophils. We have investigated whether administration of an anti-Siglec-F Ab to OVA-challenged wild-type mice would reduce levels of eosinophilic inflammation and levels of airway remodeling. Mice sensitized to OVA and challenged repetitively with OVA for 1 mo who were administered an anti-Siglec-F Ab had significantly reduced levels of peribronchial eosinophilic inflammation and significantly reduced levels of subepithelial fibrosis as assessed by either trichrome staining or lung collagen levels. The anti-Siglec-F Ab reduced the number of bone marrow, blood, and tissue eosinophils, suggesting that the anti-Siglec-F Ab was reducing the production of eosinophils. Administration of a F(ab′)2 fragment of an anti-Siglec-F Ab also significantly reduced levels of eosinophilic inflammation in the lung and blood. FACS analysis demonstrated increased numbers of apoptotic cells (annexin V+/CCR3+ bronchoalveolar lavage and bone marrow cells) in anti-Siglec-F Ab-treated mice challenged with OVA. The anti-Siglec-F Ab significantly reduced the number of peribronchial major basic protein+/TGF-β+ cells, suggesting that reduced levels of eosinophil-derived TGF-β in anti-Siglec-F Ab-treated mice contributed to reduced levels of peribronchial fibrosis. Administration of the anti-Siglec-F Ab modestly reduced levels of periodic acid-Schiff-positive mucus cells and the thickness of the smooth muscle layer. Overall, these studies suggest that administration of an anti-Siglec-F Ab can significantly reduce levels of allergen-induced eosinophilic airway inflammation and features of airway remodeling, in particular subepithelial fibrosis, by reducing the production of eosinophils and increasing the number of apoptotic eosinophils in lung and bone marrow. PMID:19783675

  17. ATP-sensitive K+ channel knockout induces cardiac proteome remodeling predictive of heart disease susceptibility.

    PubMed

    Arrell, D Kent; Zlatkovic, Jelena; Kane, Garvan C; Yamada, Satsuki; Terzic, Andre

    2009-10-01

    Forecasting disease susceptibility requires detection of maladaptive signatures prior to onset of overt symptoms. A case-in-point are cardiac ATP-sensitive K+ (K(ATP)) channelopathies, for which the substrate underlying disease vulnerability remains to be identified. Resolving molecular pathobiology, even for single genetic defects, mandates a systems platform to reliably diagnose disease predisposition. High-throughput proteomic analysis was here integrated with network biology to decode consequences of Kir6.2 K(ATP) channel pore deletion. Differential two-dimensional gel electrophoresis reproducibly resolved >800 protein species from hearts of asymptomatic wild-type and Kir6.2-knockout counterparts. K(ATP) channel ablation remodeled the cardiac proteome, significantly altering 71 protein spots, from which 102 unique identities were assigned following hybrid linear ion trap quadrupole-Orbitrap tandem mass spectrometry. Ontological annotation stratified the K(ATP) channel-dependent protein cohort into a predominant bioenergetic module (63 resolved identities), with additional focused sets representing signaling molecules (6), oxidoreductases (8), chaperones (6), and proteins involved in catabolism (6), cytostructure (8), and transcription and translation (5). Protein interaction mapping, in conjunction with expression level changes, localized a K(ATP) channel-associated subproteome within a nonstochastic scale-free network. Global assessment of the K(ATP) channel deficient environment verified the primary impact on metabolic pathways and revealed overrepresentation of markers associated with cardiovascular disease. Experimental imposition of graded stress precipitated exaggerated structural and functional myocardial defects in the Kir6.2-knockout, decreasing survivorship and validating the forecast of disease susceptibility. Proteomic cartography thus provides an integral view of molecular remodeling in the heart induced by K(ATP) channel deletion, establishing a

  18. Lymphatic anatomy and biomechanics

    PubMed Central

    Negrini, Daniela; Moriondo, Andrea

    2011-01-01

    Abstract Lymph formation is driven by hydraulic pressure gradients developing between the interstitial tissue and the lumen of initial lymphatics. While in vessels equipped with lymphatic smooth muscle cells these gradients are determined by well-synchronized spontaneous contractions of vessel segments, initial lymphatics devoid of smooth muscles rely on tissue motion to form lymph and propel it along the network. Lymphatics supplying highly moving tissues, such as skeletal muscle, diaphragm or thoracic tissues, undergo cyclic compression and expansion of their lumen imposed by local stresses arising in the tissue as a consequence of cardiac and respiratory activities. Active muscle contraction and not passive tissue displacement is required to support an efficient lymphatic drainage, as suggested by the fact that the respiratory activity promotes lymph formation during spontaneous, but not mechanical ventilation. The mechanical properties of the lymphatic wall and of the surrounding tissue also play an important role in lymphatic function. Modelling of stress distribution in the lymphatic wall suggests that compliant vessels behave as reservoirs accommodating absorbed interstitial fluid, while lymphatics with stiffer walls, taking advantage of a more efficient transmission of tissue stresses to the lymphatic lumen, propel fluid through the lumen of the lymphatic circuit. PMID:21486777

  19. Functional and Structural Remodeling of Glutamate Synapses in Prefrontal and Frontal Cortex Induced by Behavioral Stress

    PubMed Central

    Musazzi, Laura; Treccani, Giulia; Popoli, Maurizio

    2015-01-01

    Increasing evidence has shown that the pathophysiology of neuropsychiatric disorders, including mood disorders, is associated with abnormal function and regulation of the glutamatergic system. Consistently, preclinical studies on stress-based animal models of pathology showed that glucocorticoids and stress exert crucial effects on neuronal excitability and function, especially in cortical and limbic areas. In prefrontal and frontal cortex, acute stress was shown to induce enhancement of glutamate release/transmission dependent on activation of corticosterone receptors. Although the mechanisms whereby stress affects glutamate transmission have not yet been fully understood, it was shown that synaptic, non-genomic action of corticosterone is required to increase the readily releasable pool of glutamate vesicles, but is not sufficient to enhance transmission in prefrontal and frontal cortex. Slower, partly genomic mechanisms are probably necessary for the enhancement of glutamate transmission induced by stress. Combined evidence has suggested that the changes in glutamate release and transmission are responsible for the dendritic remodeling and morphological changes induced by stress and it has been argued that sustained alterations of glutamate transmission may play a key role in the long-term structural/functional changes associated with mood disorders in patients. Intriguingly, modifications of the glutamatergic system induced by stress in the prefrontal cortex seem to be biphasic. Indeed, while the fast response to stress suggests an enhancement in the number of excitatory synapses, synaptic transmission and working memory, long-term adaptive changes – including those consequent to chronic stress – induce opposite effects. Better knowledge of the cellular effectors involved in this biphasic effect of stress may be useful to understand the pathophysiology of stress-related disorders, and open new paths for the development of therapeutic approaches. PMID

  20. Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling

    PubMed Central

    Paradis, Pierre; Dali-Youcef, Nassim; Paradis, François W.; Thibault, Gaétan; Nemer, Mona

    2000-01-01

    Angiotensin II (AII) is a major determinant of arterial pressure and volume homeostasis, mainly because of its vascular action via the AII type 1 receptor (AT1R). AII has also been implicated in the development of cardiac hypertrophy because angiotensin I-converting enzyme inhibitors and AT1R antagonists prevent or regress ventricular hypertrophy in animal models and in human. However, because these treatments impede the action of AII at cardiac as well as vascular levels, and reduce blood pressure, it has been difficult to determine whether AII action on the heart is direct or a consequence of pressure-overload. To determine whether AII can induce cardiac hypertrophy directly via myocardial AT1R in the absence of vascular changes, transgenic mice overexpressing the human AT1R under the control of the mouse α-myosin heavy chain promoter were generated. Cardiomyocyte-specific overexpression of AT1R induced, in basal conditions, morphologic changes of myocytes and nonmyocytes that mimic those observed during the development of cardiac hypertrophy in human and in other mammals. These mice displayed significant cardiac hypertrophy and remodeling with increased expression of ventricular atrial natriuretic factor and interstitial collagen deposition and died prematurely of heart failure. Neither the systolic blood pressure nor the heart rate were changed. The data demonstrate a direct myocardial role for AII in the development of cardiac hypertrophy and failure and provide a useful model to elucidate the mechanisms of action of AII in the pathogenesis of cardiac diseases. PMID:10639182

  1. Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling.

    PubMed

    Paradis, P; Dali-Youcef, N; Paradis, F W; Thibault, G; Nemer, M

    2000-01-18

    Angiotensin II (AII) is a major determinant of arterial pressure and volume homeostasis, mainly because of its vascular action via the AII type 1 receptor (AT1R). AII has also been implicated in the development of cardiac hypertrophy because angiotensin I-converting enzyme inhibitors and AT1R antagonists prevent or regress ventricular hypertrophy in animal models and in human. However, because these treatments impede the action of AII at cardiac as well as vascular levels, and reduce blood pressure, it has been difficult to determine whether AII action on the heart is direct or a consequence of pressure-overload. To determine whether AII can induce cardiac hypertrophy directly via myocardial AT1R in the absence of vascular changes, transgenic mice overexpressing the human AT1R under the control of the mouse alpha-myosin heavy chain promoter were generated. Cardiomyocyte-specific overexpression of AT1R induced, in basal conditions, morphologic changes of myocytes and nonmyocytes that mimic those observed during the development of cardiac hypertrophy in human and in other mammals. These mice displayed significant cardiac hypertrophy and remodeling with increased expression of ventricular atrial natriuretic factor and interstitial collagen deposition and died prematurely of heart failure. Neither the systolic blood pressure nor the heart rate were changed. The data demonstrate a direct myocardial role for AII in the development of cardiac hypertrophy and failure and provide a useful model to elucidate the mechanisms of action of AII in the pathogenesis of cardiac diseases. PMID:10639182

  2. Protein kinase D controls voluntary-running-induced skeletal muscle remodelling

    PubMed Central

    Ellwanger, Kornelia; Kienzle, Christine; Lutz, Sylke; Jin, Zheng-Gen; Wiekowski, Maria T.; Pfizenmaier, Klaus; Hausser, Angelika

    2014-01-01

    Skeletal muscle responds to exercise by activation of signalling pathways that co-ordinate gene expression to sustain muscle performance. MEF2 (myocyte enhancer factor 2)-dependent transcriptional activation of MHC (myosin heavy chain) genes promotes the transformation from fast-twitch into slow-twitch fibres, with MEF2 activity being tightly regulated by interaction with class IIa HDACs (histone deacetylases). PKD (protein kinase D) is known to directly phosphorylate skeletal muscle class IIa HDACs, mediating their nuclear export and thus derepression of MEF2. In the present study, we report the generation of transgenic mice with inducible conditional expression of a dominant-negative PKD1kd (kinase-dead PKD1) protein in skeletal muscle to assess the role of PKD in muscle function. In control mice, long-term voluntary running experiments resulted in a switch from type IIb + IId/x to type IIa plantaris muscle fibres as measured by indirect immunofluorescence of MHCs isoforms. In mice expressing PKD1kd, this fibre type switch was significantly impaired. These mice exhibited altered muscle fibre composition and decreased running performance compared with control mice. Our findings thus indicate that PKD activity is essential for exercise-induced MEF2-dependent skeletal muscle remodelling in vivo. PMID:21848513

  3. Salt-Induced Remodeling of Spatially Restricted Clathrin-Independent Endocytic Pathways in Arabidopsis Root

    PubMed Central

    Baral, Anirban; Irani, Niloufer G.; Fujimoto, Masaru; Nakano, Akihiko; Mayor, Satyajit; Mathew, M.K.

    2015-01-01

    Endocytosis is a ubiquitous cellular process that is characterized well in animal cells in culture but poorly across intact, functioning tissue. Here, we analyze endocytosis throughout the Arabidopsis thaliana root using three classes of probes: a lipophilic dye, tagged transmembrane proteins, and a lipid-anchored protein. We observe a stratified distribution of endocytic processes. A clathrin-dependent endocytic pathway that internalizes transmembrane proteins functions in all cell layers, while a sterol-dependent, clathrin-independent pathway that takes up lipid and lipid-anchored proteins but not transmembrane proteins is restricted to the epidermal layer. Saline stress induces a third pathway that is clathrin-independent, nondiscriminatory in its choice of cargo, and operates across all layers of the root. Concomitantly, small acidic compartments in inner cell layers expand to form larger vacuole-like structures. Plants lacking function of the Rab-GEF (guanine nucleotide exchange factor) VPS9a (vacuolar protein sorting 9A) neither induce the third endocytic pathway nor expand the vacuolar system in response to salt stress. The plants are also hypersensitive to salt. Thus, saline stress reconfigures clathrin-independent endocytosis and remodels endomembrane systems, forming large vacuoles in the inner cell layers, both processes correlated by the requirement of VPS9a activity. PMID:25901088

  4. Muscle RING Finger-1 Promotes a Maladaptive Phenotype in Chronic Hypoxia-Induced Right Ventricular Remodeling

    PubMed Central

    Campen, Matthew J.; Paffett, Michael L.; Colombo, E. Sage; Lucas, Selita N.; Anderson, Tamara; Nysus, Monique; Norenberg, Jeffrey P.; Gershman, Ben; Hesterman, Jacob; Hoppin, Jack; Willis, Monte

    2014-01-01

    Exposure to chronic hypoxia (CH) induces elevated pulmonary artery pressure/resistance, leading to an eventual maladaptive right ventricular hypertrophy (RVH). Muscle RING finger-1 (MuRF1) is a muscle-specific ubiquitin ligase that mediates myocyte atrophy and has been shown to play a role in left ventricular hypertrophy and altered cardiac bioenergetics in pressure overloaded hearts. However, little is known about the contribution of MuRF1 impacting RVH in the setting of CH. Therefore, we hypothesized that MuRF1 deletion would enhance RVH compared to their wild-type littermates, while cardiac-specific overexpression would reduce hypertrophy following CH-induced pulmonary hypertension. We assessed right ventricular systolic pressure (RVSP), right ventricle to left ventricle plus septal weight ratio (RV/LV+S) and hematocrit (Hct) following a 3-wk isobaric CH exposure. Additionally, we conducted dual-isotope SPECT/CT imaging with cardiac function agent 201Tl-chloride and cell death agent 99mTc-annexin V. Predictably, CH induced pulmonary hypertension, measured by increased RVSP, RV/LV+S and Hct in WT mice compared to normoxic WT mice. Normoxic WT and MuRF1-null mice exhibited no significant differences in RVSP, RV/LV+S or Hct. CH-induced increases in RVSP were also similar between WT and MuRF1-null mice; however, RV/LV+S and Hct were significantly elevated in CH-exposed MuRF1-null mice compared to WT. In cardiac-specific MuRF1 overexpressing mice, RV/LV+S increased significantly due to CH exposure, even greater than in WT mice. This remodeling appeared eccentric, maladaptive and led to reduced systemic perfusion. In conclusion, these results are consistent with an atrophic role for MuRF1 regulating the magnitude of right ventricular hypertrophy following CH-induction of pulmonary hypertension. PMID:24811453

  5. Muscle RING finger-1 promotes a maladaptive phenotype in chronic hypoxia-induced right ventricular remodeling.

    PubMed

    Campen, Matthew J; Paffett, Michael L; Colombo, E Sage; Lucas, Selita N; Anderson, Tamara; Nysus, Monique; Norenberg, Jeffrey P; Gershman, Ben; Hesterman, Jacob; Hoppin, Jack; Willis, Monte

    2014-01-01

    Exposure to chronic hypoxia (CH) induces elevated pulmonary artery pressure/resistance, leading to an eventual maladaptive right ventricular hypertrophy (RVH). Muscle RING finger-1 (MuRF1) is a muscle-specific ubiquitin ligase that mediates myocyte atrophy and has been shown to play a role in left ventricular hypertrophy and altered cardiac bioenergetics in pressure overloaded hearts. However, little is known about the contribution of MuRF1 impacting RVH in the setting of CH. Therefore, we hypothesized that MuRF1 deletion would enhance RVH compared to their wild-type littermates, while cardiac-specific overexpression would reduce hypertrophy following CH-induced pulmonary hypertension. We assessed right ventricular systolic pressure (RVSP), right ventricle to left ventricle plus septal weight ratio (RV/LV+S) and hematocrit (Hct) following a 3-wk isobaric CH exposure. Additionally, we conducted dual-isotope SPECT/CT imaging with cardiac function agent 201Tl-chloride and cell death agent 99mTc-annexin V. Predictably, CH induced pulmonary hypertension, measured by increased RVSP, RV/LV+S and Hct in WT mice compared to normoxic WT mice. Normoxic WT and MuRF1-null mice exhibited no significant differences in RVSP, RV/LV+S or Hct. CH-induced increases in RVSP were also similar between WT and MuRF1-null mice; however, RV/LV+S and Hct were significantly elevated in CH-exposed MuRF1-null mice compared to WT. In cardiac-specific MuRF1 overexpressing mice, RV/LV+S increased significantly due to CH exposure, even greater than in WT mice. This remodeling appeared eccentric, maladaptive and led to reduced systemic perfusion. In conclusion, these results are consistent with an atrophic role for MuRF1 regulating the magnitude of right ventricular hypertrophy following CH-induction of pulmonary hypertension. PMID:24811453

  6. Shear-induced Endothelial NOS Activation and Remodeling via Heparan Sulfate, Glypican-1, and Syndecan-1

    PubMed Central

    Ebong, Eno E; Lopez-Quintero, Sandra V; Rizzo, Victor; Spray, David C; Tarbell, John M

    2014-01-01

    Mammalian epithelial cells are coated with a multifunctional surface glycocalyx (GCX). On vascular endothelial cells (EC), intact GCX is atheroprotective. It is degraded in many vascular diseases. GCX heparan sulfate (HS) is essential for healthy flow-induced EC nitric oxide (NO) release, elongation, and alignment. The HS core protein mechanisms involved in these processes are unknown. We hypothesized that the glypican-1 (GPC1) HS core protein mediates flow-induced EC NO synthase (eNOS) activation because GPC1 is anchored to caveolae where eNOS resides. We also hyphothesized that the HS core protein syndecan-1 (SDC1) mediates flow-induced EC elongation and alignment because SDC1 is linked to the cytoskeleton which impacts cell shape. We tested our hypotheses by exposing EC monolayers treated with HS degrading heparinase III (HepIII), and monolayers with RNA-silenced GPC1, or SDC1, to 3 to 24 hours of physiological shear stress. Shear-conditioned EC with intact GCX exhibited characteristic eNOS activation in short-term flow conditions. After long-term exposure, EC with intact GCX were elongated and aligned in the direction of flow. HS removal and GPC1 inhibition, not SDC1 reduction, blocked shear-induced eNOS activation. EC remodeling in response to flow was attenuated by HS degradation and in the absence of SDC1, but preserved with GPC1 knockdown. These findings clearly demonstrate that HS is involved in both centralized and decentralized GCX-mediated mechanotransduction mechanisms, with GPC1 acting as a centralized mechanotransmission agent and SDC1 functioning in decentralized mechanotransmission. This foundational work demonstrates how EC can transform fluid shear forces into diverse biomolecular and biomechanical responses. PMID:24480876

  7. Mitochondrial proteome remodelling in pressure overload-induced heart failure: the role of mitochondrial oxidative stress

    PubMed Central

    Dai, Dao-Fu; Hsieh, Edward J.; Liu, Yonggang; Chen, Tony; Beyer, Richard P.; Chin, Michael T.; MacCoss, Michael J.; Rabinovitch, Peter S.

    2012-01-01

    Aims We investigate the role of mitochondrial oxidative stress in mitochondrial proteome remodelling using mouse models of heart failure induced by pressure overload. Methods and results We demonstrate that mice overexpressing catalase targeted to mitochondria (mCAT) attenuate pressure overload-induced heart failure. An improved method of label-free unbiased analysis of the mitochondrial proteome was applied to the mouse model of heart failure induced by transverse aortic constriction (TAC). A total of 425 mitochondrial proteins were compared between wild-type and mCAT mice receiving TAC or sham surgery. The changes in the mitochondrial proteome in heart failure included decreased abundance of proteins involved in fatty acid metabolism, an increased abundance of proteins in glycolysis, apoptosis, mitochondrial unfolded protein response and proteolysis, transcription and translational control, and developmental processes as well as responses to stimuli. Overexpression of mCAT better preserved proteins involved in fatty acid metabolism and attenuated the increases in apoptotic and proteolytic enzymes. Interestingly, gene ontology analysis also showed that monosaccharide metabolic processes and protein folding/proteolysis were only overrepresented in mCAT but not in wild-type mice in response to TAC. Conclusion This is the first study to demonstrate that scavenging mitochondrial reactive oxygen species (ROS) by mCAT not only attenuates most of the mitochondrial proteome changes in heart failure, but also induces a subset of unique alterations. These changes represent processes that are adaptive to the increased work and metabolic requirements of pressure overload, but which are normally inhibited by overproduction of mitochondrial ROS. PMID:22012956

  8. Roles of Caveolin-1 in Angiotensin II-Induced Hypertrophy and Inward Remodeling of Cerebral Pial Arterioles.

    PubMed

    Umesalma, Shaikamjad; Houwen, Frederick Keith; Baumbach, Gary L; Chan, Siu-Lung

    2016-03-01

    Angiotensin II (Ang II) is a major determinant of inward remodeling and hypertrophy in pial arterioles that may have an important role in stroke during chronic hypertension. Previously, we found that epidermal growth factor receptor is critical in Ang II-mediated hypertrophy that may involve caveolin-1 (Cav-1). In this study, we examined the effects of Cav-1 and matrix metalloproteinase-9 (MMP9) on Ang II-mediated structural changes in pial arterioles. Cav-1-deficient (Cav-1(-/-)), MMP9-deficient (MMP9(-/-)), and wild-type mice were infused with either Ang II (1000 ng/kg per minute) or saline via osmotic minipumps for 28 days (n=6-8 per group). Systolic arterial pressure was measured by a tail-cuff method. Pressure and diameter of pial arterioles were measured through an open cranial window in anesthetized mice. Cross-sectional area of the wall was determined histologically in pressurized fixed pial arterioles. Expression of Cav-1, MMP9, phosphorylated epidermal growth factor receptor, and Akt was determined by Western blotting and immunohistochemistry. Deficiency of Cav-1 or MMP9 did not affect Ang II-induced hypertension. Ang II increased the expression of Cav-1, phosphorylated epidermal growth factor receptor, and Akt in wild-type mice, which was attenuated in Cav-1(-/-) mice. Ang II-induced hypertrophy, inward remodeling, and increased MMP9 expression in pial arterioles were prevented in Cav-1(-/-) mice. Ang II-mediated increases in MMP9 expression and inward remodeling, but not hypertrophy, were prevented in MMP9(-/-) mice. In conclusion, Cav-1 is essential in Ang II-mediated inward remodeling and hypertrophy in pial arterioles. Cav-1-induced MMP9 is exclusively involved in inward remodeling, not hypertrophy. Further studies are needed to determine the role of Akt in Ang II-mediated hypertrophy. PMID:26831194

  9. Nanofibrous clinical-grade collagen scaffolds seeded with human cardiomyocytes induces cardiac remodeling in dilated cardiomyopathy.

