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  1. Mild hypothermia reduces ventilator-induced lung injury, irrespective of reducing respiratory rate.

    PubMed

    Aslami, Hamid; Kuipers, Maria T; Beurskens, Charlotte J P; Roelofs, Joris J T H; Schultz, Marcus J; Juffermans, Nicole P

    2012-02-01

    In the era of lung-protective mechanical ventilation using limited tidal volumes, higher respiratory rates are applied to maintain adequate minute volume ventilation. However, higher respiratory rates may contribute to ventilator-induced lung injury (VILI). Induced hypothermia reduces carbon dioxide production and might allow for lower respiratory rates during mechanical ventilation. We hypothesized that hypothermia protects from VILI and investigated whether reducing respiratory rates enhance lung protection in an in vivo model of VILI. During 4 h of mechanical ventilation, VILI was induced by tidal volumes of 18 mL/kg in rats, with respiratory rates set at 15 or 10 breaths/min in combination with hypothermia (32°C) or normothermia (37°C). Hypothermia was induced by external cooling. A physiologic model was established. VILI was characterized by increased pulmonary neutrophil influx, protein leak, wet weights, histopathology score, and cytokine levels compared with lung protective mechanical ventilation. Hypothermia decreased neutrophil influx, pulmonary levels, systemic interleukin-6 levels, and histopathology score, and it tended to decrease the pulmonary protein leak. Reducing the respiratory rate in combination with hypothermia did not reduce the parameters of the lung injury. In conclusion, hypothermia protected from lung injury in a physiologic VILI model by reducing inflammation. Decreasing the respiratory rate mildly did not enhance protection.

  2. Exogenous surfactant preserves lung function and reduces alveolar Evans blue dye influx in a rat model of ventilation-induced lung injury.

    PubMed

    Verbrugge, S J; Vazquez de Anda, G; Gommers, D; Neggers, S J; Sorm, V; Böhm, S H; Lachmann, B

    1998-08-01

    was reduced in the groups that received 200 and 400 mg/kg exogenous surfactant. Exogenous surfactant preceding high peak inspiratory lung volumes prevents impairment of oxygenation, lung mechanics, and minimal surface tension of bronchoalveolar lavage fluid and reduces alveolar influx of Evans blue dye. These data indicate that surfactant has a beneficial effect on ventilation-induced lung injury.

  3. Ventilator-induced diaphragmatic dysfunction.

    PubMed

    Petrof, Basil J; Jaber, Samir; Matecki, Stefan

    2010-02-01

    Diaphragmatic function is a major determinant of the ability to successfully wean patients from mechanical ventilation. There is increasing recognition of a condition termed ventilator-induced diaphragmatic dysfunction. The purpose of the present review is to present evidence that mechanical ventilation can itself be a cause of diaphragmatic dysfunction, to outline our current understanding of the cellular mechanisms responsible for this phenomenon, and to discuss the implications of recent research for future therapeutic strategies. Many critically ill patients demonstrate diaphragmatic weakness. A large body of evidence from animal models, and more limited data from humans, indicates that mechanical ventilation can cause muscle fiber injury and atrophy within the diaphragm. Current data support a complex underlying pathophysiology involving oxidative stress and the activation of several intracellular proteolytic pathways involved in degradation of the contractile apparatus. This includes the calpain, caspase, and ubiquitin-proteasome systems. In addition, there is a simultaneous downregulation of protein synthesis pathways. Studies in animal models suggest that future therapies may be able to specifically target these processes, whereas for the time being current preventive measures in humans are primarily based upon allowing persistent diaphragmatic activation during mechanical ventilation. Diaphragmatic dysfunction is common in mechanically ventilated patients and is a likely cause of weaning failure. Recently, there has been a great expansion in our knowledge of how mechanical ventilation can adversely affect diaphragmatic structure and function. Future studies need to better define the evolution and mechanistic basis for ventilator-induced diaphragmatic dysfunction in humans, in order to allow the development of mechanical ventilation strategies and pharmacologic agents that will decrease the incidence of ventilator-induced diaphragmatic dysfunction.

  4. Hydrogen inhalation reduced epithelial apoptosis in ventilator-induced lung injury via a mechanism involving nuclear factor-kappa B activation

    SciTech Connect

    Huang, Chien-Sheng; Kawamura, Tomohiro; Peng, Ximei; Tochigi, Naobumi; Shigemura, Norihisa; Billiar, Timothy R.; Nakao, Atsunori; Toyoda, Yoshiya

    2011-05-06

    Highlights: {yields} Hydrogen is a regulatory molecule with antiinflammatory and antiapoptotic protective effects. {yields} There is very limited information on the pathways regulated in vivo by the hydrogen. {yields} Antiapoptotic abilities of hydrogen were explained by upregulation of the antiapoptotic gene. {yields} NF{kappa}B activation during hydrogen treatment was correlated with elevated antiapoptotic protein. {yields} NF{kappa}B activation associated with increase Bcl-2 may contribute to cytoprotection of hydrogen. -- Abstract: We recently demonstrated the inhalation of hydrogen gas, a novel medical therapeutic gas, ameliorates ventilator-induced lung injury (VILI); however, the molecular mechanisms by which hydrogen ameliorates VILI remain unclear. Therefore, we investigated whether inhaled hydrogen gas modulates the nuclear factor-kappa B (NF{