    PubMed

    Joanne, Pierre; Kitsara, Maria; Boitard, Solène-Emmanuelle; Naemetalla, Hany; Vanneaux, Valérie; Pernot, Mathieu; Larghero, Jérôme; Forest, Patricia; Chen, Yong; Menasché, Philippe; Agbulut, Onnik

    2016-02-01

    Limited data are available on the effects of stem cells in non-ischemic dilated cardiomyopathy (DCM). Since the diffuse nature of the disease calls for a broad distribution of cells, this study investigated the scaffold-based delivery of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) in a mouse model of DCM. Nanofibrous scaffolds were produced using a clinical grade atelocollagen which was electrospun and cross-linked under different conditions. As assessed by scanning electron microscopy and shearwave elastography, the optimum crosslinking conditions for hiPS-CM colonization proved to be a 10% concentration of citric acid crosslinking agent and 150 min of post-electrospinning baking. Acellular collagen scaffolds were first implanted in both healthy mice and those with induced DCM by a cardiac-specific invalidation of serum response factor (SRF). Seven and fourteen days after implantation, the safety of the scaffold was demonstrated by echocardiography and histological assessments. The subsequent step of implantation of the scaffolds seeded with hiPS-CM in DCM induced mice, using cell-free scaffolds as controls, revealed that after fourteen days heart function decreased in controls while it remained stable in the treated mice. This pattern was associated with an increased number of endothelial cells, in line with the greater vascularity of the scaffold. Moreover, a lesser degree of fibrosis consistent with the upregulation of several genes involved in extracellular matrix remodeling was observed. These results support the interest of the proposed hiPS-CM seeded electrospun scaffold for the stabilization of the DCM outcome with potential for its clinical use in the future. PMID:26708641

  10. Chronic sustained hypoxia-induced redox remodeling causes contractile dysfunction in mouse sternohyoid muscle

    PubMed Central

    Lewis, Philip; Sheehan, David; Soares, Renata; Varela Coelho, Ana; O'Halloran, Ken D.

    2015-01-01

    Chronic sustained hypoxia (CH) induces structural and functional adaptations in respiratory muscles of animal models, however the underlying molecular mechanisms are unclear. This study explores the putative role of CH-induced redox remodeling in a translational mouse model, with a focus on the sternohyoid—a representative upper airway dilator muscle involved in the control of pharyngeal airway caliber. We hypothesized that exposure to CH induces redox disturbance in mouse sternohyoid muscle in a time-dependent manner affecting metabolic capacity and contractile performance. C57Bl6/J mice were exposed to normoxia or normobaric CH (FiO2 = 0.1) for 1, 3, or 6 weeks. A second cohort of animals was exposed to CH for 6 weeks with and without antioxidant supplementation (tempol or N-acetyl cysteine in the drinking water). Following CH exposure, we performed 2D redox proteomics with mass spectrometry, metabolic enzyme activity assays, and cell-signaling assays. Additionally, we assessed isotonic contractile and endurance properties ex vivo. Temporal changes in protein oxidation and glycolytic enzyme activities were observed. Redox modulation of sternohyoid muscle proteins key to contraction, metabolism and cellular homeostasis was identified. There was no change in redox-sensitive proteasome activity or HIF-1α content, but CH decreased phospho-JNK content independent of antioxidant supplementation. CH was detrimental to sternohyoid force- and power-generating capacity and this was prevented by chronic antioxidant supplementation. We conclude that CH causes upper airway dilator muscle dysfunction due to redox modulation of proteins key to function and homeostasis. Such changes could serve to further disrupt respiratory homeostasis in diseases characterized by CH such as chronic obstructive pulmonary disease. Antioxidants may have potential use as an adjunctive therapy in hypoxic respiratory disease. PMID:25941492

  11. Chronic sustained hypoxia-induced redox remodeling causes contractile dysfunction in mouse sternohyoid muscle.

    PubMed

    Lewis, Philip; Sheehan, David; Soares, Renata; Varela Coelho, Ana; O'Halloran, Ken D

    2015-01-01

    Chronic sustained hypoxia (CH) induces structural and functional adaptations in respiratory muscles of animal models, however the underlying molecular mechanisms are unclear. This study explores the putative role of CH-induced redox remodeling in a translational mouse model, with a focus on the sternohyoid-a representative upper airway dilator muscle involved in the control of pharyngeal airway caliber. We hypothesized that exposure to CH induces redox disturbance in mouse sternohyoid muscle in a time-dependent manner affecting metabolic capacity and contractile performance. C57Bl6/J mice were exposed to normoxia or normobaric CH (FiO2 = 0.1) for 1, 3, or 6 weeks. A second cohort of animals was exposed to CH for 6 weeks with and without antioxidant supplementation (tempol or N-acetyl cysteine in the drinking water). Following CH exposure, we performed 2D redox proteomics with mass spectrometry, metabolic enzyme activity assays, and cell-signaling assays. Additionally, we assessed isotonic contractile and endurance properties ex vivo. Temporal changes in protein oxidation and glycolytic enzyme activities were observed. Redox modulation of sternohyoid muscle proteins key to contraction, metabolism and cellular homeostasis was identified. There was no change in redox-sensitive proteasome activity or HIF-1α content, but CH decreased phospho-JNK content independent of antioxidant supplementation. CH was detrimental to sternohyoid force- and power-generating capacity and this was prevented by chronic antioxidant supplementation. We conclude that CH causes upper airway dilator muscle dysfunction due to redox modulation of proteins key to function and homeostasis. Such changes could serve to further disrupt respiratory homeostasis in diseases characterized by CH such as chronic obstructive pulmonary disease. Antioxidants may have potential use as an adjunctive therapy in hypoxic respiratory disease. PMID:25941492

  12. Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II.

    PubMed

    Takayanagi, Takehiko; Kawai, Tatsuo; Forrester, Steven J; Obama, Takashi; Tsuji, Toshiyuki; Fukuda, Yamato; Elliott, Katherine J; Tilley, Douglas G; Davisson, Robin L; Park, Joon-Young; Eguchi, Satoru

    2015-06-01

    The mechanisms by which angiotensin II (AngII) elevates blood pressure and enhances end-organ damage seem to be distinct. However, the signal transduction cascade by which AngII specifically mediates vascular remodeling such as medial hypertrophy and perivascular fibrosis remains incomplete. We have previously shown that AngII-induced epidermal growth factor receptor (EGFR) transactivation is mediated by disintegrin and metalloproteinase domain 17 (ADAM17), and that this signaling is required for vascular smooth muscle cell hypertrophy but not for contractile signaling in response to AngII. Recent studies have implicated endoplasmic reticulum (ER) stress in hypertension. Interestingly, EGFR is capable of inducing ER stress. The aim of this study was to test the hypothesis that activation of EGFR and ER stress are critical components required for vascular remodeling but not hypertension induced by AngII. Mice were infused with AngII for 2 weeks with or without treatment of EGFR inhibitor, erlotinib, or ER chaperone, 4-phenylbutyrate. AngII infusion induced vascular medial hypertrophy in the heart, kidney and aorta, and perivascular fibrosis in heart and kidney, cardiac hypertrophy, and hypertension. Treatment with erlotinib as well as 4-phenylbutyrate attenuated vascular remodeling and cardiac hypertrophy but not hypertension. In addition, AngII infusion enhanced ADAM17 expression, EGFR activation, and ER/oxidative stress in the vasculature, which were diminished in both erlotinib-treated and 4-phenylbutyrate-treated mice. ADAM17 induction and EGFR activation by AngII in vascular cells were also prevented by inhibition of EGFR or ER stress. In conclusion, AngII induces vascular remodeling by EGFR activation and ER stress via a signaling mechanism involving ADAM17 induction independent of hypertension. PMID:25916723

  13. Early structural and metabolic cardiac remodelling in response to inducible adipose triglyceride lipase ablation

    PubMed Central

    Kienesberger, Petra C.; Pulinilkunnil, Thomas; Nagendran, Jeevan; Young, Martin E.; Bogner-Strauss, Juliane G.; Hackl, Hubert; Khadour, Rammy; Heydari, Emma; Haemmerle, Guenter; Zechner, Rudolf; Kershaw, Erin E.; Dyck, Jason R. B.

    2013-01-01

    Aims While chronic alterations in cardiac triacylglycerol (TAG) metabolism and accumulation are associated with cardiomyopathy, it is unclear whether TAG catabolizing enzymes such as adipose triglyceride lipase (ATGL) play a role in acquired cardiomyopathies. Importantly, germline deletion of ATGL leads to marked cardiac steatosis and heart failure in part through reducing peroxisome proliferator-activated receptor α (PPARα) activity and subsequent fatty acid oxidation (FAO). However, whether ATGL deficiency specifically in adult cardiomyocytes contributes to impaired PPARα activity, cardiac function, and metabolism is not known. Methods and results To study the effects of acquired cardiac ATGL deficiency on cardiac PPARα activity, function, and metabolism, we generated adult mice with tamoxifen-inducible cardiomyocyte-specific ATGL deficiency (icAtglKO). Within 4–6 weeks following ATGL ablation, icAtglKO mice had markedly increased myocardial TAG accumulation, fibrotic remodelling, and pathological hypertrophy. Echocardiographic analysis of hearts in vivo revealed that contractile function was moderately reduced in icAtglKO mice. Analysis of energy metabolism in ex vivo perfused working hearts showed diminished FAO rates which was not paralleled by markedly impaired PPARα target gene expression. Conclusions This study shows that acquired cardiomyocyte-specific ATGL deficiency in adult mice is sufficient to promote fibrotic and hypertrophic cardiomyopathy and impair myocardial FAO in the absence of markedly reduced PPARα signalling. PMID:23708736

  14. Remodeling of Glucose Metabolism Precedes Pressure Overload -Induced Left Ventricular Hypertrophy: Review of a Hypothesis

    PubMed Central

    Kundu, Bijoy K.; Zhong, Min; Sen, Shiraj; Davogustto, Giovanni; Keller, Susanna R.; Taegtmeyer, Heinrich

    2015-01-01

    When subjected to pressure overload, the ventricular myocardium shifts from fatty acids to glucose as its main source for energy provision and frequently increases its mass. Here, we review the evidence in support of the concept that metabolic remodeling, measured as increased myocardial glucose uptake using dynamic positron emission tomography (PET) with the glucose analogue 2-deoxy-2-[18F]-fluoro-D-glucose (FDG), precedes the onset of left ventricular hypertrophy (LVH) and heart failure. Consistent with this, early intervention with propranolol, which attenuates glucose uptake, prevents the maladaptive metabolic response and preserves cardiac function in vivo. We also review ex vivo studies suggesting a link between dysregulated myocardial glucose metabolism, intracellular accumulation of glucose 6-phosphate (G6P) and contractile dysfunction of the heart. G6P levels correlate with activation of mTOR (mechanistic target of rapamycin) and endoplasmic reticulum stress. This sequence of events could be prevented by pre-treatment with rapamycin (mTOR inhibition) or metformin (enzyme 5′-AMP-activated protein kinase activation ). In conclusion, we propose that metabolic imaging with FDG PET may provide a novel approach to guide the treatment of patients with hypertension-induced LVH. PMID:25791172

  15. Simulating the effects of atrial fibrillation induced electrical remodeling: a comprehensive simulation study.

    PubMed

    Kharche, Sanjay; Zhang, Henggui

    2008-01-01

    Mechanisms underlying atrial fibrillation (AF) are poorly understood. In this study, we computationally evaluated the functional roles of AF induced electrical remodeling (AFER) on atrial electrical excitations. Experimental data of AFER on human atrial myocytes were incorporated into a biophysically detailed model of human atrial cells to simulate the effects of AFER at cellular and tissue levels. Our results show that AFER dramatically abbreviated atrial action potential duration (APD90) and effective refractory period that were quantitatively consistent with experimental data. A typical feature of loss in rate dependent accommodation of APD90 was observed. AFER slowed down atrial conduction velocity, but facilitated atrial conduction at high excitation rates. AFER increased tissue's spatial vulnerability for initiation and maintenance of AF remarkably. The overall susceptibility of human atrium to arrhythmia was increased. Most importantly AFER increased the stability of reentrant waves in 2D and 3D models prolonging their lifespan. While reentrant excitation waves self-terminated under Control conditions, the same became persistent or degenerated into multiple wavelets leading to spatio-temporal chaos under AFER conditions with accelerated re-entrant excitation rates. There was an increase in dominant frequency. In conclusion, our simulations substantiated a link between AFER and persistence of AF, providing mechanistic insights towards better understanding of "AF begets AF". PMID:19162725

  16. Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts

    PubMed Central

    Chiao, Ying Ann; Kolwicz, Stephen C.; Basisty, Nathan; Gagnidze, Arni; Zhang, Julia; Gu, Haiwei; Djukovic, Danijel; Beyer, Richard P.; Raftery, Daniel; MacCoss, Michael; Tian, Rong; Rabinovitch, Peter S.

    2016-01-01

    Rapamycin, an inhibitor of mTOR signaling, has been shown to reverse diastolic dysfunction in old mice in 10 weeks, highlighting its therapeutic potential for a poorly treatable condition. However, the mechanisms and temporal regulation of its cardiac benefits remain unclear. We show that improved diastolic function in old mice begins at 2-4 weeks, progressing over the course of 10-week treatment. While TORC1-mediated S6 phosphorylation and TORC2 mediated AKT and PKCα phosphorylation are inhibited throughout the course of treatment, rapamycin inhibits ULK phosphorylation and induces autophagy during just the first week of treatment, returning to baseline at two weeks and after. Concordantly, markers of mitochondrial biogenesis increase over the first two weeks of treatment and return to control levels thereafter. This transient induction of autophagy and mitochondrial biogenesis suggests that damaged mitochondria are replaced by newly synthesized ones to rejuvenate mitochondrial homeostasis. This remodeling is shown to rapidly reverse the age-related reduction in fatty acid oxidation to restore a more youthful substrate utilization and energetic profile in old isolated perfused hearts, and modulates the myocardial metabolome in vivo. This study demonstrates the differential and dynamic mechanisms following rapamycin treatment and highlights the importance of understanding the temporal regulation of rapamycin effects. PMID:26872208

  17. Influences of rapid pacing-induced electrical remodeling on pharmacological manipulation of the atrial refractoriness in rabbits.

    PubMed

    Chiba, Toshiki; Kondo, Naoto; Takahara, Akira

    2016-03-01

    Electrical remodeling plays a pivotal role in maintaining the reentry during atrial fibrillation. In this study, we assessed influence of electrical remodeling on pharmacological manipulation of the atrial refractoriness in rabbits. We used an atrial electrical remodeling model of the rabbit, subjected to rapid atrial pacing (RAP; 600 beats/min) for 2-4 weeks, leading to shortening of atrial effective refractory period (AERP). Intravenous administration of dl-sotalol (6 mg/kg), bepridil (1 mg/kg), amiodarone (10 mg/kg) or vernakalant (3 mg/kg) significantly prolonged the AERP both in the control and RAP rabbits. The extents in the RAP rabbits were similar to those in the control animals. On the other hand, prolonging effects of intravenously administered ranolazine (10 mg/kg) or tertiapin-Q (0.03 mg/kg) on the AERP in the RAP rabbits were more potent than those in the control animals. These results suggest that rapid pacing-induced electrical remodeling effectively modified the prolonging effects of ranolazine and tertiapin-Q on the AERP in contrast to those of clinically available antiarrhythmic drugs, dl-sotalol, bepridil amiodarone and vernakalant. PMID:27032905

  18. Neural Cell Adhesion Molecule NrCAM Regulates Semaphorin 3F-Induced Dendritic Spine Remodeling

    PubMed Central

    Demyanenko, Galina P.; Mohan, Vishwa; Zhang, Xuying; Brennaman, Leann H.; Dharbal, Katherine E.S.; Tran, Tracy S.; Manis, Paul B.

    2014-01-01

    Neuron-glial related cell adhesion molecule (NrCAM) is a regulator of axon growth and repellent guidance, and has been implicated in autism spectrum disorders. Here a novel postsynaptic role for NrCAM in Semaphorin3F (Sema3F)-induced dendritic spine remodeling was identified in pyramidal neurons of the primary visual cortex (V1). NrCAM localized to dendritic spines of star pyramidal cells in postnatal V1, where it was coexpressed with Sema3F. NrCAM deletion in mice resulted in elevated spine densities on apical dendrites of star pyramidal cells at both postnatal and adult stages, and electron microscopy revealed increased numbers of asymmetric synapses in layer 4 of V1. Whole-cell recordings in cortical slices from NrCAM-null mice revealed increased frequency of mEPSCs in star pyramidal neurons. Recombinant Sema3F-Fc protein induced spine retraction on apical dendrites of wild-type, but not NrCAM-null cortical neurons in culture, while re-expression of NrCAM rescued the spine retraction response. NrCAM formed a complex in brain with Sema3F receptor subunits Neuropilin-2 (Npn-2) and PlexinA3 (PlexA3) through an Npn-2-binding sequence (TARNER) in the extracellular Ig1 domain. A trans heterozygous genetic interaction test demonstrated that Sema3F and NrCAM pathways interacted in vivo to regulate spine density in star pyramidal neurons. These findings reveal NrCAM as a novel postnatal regulator of dendritic spine density in cortical pyramidal neurons, and an integral component of the Sema3F receptor complex. The results implicate NrCAM as a contributor to excitatory/inhibitory balance in neocortical circuits. PMID:25143608

  19. HMGB1-RAGE Axis Makes No Contribution to Cardiac Remodeling Induced by Pressure-Overload

    PubMed Central

    Xie, Jiahe; Hao, Huixin; Zhang, Yingxue; Chen, Zhenhuan; Yamamoto, Hiroshi; Liao, Wangjun; Bin, Jianping; Cao, Shiping; Huang, Xiaobo

    2016-01-01

    High-mobility group box1 (HMGB1) exerts effects on inflammation by binding to receptor for advanced glycation end products (RAGE) or Toll-like receptor 4. Considering that inflammation is involved in pressure overload-induced cardiac hypertrophy, we herein attempted to investigate whether HMGB1 plays a role in myocardial hypertrophy in RAGE knockout mice as well as in the growth and apoptosis of cardiomyocytes. The myocardial expression of RAGE was not significantly changed while TLR4 mRNA was upregulated in response to transverse aortic constriction (TAC) for 1 week. The myocardial expression of HMGB1 protein was markedly increased in TAC group when compared to the sham group. Heart weight to body weight ratio (HW/BW) and lung weight to body weight ratio (LW/BW) were evaluated in RAGE knockout (KO) and wild-type (WT) mice 1 week after TAC. Significant larger HW/BW and LW/BW ratios were found in TAC groups than the corresponding sham groups, but no significant difference was found between KO and WT TAC mice. Similar results were also found when TAC duration was extended to 4 weeks. Cultured neonatal rat cardiomyocytes were treated with different concentrations of recombinant HMGB1, then cell viability was determined using MTT and CCK8 assays and cell apoptosis was determined by Hoechst staining and TUNEL assay. The results came out that HMGB1 exerted no influence on viability or apoptosis of cardiomyocytes. Besides, the protein expression levels of Bax and Bcl2 in response to different concentrations of HMGB1 were similar. These findings indicate that HMGB1 neither exerts influence on cardiac remodeling by binding to RAGE nor induces apoptosis of cardiomyocytes under physiological condition. PMID:27355349

  20. Functional Effects of WNT1-Inducible Signaling Pathway Protein-1 on Bronchial Smooth Muscle Cell Migration and Proliferation in OVA-Induced Airway Remodeling.

    PubMed

    Yang, Mingjin; Du, Yuejun; Xu, Zhibo; Jiang, Youfan

    2016-02-01

    Upregulation of WISP1 has been demonstrated in lung remodeling. Moreover, it has been recently found that some signaling components of WNT pathway can activate GSK3β signaling to mediate remodeling of airway smooth muscle (ASM) in asthma. Therefore, we hypothesized that WISP1, a signaling molecule downstream of the WNT signaling pathway, is involved in PI3K/GSK3β signaling to mediate ASM remodeling in asthma. Our results showed that WISP1 depletion partly suppressed OVA-induced ASM hypertrophy in vivo. In vitro, WISP1 could induce hBSMC hypertrophy and proliferation, accompanied by upregulation of levels of PI3K, p-Akt, p-GSK3β, and its own expression. TGF-β treatment could increase expression of PI3K, p-Akt, p-GSK3β, and WISP1. SH-5 treatment could partly suppress TGF-β-induced hypertrophy and proliferation of hBSMC, and depress expression of p-GSK3β and WISP1. In conclusion, WISP1 may be a potential inducer of ASM proliferation and hypertrophy in asthma. The pro-remodeling effect of WISP1 is likely due to be involved in PI3K-GSK3β-dependent noncanonical TGF-β signaling. PMID:26242865

  1. Endothelial nitric oxide synthase mediates lymphangiogenesis and lymphatic metastasis

    PubMed Central

    Lahdenranta, Johanna; Hagendoorn, Jeroen; Padera, Timothy P.; Hoshida, Tohru; Nelson, Gregory; Kashiwagi, Satoshi; Jain, Rakesh K.; Fukumura, Dai

    2009-01-01

    Lymphatic metastasis is a critical determinant of cancer prognosis. Recently, several lymphangiogenic molecules such as vafscular endothelial growth factor (VEGF)-C and -D were identified. However, the mechanistic understanding of lymphatic metastasis is still in infancy. Nitric oxide (NO) plays a crucial role in regulating blood vessel growth and function as well as lymphatic vessel function. NOS expression correlates with lymphatic metastasis. However, causal relationship between NOS and lymphatic metastasis has not been documented. To this end, we first show that both VEGF receptor-2 and -3 stimulation activate eNOS in lymphatic endothelial cells and that NO donors induce proliferation and/or survival of cultured lymphatic endothelial cells in a dose dependent manner. We find that an NOS inhibitor L-NMMA blocked regeneration of lymphatic vessels. Using intravital microscopy that allows us to visualize the steps of lymphatic metastasis, we show that genetic deletion of eNOS as well as NOS blockade attenuates peritumor lymphatic hyperplasia of VEGF-C-overexpressing T241 fibrosarcomas and decreases the delivery of metastatic tumor cells to the draining lymph nodes. Genetic deletion of eNOS in the host also leads to a decrease in T241 tumor cell dissemination to the lymph nodes and macroscopic lymph node metastasis of B16F10 melanoma. These findings indicate that eNOS mediates VEGF-C induced lymphangiogenesis and, consequently, plays a critical role in lymphatic metastasis. Our findings explain the correlation between NOS and lymphatic metastasis seen in a number of human tumors and open the door for potential therapies exploiting NO signaling to treat diseases of the lymphatic system. PMID:19318557

  2. Vibration Induced Osteogenic Commitment of Mesenchymal Stem Cells is Enhanced by Cytoskeletal Remodeling but not Fluid Shear

    PubMed Central

    Uzer, Gunes; Pongkitwitoon, Suphannee; Chan, M Ete; Judex, Stefan

    2013-01-01

    Consistent across studies in humans, animals and cells, the application of vibrations can be anabolic and/or anti-catabolic to bone. The physical mechanisms modulating the vibration-induced response have not been identified. Recently, we developed an in vitro model in which candidate parameters including acceleration magnitude and fluid shear can be controlled independently during vibrations. Here, we hypothesized that vibration induced fluid shear does not modulate mesenchymal stem cell (MSC) proliferation and mineralization and that cell’s sensitivity to vibrations can be promoted via actin stress fiber formation. Adipose derived human MSCs were subjected to vibration frequencies and acceleration magnitudes that induced fluid shear stress ranging from 0.04Pa to 5Pa. Vibrations were applied at magnitudes of 0.15g, 1g, and 2g using frequencies of both 100Hz and 30Hz. After 14d and under low fluid shear conditions associated with 100Hz oscillations, mineralization was greater in all vibrated groups than in controls. Greater levels of fluid shear produced by 30Hz vibrations enhanced mineralization only in the 2g group. Over 3d, vibrations led to the greatest increase in total cell number with the frequency/acceleration combination that induced the smallest level of fluid shear. Acute experiments showed that actin remodeling was necessary for early mechanical up-regulation of RUNX-2 mRNA levels. During osteogenic differentiation, mechanically induced up-regulation of actin remodeling genes including Wiskott-Aldrich syndrome (WAS) protein, a critical regulator of Arp2/3 complex, was related to the magnitude of the applied acceleration but not to fluid shear. These data demonstrate that fluid shear does not regulate vibration induced proliferation and mineralization and that cytoskeletal remodeling activity may play a role in MSC mechanosensitivity. PMID:23870506

  3. Sildenafil ameliorates left ventricular T-tubule remodeling in a pressure overload-induced murine heart failure model

    PubMed Central

    Huang, Chun-kai; Chen, Bi-yi; Guo, Ang; Chen, Rong; Zhu, Yan-qi; Kutschke, William; Hong, Jiang; Song, Long-sheng

    2016-01-01

    Aim: Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has been shown to exert beneficial effects in heart failure. The purpose of this study was to test whether sildenafil suppressed transverse-tubule (T-tubule) remodeling in left ventricular (LV) failure and thereby providing the therapeutic benefits. Methods: A pressure overload-induced murine heart failure model was established in mice by thoracic aortic banding (TAB). One day after TAB, the mice received sildenafil (100 mg·kg−1·d−1, sc) or saline for 5 weeks. At the end of treatment, echocardiography was used to examine LV function. Then the intact hearts were dissected out and placed in Langendorff-perfusion chamber for in situ confocal imaging of T-tubule ultrastructure from epicardial myocytes. Results: TAB surgery resulted in heart failure accompanied by remarkable T-tubule remodeling. Sildenafil treatment significantly attenuated TAB-induced cardiac hypertrophy and congestive heart failure, improved LV contractile function, and preserved T-tubule integrity in LV cardiomyocytes. But sildenafil treatment did not significantly affect the chamber dilation. The integrity of LV T-tubule structure was correlated with cardiac hypertrophy (R2=0.74, P<0.01) and global LV function (R2=0.47, P<0.01). Conclusion: Sildenafil effectively ameliorates LV T-tubule remodeling in TAB mice, revealing a novel mechanism underlying the therapeutic benefits of sildenafil in heart failure. PMID:26972492

  4. The Epidermal Growth Factor Receptor Is Involved in Angiotensin II But Not Aldosterone/Salt-Induced Cardiac Remodelling

    PubMed Central

    Griol-Charhbili, Violaine; Escoubet, Brigitte; Sadoshima, Junichi; Farman, Nicolette; Jaisser, Frederic

    2012-01-01

    Experimental and clinical studies have shown that aldosterone/mineralocorticoid receptor (MR) activation has deleterious effects in the cardiovascular system; however, the signalling pathways involved in the pathophysiological effects of aldosterone/MR in vivo are not fully understood. Several in vitro studies suggest that Epidermal Growth Factor Receptor (EGFR) plays a role in the cardiovascular effects of aldosterone. This hypothesis remains to be demonstrated in vivo. To investigate this question, we analyzed the molecular and functional consequences of aldosterone exposure in a transgenic mouse model with constitutive cardiomyocyte-specific overexpression of a mutant EGFR acting as a dominant negative protein (DN-EGFR). As previously reported, Angiotensin II-mediated cardiac remodelling was prevented in DN-EGFR mice. However, when chronic MR activation was induced by aldosterone-salt-uninephrectomy, cardiac hypertrophy was similar between control littermates and DN-EGFR. In the same way, mRNA expression of markers of cardiac remodelling such as ANF, BNF or β-Myosin Heavy Chain as well as Collagen 1a and 3a was similarly induced in DN-EGFR mice and their CT littermates. Our findings confirm the role of EGFR in AngII mediated cardiac hypertrophy, and highlight that EGFR is not involved in vivo in the damaging effects of aldosterone on cardiac function and remodelling. PMID:22291909

  5. MDA—Lymphatic Filariasis

    PubMed Central

    2014-01-01

    Lymphatic filariasis is one of the neglected tropical diseases. It is estimated that 120 million people are currently infected in 73 countries where filariasis is endemic. Lymphatic filariasis is a leading cause of chronic disability worldwide, including of 15 million people who have lymphoedema (elephantiasis) and 25 million men who have hydrocoele. PMID:25425947

  6. Disease Modification of Breast Cancer–Induced Bone Remodeling by Cannabinoid 2 Receptor Agonists

    PubMed Central

    Symons-Liguori, Ashley M; Largent-Milnes, Tally M; Havelin, Josh J; Ferland, Henry L; Chandramouli, Anupama; Owusu-Ankomah, Mabel; Nikolich-Zugich, Tijana; Bloom, Aaron P; Jimenez-Andrade, Juan Miguel; King, Tamara; Porreca, Frank; Nelson, Mark A; Mantyh, Patrick W; Vanderah, Todd W

    2015-01-01

    Most commonly originating from breast malignancies, metastatic bone cancer causes bone destruction and severe pain. Although novel chemotherapeutic agents have increased life expectancy, patients are experiencing higher incidences of fracture, pain, and drug-induced side effects; furthermore, recent findings suggest that patients are severely undertreated for their cancer pain. Strong analgesics, namely opiates, are first-line therapy in alleviating cancer-related pain despite the severe side effects, including enhanced bone destruction with sustained administration. Bone resorption is primarily treated with bisphosphonates, which are associated with highly undesirable side effects, including nephrotoxicity and osteonecrosis of the jaw. In contrast, cannabinoid receptor 2 (CB2) receptor-specific agonists have been shown to reduce bone loss and stimulate bone formation in a model of osteoporosis. CB2 agonists produce analgesia in both inflammatory and neuropathic pain models. Notably, mixed CB1/CB2 agonists also demonstrate a reduction in ErbB2-driven breast cancer progression. Here we demonstrate for the first time that CB2 agonists reduce breast cancer–induced bone pain, bone loss, and breast cancer proliferation via cytokine/chemokine suppression. Studies used the spontaneously-occurring murine mammary cell line (66.1) implanted into the femur intramedullary space; measurements of spontaneous pain, bone loss, and cancer proliferation were made. The systemic administration of a CB2 agonist, JWH015, for 7 days significantly attenuated bone remodeling, assuaged spontaneous pain, and decreased primary tumor burden. CB2-mediated effects in vivo were reversed by concurrent treatment with a CB2 antagonist/inverse agonist but not with a CB1 antagonist/inverse agonist. In vitro, JWH015 reduced cancer cell proliferation and inflammatory mediators that have been shown to promote pain, bone loss, and proliferation. Taken together, these results suggest CB2 agonists as a

  7. CD8+ T cells suppress viral replication in the cornea but contribute to VEGF-C-induced lymphatic vessel genesis.

    PubMed

    Conrady, Christopher D; Zheng, Min; Stone, Donald U; Carr, Daniel J J

    2012-07-01

    HSV-1 is the leading cause of infectious corneal blindness in the industrialized world. CD4(+) T cells are thought to be the major leukocyte population mediating immunity to HSV-1 in the cornea as well as the likely source of immunopathology that reduces visual acuity. However, the role of CD8(+) T cells in immune surveillance of the cornea is unclear. Thus, we sought to evaluate the role of CD8(+) T cells in ocular immunity using transgenic mice in which >98% of CD8(+) T cells are specific for the immunodominant HSV-1 epitope (gBT-I.1). We found a significant reduction in virus, elevation in HSV-specific CD8(+) T cell influx, and more CD8(+) T cells expressing CXCR3 in the cornea of transgenic mice compared with those in the cornea of wild-type controls yet similar acute corneal pathology. However, by day 30 postinfection, wild-type mice had drastically more blood and lymphatic vessel projections into the cornea compared with gBT-I.1 mice, in which only lymphatic vessel growth in response to VEGF-C could be appreciated. Taken together, these results show that CD8(+) T cells are required to eliminate virus more efficiently from the cornea but play a minimal role in immunopathology as a source of VEGF-C. PMID:22649204

  8. Cardiomyocyte-specific expression of CYP2J2 prevents development of cardiac remodelling induced by angiotensin II

    PubMed Central

    He, Zuowen; Zhang, Xu; Chen, Chen; Wen, Zheng; Hoopes, Samantha L.; Zeldin, Darryl C.; Wang, Dao Wen

    2015-01-01

    Aims Cardiac remodelling is one of the key pathological changes that occur with cardiovascular disease. Previous studies have demonstrated the beneficial effects of CYP2J2 expression on cardiac injury. In the present study, we investigated the effects of cardiomyocyte-specific CYP2J2 expression and EET treatment on angiotensin II-induced cardiac remodelling and sought to determine the underlying molecular mechanisms involved in this process. Methods and results Eight-week-old mice with cardiomyocyte-specific CYP2J2 expression (αMHC-CYP2J2-Tr) and wild-type (WT) control mice were treated with Ang-II. Ang-II treatment of WT mice induced changes in heart morphology, cardiac hypertrophy and dysfunction, as well as collagen accumulation; however, cardiomyocyte-specific expression of CYP2J2 attenuated these effects. The cardioprotective effects observed in α-MHC-CYP2J2-Tr mice were associated with peroxisome proliferator-activated receptor (PPAR)-γ activation, reduced oxidative stress, reduced NF-κB p65 nuclear translocation, and inhibition of TGF-β1/smad pathway. The effects seen with cardiomyocyte-specific expression of CYP2J2 were partially blocked by treatment with PPAR-γ antagonist GW9662. In in vitro studies, 11,12-EET(1 μmol/L) treatment attenuated cardiomyocyte hypertrophy and remodelling-related protein (collagen I, TGF-β1, TIMP1) expression by inhibiting the oxidative stress-mediated NF-κB pathway via PPAR-γ activation. Furthermore, conditioned media from neonatal cardiomyocytes treated with 11,12-EET inhibited activation of cardiac fibroblasts and TGF-β1/smad pathway. Conclusion Cardiomyocyte-specific expression of CYP2J2 or treatment with EETs protects against cardiac remodelling by attenuating oxidative stress-mediated NF-κBp65 nuclear translocation via PPAR-γ activation. PMID:25618409

  9. Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II-Induced Vascular Remodeling via Downregulation of β-Catenin.

    PubMed

    Cui, Mingli; Cai, Zhaohua; Chu, Shichun; Sun, Zhe; Wang, Xiaolei; Hu, Liuhua; Yi, Jing; Shen, Linghong; He, Ben

    2016-01-01

    Angiotensin II (Ang II) is the predominant effector peptide of the renin-angiotensin system. Ang II contributes to vascular remodeling in many cardiovascular diseases (eg, hypertension, atherosclerosis, restenosis, and aneurysm). Orphan nuclear receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II-induced vascular remodeling. Nur77 expression was initially found to be elevated in medial vascular smooth muscle cells (VSMCs) of thoracic aortas from mice continuously infused with Ang II for 2 weeks using a subcutaneous osmotic minipump. Cellular studies revealed that Nur77 expression was upregulated by Ang II via the MAPK/PKA-CREB signaling pathway. Ang II-induced proliferation, migration, and phenotypic switching were significantly enhanced in VSMCs isolated from Nur77(-/-) mice compared with wild-type VSMCs. Consistent with the role in VSMCs, we found that compared with wild-type mice, Nur77(-/-) mice had elevated aortic medial areas and luminal diameters, more severe elastin disruption and collagen deposition, increased VSMC proliferation and matrix metalloproteinase production, and decreased VSMC-specific genes SM-22α and α-actin expression, after 2 weeks of exogenous Ang II administration. The results of additional experiments suggested that Nur77 suppressed Ang II-induced β-catenin signaling pathway activation by promoting β-catenin degradation and inhibiting its transcriptional activity. Our findings indicated that Nur77 is a critical negative regulator of Ang II-induced VSMC proliferation, migration, and phenotypic switching via the downregulation of β-catenin activity. Nur77 may reduce Ang II-induced vascular remodeling involved in many cardiovascular diseases. PMID:26597820

  10. Overexpression of VEGF-C attenuates chronic high salt intake-induced left ventricular maladaptive remodeling in spontaneously hypertensive rats.

    PubMed

    Yang, Guo-Hong; Zhou, Xin; Ji, Wen-Jie; Zeng, Shan; Dong, Yan; Tian, Lu; Bi, Ying; Guo, Zhao-Zeng; Gao, Fei; Chen, Hong; Jiang, Tie-Min; Li, Yu-Ming

    2014-02-15

    Recent studies have shown that the tonicity-responsive enhancer binding protein (TonEBP)/vascular endothelial growth factor-C (VEGF-C) signaling pathway-induced lymphangiogenesis provides a buffering mechanism for high salt (HS) intake-induced elevation of blood pressure (BP). Moreover, blocking of TonEBP/VEGF-C signaling by mononuclear phagocyte depletion can induce salt-sensitive hypertension in rats. We hypothesized that HS intake could have an impact on cardiac lymphangiogenesis, and regulation of VEGF-C bioactivity, which is largely through the main receptor for VEGFR-3, may modulate HS intake-induced left ventricular remodeling. We demonstrated upregulation of TonEBP, increased macrophage infiltration, and enhanced lymphangiogenesis in the left ventricles of spontaneously hypertensive rats (SHR) that were fed a HS diet (8.0% NaCl). Then, retrovirus vectors capable of overexpression (ΔNΔC/VEGF-C/Cys152Ser, used for overexpressing VEGF-C) and blocking (VEGFR-3-Rg, used for trapping of bioactive VEGF-C) of VEGF-C and control vector (pLPCX) were intravenously administered to SHR from week 9 of a 12-wk HS loading period. At the end of the HS challenge, overexpression of VEGF-C led to enhanced cardiac lymphangiogenesis, decreased myocardial fibrosis, and macrophage infiltration, preserved left ventricular functions, as well as decreased blood pressure level compared with the HS group and the control vector-treated HS group. In contrast, systemic blocking of VEGF-C was associated with elevation of blood pressure level and an exacerbation of hypertensive left ventricular remodeling, as indicated by increased fibrosis and macrophage infiltration, and diminished lymphangiogenesis. Hence, our findings highlight that VEGF-C/VEGFR-3 is a promising therapeutic target to attenuate hypertensive left ventricular remodeling induced by HS intake, presumably via blood pressure-dependent and -independent mechanisms. PMID:24337460

  11. Viral infection of the marine alga Emiliania huxleyi triggers lipidome remodeling and induces the production of highly saturated triacylglycerol.

    PubMed

    Malitsky, Sergey; Ziv, Carmit; Rosenwasser, Shilo; Zheng, Shuning; Schatz, Daniella; Porat, Ziv; Ben-Dor, Shifra; Aharoni, Asaph; Vardi, Assaf

    2016-04-01

    Viruses that infect marine photosynthetic microorganisms are major ecological and evolutionary drivers of microbial food webs, estimated to turn over more than a quarter of the total photosynthetically fixed carbon. Viral infection of the bloom-forming microalga Emiliania huxleyi induces the rapid remodeling of host primary metabolism, targeted towards fatty acid metabolism. We applied a liquid chromatography-mass spectrometry (LC-MS)-based lipidomics approach combined with imaging flow cytometry and gene expression profiling to explore the impact of viral-induced metabolic reprogramming on lipid composition. Lytic viral infection led to remodeling of the cellular lipidome, by predominantly inducing the biosynthesis of highly saturated triacylglycerols (TAGs), coupled with a significant accumulation of neutral lipids within lipid droplets. Furthermore, TAGs were found to be a major component (77%) of the lipidome of isolated virions. Interestingly, viral-induced TAGs were significantly more saturated than TAGs produced under nitrogen starvation. This study highlights TAGs as major products of the viral-induced metabolic reprogramming during the host-virus interaction and indicates a selective mode of membrane recruitment during viral assembly, possibly by budding of the virus from specialized subcellular compartments. These findings provide novel insights into the role of viruses infecting microalgae in regulating metabolism and energy transfer in the marine environment and suggest their possible biotechnological application in biofuel production. PMID:26856244

  12. Allergen-induced airway remodeling is impaired in galectin-3 deficient mice1

    PubMed Central

    Ge, Xiao Na; Bahaie, Nooshin S.; Kang, Bit Na; Hosseinkhani, Reza M.; Ha, Sung Gil; Frenzel, Elizabeth M.; Liu, Fu-Tong; Rao, Savita P.; Sriramarao, P.

    2010-01-01

    The role played by the β-galactoside-binding lectin galectin-3 (Gal-3) in airway remodeling, a characteristic feature of asthma that leads to airway dysfunction and poor clinical outcome in humans, was investigated in a murine model of chronic allergic airway inflammation. Wild-type (WT) and Gal-3 knock-out (KO) mice were subjected to repetitive allergen challenge with ovalbumin (OVA) up to 12 weeks and bronchoalveolar lavage fluid (BALF) and lung tissue collected after the last challenge were evaluated for cellular features associated with airway remodeling. Compared to WT mice, chronic OVA challenge in Gal-3 KO mice resulted in diminished remodeling of the airways with significantly reduced mucus secretion, sub-epithelial fibrosis, smooth muscle thickness, and peribronchial angiogenesis. The higher degree of airway remodeling in WT mice was associated with higher Gal-3 expression in the BALF as well as lung tissue. Cell counts in BALF and lung immunohistology demonstrated that eosinophil infiltration in OVA-challenged Gal-3 KO mice was significantly reduced compared to WT mice. Evaluation of cellular mediators associated with eosinophil recruitment and airway remodeling revealed that levels of eotaxin-1, IL-5, IL-13, FIZZ1 and TGF-β were substantially lower in Gal-3 KO mice. Finally, leukocytes from Gal-3 KO mice demonstrated decreased trafficking (rolling) on vascular endothelial adhesion molecules compared to WT cells. Overall, these studies demonstrate that Gal-3 is an important lectin that promotes airway remodeling via airway recruitment of inflammatory cells, specifically eosinophils, and the development of a Th2 phenotype as well as increased expression of eosinophil-specific chemokines, pro-fibrogenic and angiogenic mediators. PMID:20543100

  13. Iron-induced remodeling in cultured rat pulmonary artery endothelial cells.

    PubMed

    Gorbunov, Nikolai V; Atkins, James L; Gurusamy, Narasimman; Pitt, Bruce R

    2012-02-01

    Although iron is known to be a component of the pathogenesis and/or maintenance of acute lung injury (ALI) in experimental animals and human subjects, the majority of these studies have focused on disturbances in iron homeostasis in the airways resulting from exposure to noxious gases and particles. Considerably less is known about the effect of increased plasma levels of redox-reactive non-transferrin bound iron (NTBI) and its impact on pulmonary endothelium. Plasma levels of NTBI can increase under various pathophysiological conditions, including those associated with ALI, and multiple mechanisms are in place to affect the [Fe(2+)]/[Fe(3+)] redox steady state. It is well accepted, however, that intracellular transport of NTBI occurs after reduction of [Fe(3+)] to [Fe(2+)] (and is mediated by divalent metal transporters). Accordingly, as an experimental model to investigate mechanisms mediating vascular effects of redox reactive iron, rat pulmonary artery endothelial cells (RPAECs) were subjected to pulse treatment (10 min) with [Fe(2+)] nitriloacetate (30 μM) in the presence of pyrithione, an iron ionophore, to acutely increase intracellular labile pool of iron. Cellular iron influx and cell shape profile were monitored with time-lapse imaging techniques. Exposure of RPAECs to [Fe(2+)] resulted in: (i) an increase in intracellular iron as detected by the iron sensitive fluorophore, PhenGreen; (ii) depletion of cell glutathione; and (iii) nuclear translocation of stress-response transcriptional factors Nrf2 and NFkB (p65). The resulting iron-induced cell alterations were characterized by cell polarization and formation of membrane cuplike and microvilli-like projections abundant with ICAM-1, caveolin-1, and F-actin. The iron-induced re-arrangements in cytoskeleton, alterations in focal cell-cell interactions, and cell buckling were accompanied by decrease in electrical resistance of RPAEC monolayer. These effects were partially eliminated in the presence of N

  14. [Bone formation and corticotomy-induced accelerated bone remodeling: can alveolar corticotomy induce bone formation?].

    PubMed

    Moreau, Nathan; Charrier, Jean-Baptiste

    2015-03-01

    Current orthodontic treatments must answer an increasing demand for faster yet as efficient treatments, especially in adult patients. These past years, the amelioration of orthodontic, anesthetic and orthognathic surgery techniques have allowed considerable improvement of orthodontico-surgical treatments and of adult orthodontic treatments. Alveolar corticotomy (an example of such techniques) accelerates orthodontic tooth movements by local modifications of bone metabolism, inducing a transient osteopenia. This osteopenia allows greater tooth movements than conventional techniques. Whereas there is a growing understanding of the underlying biological mechanisms of alveolar corticotomies, there is little data regarding the osteogenic potential of such technique. In the present article, we review the literature pertaining to alveolar corticotomies and their underlying biological mechanisms and present a clinical case underlining the osteogenic potential of the technique. PMID:25888047

  15. α-Synuclein Senses Lipid Packing Defects and Induces Lateral Expansion of Lipids Leading to Membrane Remodeling*

    PubMed Central

    Ouberai, Myriam M.; Wang, Juan; Swann, Marcus J.; Galvagnion, Celine; Guilliams, Tim; Dobson, Christopher M.; Welland, Mark E.

    2013-01-01

    There is increasing evidence for the involvement of lipid membranes in both the functional and pathological properties of α-synuclein (α-Syn). Despite many investigations to characterize the binding of α-Syn to membranes, there is still a lack of understanding of the binding mode linking the properties of lipid membranes to α-Syn insertion into these dynamic structures. Using a combination of an optical biosensing technique and in situ atomic force microscopy, we show that the binding strength of α-Syn is related to the specificity of the lipid environment (the lipid chemistry and steric properties within a bilayer structure) and to the ability of the membranes to accommodate and remodel upon the interaction of α-Syn with lipid membranes. We show that this interaction results in the insertion of α-Syn into the region of the headgroups, inducing a lateral expansion of lipid molecules that can progress to further bilayer remodeling, such as membrane thinning and expansion of lipids out of the membrane plane. We provide new insights into the affinity of α-Syn for lipid packing defects found in vesicles of high curvature and in planar membranes with cone-shaped lipids and suggest a comprehensive model of the interaction between α-Syn and lipid bilayers. The ability of α-Syn to sense lipid packing defects and to remodel membrane structure supports its proposed role in vesicle trafficking. PMID:23740253

  16. Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs.

    PubMed

    Grasemann, Hartmut; Dhaliwal, Rupinder; Ivanovska, Julijana; Kantores, Crystal; McNamara, Patrick J; Scott, Jeremy A; Belik, Jaques; Jankov, Robert P

    2015-03-15

    Arginase is an enzyme that limits substrate L-arginine bioavailability for the production of nitric oxide by the nitric oxide synthases and produces L-ornithine, which is a precursor for collagen formation and tissue remodeling. We studied the pulmonary vascular effects of arginase inhibition in an established model of repeated systemic bleomycin sulfate administration in neonatal rats that results in pulmonary hypertension and lung injury mimicking the characteristics typical of bronchopulmonary dysplasia. We report that arginase expression is increased in the lungs of bleomycin-exposed neonatal rats and that treatment with the arginase inhibitor amino-2-borono-6-hexanoic acid prevented the bleomycin-induced development of pulmonary hypertension and deposition of collagen. Arginase inhibition resulted in increased L-arginine and L-arginine bioavailability and increased pulmonary nitric oxide production. Arginase inhibition also normalized the expression of inducible nitric oxide synthase, and reduced bleomycin-induced nitrative stress while having no effect on bleomycin-induced inflammation. Our data suggest that arginase is a promising target for therapeutic interventions in neonates aimed at preventing lung vascular remodeling and pulmonary hypertension. PMID:25595650

  17. Mesoscale computational studies of membrane bilayer remodeling by curvature-inducing proteins

    NASA Astrophysics Data System (ADS)

    Ramakrishnan, N.; Sunil Kumar, P. B.; Radhakrishnan, Ravi

    2014-10-01

    Biological membranes constitute boundaries of cells and cell organelles. These membranes are soft fluid interfaces whose thermodynamic states are dictated by bending moduli, induced curvature fields, and thermal fluctuations. Recently, there has been a flood of experimental evidence highlighting active roles for these structures in many cellular processes ranging from trafficking of cargo to cell motility. It is believed that the local membrane curvature, which is continuously altered due to its interactions with myriad proteins and other macromolecules attached to its surface, holds the key to the emergent functionality in these cellular processes. Mechanisms at the atomic scale are dictated by protein-lipid interaction strength, lipid composition, lipid distribution in the vicinity of the protein, shape and amino acid composition of the protein, and its amino acid contents. The specificity of molecular interactions together with the cooperativity of multiple proteins induce and stabilize complex membrane shapes at the mesoscale. These shapes span a wide spectrum ranging from the spherical plasma membrane to the complex cisternae of the Golgi apparatus. Mapping the relation between the protein-induced deformations at the molecular scale and the resulting mesoscale morphologies is key to bridging cellular experiments across various length scales. In this review, we focus on the theoretical and computational methods used to understand the phenomenology underlying protein-driven membrane remodeling. Interactions at the molecular scale can be computationally probed by all atom and coarse grained molecular dynamics (MD, CGMD), as well as dissipative particle dynamics (DPD) simulations, which we only describe in passing. We choose to focus on several continuum approaches extending the Canham-Helfrich elastic energy model for membranes to include the effect of curvature-inducing proteins and explore the conformational phase space of such systems. In this description, the

  18. Mesoscale computational studies of membrane bilayer remodeling by curvature-inducing proteins.

    PubMed

    Ramakrishnan, N; Sunil Kumar, P B; Radhakrishnan, Ravi

    2014-10-01

    Biological membranes constitute boundaries of cells and cell organelles. These membranes are soft fluid interfaces whose thermodynamic states are dictated by bending moduli, induced curvature fields, and thermal fluctuations. Recently, there has been a flood of experimental evidence highlighting active roles for these structures in many cellular processes ranging from trafficking of cargo to cell motility. It is believed that the local membrane curvature, which is continuously altered due to its interactions with myriad proteins and other macromolecules attached to its surface, holds the key to the emergent functionality in these cellular processes. Mechanisms at the atomic scale are dictated by protein-lipid interaction strength, lipid composition, lipid distribution in the vicinity of the protein, shape and amino acid composition of the protein, and its amino acid contents. The specificity of molecular interactions together with the cooperativity of multiple proteins induce and stabilize complex membrane shapes at the mesoscale. These shapes span a wide spectrum ranging from the spherical plasma membrane to the complex cisternae of the Golgi apparatus. Mapping the relation between the protein-induced deformations at the molecular scale and the resulting mesoscale morphologies is key to bridging cellular experiments across the various length scales. In this review, we focus on the theoretical and computational methods used to understand the phenomenology underlying protein-driven membrane remodeling. Interactions at the molecular scale can be computationally probed by all atom and coarse grained molecular dynamics (MD, CGMD), as well as dissipative particle dynamics (DPD) simulations, which we only describe in passing. We choose to focus on several continuum approaches extending the Canham - Helfrich elastic energy model for membranes to include the effect of curvature-inducing proteins and explore the conformational phase space of such systems. In this

  19. Mesoscale computational studies of membrane bilayer remodeling by curvature-inducing proteins

    PubMed Central

    Ramakrishnan, N.; Sunil Kumar, P. B.; Radhakrishnan, Ravi

    2014-01-01

    Biological membranes constitute boundaries of cells and cell organelles. These membranes are soft fluid interfaces whose thermodynamic states are dictated by bending moduli, induced curvature fields, and thermal fluctuations. Recently, there has been a flood of experimental evidence highlighting active roles for these structures in many cellular processes ranging from trafficking of cargo to cell motility. It is believed that the local membrane curvature, which is continuously altered due to its interactions with myriad proteins and other macromolecules attached to its surface, holds the key to the emergent functionality in these cellular processes. Mechanisms at the atomic scale are dictated by protein-lipid interaction strength, lipid composition, lipid distribution in the vicinity of the protein, shape and amino acid composition of the protein, and its amino acid contents. The specificity of molecular interactions together with the cooperativity of multiple proteins induce and stabilize complex membrane shapes at the mesoscale. These shapes span a wide spectrum ranging from the spherical plasma membrane to the complex cisternae of the Golgi apparatus. Mapping the relation between the protein-induced deformations at the molecular scale and the resulting mesoscale morphologies is key to bridging cellular experiments across the various length scales. In this review, we focus on the theoretical and computational methods used to understand the phenomenology underlying protein-driven membrane remodeling. Interactions at the molecular scale can be computationally probed by all atom and coarse grained molecular dynamics (MD, CGMD), as well as dissipative particle dynamics (DPD) simulations, which we only describe in passing. We choose to focus on several continuum approaches extending the Canham - Helfrich elastic energy model for membranes to include the effect of curvature-inducing proteins and explore the conformational phase space of such systems. In this

  20. Levofloxacin decreased chest wall mechanical inhomogeneities and airway and vascular remodeling in rats with induced hepatopulmonary syndrome.

    PubMed

    Gaio, Eduardo; Amado, Veronica; Rangel, Leonardo; Huang, Wilson; Storck, Rodrigo; Melo-Silva, César Augusto

    2013-12-01

    The administration of antibiotics decreases bacterial translocation, reduces the activity of nitric oxide synthase and improves the gas exchange of hepatopulmonary syndrome (HPS) in rats. We hypothesized that levofloxacin could reduce HPS-induced respiratory mechanical inhomogeneities and airway and pulmonary vascular remodeling. We assessed the respiratory mechanical properties and lung tissue structure in 24 rats assigned to the control, HPS (eHPS) and HPS+levofloxacin (eHPS+L) groups. The administration of levofloxacin reduced the HPS-induced chest wall but not the lung mechanical inhomogeneities. The eHPS airway proportion of elastic fibers increased 20% but was similar between the control and eHPS+L groups. The eHPS vascular collagen increased 25% in eHPS but was similar between the control and eHPS+L groups. Compared to the control group, the vascular proportion of elastic fibers of the eHPS and eHPS+L groups increased by 60% and 16%, respectively. The administration of levofloxacin decreased the HPS-induced chest wall mechanical inhomogeneities and airway and vascular remodeling. PMID:23994178

  1. Lymphatics and the breast

    MedlinePlus Videos and Cool Tools

    ... very worrisome role in the spread of breast cancer. Components of the lymphatic system called lymph nodes ... may result in the formation of a secondary cancer mass in a different location of the body. ...

  2. Genetics of lymphatic anomalies

    PubMed Central

    Brouillard, Pascal; Boon, Laurence; Vikkula, Miikka

    2014-01-01

    Lymphatic anomalies include a variety of developmental and/or functional defects affecting the lymphatic vessels: sporadic and familial forms of primary lymphedema, secondary lymphedema, chylothorax and chylous ascites, lymphatic malformations, and overgrowth syndromes with a lymphatic component. Germline mutations have been identified in at least 20 genes that encode proteins acting around VEGFR-3 signaling but also downstream of other tyrosine kinase receptors. These mutations exert their effects via the RAS/MAPK and the PI3K/AKT pathways and explain more than a quarter of the incidence of primary lymphedema, mostly of inherited forms. More common forms may also result from multigenic effects or post-zygotic mutations. Most of the corresponding murine knockouts are homozygous lethal, while heterozygotes are healthy, which suggests differences in human and murine physiology and the influence of other factors. PMID:24590274

  3. Imperatorin derivative OW1 inhibits the upregulation of TGF-β and MMP-2 in renovascular hypertension-induced cardiac remodeling

    PubMed Central

    ZHOU, NAN; ZHU, YANING; ZHANG, PENG; ZHANG, YU; ZHOU, MINGYAO; WANG, TAO; HE, LANGCHONG

    2016-01-01

    Chronic hypertension induces vascular and cardiac remodeling. OW1 is a novel imperatorin derivative that was previously reported to inhibit vascular remodeling and improve kidney function affected by hypertension. In the present study, the effect of OW1 on the cardiac remodeling induced by hypertension was investigated. OW1 inhibited vascular smooth muscle cell (VSMC) proliferation and the phenotypic modulation of VSMCs induced by angiotensin II (Ang II). The OW1-induced vasodilatation of rat cardiac arteries was evaluated in vitro. Renovascular hypertensive rats were developed using the two-kidney one-clip method and treated with OW1 (40 or 80 mg/kg/day) or nifedipine (30 mg/kg per day) for 5 weeks. OW1 markedly reduced the systolic and diastolic blood pressure compared with that in the hypertension group or the respective baseline value during the first week. OW1 also reduced cardiac weight, and the concentrations of Ang II, aldosterone and transforming growth factor-β1 (TGF-β1). Histological examination demonstrated that OW1 exerted an inhibitory effect on vascular and cardiac remodeling. These inhibitory effects were associated with decreased cardiac levels of Ang II, matrix metalloproteinase-2 and TGF-β1 in the hypertensive rats. In summary, OW1 exhibited a clear antihypertensive effect. More importantly, it inhibited vascular and cardiovascular remodeling, which may reduce the risk of hypertension-induced cardiovascular diseases. These results have potential implications in the development of new antihypertensive drugs. PMID:27168797

  4. Lattice Boltzmann simulations of lymphatic pumping

    NASA Astrophysics Data System (ADS)

    Kunert, Christian; Padera, Tim P.; Munn, Lance L.

    2012-02-01

    Lymphatic flow plays an important role in the progress of many diseases, including lymphedema and metastasis. However lymphatic pumping and flow is poorly understood. Here, we present a computer model that is based on biological observations of lymphatic pumping. Fluid flow is simulated by a D2Q9 lattice Boltzmann model. The boundary of the vessels moves according to shear-induced nitric oxide production, and wall motion transfers momentum to the fluid to induce flow. Because the model only includes local properties, it can be highly parallelized. In our case we utilize graphic processors (GPU) to achieve high performance computation. We show that the model provides stable pumping over a wide range of parameter values, with optimum flow achieved in the biological ranges. Furthermore, we investigate the efficiency by analyzing the flow rate and pumping frequency in order to compare the behavior of the model with existing in vivo data.

  5. Adipose Mesenchymal Stem Cell Secretome Modulated in Hypoxia for Remodeling of Radiation-Induced Salivary Gland Damage

    PubMed Central

    An, Hye-Young; Shin, Hyun-Soo; Choi, Jeong-Seok; Kim, Hun Jung

    2015-01-01

    Background and Purpose This study was conducted to determine whether a secretome from mesenchymal stem cells (MSC) modulated by hypoxic conditions to contain therapeutic factors contributes to salivary gland (SG) tissue remodeling and has the potential to improve irradiation (IR)-induced salivary hypofunction in a mouse model. Materials and Methods Human adipose mesenchymal stem cells (hAdMSC) were isolated, expanded, and exposed to hypoxic conditions (O2 < 5%). The hypoxia-conditioned medium was then filtered to a high molecular weight fraction and prepared as a hAdMSC secretome. The hAdMSC secretome was subsequently infused into the tail vein of C3H mice immediately after local IR once a day for seven consecutive days. The control group received equal volume (500 μL) of vehicle (PBS) only. SG function and structural tissue remodeling by the hAdMSC secretome were investigated. Human parotid epithelial cells (HPEC) were obtained, expanded in vitro, and then irradiated and treated with either the hypoxia-conditioned medium or a normoxic control medium. Cell proliferation and IR-induced cell death were examined to determine the mechanism by which the hAdMSC secretome exerted its effects. Results The conditioned hAdMSC secretome contained high levels of GM-CSF, VEGF, IL-6, and IGF-1. Repeated systemic infusion with the hAdMSC secretome resulted in improved salivation capacity and increased levels of salivary proteins, including amylase and EGF, relative to the PBS group. The microscopic structural integrity of SG was maintained and salivary epithelial (AQP-5), endothelial (CD31), myoepithelial (α-SMA) and SG progenitor cells (c-Kit) were successfully protected from radiation damage and remodeled. The hAdMSC secretome strongly induced proliferation of HPEC and led to a significant decrease in cell death in vivo and in vitro. Moreover, the anti-apoptotic effects of the hAdMSC secretome were found to be promoted after hypoxia-preconditioning relative to normoxia

  6. Estrogen attenuates chronic volume overload induced structural and functional remodeling in male rat hearts

    PubMed Central

    Murray, David B.; Voloshenyuk, Tetyana G.; Brower, Gregory L.; Bradley, Jessica M.; Janicki, Joseph S.

    2010-01-01

    We have previously reported gender differences in ventricular remodeling and development of heart failure using the aortocaval fistula model of chronic volume overload in rats. In contrast to males, female rats exhibited no adverse ventricular remodeling and less mortality in response to volume overload. This gender-specific cardioprotection was lost following ovariectomy and was partially restored using estrogen replacement. However, it is not known if estrogen treatment would be as effective in males. The purpose of this study was to evaluate the structural and functional effects of estrogen in male rats subjected to chronic volume overload. Four groups of male rats were studied at 3 days and 8 wk postsurgery as follows: fistula and sham-operated controls, with and without estrogen treatment. Biochemical and histological studies were performed at 3 days postsurgery, with chronic structural and functional effects studied at 8 wk. Measurement of systolic and diastolic pressure-volume relationships was obtained using a blood-perfused isolated heart preparation. Both fistula groups developed significant ventricular hypertrophy after 8 wk of volume overload. Untreated rats with fistula exhibited extensive ventricular dilatation, which was coupled with a loss of systolic function. Estrogen attenuated left ventricular dilatation and maintained function in treated rats. Estrogen treatment was also associated with a reduction in oxidative stress and circulating endothelin-1 levels, as well as prevention of matrix metalloproteinase-2 and -9 activation and breakdown of ventricular collagen in the early stage of remodeling. These data demonstrate that estrogen attenuates ventricular remodeling and disease progression in male rats subjected to chronic volume overload. PMID:19933421

  7. Fatty acid induced remodeling within the human liver fatty acid-binding protein.

    PubMed

    Sharma, Ashwani; Sharma, Amit

    2011-09-01

    We crystallized human liver fatty acid-binding protein (LFABP) in apo, holo, and intermediate states of palmitic acid engagement. Structural snapshots of fatty acid recognition, entry, and docking within LFABP support a heads-in mechanism for ligand entry. Apo-LFABP undergoes structural remodeling, where the first palmitate ingress creates the atomic environment for placement of the second palmitate. These new mechanistic insights will facilitate development of pharmacological agents against LFABP. PMID:21757748

  8. Lymphatic Function Regulates Contact Hypersensitivity Dermatitis in Obesity.

    PubMed

    Savetsky, Ira L; Albano, Nicholas J; Cuzzone, Daniel A; Gardenier, Jason C; Torrisi, Jeremy S; García Nores, Gabriela D; Nitti, Matthew D; Hespe, Geoffrey E; Nelson, Tyler S; Kataru, Raghu P; Dixon, J Brandon; Mehrara, Babak J

    2015-11-01

    Obesity is a major risk factor for inflammatory dermatologic diseases, including atopic dermatitis and psoriasis. In addition, recent studies have shown that obesity impairs lymphatic function. As the lymphatic system is a critical regulator of inflammatory reactions, we tested the hypothesis that obesity-induced lymphatic dysfunction is a key regulator of cutaneous hypersensitivity reactions in obese mice. We found that obese mice have impaired lymphatic function, characterized by leaky capillary lymphatics and decreased collecting vessel pumping capacity. In addition, obese mice displayed heightened dermatitis responses to inflammatory skin stimuli, resulting in both higher peak inflammation and a delayed clearance of inflammatory responses. Injection of recombinant vascular endothelial growth factor-C remarkably increased lymphangiogenesis, lymphatic function, and lymphatic endothelial cell expression of chemokine (C-C motif) ligand 21, while decreasing inflammation and expression of inducible nitrous oxide synthase. These changes resulted in considerably decreased dermatitis responses in both lean and obese mice. Taken together, our findings suggest that obesity-induced changes in the lymphatic system result in an amplified and a prolonged inflammatory response. PMID:26176761

  9. Noradrenergic activation of the basolateral amygdala enhances object recognition memory and induces chromatin remodeling in the insular cortex

    PubMed Central

    Beldjoud, Hassiba; Barsegyan, Areg; Roozendaal, Benno

    2015-01-01

    It is well established that arousal-induced memory enhancement requires noradrenergic activation of the basolateral complex of the amygdala (BLA) and modulatory influences on information storage processes in its many target regions. While this concept is well accepted, the molecular basis of such BLA effects on neural plasticity changes within other brain regions remains to be elucidated. The present study investigated whether noradrenergic activation of the BLA after object recognition training induces chromatin remodeling through histone post-translational modifications in the insular cortex (IC), a brain region that is importantly involved in object recognition memory. Male Sprague—Dawley rats were trained on an object recognition task, followed immediately by bilateral microinfusions of norepinephrine (1.0 μg) or saline administered into the BLA. Saline-treated control rats exhibited poor 24-h retention, whereas norepinephrine treatment induced robust 24-h object recognition memory. Most importantly, this memory-enhancing dose of norepinephrine induced a global reduction in the acetylation levels of histone H3 at lysine 14, H2B and H4 in the IC 1 h later, whereas it had no effect on the phosphorylation of histone H3 at serine 10 or tri-methylation of histone H3 at lysine 27. Norepinephrine administered into the BLA of non-trained control rats did not induce any changes in the histone marks investigated in this study. These findings indicate that noradrenergic activation of the BLA induces training-specific effects on chromatin remodeling mechanisms, and presumably gene transcription, in its target regions, which may contribute to the understanding of the molecular mechanisms of stress and emotional arousal effects on memory consolidation. PMID:25972794

  10. MAPKAPK-2-mediated LIM-kinase activation is critical for VEGF-induced actin remodeling and cell migration

    PubMed Central

    Kobayashi, Miho; Nishita, Michiru; Mishima, Toshiaki; Ohashi, Kazumasa; Mizuno, Kensaku

    2006-01-01

    Vascular endothelial growth factor-A (VEGF-A) induces actin reorganization and migration of endothelial cells through a p38 mitogen-activated protein kinase (MAPK) pathway. LIM-kinase 1 (LIMK1) induces actin remodeling by phosphorylating and inactivating cofilin, an actin-depolymerizing factor. In this study, we demonstrate that activation of LIMK1 by MAPKAPK-2 (MK2; a downstream kinase of p38 MAPK) represents a novel signaling pathway in VEGF-A-induced cell migration. VEGF-A induced LIMK1 activation and cofilin phosphorylation, and this was inhibited by the p38 MAPK inhibitor SB203580. Although p38 phosphorylated LIMK1 at Ser-310, it failed to activate LIMK1 directly; however, MK2 activated LIMK1 by phosphorylation at Ser-323. Expression of a Ser-323-non-phosphorylatable mutant of LIMK1 suppressed VEGF-A-induced stress fiber formation and cell migration; however, expression of a Ser-323-phosphorylation-mimic mutant enhanced these processes. Knockdown of MK2 by siRNA suppressed VEGF-A-induced LIMK1 activation, stress fiber formation, and cell migration. Expression of kinase-dead LIMK1 suppressed VEGF-A-induced tubule formation. These findings suggest that MK2-mediated LIMK1 phosphorylation/activation plays an essential role in VEGF-A-induced actin reorganization, migration, and tubule formation of endothelial cells. PMID:16456544

  11. Multiphoton microscopy of engineered dermal substitutes: assessment of 3-D collagen matrix remodeling induced by fibroblast contraction

    NASA Astrophysics Data System (ADS)

    Pena, Ana-Maria; Fagot, Dominique; Olive, Christian; Michelet, Jean-François; Galey, Jean-Baptiste; Leroy, Frédéric; Beaurepaire, Emmanuel; Martin, Jean-Louis; Colonna, Anne; Schanne-Klein, Marie-Claire

    2010-09-01

    Dermal fibroblasts are responsible for the generation of mechanical forces within their surrounding extracellular matrix and can be potentially targeted by anti-aging ingredients. Investigation of the modulation of fibroblast contraction by these ingredients requires the implementation of three-dimensional in situ imaging methodologies. We use multiphoton microscopy to visualize unstained engineered dermal tissue by combining second-harmonic generation that reveals specifically fibrillar collagen and two-photon excited fluorescence from endogenous cellular chromophores. We study the fibroblast-induced reorganization of the collagen matrix and quantitatively evaluate the effect of Y-27632, a RhoA-kinase inhibitor, on dermal substitute contraction. We observe that collagen fibrils rearrange around fibroblasts with increasing density in control samples, whereas collagen fibrils show no remodeling in the samples containing the RhoA-kinase inhibitor. Moreover, we show that the inhibitory effects are reversible. Our study demonstrates the relevance of multiphoton microscopy to visualize three-dimensional remodeling of the extracellular matrix induced by fibroblast contraction or other processes.

  12. Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells

    PubMed Central

    Tewalt, Eric F.; Cohen, Jarish N.; Rouhani, Sherin J.; Guidi, Cynthia J.; Qiao, Hui; Fahl, Shawn P.; Conaway, Mark R.; Bender, Timothy P.; Tung, Kenneth S.; Vella, Anthony T.; Adler, Adam J.; Chen, Lieping

    2012-01-01

    Lymphatic endothelial cells (LECs) induce peripheral tolerance by direct presentation to CD8 T cells (TCD8). We demonstrate that LECs mediate deletion only via programmed cell death-1 (PD-1) ligand 1, despite expressing ligands for the CD160, B- and T-lymphocyte attenuator, and lymphocyte activation gene-3 inhibitory pathways. LECs induce activation and proliferation of TCD8, but lack of costimulation through 4-1BB leads to rapid high-level expression of PD-1, which in turn inhibits up-regulation of the high-affinity IL-2 receptor that is necessary for TCD8 survival. Rescue of tyrosinase-specific TCD8 by interference with PD-1 or provision of costimulation results in autoimmune vitiligo, demonstrating that LECs are significant, albeit suboptimal, antigen-presenting cells. Because LECs express numerous peripheral tissue antigens, lack of costimulation coupled to rapid high-level up-regulation of inhibitory receptors may be generally important in systemic peripheral tolerance. PMID:22993390

  13. Mechanical forces and lymphatic transport.

    PubMed

    Breslin, Jerome W

    2014-11-01

    This review examines the current understanding of how the lymphatic vessel network can optimize lymph flow in response to various mechanical forces. Lymphatics are organized as a vascular tree, with blind-ended initial lymphatics, precollectors, prenodal collecting lymphatics, lymph nodes, postnodal collecting lymphatics and the larger trunks (thoracic duct and right lymph duct) that connect to the subclavian veins. The formation of lymph from interstitial fluid depends heavily on oscillating pressure gradients to drive fluid into initial lymphatics. Collecting lymphatics are segmented vessels with unidirectional valves, with each segment, called a lymphangion, possessing an intrinsic pumping mechanism. The lymphangions propel lymph forward against a hydrostatic pressure gradient. Fluid is returned to the central circulation both at lymph nodes and via the larger lymphatic trunks. Several recent developments are discussed, including evidence for the active role of endothelial cells in lymph formation; recent developments on how inflow pressure, outflow pressure, and shear stress affect the pump function of the lymphangion; lymphatic valve gating mechanisms; collecting lymphatic permeability; and current interpretations of the molecular mechanisms within lymphatic endothelial cells and smooth muscle. An improved understanding of the physiological mechanisms by which lymphatic vessels sense mechanical stimuli, integrate the information, and generate the appropriate response is key for determining the pathogenesis of lymphatic insufficiency and developing treatments for lymphedema. PMID:25107458

  14. Mechanical Forces and Lymphatic Transport

    PubMed Central

    Breslin, Jerome W.

    2014-01-01

    This review examines current understanding of how the lymphatic vessel network can optimize lymph flow in response to various mechanical forces. Lymphatics are organized as a vascular tree, with blind-ended initial lymphatics, precollectors, prenodal collecting lymphatics, lymph nodes, postnodal collecting lymphatics and the larger trunks (thoracic duct and right lymph duct) that connect to the subclavian veins. The formation of lymph from interstitial fluid depends heavily on oscillating pressure gradients to drive fluid into initial lymphatics. Collecting lymphatics are segmented vessels with unidirectional valves, with each segment, called a lymphangion, possessing an intrinsic pumping mechanism. The lymphangions propel lymph forward against a hydrostatic pressure gradient. Fluid is returned to the central circulation both at lymph nodes and via the larger lymphatic trunks. Several recent developments are discussed, including: evidence for the active role of endothelial cells in lymph formation; recent developments on how inflow pressure, outflow pressure, and shear stress affect pump function of the lymphangion; lymphatic valve gating mechanisms; collecting lymphatic permeability; and current interpretations of the molecular mechanisms within lymphatic endothelial cells and smooth muscle. Improved understanding of the physiological mechanisms by lymphatic vessels sense mechanical stimuli, integrate the information, and generate the appropriate response is key for determining the pathogenesis of lymphatic insufficiency and developing treatments for lymphedema. PMID:25107458

  15. Expression and activation of TGF‐β isoforms in acute allergen‐induced remodelling in asthma

    PubMed Central

    Torrego, Alfons; Hew, Mark; Oates, Tim; Sukkar, Maria; Chung, Kian Fan

    2007-01-01

    Background Airway wall remodelling and inflammation are features of chronic asthma. Transforming growth factor β (TGF‐β) has been implicated in these processes. Aim To determine the effect of allergen challenge on airway inflammation and remodelling and whether TGF‐β isoforms and the Smad signalling pathways are involved. Methods Thirteen patients with atopic asthma underwent inhalational challenge with 0.9% saline, followed by allergen 3–4 weeks later. After both challenges, fibreoptic bronchoscopy was undertaken to obtain bronchial biopsies and tissue samples were processed for immunohistochemistry and examined by microscopy. Results Forced expiratory volume in 1 s (FEV1) fell after allergen challenge (mean (SE) −28.1 (0.9)% at 30 min with a late response at 7 hours (−23.0 (1.2)%). Allergen challenge caused an increase in neutrophils and eosinophils in the bronchial mucosa compared with saline. Sub‐basement membrane (SBM) thickness did not change after allergen, but tenascin deposition in SBM was increased. Intranuclear (activated) Smad 2/3 and Smad 4 detected by immunohistochemistry were increased after allergen challenge in epithelial and subepithelial cells of bronchial biopsies. No inhibitory Smad (Smad 7) protein was detected. TGF‐β isoforms 1, 2 and 3 were expressed predominantly in bronchial epithelium after saline and allergen challenges, but only TGF‐β2 expression was increased after allergen. Double immunostaining showed an increase in TGF‐β2 positive eosinophils and neutrophils but not in TGF‐β1 positive eosinophils and neutrophils after allergen challenge. Conclusions TGF‐β2 may contribute to the remodelling changes in allergic asthma following single allergen exposure. PMID:17251317

  16. Vagus nerve stimulation mitigates intrinsic cardiac neuronal remodeling and cardiac hypertrophy induced by chronic pressure overload in guinea pig.

    PubMed

    Beaumont, Eric; Wright, Gary L; Southerland, Elizabeth M; Li, Ying; Chui, Ray; KenKnight, Bruce H; Armour, J Andrew; Ardell, Jeffrey L

    2016-05-15

    Our objective was to determine whether chronic vagus nerve stimulation (VNS) mitigates pressure overload (PO)-induced remodeling of the cardioneural interface. Guinea pigs (n = 48) were randomized to right or left cervical vagus (RCV or LCV) implant. After 2 wk, chronic left ventricular PO was induced by partial (15-20%) aortic constriction. Of the 31 animals surviving PO induction, 10 were randomized to RCV VNS, 9 to LCV VNS, and 12 to sham VNS. VNS was delivered at 20 Hz and 1.14 ± 0.03 mA at a 22% duty cycle. VNS commenced 10 days after PO induction and was maintained for 40 days. Time-matched controls (n = 9) were evaluated concurrently. Echocardiograms were obtained before and 50 days after PO. At termination, intracellular current-clamp recordings of intrinsic cardiac (IC) neurons were studied in vitro to determine effects of therapy on soma characteristics. Ventricular cardiomyocyte sizes were assessed with histology along with immunoblot analysis of selected proteins in myocardial tissue extracts. In sham-treated animals, PO increased cardiac output (34%, P < 0.004), as well as systolic (114%, P < 0.04) and diastolic (49%, P < 0.002) left ventricular volumes, a hemodynamic response prevented by VNS. PO-induced enhancements of IC synaptic efficacy and muscarinic sensitivity of IC neurons were mitigated by chronic VNS. Increased myocyte size, which doubled in PO (P < 0.05), was mitigated by RCV. PO hypertrophic myocardium displayed decreased glycogen synthase (GS) protein levels and accumulation of the phosphorylated (inactive) form of GS. These PO-induced changes in GS were moderated by left VNS. Chronic VNS targets IC neurons accompanying PO to obtund associated adverse cardiomyocyte remodeling. PMID:26993230

  17. Fasudil, a Rho-kinase inhibitor, prevents intima-media thickening in a partially ligated carotid artery mouse model: Effects of fasudil in flow-induced vascular remodeling

    PubMed Central

    Zhang, Xiangyu; Zhang, Tao; Gao, Fu; Li, Qingle; Shen, Chenyang; Li, Yankui; Li, Wei; Zhang, Xiaoming

    2015-01-01

    Vascular remodeling in response to hemodynamic alterations is a physiological process that requires coordinated signaling between endothelial, inflammatory and vascular smooth muscle cells (VSMCs). Extensive experimental and clinical studies have indicated the critical role of the Ras homolog gene family, member A/Rho-associated kinase (ROCK) signaling pathway in the pathogenesis of cardiovascular disease, where ROCK activation has been demonstrated to promote inflammation and remodeling through inducing the expression of proinflammatory cytokines and adhesion molecules in endothelial cells and VSMCs. However, the role of ROCK in flow-induced vascular remodeling has not been fully defined. The current study aimed to investigate the effect of the ROCK signaling pathway in flow-induced vascular remodeling by comparing the responses to partial carotid artery ligation in mice treated with fasudil (a ROCK inhibitor) and untreated mice. Intima-media thickness and neointima formation were evaluated by morphology. VSMC proliferation and inflammation of the vessel wall were assessed by immunohistochemistry. In addition, the expression levels of ROCK and the downstream effectors of ROCK, myosin light chain (MLC) and phosphorylated-MLC (p-MLC), were quantified by western blot analysis. Following a reduction in blood flow, ROCK1 and p-MLC expression increased in the untreated left common carotid arteries (LCA). Fasudil-treated mice developed a significantly smaller intima-media thickness compared with the untreated mice. Quantitative immunohistochemistry of the fasudil-treated LCA indicated that there was a reduction in proliferation when compared with untreated vessels. There were fewer CD45+ cells observed in the fasudil-treated LCA compared with the untreated LCA. In conclusion, the expression of ROCK was enhanced in flow-induced carotid artery remodeling and ROCK inhibition as a result of fasudil treatment may attenuate flow-induced carotid artery remodeling. PMID:26458725

  18. Cadmium-Induced Proteome Remodeling Regulated by Spc1/Sty1 and Zip1 in Fission Yeast

    PubMed Central

    Russell, Paul

    2012-01-01

    Stress-activated protein kinases and transcription factors are crucial for surviving exposure to cadmium and other environmental toxicants, but their effects on the proteome remain largely unexplored. In this study, isobaric tag for relative and absolute quantitation reveals that cadmium stress triggers rapid proteome remodeling in the fission yeast Schizosaccharomyces pombe. Spc1/Sty1, a mitogen/stress-activated protein kinase homologous to human p38 and Saccharomyces cerevisiae Hog1, controls many of these changes, including enzymes of the oxidative phase of the pentose phosphate pathway and trehalose metabolism. Genetic studies indicate that control of carbohydrate metabolism by Spc1 is required for cadmium tolerance. The bZIP transcription factor Zip1, which is functionally related to human Nrf2 and S. cerevisiae Met4, has a smaller effect on cadmium-induced proteome remodeling, but it is required for production of key proteins involved in sulfur metabolism, which are essential for cadmium resistance. These studies reveal how Spc1 and Zip1 independently reshape the proteome to modulate cellular defense mechanisms against the toxic effects of cadmium. PMID:22610605

  19. Exendin-4 attenuates adverse cardiac remodelling in streptozocin-induced diabetes via specific actions on infiltrating macrophages.

    PubMed

    Tate, Mitchel; Robinson, Emma; Green, Brian D; McDermott, Barbara J; Grieve, David J

    2016-01-01

    In addition to its' established metabolic and cardioprotective effects, glucagon-like peptide-1 (GLP-1) reduces post-infarction heart failure via preferential actions on the extracellular matrix (ECM). Here, we investigated whether the GLP-1 mimetic, exendin-4, modulates cardiac remodelling in experimental diabetes by specifically targeting inflammatory/ECM pathways, which are characteristically dysregulated in this setting. Adult mice were subjected to streptozotocin (STZ) diabetes and infused with exendin-4/insulin/saline from 0 to 4 or 4-12 weeks. Exendin-4 and insulin improved metabolic parameters in diabetic mice after 12 weeks, but only exendin-4 reduced cardiac diastolic dysfunction and interstitial fibrosis in parallel with altered ECM gene expression. Whilst myocardial inflammation was not evident at 12 weeks, CD11b-F4/80(++) macrophage infiltration at 4 weeks was increased and reduced by exendin-4, together with an improved cytokine profile. Notably, media collected from high glucose-treated macrophages induced cardiac fibroblast differentiation, which was prevented by exendin-4, whilst several cytokines/chemokines were differentially expressed/secreted by exendin-4-treated macrophages, some of which were modulated in STZ exendin-4-treated hearts. Our findings suggest that exendin-4 preferentially protects against ECM remodelling and diastolic dysfunction in experimental diabetes via glucose-dependent modulation of paracrine communication between infiltrating macrophages and resident fibroblasts, thereby indicating that cell-specific targeting of GLP-1 signalling may be a viable therapeutic strategy in this setting. PMID:26597728

  20. Interleukin-6 Induces Vascular Endothelial Growth Factor-C Expression via Src-FAK-STAT3 Signaling in Lymphatic Endothelial Cells

    PubMed Central

    Huang, Shiu-Wen; Ou, George; Hsu, Ya-Fen; Hsu, Ming-Jen

    2016-01-01

    Elevated serum interleukin-6 (IL-6) levels correlates with tumor grade and poor prognosis in cancer patients. IL-6 has been shown to promote tumor lymphangiogenesis through vascular endothelial growth factor-C (VEGF-C) induction in tumor cells. We recently showed that IL-6 also induced VEGF-C expression in lymphatic endothelial cells (LECs). However, the signaling mechanisms involved in IL-6-induces VEGF-C induction in LECs remain incompletely understood. In this study, we explored the causal role of focal adhesion kinase (FAK) in inducing VEGF-C expression in IL-6-stimulated murine LECs (SV-LECs). FAK signaling blockade by NSC 667249 (a FAK inhibitor) attenuated IL-6-induced VEGF-C expression and VEGF-C promoter-luciferase activities. IL-6’s enhancing effects of increasing FAK, ERK1/2, p38MAPK, C/EBPβ, p65 and STAT3 phosphorylation as well as C/EBPβ-, κB- and STAT3-luciferase activities were reduced in the presence of NSC 667249. STAT3 knockdown by STAT3 siRNA abrogated IL-6’s actions in elevating VEGF-C mRNA and protein levels. Moreover, Src-FAK signaling blockade reduced IL-6’s enhancing effects of increasing STAT3 binding to the VEGF-C promoter region, cell migration and endothelial tube formation of SV-LECs. Together these results suggest that IL-6 increases VEGF-C induction and lymphangiogenesis may involve, at least in part, Src-FAK-STAT3 cascade in LECs. PMID:27383632

  1. Lipid emulsions differentially affect LPS-induced acute monocytes inflammation: in vitro effects on membrane remodeling and cell viability.

    PubMed

    Boisramé-Helms, Julie; Delabranche, Xavier; Klymchenko, Andrey; Drai, Jocelyne; Blond, Emilie; Zobairi, Fatiha; Mely, Yves; Hasselmann, Michel; Toti, Florence; Meziani, Ferhat

    2014-11-01

    The aim of this study was to assess how lipid emulsions for parenteral nutrition affect lipopolysaccharide (LPS)-induced acute monocyte inflammation in vitro. An 18 h long LPS induced human monocyte leukemia cell stimulation was performed and the cell-growth medium was supplemented with three different industrial lipid emulsions: Intralipid(®), containing long-chain triglycerides (LCT--soybean oil); Medialipid(®), containing LCT (soybean oil) and medium-chain triglycerides (MCT--coconut oil); and SMOFlipid(®), containing LCT, MCT, omega-9 and -3 (soybean, coconut, olive and fish oils). Cell viability and apoptosis were assessed by Trypan blue exclusion and flow cytometry respectively. Monocyte composition and membrane remodeling were studied using gas chromatography and NR12S staining. Microparticles released in supernatant were measured by prothrombinase assay. After LPS challenge, both cellular necrosis and apoptosis were increased (threefold and twofold respectively) and microparticle release was enhanced (sevenfold) after supplementation with Medialipid(®) compared to Intralipid(®), SMOFlipid(®) and monocytes in the standard medium. The monocytes differentially incorporated fatty acids after lipid emulsion challenge. Finally, lipid-treated cells displayed microparticles characterized by disrupted membrane lipid order, reflecting lipid remodeling of the parental cell plasma membrane. Our data suggest that lipid emulsions differentially alter cell viability, monocyte composition and thereby microparticle release. While MCT have deleterious effects, we have shown that parenteral nutrition emulsion containing LCT or LCT and MCT associated to n-3 and n-9 fatty acids have no effect on endotoxin-induced cell death and inflammation. PMID:25038627

  2. Internal associations and dynamic expression of c-kit and nanog genes in ventricular remodelling induced by adriamycin

    PubMed Central

    Liu, Zhen; Li, Shuo; Liu, Lingling; Guo, Zhikun; Wang, Pengfei

    2016-01-01

    The present study aimed to investigate the dynamic expression of the c-kit and nanog genes in rats with left ventricular remodelling induced by adriamycin (ADR), and explore its internal association and mechanism of action. Sprague-Dawley male rats were randomly divided into a normal control group and a heart failure model group. Heart failure was induced by a single intraperitoneal injection of ADR (4 mg/kg) weekly for six weeks. The normal control group was given the same amount of saline. At the eighth week, rat cardiac function was examined to demonstrate the formation of heart failure. The rat hearts were harvested frozen and sectioned, and the expression levels of the nanog and c-kit genes in the myocardial tissue samples were detected using immunohistochemistry, immunofluorescence and reverse transcription-polymerase chain reaction (RT-PCR). Hematoxylin and eosin staining demonstrated various pathological changes in the myocardial cells in the heart failure model group, whereas myocardial infarction was not observed in the normal control group. Immunohistochemistry and immunofluorescence demonstrated that nanog-positive cells were predominantly expressed in the vascular endothelium, with a few myocardial cells and stem cells in normal myocardium. The expression levels of c-kit and nanog in the myocardium of the rats with heart failure decreased significantly. c-kit-positive cells clustered together in the epicardium and its vicinity, and c-kit expression significantly decreased in the myocardium of rats with heart failure, as compared with normal rats. In both groups, some cells co-expressed both the c-kit and nanog genes. The RT-PCR results demonstrated that the expression levels of the two genes in the heart failure model group were significantly lower compared with those in the normal control group (P<0.05). In conclusion, the c-kit- and nanog-positive stem cells decreased in the myocardium of the rats with left ventricular remodelling induced by ADR

  3. Lymph transport in rat mesenteric lymphatics experiencing edemagenic stress

    PubMed Central

    Rahbar, Elaheh; Akl, Tony; Coté, Gerard L.; Moore, James E.; Zawieja, David C.

    2014-01-01

    Objective To assess lymphatic flow adaptations to edema, we evaluated lymph transport function in rat mesenteric lymphatics under normal and edemagenic conditions in situ. Methods Twelve rats were infused with saline (intravenous infusion, 0.2 ml/min/100g body weight) to induce edema. We intravitally measured mesenteric lymphatic diameter and contraction frequency, as well as immune cell velocity and density before, during and after infusion. Results A 10-fold increase in lymph velocity (0.1–1 mm/s) and a 6-fold increase in flow rate (0.1–0.6 μL/min), were observed post-infusion, respectively. There were also increases in contraction frequency and fractional pump flow 1-minute post-infusion. Time-averaged wall shear stress increased 10 fold post-infusion to nearly 1.5 dynes/cm2. Similarly, maximum shear stress rose from 5 dynes/cm2 to 40 dynes/cm2. Conclusions Lymphatic vessels adapted to edemagenic stress by increasing lymph transport. Specifically, the increases in lymphatic contraction frequency, lymph velocity, and shear stress were significant. Lymph pumping increased post-infusion, though changes in lymphatic diameter were not statistically significant. These results indicate that edemagenic conditions stimulate lymph transport via increases in lymphatic contraction frequency, lymph velocity and flow. These changes, consequently, resulted in large increases in wall shear stress, which could then activate NO pathways and modulate lymphatic transport function. PMID:24397756

  4. Immunopathogenesis of lymphatic filarial disease1

    PubMed Central

    Babu, Subash; Nutman, Thomas B.

    2012-01-01

    Although two-thirds of the 120 million people infected with lymph-dwelling filarial parasites have subclinical infections, ~ 40 million have lymphedema and/or other pathologic manifestations including hydroceles (and other forms of urogenital disease), episodic adenolymphangitis, tropical pulmonary eosinophilia, lymphedema, and (in its most severe form) elephantiasis. Adult filarial worms reside in the lymphatics and lymph nodes and induce changes that result in dilatation of lymphatics and thickening of the lymphatic vessel walls. Progressive lymphatic damage and pathology results from the summation of the effect of tissue alterations induced by both living and nonliving adult parasites, the host inflammatory response to the parasites and their secreted antigens, the host inflammatory response to the endosymbiont Wolbachia, and those seen as a consequence of secondary bacterial or fungal infections. Inflammatory damage induced by filarial parasites appears to be multifactorial, with endogenous parasite products, Wolbachia, and host immunity all playing important roles. This review will initially examine the prototypical immune responses engendered by the parasite and delineate the regulatory mechanisms elicited to prevent immune-mediated pathology. This will be followed by a discussion of the proposed mechanisms underlying pathogenesis, with the central theme being that pathogenesis is a two-step process - the first initiated by the parasite and host innate immune system and the second propagated mainly by the host’s adaptive immune system and by other factors (including secondary infections). PMID:23053393

  5. Differential Expression of SWI/SNF Chromatin Remodeler Subunits Brahma and Brahma-Related Gene During Drug-Induced Liver Injury and Regeneration in Mouse Model.

    PubMed

    Sinha, Sonal; Verma, Sudhir; Chaturvedi, Madan M

    2016-08-01

    The chromatin remodeling activity of mammalian SWI/SNF complex is carried out by either Brahma (BRM) or Brahma-related gene (BRG-1). The BRG-1 regulates genes involved in cell proliferation, whereas BRM is associated with cell differentiation, and arrest of cell growth. Global modifications of histones and expression of genes of chromatin-remodeling subunits have not been studied in in vivo model systems. In the present study, we investigate epigenetic modifications of histones and the expression of genes in thioacetamide (TAA)-induced liver injury and regeneration in a mouse model. In the present study, we report that hepatocyte proliferation and H3S10 phosphorylation occur during 60 to 72 h post TAA treatment in mice. Furthermore, there was change in the H3K9 acetylation and H3K9 trimethylation pattern with respect to liver injury and regeneration phase. Looking into the expression pattern of Brg-1 and Brm, it is evident that they contribute substantially to the process of liver regeneration. The SWI/SNF remodeler might contain BRG-1 as its ATPase subunit during injury phase. Whereas, BRM-associated SWI/SNF remodeler might probably be predominant during decline of injury phase and initiation of regeneration phase. Furthermore, during the regeneration phase, BRG-1-containing remodeler again predominates. Considering all these observations, the present study depicts an interplay between chromatin interacting machineries in different phases of thioacetamide-induced liver injury and regeneration. PMID:27097303

  6. Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septotemporal axis in adulthood and middle age.

    PubMed

    McAvoy, Kathleen; Russo, Craig; Kim, Shannen; Rankin, Genelle; Sahay, Amar

    2015-11-01

    Fluoxetine, a selective serotonin-reuptake inhibitor (SSRI), is known to induce structural rearrangements and changes in synaptic transmission in hippocampal circuitry. In the adult hippocampus, structural changes include neurogenesis, dendritic, and axonal plasticity of pyramidal and dentate granule neurons, and dedifferentiation of dentate granule neurons. However, much less is known about how chronic fluoxetine affects these processes along the septotemporal axis and during the aging process. Importantly, studies documenting the effects of fluoxetine on density and distribution of spines along different dendritic segments of dentate granule neurons and CA1 pyramidal neurons along the septotemporal axis of hippocampus in adulthood and during aging are conspicuously absent. Here, we use a transgenic mouse line in which mature dentate granule neurons and CA1 pyramidal neurons are genetically labeled with green fluorescent protein (GFP) to investigate the effects of chronic fluoxetine treatment (18 mg/kg/day) on input-specific spine remodeling and mossy fiber structural plasticity in the dorsal and ventral hippocampus in adulthood and middle age. In addition, we examine levels of adult hippocampal neurogenesis, maturation state of dentate granule neurons, neuronal activity, and glutamic acid decarboxylase-67 expression in response to chronic fluoxetine in adulthood and middle age. Our studies reveal that while chronic fluoxetine fails to augment adult hippocampal neurogenesis in middle age, the middle-aged hippocampus retains high sensitivity to changes in the dentate gyrus (DG) such as dematuration, hypoactivation, and increased glutamic acid decarboxylase 67 (GAD67) expression. Interestingly, the middle-aged hippocampus shows greater sensitivity to fluoxetine-induced input-specific synaptic remodeling than the hippocampus in adulthood with the stratum-oriens of CA1 exhibiting heightened structural plasticity. The input-specific changes and circuit

  7. Metabolic Remodeling in Moderate Synchronous versus Dyssynchronous Pacing-Induced Heart Failure: Integrated Metabolomics and Proteomics Study

    PubMed Central

    Shibayama, Junko; Yuzyuk, Tatiana N.; Cox, James; Makaju, Aman; Miller, Mickey; Lichter, Justin; Li, Hui; Leavy, Jane D.; Franklin, Sarah; Zaitsev, Alexey V.

    2015-01-01

    Heart failure (HF) is accompanied by complex alterations in myocardial energy metabolism. Up to 40% of HF patients have dyssynchronous ventricular contraction, which is an independent indicator of mortality. We hypothesized that electromechanical dyssynchrony significantly affects metabolic remodeling in the course of HF. We used a canine model of tachypacing-induced HF. Animals were paced at 200 bpm for 6 weeks either in the right atrium (synchronous HF, SHF) or in the right ventricle (dyssynchronous HF, DHF). We collected biopsies from left ventricular apex and performed comprehensive metabolic pathway analysis using multi-platform metabolomics (GC/MS; MS/MS; HPLC) and LC-MS/MS label-free proteomics. We found important differences in metabolic remodeling between SHF and DHF. As compared to Control, ATP, phosphocreatine (PCr), creatine, and PCr/ATP (prognostic indicator of mortality in HF patients) were all significantly reduced in DHF, but not SHF. In addition, the myocardial levels of carnitine (mitochondrial fatty acid carrier) and fatty acids (12:0, 14:0) were significantly reduced in DHF, but not SHF. Carnitine parmitoyltransferase I, a key regulatory enzyme of fatty acid ß-oxidation, was significantly upregulated in SHF but was not different in DHF, as compared to Control. Both SHF and DHF exhibited a reduction, but to a different degree, in creatine and the intermediates of glycolysis and the TCA cycle. In contrast to this, the enzymes of creatine kinase shuttle were upregulated, and the enzymes of glycolysis and the TCA cycle were predominantly upregulated or unchanged in both SHF and DHF. These data suggest a systemic mismatch between substrate supply and demand in pacing-induced HF. The energy deficit observed in DHF, but not in SHF, may be associated with a critical decrease in fatty acid delivery to the ß-oxidation pipeline, primarily due to a reduction in myocardial carnitine content. PMID:25790351

  8. Impact of Leucine Supplementation on Exercise Training Induced Anti-Cardiac Remodeling Effect in Heart Failure Mice

    PubMed Central

    de Moraes, Wilson Max Almeida Monteiro; Melara, Thaís Plasti; de Souza, Pamella Ramona Moraes; de Salvi Guimarães, Fabiana; Bozi, Luiz Henrique Marchesi; Brum, Patricia Chakur; Medeiros, Alessandra

    2015-01-01

    Leucine supplementation potentiates the effects of aerobic exercise training (AET) on skeletal muscle; however, its potential effects associated with AET on cardiac muscle have not been clarified yet. We tested whether leucine supplementation would potentiate the anti-cardiac remodeling effect of AET in a genetic model of sympathetic hyperactivity-induced heart failure in mice (α2A/α2CARKO). Mice were assigned to five groups: wild type mice treated with placebo and sedentary (WT, n = 11), α2A/α2CARKO treated with placebo and sedentary (KO, n = 9), α2A/α2CARKO treated with leucine and sedentary (KOL, n = 11), α2A/α2CARKO treated with placebo and AET (KOT, n = 12) or α2A/α2CARKO treated with leucine and AET (KOLT, n = 12). AET consisted of four weeks on a treadmill with 60 min sessions (six days/week, 60% of maximal speed) and administration by gavage of leucine (1.35 g/kg/day) or placebo (distilled water). The AET significantly improved exercise capacity, fractional shortening and re-established cardiomyocytes’ diameter and collagen fraction in KOT. Additionally, AET significantly prevented the proteasome hyperactivity, increased misfolded proteins and HSP27 expression. Isolated leucine supplementation displayed no effect on cardiac function and structure (KOL), however, when associated with AET (KOLT), it increased exercise tolerance to a higher degree than isolated AET (KOT) despite no additional effects on AET induced anti-cardiac remodeling. Our results provide evidence for the modest impact of leucine supplementation on cardiac structure and function in exercised heart failure mice. Leucine supplementation potentiated AET effects on exercise tolerance, which might be related to its recognized impact on skeletal muscle. PMID:25988767

  9. SIZ1 regulation of phosphate starvation-induced root architecture remodeling involves the control of auxin accumulation.

    PubMed

    Miura, Kenji; Lee, Jiyoung; Gong, Qingqiu; Ma, Shisong; Jin, Jing Bo; Yoo, Chan Yul; Miura, Tomoko; Sato, Aiko; Bohnert, Hans J; Hasegawa, Paul M

    2011-02-01

    Phosphate (Pi) limitation causes plants to modulate the architecture of their root systems to facilitate the acquisition of Pi. Previously, we reported that the Arabidopsis (Arabidopsis thaliana) SUMO E3 ligase SIZ1 regulates root architecture remodeling in response to Pi limitation; namely, the siz1 mutations cause the inhibition of primary root (PR) elongation and the promotion of lateral root (LR) formation. Here, we present evidence that SIZ1 is involved in the negative regulation of auxin patterning to modulate root system architecture in response to Pi starvation. The siz1 mutations caused greater PR growth inhibition and LR development of seedlings in response to Pi limitation. Similar root phenotypes occurred if Pi-deficient wild-type seedlings were supplemented with auxin. N-1-Naphthylphthalamic acid, an inhibitor of auxin efflux activity, reduced the Pi starvation-induced LR root formation of siz1 seedlings to a level equivalent to that seen in the wild type. Monitoring of the auxin-responsive reporter DR5::uidA indicated that auxin accumulates in PR tips at early stages of the Pi starvation response. Subsequently, DR5::uidA expression was observed in the LR primordia, which was associated with LR elongation. The time-sequential patterning of DR5::uidA expression occurred earlier in the roots of siz1 as compared with the wild type. In addition, microarray analysis revealed that several other auxin-responsive genes, including genes involved in cell wall loosening and biosynthesis, were up-regulated in siz1 relative to wild-type seedlings in response to Pi starvation. Together, these results suggest that SIZ1 negatively regulates Pi starvation-induced root architecture remodeling through the control of auxin patterning. PMID:21156857

  10. Calcium antagonists, diltiazem and nifedipine, protect broilers against low temperature-induced pulmonary hypertension and pulmonary vascular remodeling.

    PubMed

    Yang, Ying; Gao, Mingyu; Guo, Yuming; Qiao, Jian

    2010-08-01

    This study was designed to determine whether calcium antagonists, diltiazem and nifedipine, can depress low temperature-induced pulmonary hypertension (PH) in broilers (also known as ascites) and to characterize their efficacy on hemodynamics and pulmonary artery function. Chicks were randomly allocated into six experimental groups and orally administered with vehicle, 5.0 mg/kg body weight (BW)/12 h nifedipine or 15.0 mg/kg BW/12 h diltiazem from 16 to 43 days of age under low temperature. The mean pulmonary arterial pressure (mPAP), the ascites heart index (AHI), the erythrocyte packed cell volume (PCV) and the relative percentage of medial pulmonary artery thickness were examined on days 29, 36 and 43. The data showed that administration of diltiazem protected broilers from low temperature-induced pulmonary hypertension and vascular remodeling. Although nifedipine prevented mPAP from increasing during the early stage, it did not suppress the development of PH during the late stage and did not keep heart rate (HR), PCV, AHI and the thickness of pulmonary small artery smooth muscle layer at the normal levels. Taken together, our results showed that diltiazem can effectively prevent low temperature-induced pulmonary hypertension in broilers with fewer side-effects and may be a potential compound for the prevention of this disease in poultry industry. PMID:20662820

  11. S-diclofenac Protects against Doxorubicin-Induced Cardiomyopathy in Mice via Ameliorating Cardiac Gap Junction Remodeling

    PubMed Central

    Zhang, Huili; Zhang, Alian; Guo, Changfa; Shi, Chunzhi; Zhang, Yang; Liu, Qing; Sparatore, Anna; Wang, Changqian

    2011-01-01

    Hydrogen sulfide (H2S), as a novel gaseous mediator, plays important roles in mammalian cardiovascular tissues. In the present study, we investigated the cardioprotective effect of S-diclofenac (2-[(2,6-dichlorophenyl)amino] benzeneacetic acid 4-(3H-1,2,dithiol-3-thione-5-yl)phenyl ester), a novel H2S-releasing derivative of diclofenac, in a murine model of doxorubicin-induced cardiomyopathy. After a single dose injection of doxorubicin (15 mg/kg, i.p.), male C57BL/6J mice were given daily treatment of S-diclofenac (25 and 50 µmol/kg, i.p.), diclofenac (25 and 50 µmol/kg, i.p.), NaHS (50 µmol/kg, i.p.), or same volume of vehicle. The cardioprotective effect of S-diclofenac was observed after 14 days. It showed that S-diclofenac, but not diclofenac, dose-dependently inhibited the doxorubicin-induced downregulation of cardiac gap junction proteins (connexin 43 and connexin 45) and thus reversed the remodeling of gap junctions in hearts. It also dose-dependently suppressed doxorubicin-induced activation of JNK in hearts. Furthermore, S-diclofenac produced a dose-dependent anti-inflammatory and anti-oxidative effect in this model. As a result, S-diclofenac significantly attenuated doxorubicin-related cardiac injury and cardiac dysfunction, and improved the survival rate of mice with doxorubicin-induced cardiomyopathy. These effects of S-diclofenac were mimicked in large part by NaHS. Therefore, we propose that H2S released from S-diclofenac in vivo contributes to the protective effect in doxorubicin-induced cardiomyopathy. These data also provide evidence for a critical role of H2S in the pathogenesis of doxorubicin-induced cardiomyopathy. PMID:22039489

  12. Increased susceptibility of Cftr-/- mice to LPS-induced lung remodeling.

    PubMed

    Bruscia, Emanuela M; Zhang, Ping-Xia; Barone, Christina; Scholte, Bob J; Homer, Robert; Krause, Diane S; Egan, Marie E

    2016-04-15

    Cystic fibrosis (CF) is caused by homozygous mutations of the CF transmembrane conductance regulator (CFTR) Cl(-) channel, which result in chronic pulmonary infection and inflammation, the major cause of morbidity and mortality. Although these processes are clearly related to each other, each is likely to contribute to the pathology differently. Understanding the contribution of each of these processes to the overall pathology has been difficult, because they are usually so intimately connected. Various CF mouse models have demonstrated abnormal immune responses compared with wild-type (WT) littermates when challenged with live bacteria or bacterial products acutely. However, these studies have not investigated the consequences of persistent inflammation on lung tissue in CF mice, which may better model the lung pathology in patients. We characterized the lung pathology and immune response of Cftr(-/-) (CF) and Cftr(+/+) (WT) mice to chronic administration of Pseudomonas aeruginosa lipopolysaccharide (LPS). We show that, after long-term repeated LPS exposure, CF mice develop an abnormal and persistent immune response, which is associated with more robust structural changes in the lung than those observed in WT mice. Although CF mice and their WT littermates develop lung pathology after chronic exposure to LPS, the inflammation and damage resolve in WT mice. However, CF mice do not recover efficiently, and, as a consequence of their chronic inflammation, CF mice are more susceptible to morphological changes and lung remodeling. This study shows that chronic inflammation alone contributes significantly to aspects of CF lung pathology. PMID:26851259

  13. Cardiac MRI: a Translational Imaging Tool for Characterizing Anthracycline-Induced Myocardial Remodeling.

    PubMed

    Nguyen, Kim-Lien; Hu, Peng; Ennis, Daniel B; Shao, Jiaxin; Pham, Kimberly A; Chen, Joseph J

    2016-08-01

    Cardiovascular side effects of cancer therapeutics are the leading causes of morbidity and mortality in cancer survivors. Anthracyclines (AC) serve as the backbone of many anti-cancer treatment strategies, but dose-dependent myocardial injury limits their use. Cumulative AC exposure can disrupt the dynamic equilibrium of the myocardial microarchitecture while repeated injury and repair leads to myocyte loss, interstitial myocardial fibrosis, and impaired contractility. Although children are assumed to have greater myocardial plasticity, AC exposure at a younger age portends worse prognosis. In older patients, there is lower overall survival once they develop cardiovascular disease. Because aberrations in the myocardial architecture predispose the heart to a decline in function, early detection with sensitive imaging tools is crucial and the implications for resource utilization are substantial. As a comprehensive imaging modality, cardiac magnetic resonance (CMR) imaging is able to go beyond quantification of ejection fraction and myocardial deformation to characterize adaptive microstructural and microvascular changes that are important to myocardial tissue health. Herein, we describe CMR as an established translational imaging tool that can be used clinically to characterize AC-associated myocardial remodeling. PMID:27292153

  14. Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope

    PubMed Central

    Tsai, Shang-Yi A.; Chuang, Jian-Ying; Tsai, Meng-Shan; Wang, Xiao-fei; Hung, Jan-Jong; Chang, Wen-Chang; Bonci, Antonello; Su, Tsung-Ping

    2015-01-01

    The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER–mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal. PMID:26554014

  15. Angiotensin-(1–7) attenuates angiotensin II-induced cardiac remodeling associated with upregulation of dual-specificity phosphatase 1

    PubMed Central

    McCollum, LaTronya T.; Gallagher, Patricia E.

    2012-01-01

    Chronic hypertension induces cardiac remodeling, including left ventricular hypertrophy and fibrosis, through a combination of both hemodynamic and humoral factors. In previous studies, we showed that the heptapeptide ANG-(1–7) prevented mitogen-stimulated growth of cardiac myocytes in vitro, through a reduction in the activity of the MAPKs ERK1 and ERK2. In this study, saline- or ANG II-infused rats were treated with ANG-(1–7) to determine whether the heptapeptide reduces myocyte hypertrophy in vivo and to identify the signaling pathways involved in the process. ANG II infusion into normotensive rats elevated systolic blood pressure >50 mmHg, in association with increased myocyte cross-sectional area, ventricular atrial natriuretic peptide mRNA, and ventricular brain natriuretric peptide mRNA. Although infusion with ANG-(1–7) had no effect on the ANG II-stimulated elevation in blood pressure, the heptapeptide hormone significantly reduced the ANG II-mediated increase in myocyte cross-sectional area, interstitial fibrosis, and natriuretic peptide mRNAs. ANG II increased phospho-ERK1 and phospho-ERK2, whereas cotreatment with ANG-(1–7) reduced the phosphorylation of both MAPKs. Neither ANG II nor ANG-(1–7) altered the ERK1/2 MAPK kinase MEK1/2. However, ANG-(1–7) infusion, with or without ANG II, increased the MAPK phosphatase dual-specificity phosphatase (DUSP)-1; in contrast, treatment with ANG II had no effect on DUSP-1, suggesting that ANG-(1–7) upregulates DUSP-1 to reduce ANG II-stimulated ERK activation. These results indicate that ANG-(1–7) attenuates cardiac remodeling associated with a chronic elevation in blood pressure and upregulation of a MAPK phosphatase and may be cardioprotective in patients with hypertension. PMID:22140049

  16. Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope.

    PubMed

    Tsai, Shang-Yi A; Chuang, Jian-Ying; Tsai, Meng-Shan; Wang, Xiao-Fei; Xi, Zheng-Xiong; Hung, Jan-Jong; Chang, Wen-Chang; Bonci, Antonello; Su, Tsung-Ping

    2015-11-24

    The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER-mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal. PMID:26554014

  17. Lymphatic Vessels, Inflammation, and Immunity in Skin Cancer

    PubMed Central

    Lund, Amanda W.; Medler, Terry R.; Leachman, Sancy A.; Coussens, Lisa M.

    2015-01-01

    Skin is a highly ordered immune organ that coordinates rapid responses to external insult while maintaining self-tolerance. In healthy tissue, lymphatic vessels drain fluid and coordinate local immune responses; however, environmental factors induce lymphatic vessel dysfunction, leading to lymph stasis and perturbed regional immunity. These same environmental factors drive the formation of local malignancies, which are also influenced by local inflammation. Herein, we discuss clinical and experimental evidence supporting the tenet that lymphatic vessels participate in regulation of cutaneous inflammation and immunity, are important contributors to malignancy and potential biomarkers and targets for immunotherapy. PMID:26552413

  18. Tissue remodeling: a mating-induced differentiation program for the Drosophila oviduct

    PubMed Central

    Kapelnikov, Anat; Rivlin, Patricia K; Hoy, Ronald R; Heifetz, Yael

    2008-01-01

    Background In both vertebrates and invertebrates, the oviduct is an epithelial tube surrounded by visceral muscles that serves as a conduit for gamete transport between the ovary and uterus. While Drosophila is a model system for tubular organ development, few studies have addressed the development of the fly's oviduct. Recent studies in Drosophila have identified mating-responsive genes and proteins whose levels in the oviduct are altered by mating. Since many of these molecules (e.g. Muscle LIM protein 84B, Coracle, Neuroglian) have known roles in the differentiation of muscle and epithelia of other organs, mating may trigger similar differentiation events in the oviduct. This led us to hypothesize that mating mediates the last stages of oviduct differentiation in which organ-specific specializations arise. Results Using electron- and confocal-microscopy we identified tissue-wide post-mating changes in the oviduct including differentiation of cellular junctions, remodeling of extracellular matrix, increased myofibril formation, and increased innervation. Analysis of once- and twice-mated females reveals that some mating-responsive proteins respond only to the first mating, while others respond to both matings. Conclusion We uncovered ultrastructural changes in the mated oviduct that are consistent with the roles that mating-responsive proteins play in muscle and epithelial differentiation elsewhere. This suggests that mating triggers the late differentiation of the oviduct. Furthermore, we suggest that mating-responsive proteins that respond only to the first mating are involved in the final maturation of the oviduct while proteins that remain responsive to later matings are also involved in maintenance and ongoing function of the oviduct. Taken together, our results establish the oviduct as an attractive system to address mechanisms that regulate the late stages of differentiation and maintenance of a tubular organ. PMID:19063748

  19. Lysophosphatidic acid does not cause blood/lymphatic vessel plasticity in the rat mesentery culture model.

    PubMed

    Sweat, Richard S; Azimi, Mohammad S; Suarez-Martinez, Ariana D; Katakam, Prasad; Murfee, Walter L

    2016-07-01

    Understanding the mechanisms behind endothelial cell identity is crucial for the goal of manipulating microvascular networks. Lysophosphatidic acid (LPA) and serum stimulation have been suggested to induce a lymphatic identity in blood endothelial cells in vitro. The objective of this study was to determine if LPA or serum induces blood-to-lymphatic vessel phenotypic transition in microvascular networks. The rat mesentery culture model was used to observe the effect of stimulation on blood and lymphatic microvascular networks ex vivo. Vascularized mesenteric tissues were harvested from adult Wistar rats and cultured with LPA or 10% serum for up to 5 days. Tissues were then immunolabeled with PECAM to identify blood vessels and LYVE-1 or Prox1 to identify lymphatic vessels. We show that while LPA caused capillary sprouting and increased vascular length density in adult microvascular networks, LPA did not cause a blood-to-lymphatic phenotypic transition. The results suggest that LPA is not sufficient to cause blood endothelial cells to adopt a lymphatic identity in adult microvascular networks. Similarly, serum stimulation caused robust angiogenesis and increased lymphatic/blood vessel connections, yet did not induce a blood-to-lymphatic phenotypic transition. Our study highlights an understudied area of lymphatic research and warrants future investigation into the mechanisms responsible for the maintenance of blood and lymphatic vessel identity. PMID:27401461

  20. Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication.

    PubMed

    Ganss, Ruth; Ryschich, Eduard; Klar, Ernst; Arnold, Bernd; Hämmerling, Günter J

    2002-03-01

    In a transgenic mouse model of multistep carcinogenesis, highly angiogenic insulinomas contain an irregular vascular network and develop an intrinsic resistance to leukocyte infiltration and effector function. Even persistently high levels of activated tumor-specific T lymphocytes fail to eradicate the tumors. In contrast, we show that irradiation before adoptive transfer results in complete macroscopic tumor regression. Thus, effective tumor therapy requires a proinflammatory microenvironment that permits T cells to extravasate and to destroy the tumor. Early after initiation of the irradiation/adoptive transfer therapy, the capillary network reacquires an almost normal appearance, a likely consequence of strong induction of the chemokines monokine induced by IFN-gamma (Mig) and IFN-inducible protein 10 (IP10). This remodeling of the vasculature in a proinflammatory environment may directly affect lymphocyte extravasation and effector function. Therefore, irradiation/adoptive transfer therapy combines antigen-driven tumor cell eradication with anti-angiogenic effects on tumor endothelium, a powerful synergy that has not been previously appreciated. PMID:11888921

  1. 18-HEPE, an n-3 fatty acid metabolite released by macrophages, prevents pressure overload-induced maladaptive cardiac remodeling.

    PubMed

    Endo, Jin; Sano, Motoaki; Isobe, Yosuke; Fukuda, Keiichi; Kang, Jing X; Arai, Hiroyuki; Arita, Makoto

    2014-07-28

    N-3 polyunsaturated fatty acids (PUFAs) have potential cardiovascular benefit, although the mechanisms underlying this effect remain poorly understood. Fat-1 transgenic mice expressing Caenorhabditis elegans n-3 fatty acid desaturase, which is capable of producing n-3 PUFAs from n-6 PUFAs, exhibited resistance to pressure overload-induced inflammation and fibrosis, as well as reduced cardiac function. Lipidomic analysis revealed selective enrichment of eicosapentaenoic acid (EPA) in fat-1 transgenic bone marrow (BM) cells and EPA-metabolite 18-hydroxyeicosapentaenoic acid (18-HEPE) in fat-1 transgenic macrophages. BM transplantation experiments revealed that fat-1 transgenic BM cells, but not fat-1 transgenic cardiac cells, contributed to the antiremodeling effect and that the 18-HEPE-rich milieu in the fat-1 transgenic heart was generated by BM-derived cells, most likely macrophages. 18-HEPE inhibited macrophage-mediated proinflammatory activation of cardiac fibroblasts in culture, and in vivo administration of 18-HEPE reproduced the fat-1 mice phenotype, including resistance to pressure overload-induced maladaptive cardiac remodeling. PMID:25049337

  2. CHANGES IN CARBOHYDRATE COORDINATED PARTITIONING AND CELL WALL REMODELING WITH STRESS-INDUCED PATHOGENESIS IN WHEAT SHEATHS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plant cell walls are dynamic structures that undergo specific remodeling events during plant defense responses. Changes in the coordinated partitioning of carbohydrates between the cytosol and the extracellular milieu may direct sheath cell wall remodeling that occurs in a wheat-endophytic interacti...

  3. The lymphatic vasculature in disease.

    PubMed

    Alitalo, Kari

    2011-01-01

    Blood vessels form a closed circulatory system, whereas lymphatic vessels form a one-way conduit for tissue fluid and leukocytes. In most vertebrates, the main function of lymphatic vessels is to collect excess protein-rich fluid that has extravasated from blood vessels and transport it back into the blood circulation. Lymphatic vessels have an important immune surveillance function, as they import various antigens and activated antigen-presenting cells into the lymph nodes and export immune effector cells and humoral response factors into the blood circulation. Defects in lymphatic function can lead to lymph accumulation in tissues, dampened immune responses, connective tissue and fat accumulation, and tissue swelling known as lymphedema. This review highlights the most recent developments in lymphatic biology and how the lymphatic system contributes to the pathogenesis of various diseases involving immune and inflammatory responses and its role in disseminating tumor cells. PMID:22064427

  4. Bone morphogenic protein-2 regulates the myogenic differentiation of PMVECs in CBDL rat serum-induced pulmonary microvascular remodeling.

    PubMed

    Liu, Chang; Chen, Lin; Zeng, Jing; Cui, Jian; Ning, Jiao-Nin; Wang, Guan-Song; Belguise, Karine; Wang, Xiaobo; Qian, Gui-Sheng; Lu, Kai-Zhi; Yi, Bin

    2015-08-01

    Hepatopulmonary syndrome (HPS) is characterized by an arterial oxygenation defect induced by intrapulmonary vasodilation (IPVD) that increases morbidity and mortality. In our previous study, it was determined that both the proliferation and the myogenic differentiation of pulmonary microvascular endothelial cells (PMVECs) play a key role in the development of IPVD. However, the molecular mechanism underlying the relationship between IPVD and the myogenic differentiation of PMVECs remains unknown. Additionally, it has been shown that bone morphogenic protein-2 (BMP2), via the control of protein expression, may regulate cell differentiation including cardiomyocyte differentiation, neuronal differentiation and odontoblastic differentiation. In this study, we observed that common bile duct ligation (CBDL)-rat serum induced the upregulation of the expression of several myogenic proteins (SM-α-actin, calponin, SM-MHC) and enhanced the expression levels of BMP2 mRNA and protein in PMVECs. We also observed that both the expression levels of Smad1/5 and the activation of phosphorylated Smad1/5 were significantly elevated in PMVECs following exposure to CBDL-rat serum, which was accompanied by the down-regulation of Smurf1. The blockage of the BMP2/Smad signaling pathway with Noggin inhibited the myogenic differentiation of PMVECs, a process that was associated with relatively low expression levels of both SM-α-actin and calponin in the setting of CBDL-rat serum exposure, although SM-MHC expression was not affected. These findings suggested that the BMP2/Smad signaling pathway is involved in the myogenic differentiation of the PMVECs. In conclusion, our data highlight the pivotal role of BMP2 in the CBDL-rat serum-induced myogenic differentiation of PMVECs via the activation of both Smad1 and Smad5 and the down-regulation of Smurf1, which may represent a potential therapy for HPS-induced pulmonary vascular remodeling. PMID:26071935

  5. Nonmalignant Adult Thoracic Lymphatic Disorders.

    PubMed

    Itkin, Maxim; McCormack, Francis X

    2016-09-01

    The thoracic lymphatic disorders are a heterogeneous group of uncommon conditions that are associated with thoracic masses, interstitial pulmonary infiltrates, and chylous complications. Accurate diagnosis of the thoracic lymphatic disorders has important implications for the newest approaches to management, including embolization and treatment with antilymphangiogenic drugs. New imaging techniques to characterize lymphatic flow, such as dynamic contrast-enhanced magnetic resonance lymphangiogram, are redefining approaches to disease classification and therapy. PMID:27514588

  6. Substrate stiffness influences TGF-β1-induced differentiation of bronchial fibroblasts into myofibroblasts in airway remodeling.

    PubMed

    Shi, Yanling; Dong, Yuhui; Duan, Yiyuan; Jiang, Xuemei; Chen, Cheng; Deng, Linhong

    2013-02-01

    Chronic inflammation and remodeling of the bronchial wall are basic hallmarks of asthma. During the process of bronchial wall remodeling, inflammatory factors, such as transforming growth factor-β1 (TGF-β1), are known to induce the differentiation of fibroblasts into myofibroblasts, which leads to excessive synthesis and secretion of extracellular matrix (ECM) proteins, thus thickening and stiffening the basement membrane. However, it has not been thoroughly studied whether or not substrate stiffening affects the TGF-β1‑induced myofibroblast differentiation. In the present study, the influence of substrate stiffness on the process of bronchial fibroblast differentiation into myofibroblasts in the presence of TGF-β1 was investigated. To address this question, we synthesized polydimethylsiloxane (PDMS) substrates with varying degrees of stiffness (Young's modulus of 1, 10 and 50 kPa, respectively). We cultured bronchial fibroblasts on the substrates of varying stiffness in media containing TGF-β1 (10 ng/ml) to stimulate the differentiation of fibroblasts into myofibroblasts. Myofibroblast differentiation was examined using semi-quantitative RT-PCR for the expression of α-smooth muscle actin (α-SMA) mRNA and collagen I mRNA, the enzyme-linked immunosorbent assay method was used to assess the expression of collagen I protein and western blotting to assess the expression of α-SMA protein. The optical magnetic twisting cytometry (OMTC) method was used for the changing of cell mechanical properties. Our findings suggest that when fibroblasts were incubated with TGF-β1 (10 ng/ml) on substrate of varying stiffness, the differentiation of fibroblasts into myofibroblasts was enhanced by increasing substrate stiffness. Compared with those cultured on substrate with Young's modulus of 1 kPa, the mRNA and protein expression of collagen I and α-SMA of fibroblasts cultured on substrates with Young's modulus of 10 and 50 kPa were increased. Furthermore, with the

  7. Akacid Medical Formulation Induces Apoptosis in Myeloid and Lymphatic Leukemic Cell Lines In Vitro and In Vivo

    PubMed Central

    Neuwirt, Hannes; Wabnig, Elisabeth; Feistritzer, Clemens; Eder, Iris E.; Salvador, Christina; Puhr, Martin; Culig, Zoran; Massoner, Petra; Tiefenthaler, Martin; Steurer, Michael; Konwalinka, Guenther

    2015-01-01

    Akacid medical formulation (AMF) is an oligoguanidine that exerts biocidal activity against airborne and surface microorganisms including bacteria, viruses, fungi, and molds, while showing relatively low toxicity to humans. We have previously shown that AMF exerts antiproliferative effects on a variety of solid tumor cell lines. In this study we raised the question whether AMF could also substantially inhibit cell growth or induce apoptosis in cell lines derived from hematologic malignancies such as leukemia or lymphoma. We found that AMF has antiproliferative effects on various hematologic cell lines derived from human leukemia and lymphoma. Additionally, we show that AMF induces apoptosis in leukemia cell lines not only via the extrinsic and intrinsic pathway, but also in a caspase-independent manner. This effect was found also in G0-arrested cells. Finally, in our animal experiments utilizing male nu/nu Balb/c mice we found a significant growth retardation, which was immunohistochemically associated with a significantly lower number of KI67-positive cells and caspase-3 induction in AMF-treated mice. PMID:25680181

  8. Aberrant Lymphatic Endothelial Progenitors in Lymphatic Malformation Development

    PubMed Central

    Wu, June K.; Kitajewski, Christopher; Reiley, Maia; Keung, Connie H.; Monteagudo, Julie; Andrews, John P.; Liou, Peter; Thirumoorthi, Arul; Wong, Alvin

    2015-01-01

    Lymphatic malformations (LMs) are vascular anomalies thought to arise from dysregulated lymphangiogenesis. These lesions impose a significant burden of disease on affected individuals. LM pathobiology is poorly understood, hindering the development of effective treatments. In the present studies, immunostaining of LM tissues revealed that endothelial cells lining aberrant lymphatic vessels and cells in the surrounding stroma expressed the stem cell marker, CD133, and the lymphatic endothelial protein, podoplanin. Isolated patient-derived CD133+ LM cells expressed stem cell genes (NANOG, Oct4), circulating endothelial cell precursor proteins (CD90, CD146, c-Kit, VEGFR-2), and lymphatic endothelial proteins (podoplanin, VEGFR-3). Consistent with a progenitor cell identity, CD133+ LM cells were multipotent and could be differentiated into fat, bone, smooth muscle, and lymphatic endothelial cells in vitro. CD133+ cells were compared to CD133− cells isolated from LM fluids. CD133− LM cells had lower expression of stem cell genes, but expressed circulating endothelial precursor proteins and high levels of lymphatic endothelial proteins, VE-cadherin, CD31, podoplanin, VEGFR-3 and Prox1. CD133− LM cells were not multipotent, consistent with a differentiated lymphatic endothelial cell phenotype. In a mouse xenograft model, CD133+ LM cells differentiated into lymphatic endothelial cells that formed irregularly dilated lymphatic channels, phenocopying human LMs. In vivo, CD133+ LM cells acquired expression of differentiated lymphatic endothelial cell proteins, podoplanin, LYVE1, Prox1, and VEGFR-3, comparable to expression found in LM patient tissues. Taken together, these data identify a novel LM progenitor cell population that differentiates to form the abnormal lymphatic structures characteristic of these lesions, recapitulating the human LM phenotype. This LM progenitor cell population may contribute to the clinically refractory behavior of LMs. PMID:25719418

  9. Blockade of FLT4 suppresses metastasis of melanoma cells by impaired lymphatic vessels.

    PubMed

    Lee, Ji Yoon; Hong, Seok-Ho; Shin, Minsang; Heo, Hye-Ryeon; Jang, In Ho

    2016-09-16

    The metastatic spread of tumor cells via lymphatic vessels affects the relapse of tumor patients. New lymphatic vessel formation, including lymphangiogenesis, is promoted in the tumor environment. The lymphangiogenic factor VEGF-C can mediate lymphatic vessel formation and induce tumor metastasis by binding with FLT4. In melanoma, metastasis via lymphatics such as lymph nodes is one of the main predictors of poor outcome. Thus, we investigated whether blockade of FLT4 can reduce metastasis via the suppression of lymphatic capillaries. Proliferative lymphatic capillaries in melanoma were estimated by immunohistochemistry using FLT4 antibody after the injection of the FLT4 antagonist MAZ51. The numbers of tumor modules in metastasised lungs were calculated by gross examination and lymphatic related factors were examined by qRT-PCR. MAZ51 injection resulted in the suppression of tumor size and module number and the inhibition of proliferative lymphatic vessels in the intratumoral region in the lung and proliferating melanoma cells in the lung compared to those of untreated groups. Additionally, high FLT4 and TNF-alpha were detected in melanoma-induced tissue, while lymphatic markers such as VEGF-C, FLT4 and Prox-1 were significantly decreased in MAZ51 treated groups, implying that anti-lymphangiogenesis by MAZ51 may provide a potential strategy to prevent tumor metastasis in melanoma and high number of lymphatic capillaries could be used diagnosis for severe metastasis. PMID:27507214

  10. Reactivation of Endogenous Genes and Epigenetic Remodeling Are Barriers for Generating Transgene-Free Induced Pluripotent Stem Cells in Pig

    PubMed Central

    Choi, Kwang-Hwan; Park, Jin-Kyu; Son, Dongchan; Hwang, Jae Yeon; Lee, Dong-Kyung; Ka, Hakhyun; Park, Joonghoon; Lee, Chang-Kyu

    2016-01-01

    Cellular reprogramming of committed cells into a pluripotent state can be induced by ectopic expression of genes such as OCT4, SOX2, KLF4, and MYC. Reprogrammed cells can be maintained by activating endogenous pluripotent networks without transgene expression. Although various research groups have attempted to generate pig induced pluripotent stem cells (iPSCs), authentic iPSCs have not be obtained, instead showing dependence on transgene expression. In this study, iPSCs were derived from porcine fetal fibroblasts via drug-inducible vectors carrying human transcription factors (OCT4, SOX2, KLF4, and MYC). Therefore, this study investigated characteristics of iPSCs and reprogramming mechanisms in pig. The iPSCs were stably maintained over an extended period with potential in vitro differentiation into three germ layers. In addition, the pluripotent state of iPSCs was regulated by modulating culture conditions. They showed naive- or primed-like pluripotent states in LIF or bFGF supplemented culture conditions, respectively. However, iPSCs could not be maintained without ectopic expression of transgenes. The cultured iPSCs expressed endogenous transcription factors such as OCT4 and SOX2, but not NANOG (a known gateway to complete reprogramming). Endogenous genes related to mesenchymal-to-epithelial transition (DPPA2, CDH1, EPCAM, and OCLN) were not sufficiently reactivated, as measured by qPCR. DNA methylation analysis for promoters of OCT4, NANOG, and XIST showed that epigenetic reprogramming did not occur in female iPSCs. Based on our results, expression of exogenous genes could not sufficiently activate the essential endogenous genes and remodel the epigenetic milieu to achieve faithful pluripotency in pig. Accordingly, investigating iPSCs could help us improve and develop reprogramming methods by understanding reprogramming mechanisms in pig. PMID:27336671

  11. Reactivation of Endogenous Genes and Epigenetic Remodeling Are Barriers for Generating Transgene-Free Induced Pluripotent Stem Cells in Pig.

    PubMed

    Choi, Kwang-Hwan; Park, Jin-Kyu; Son, Dongchan; Hwang, Jae Yeon; Lee, Dong-Kyung; Ka, Hakhyun; Park, Joonghoon; Lee, Chang-Kyu

    2016-01-01

    Cellular reprogramming of committed cells into a pluripotent state can be induced by ectopic expression of genes such as OCT4, SOX2, KLF4, and MYC. Reprogrammed cells can be maintained by activating endogenous pluripotent networks without transgene expression. Although various research groups have attempted to generate pig induced pluripotent stem cells (iPSCs), authentic iPSCs have not be obtained, instead showing dependence on transgene expression. In this study, iPSCs were derived from porcine fetal fibroblasts via drug-inducible vectors carrying human transcription factors (OCT4, SOX2, KLF4, and MYC). Therefore, this study investigated characteristics of iPSCs and reprogramming mechanisms in pig. The iPSCs were stably maintained over an extended period with potential in vitro differentiation into three germ layers. In addition, the pluripotent state of iPSCs was regulated by modulating culture conditions. They showed naive- or primed-like pluripotent states in LIF or bFGF supplemented culture conditions, respectively. However, iPSCs could not be maintained without ectopic expression of transgenes. The cultured iPSCs expressed endogenous transcription factors such as OCT4 and SOX2, but not NANOG (a known gateway to complete reprogramming). Endogenous genes related to mesenchymal-to-epithelial transition (DPPA2, CDH1, EPCAM, and OCLN) were not sufficiently reactivated, as measured by qPCR. DNA methylation analysis for promoters of OCT4, NANOG, and XIST showed that epigenetic reprogramming did not occur in female iPSCs. Based on our results, expression of exogenous genes could not sufficiently activate the essential endogenous genes and remodel the epigenetic milieu to achieve faithful pluripotency in pig. Accordingly, investigating iPSCs could help us improve and develop reprogramming methods by understanding reprogramming mechanisms in pig. PMID:27336671

  12. Adiponectin Attenuates Angiotensin II-Induced Vascular Smooth Muscle Cell Remodeling through Nitric Oxide and the RhoA/ROCK Pathway

    PubMed Central

    Nour-Eldine, Wared; Ghantous, Crystal M.; Zibara, Kazem; Dib, Leila; Issaa, Hawraa; Itani, Hana A.; El-Zein, Nabil; Zeidan, Asad

    2016-01-01

    Introduction: Adiponectin (APN), an adipocytokine, exerts protective effects on cardiac remodeling, while angiotensin II (Ang II) induces hypertension and vascular remodeling. The potential protective role of APN on the vasculature during hypertension has not been fully elucidated yet. Here, we evaluate the molecular mechanisms of the protective role of APN in the physiological response of the vascular wall to Ang II. Methods and Results: Rat aortic tissues were used to investigate the effect of APN on Ang II-induced vascular remodeling and hypertrophy. We investigated whether nitric oxide (NO), the RhoA/ROCK pathway, actin cytoskeleton remodeling, and reactive oxygen species (ROS) mediate the anti-hypertrophic effect of APN. Ang II-induced protein synthesis was attenuated by pre-treatment with APN, NO donor S-nitroso-N-acetylpenicillamine (SNAP), or cGMP. The hypertrophic response to Ang II was associated with a significant increase in RhoA activation and vascular force production, which were prevented by APN and SNAP. NO was also associated with inhibition of Ang II-induced phosphorylation of cofilin. In addition, immunohistochemistry revealed that 24 h Ang II treatment increased the F- to G-actin ratio, an effect that was inhibited by SNAP. Ang II-induced ROS formation and upregulation of p22phox mRNA expression were inhibited by APN and NO. Both compounds failed to inhibit Nox1 and p47phox expression. Conclusion: Our results suggest that the anti-hypertrophic effects of APN are due, in part, to NO-dependent inhibition of the RhoA/ROCK pathway and ROS formation. PMID:27092079

  13. Natural killer T cells are dispensable in the development of allergen-induced airway hyperresponsiveness, inflammation and remodelling in a mouse model of chronic asthma.

    PubMed

    Koh, Y-I; Shim, J-U; Lee, J-H; Chung, I-J; Min, J-J; Rhee, J H; Lee, H C; Chung, D H; Wi, J-O

    2010-07-01

    Natural killer T (NK T) cells have been shown to play an essential role in the development of allergen-induced airway hyperresponsiveness (AHR) and/or airway inflammation in mouse models of acute asthma. Recently, NK T cells have been reported to be required for the development of AHR in a virus induced chronic asthma model. We investigated whether NK T cells were required for the development of allergen-induced AHR, airway inflammation and airway remodelling in a mouse model of chronic asthma. CD1d-/- mice that lack NK T cells were used for the experiments. In the chronic model, AHR, eosinophilic inflammation, remodelling characteristics including mucus metaplasia, subepithelial fibrosis and increased mass of the airway smooth muscle, T helper type 2 (Th2) immune response and immunoglobulin (Ig)E production were equally increased in both CD1d-/- mice and wild-type mice. However, in the acute model, AHR, eosinophilic inflammation, Th2 immune response and IgE production were significantly decreased in the CD1d-/- mice compared to wild-type. CD1d-dependent NK T cells may not be required for the development of allergen-induced AHR, eosinophilic airway inflammation and airway remodelling in chronic asthma model, although they play a role in the development of AHR and eosinophilic inflammation in acute asthma model. PMID:20456411

  14. Mechanism of IFN-γ in regulating OPN/Th17 pathway during vascular collagen remodeling of hypertension induced by ANG II

    PubMed Central

    Jiang, Lei; He, Pengcheng; Liu, Yong; Chen, Jiyan; Wei, Xuebiao; Tan, Ning

    2015-01-01

    More and more researches show that hypertensive vascular remodeling is closely related to the imbalance of immune system in recent years. IFN-γ is natural protein with the function of immune regulation and has resistance effect on vascular remodeling. However, the mechanism of IFN-γ is to be defined. This paper is to explore the mechanism of IFN-γ in regulating OPN/Th17 pathway. In this research, animal models of vascular collagen remodeling were established by inducing hypertensive mice with ANG II. There was no statistical significance when the systolic blood pressures and the percentages of wall thickness/lumen diameter in both groups of WT + AngII + IFN-γ and WT + PBS were compared (P=0.219>0.05, P=0.118>0.05). The concentration of serum precollagen-type I and III and their ratio in WT + AngII + IFN-γ group were decreased after the IFN-γ being given (P<0.01). Expression of OPN within tissue in WT + Ang II group was relatively high, but lowered after treated by IFN-γ. Th17 cell ratio was decreased in WT + AngII + IFN-γ group (P<0.01). Expressions of RORα and RORγt mRNA within Th17 cell were decreased (P<0.01). The content of IL-23 in WT + AngII + IFN-γ group was increased, while IL-10 and TGF-β decreased. It has proved that IFN-γ can regulate the hypertensive vascular collagen remodeling induced by ANG II, lower the systolic pressure and reduce the pathological damage of vascular collagen remodeling and the collagen synthesis. The mechanism may that the differentiation of Th17 is inhibited by suppressing the OPN expression and regulating the secretion of inflammatory cytokines. PMID:26823760

  15. Diet-induced Obesity Alters Bone Remodeling Leading to Decreased Femoral Trabecular Bone Mass in Mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Body mass derived from an obesity condition may be detrimental to bone health but the mechanism is unknown. This study was to examine changes in bone structure and serum cytokines related to bone metabolism in obese mice induced by a high-fat diet(HFD). Mice fed the HFD were obese and had higher ser...

  16. Qingxuan Jiangya Decoction Reverses Vascular Remodeling by Inducing Vascular Smooth Muscle Cell Apoptosis in Spontaneously Hypertensive Rats.

    PubMed

    Xiao, Fei; He, Fei; Chen, Hongwei; Lin, Shan; Shen, Aling; Chen, Youqin; Chu, Jianfeng; Peng, Jun

    2016-01-01

    Qingxuan Jiangya Decoction (QXJYD), a traditional Chinese medicine formula prescribed by academician Ke-ji Chen, has been used in China to clinically treat hypertension for decades of years. However, the molecular mechanisms of its action remain largely unknown. In this study, we examined the therapeutic efficacy of QXJYD against elevated systolic blood pressure in the spontaneously hypertensive rat (SHR) model, and investigated the underlying molecular mechanisms. We found that oral administration of QXJYD significantly reduced the elevation of systolic blood pressure in SHR but had no effect on body weight change. Additionally, QXJYD treatment significantly decreased the media thickness and ratio of media thickness/lumen diameter in the carotid arteries of SHR. Moreover, QXJYD remarkably promoted apoptosis of vascular smooth muscle cells and reduced the expression of anti-apoptotic B-cell leukemia/lymphoma 2. Furthermore, QXJYD significantly decreased the plasma Angiotensin II level in SHR. Collectively, our findings suggest that reversing vascular remodeling via inducing VSMC apoptosis could be one of the mechanisms whereby QXJYD treats hypertension. PMID:27455221

  17. Impaired skin regeneration and remodeling after cutaneous injury and chemically induced hyperplasia in taps-transgenic mice.

    PubMed

    Hildenbrand, Maike; Rhiemeier, Verena; Hartenstein, Bettina; Lahrmann, Bernd; Grabe, Niels; Angel, Peter; Hess, Jochen

    2010-07-01

    Recently, we identified an AP-1-dependent target gene in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated mouse back skin, which encodes a retroviral-like aspartic proteinase (Taps/Asprv1). Taps expression was detected almost exclusively in stratified epithelia of mouse embryos and adult tissues, and enhanced protein levels were present in several non-neoplastic human skin disorders, implicating a crucial role for differentiation and homeostasis of multilayered epithelia. Here, we generated a mouse model in which Taps transgene expression is under the control of the human ubiquitin C promoter (UBC-Taps). Although no obvious phenotype was observed in normal skin development and homeostasis, these mice showed a significant delay in cutaneous wound closure compared with control animals. Shortly after re-epithelialization, we found an increase in keratinocytes in the stratum granulosum, which express Filaggrin, a late differentiation marker. A hypergranulosum-like phenotype with increased numbers of Filaggrin-positive keratinocytes was also observed in UBC-Taps mice after administration of TPA. In summary, these data show that aberrant Taps expression causes impaired skin regeneration and skin remodeling after cutaneous injury and chemically induced hyperplasia. PMID:20237492

  18. Dietary saffron reduced the blood pressure and prevented remodeling of the aorta in L-NAME-induced hypertensive rats

    PubMed Central

    Nasiri, Zohreh; Sameni, Hamid Reza; Vakili, Abedin; Jarrahi, Morteza; Khorasani, Mahdi Zahedi

    2015-01-01

    Objective(s): The aim of this study was to investigate the effects of nutritional saffron (Crocus sativus L.) stigma hydroalcoholic extract on blood pressure (BP) and histology of the aorta in normotensive and hypertensive rats. Materials and Methods: Saffron (200 mg/kg/day) was given orally for 5 weeks to normotensive and hypertensive rats. Hypertension was induced by NG-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg/day) administration in drinking water, and BP was measured weekly. Histological examination of the thoracic aorta included staining with hematoxylin and eosin, orcein, and periodic acid Schiff methods. Results: Saffron had no effect on normotensive rats, but on hypertensive rats, prevented BP elevation form the third week of treatment (P<0.001). Furthermore, saffron reduced the cross-section area, media thickness, and elastic lamellae number of the aorta (P<0.05). Conclusion: Nutritional saffron prevented BP increases and remodeling of the aorta in hypertensive rats. It may be useful for preventing hypertension. PMID:26949504

  19. Unconventional Human T Cells Accumulate at the Site of Infection in Response to Microbial Ligands and Induce Local Tissue Remodeling

    PubMed Central

    Liuzzi, Anna Rita; Kift-Morgan, Ann; Lopez-Anton, Melisa; Friberg, Ida M.; Zhang, Jingjing; Brook, Amy C.; Roberts, Gareth W.; Donovan, Kieron L.; Colmont, Chantal S.; Toleman, Mark A.; Bowen, Timothy; Johnson, David W.; Topley, Nicholas; Moser, Bernhard; Fraser, Donald J.

    2016-01-01

    The antimicrobial responsiveness and function of unconventional human T cells are poorly understood, with only limited access to relevant specimens from sites of infection. Peritonitis is a common and serious complication in individuals with end-stage kidney disease receiving peritoneal dialysis. By analyzing local and systemic immune responses in peritoneal dialysis patients presenting with acute bacterial peritonitis and monitoring individuals before and during defined infectious episodes, our data show that Vγ9/Vδ2+ γδ T cells and mucosal-associated invariant T cells accumulate at the site of infection with organisms producing (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate and vitamin B2, respectively. Such unconventional human T cells are major producers of IFN-γ and TNF-α in response to these ligands that are shared by many microbial pathogens and affect the cells lining the peritoneal cavity by triggering local inflammation and inducing tissue remodeling with consequences for peritoneal membrane integrity. Our data uncover a crucial role for Vγ9/Vδ2 T cells and mucosal-associated invariant T cells in bacterial infection and suggest that they represent a useful predictive marker for important clinical outcomes, which may inform future stratification and patient management. These findings are likely to be applicable to other acute infections where local activation of unconventional T cells contributes to the antimicrobial inflammatory response. PMID:27527598

  20. CDK5 Is Essential for Soluble Amyloid β-Induced Degradation of GKAP and Remodeling of the Synaptic Actin Cytoskeleton

    PubMed Central

    Roselli, Francesco; Livrea, Paolo; Almeida, Osborne F. X.

    2011-01-01

    The early stages of Alzheimer's disease are marked by synaptic dysfunction and loss. This process results from the disassembly and degradation of synaptic components, in particular of scaffolding proteins that compose the post-synaptic density (PSD), namely PSD95, Homer and Shank. Here we investigated in rat frontal cortex dissociated culture the mechanisms involved in the downregulation of GKAP (SAPAP1), which links the PSD95 complex to the Shank complex and cytoskeletal structures within the PSD. We show that Aβ causes the rapid loss of GKAP from synapses through a pathway that critically requires cdk5 activity, and is set in motion by NMDAR activity and Ca2+ influx. We show that GKAP is a direct substrate of cdk5 and that its phosphorylation results in polyubiquitination and proteasomal degradation of GKAP and remodeling (collapse) of the synaptic actin cytoskeleton; the latter effect is abolished in neurons expressing GKAP mutants that are resistant to phosphorylation by cdk5. Given that cdk5 also regulates degradation of PSD95, these results underscore the central position of cdk5 in mediating Aβ-induced PSD disassembly and synapse loss. PMID:21829588

  1. Insights into the Pathogenesis of Disease in Human Lymphatic Filariasis

    PubMed Central

    2013-01-01

    Abstract Although two thirds of the 120 million people infected with lymph-dwelling filarial parasites have subclinical infections, ∼40 million have lymphedema and/or other pathologic manifestations including hydroceles (and other forms of urogenital disease), episodic adenolymphangitis, lymphedema, and (in its most severe form) elephantiasis. Adult filarial worms reside in the lymphatics and lymph nodes and induce lymphatic dilatation. Progressive lymphatic damage and pathology results primarily from the host inflammatory response to the parasites but also perhaps from the host inflammatory response to the parasite's Wolbachia endosymbiont and as a consequence of superimposed bacterial or fungal infections. This review will attempt to shed light on disease pathogenesis in lymphatic filariasis. PMID:24044755

  2. Diet-induced obesity alters bone remodeling leading to decreased femoral trabecular bone mass in mice.

    PubMed

    Cao, Jay J; Sun, Li; Gao, Hongwei

    2010-03-01

    Obesity-derived body mass may be detrimental to bone health through not well-defined mechanisms. In this study we determined changes in bone structure and serum cytokines related to bone metabolism in diet-induced obese mice. Mice fed a high-fat diet (HFD) had higher serum tartrate-resistant acid phosphatase (TRAP) and leptin but lower osteocalcin concentrations than those fed the normal-fat diet. The HFD increased multinucleated TRAP-positive osteoclasts in bone marrow compared to the control diet. Despite being much heavier, mice fed the HFD had lower femoral bone volume, trabecular number, and connectivity density and higher trabecular separation than mice on the control diet. These findings suggest that obesity induced by a HFD increases bone resorption that may blunt any positive effects of increased body weight on bone. PMID:20392249

  3. Keratinocyte Apoptosis in Epidermal Remodeling and Clearance of Psoriasis Induced by UV Radiation

    PubMed Central

    Weatherhead, Sophie C; Farr, Peter M; Jamieson, David; Hallinan, Jennifer S; Lloyd, James J; Wipat, Anil; Reynolds, Nick J

    2011-01-01

    Psoriasis is a common chronic skin disorder, but the mechanisms involved in the resolution and clearance of plaques remain poorly defined. We investigated the mechanism of action of UVB, which is highly effective in clearing psoriasis and inducing remission, and tested the hypothesis that apoptosis is a key mechanism. To distinguish bystander effects, equal erythemal doses of two UVB wavelengths were compared following in vivo irradiation of psoriatic plaques; one is clinically effective (311 nm) and one has no therapeutic effect on psoriasis (290 nm). Only 311 nm UVB induced significant apoptosis in lesional epidermis, and most apoptotic cells were keratinocytes. To determine clinical relevance, we created a computational model of psoriatic epidermis. Modeling predicted apoptosis would occur in both stem and transit-amplifying cells to account for plaque clearance; this was confirmed and quantified experimentally. The median rate of keratinocyte apoptosis from onset to cell death was 20 minutes. These data were fed back into the model and demonstrated that the observed level of keratinocyte apoptosis was sufficient to explain UVB-induced plaque resolution. Our human studies combined with a systems biology approach demonstrate that keratinocyte apoptosis is a key mechanism in psoriatic plaques clearance, providing the basis for future molecular investigation and therapeutic development. PMID:21614017

  4. STRUCTURAL REMODELING OF PROTEOGLYCANS UPON RETINOIC ACID-INDUCED DIFFERENTIATION OF NCCIT CELLS*

    PubMed Central

    Gasimli, Leyla; Stansfield, Hope E.; Nairn, Alison V.; Liu, Haiying; Paluh, Janet L.; Yang, Bo; Dordick, Jonathan S.; Moremen, Kelley W.; Linhardt, Robert J.

    2012-01-01

    Pluripotent and multipotent cells become increasingly lineage restricted through differentiation. Alterations to the cellular proteoglycan composition and structure should accompany these changes to influence cell proliferation, delineation of tissues and acquisition of cell migration capabilities. Retinoic acid plays an important role in pre-patterning of the early embryo. Retinoic acid can be used in vitro to induce differentiation, causing pluripotent and multipotent cells to become increasingly lineage restricted. We examined retinoic acid-induced changes in the cellular proteoglycan composition of the well-characterized teratocarcinoma line NCCIT. Our analysis revealed changes in the abundance of transcripts for genes encoding core proteins, enzymes that are responsible for early and late linkage region biosynthesis, as well as enzymes for GAG chain extension and modification. Transcript levels for genes encoding core proteins used as backbones for polysaccharide synthesis revealed highly significant increases in expression of lumican and decorin, 1500-fold and 2800-fold, respectively. Similarly, glypican 3, glypican 5, versican and glypican 6 showed increases between 5 and 70-fold. Significant decreases in biglycan, serglycin, glypican 4, aggrecan, neurocan, CD74 and glypican 1 were observed. Disaccharide analysis of the glycans in heparin/heparan sulfate and chondroitin/dermatan sulfate revealed retinoic acid-induced changes restricted to chondroitin/dermatan sulfate glycans. Our study provides the first detailed analysis of changes in the glycosaminoglycan profile of human pluripotent cells upon treatment with the retinoic acid morphogen. PMID:23053635

  5. Structural remodeling of proteoglycans upon retinoic acid-induced differentiation of NCCIT cells.

    PubMed

    Gasimli, Leyla; Stansfield, Hope E; Nairn, Alison V; Liu, Haiying; Paluh, Janet L; Yang, Bo; Dordick, Jonathan S; Moremen, Kelley W; Linhardt, Robert J

    2013-07-01

    Pluripotent and multipotent cells become increasingly lineage restricted through differentiation. Alterations to the cellular proteoglycan composition and structure should accompany these changes to influence cell proliferation, delineation of tissues and acquisition of cell migration capabilities. Retinoic acid plays an important role in pre-patterning of the early embryo. Retinoic acid can be used in vitro to induce differentiation, causing pluripotent and multipotent cells to become increasingly lineage restricted. We examined retinoic acid-induced changes in the cellular proteoglycan composition of the well-characterized teratocarcinoma line NCCIT. Our analysis revealed changes in the abundance of transcripts for genes encoding core proteins, enzymes that are responsible for early and late linkage region biosynthesis, as well as enzymes for GAG chain extension and modification. Transcript levels for genes encoding core proteins used as backbones for polysaccharide synthesis revealed highly significant increases in expression of lumican and decorin, 1,500-fold and 2,800-fold, respectively. Similarly, glypican 3, glypican 5, versican and glypican 6 showed increases between 5 and 70-fold. Significant decreases in biglycan, serglycin, glypican 4, aggrecan, neurocan, CD74 and glypican 1 were observed. Disaccharide analysis of the glycans in heparin/heparan sulfate and chondroitin/dermatan sulfate revealed retinoic acid-induced changes restricted to chondroitin/dermatan sulfate glycans. Our study provides the first detailed analysis of changes in the glycosaminoglycan profile of human pluripotent cells upon treatment with the retinoic acid morphogen. PMID:23053635

  6. Visualisation and stereological assessment of blood and lymphatic vessels.

    PubMed

    Lokmic, Zerina; Mitchell, Geraldine M

    2011-06-01

    The physiological processes involved in tissue development and regeneration also include the parallel formation of blood and lymphatic vessel circulations which involves their growth, maturation and remodelling. Both vascular systems are also frequently involved in the development and progression of pathological conditions in tissues and organs. The blood vascular system circulates oxygenated blood and nutrients at appropriate physiological levels for tissue survival, and efficiently removes all waste products including carbon dioxide. This continuous network consists of the heart, aorta, arteries, arterioles, capillaries, post-capillary venules, venules, veins and vena cava. This system exists in an interstitial environment together with the lymphatic vascular system, including lymph nodes, which aids maintenance of body fluid balance and immune surveillance. To understand the process of vascular development, vascular network stability, remodelling and/or regression in any research model under any experimental conditions, it is necessary to clearly and unequivocally identify and quantify all elements of the vascular network. By utilising stereological methods in combination with cellular markers for different vascular cell components, it is possible to estimate parameters such as surface density and surface area of blood vessels, length density and length of blood vessels as well as absolute vascular volume. This review examines the current strategies used to visualise blood vessels and lymphatic vessels in two- and three-dimensions and the basic principles of vascular stereology used to quantify vascular network parameters. PMID:21472692

  7. Partially Silencing Brain Toll-Like Receptor 4 Prevents in Part Left Ventricular Remodeling with Sympathoinhibition in Rats with Myocardial Infarction-Induced Heart Failure

    PubMed Central

    Ogawa, Kiyohiro; Hirooka, Yoshitaka; Kishi, Takuya; Ide, Tomomi; Sunagawa, Kenji

    2013-01-01

    Background Left ventricular (LV) remodeling and activation of sympathetic nervous system (SNS) are cardinal features of heart failure. We previously demonstrated that enhanced central sympathetic outflow is associated with brain toll-like receptor 4 (TLR4) probably mediated by brain angiotensin II type 1 receptor in mice with myocardial infarction (MI)-induced heart failure. The purpose of the present study was to examine whether silencing brain TLR4 could prevent LV remodeling with sympathoinhibition in MI-induced heart failure. Methodology/Principal Findings MI-induced heart failure model rats were created by ligation of left coronary artery. The expression level of TLR4 in brainstem was significantly higher in MI-induced heart failure treated with intracerebroventricular (ICV) injection of hGAPDH-SiRNA than in sham. TLR4 in brainstem was significantly lower in MI-induced heart failure treated with ICV injection of TLR4-SiRNA than in that treated with ICV injection of hGAPDH-SiRNA. Lung weight, urinary norepinephrine excretion, and LV end-diastolic pressure were significantly lower and LV dimension was significantly smaller in MI-induced heart failure treated with TLR4-SiRNA than in that treated with hGAPDH-SiRNA for 2 weeks. Conclusions Partially silencing brain TLR4 by ICV injection of TLR4-SiRNA for 2 weeks could in part prevent LV remodeling with sympathoinhibition in rats with MI-induced heart failure. Brain TLR4 has a potential to be a target of the treatment for MI-induced heart failure. PMID:23874864

  8. Assessment of Vascular Geometry for Bilateral Carotid Artery Ligation to Induce Early Basilar Terminus Aneurysmal Remodeling in Rats.

    PubMed

    Tutino, Vincent Matthew; Liaw, Nicholas; Spernyak, Joseph Andrew; Ionita, Ciprian Nicolae; Siddiqui, Adnan Hussain; Kolega, John; Meng, Hui

    2016-01-01

    Bilateral common carotid artery (CCA) ligation in rabbits is a model for basilar terminus (BT) aneurysm formation. We asked if this model could be replicated in rats. Fourteen female Sprague Dawley rats underwent bilateral CCA ligation (n=8) or sham surgery (n=6). After 7 days, 5 ligated and 3 sham rats were euthanized for histological evaluation of BT aneurysm formation, while the remaining rats were imaged with magnetic resonance angiography, euthanized, and subjected to corrosion casting of the Circle of Willis (CoW). 3D micro computed tomography images of CoW casts were used for flow simulations at the rat BT, and electron micrographs of the casts were analyzed for aneurysmal and morphological changes. Results from these analyses were compared to rabbit model data (n=10 ligated and n=6 sham). Bilateral CCA ligation did not produce aneurysmal damage at the rat BT. While the surgical manipulation increased rat basilar artery flow, fluid dynamics simulations showed that the initial hemodynamic stress at the rat BT was significantly less than in rabbits. Rats also exhibited fewer morphological and pathological changes (minor changes only occurred in the posterior CoW) than rabbits, which had drastic changes throughout the CoW. A comparison of CoW anatomies demonstrated a greater number of branching arteries at the BT, larger CoW arteries in relation to basilar artery, and a steeper BT bifurcation angle in the rat. These differences could account for the lower hemodynamic stress at the BT and in the cerebrovasculature of the rat. In conclusion, bilateral CCA ligation in rats does not recapitulate the rabbit model of early flow-induced BT aneurysm. We suspect that the different CoW morphology of the rat lessens hemodynamic insults, thereby diminishing flow-induced aneurysmal remodeling. PMID:26503026

  9. Hypoxia-inducible Factor 1 (HIF-1) Promotes Extracellular Matrix Remodeling under Hypoxic Conditions by Inducing P4HA1, P4HA2, and PLOD2 Expression in Fibroblasts*

    PubMed Central

    Gilkes, Daniele M.; Bajpai, Saumendra; Chaturvedi, Pallavi; Wirtz, Denis; Semenza, Gregg L.

    2013-01-01

    Extracellular matrix (ECM) composition, organization, and compliance provide both architectural and chemical cues that modulate tissue structure and function. ECM produced by stromal fibroblasts plays a key role in breast cancer invasion and metastasis, which are also stimulated by intratumoral hypoxia. Here, we demonstrate that hypoxia-inducible factor 1 (HIF-1) is a critical regulator of ECM remodeling by fibroblasts under hypoxic conditions. HIF-1 activates expression of genes encoding collagen prolyl (P4HA1 and P4HA2) and lysyl (PLOD2) hydroxylases. P4HA1 and P4HA2 are required for collagen deposition, whereas PLOD2 is required for ECM stiffening and collagen fiber alignment. Together P4HA1, P4HA2, and PLOD2 mediate remodeling of ECM composition, alignment, and mechanical properties in response to hypoxia. HIF-1-dependent ECM remodeling by hypoxic fibroblasts induces changes in breast cancer cell morphology, adhesion, and motility that promote invasion and metastasis. PMID:23423382

  10. Bone morphogenic protein-2 regulates the myogenic differentiation of PMVECs in CBDL rat serum-induced pulmonary microvascular remodeling

    SciTech Connect

    Liu, Chang; Chen, Lin; Zeng, Jing; Cui, Jian; Ning, Jiao-nin; Wang, Guan-song; Belguise, Karine; Wang, Xiaobo; Qian, Gui-sheng; Lu, Kai-zhi; Yi, Bin

    2015-08-01

    Hepatopulmonary syndrome (HPS) is characterized by an arterial oxygenation defect induced by intrapulmonary vasodilation (IPVD) that increases morbidity and mortality. In our previous study, it was determined that both the proliferation and the myogenic differentiation of pulmonary microvascular endothelial cells (PMVECs) play a key role in the development of IPVD. However, the molecular mechanism underlying the relationship between IPVD and the myogenic differentiation of PMVECs remains unknown. Additionally, it has been shown that bone morphogenic protein-2 (BMP2), via the control of protein expression, may regulate cell differentiation including cardiomyocyte differentiation, neuronal differentiation and odontoblastic differentiation. In this study, we observed that common bile duct ligation (CBDL)-rat serum induced the upregulation of the expression of several myogenic proteins (SM-α-actin, calponin, SM-MHC) and enhanced the expression levels of BMP2 mRNA and protein in PMVECs. We also observed that both the expression levels of Smad1/5 and the activation of phosphorylated Smad1/5 were significantly elevated in PMVECs following exposure to CBDL-rat serum, which was accompanied by the down-regulation of Smurf1. The blockage of the BMP2/Smad signaling pathway with Noggin inhibited the myogenic differentiation of PMVECs, a process that was associated with relatively low expression levels of both SM-α-actin and calponin in the setting of CBDL-rat serum exposure, although SM-MHC expression was not affected. These findings suggested that the BMP2/Smad signaling pathway is involved in the myogenic differentiation of the PMVECs. In conclusion, our data highlight the pivotal role of BMP2 in the CBDL-rat serum-induced myogenic differentiation of PMVECs via the activation of both Smad1 and Smad5 and the down-regulation of Smurf1, which may represent a potential therapy for HPS-induced pulmonary vascular remodeling. - Highlights: • CBDL-rat serum promotes the myogenic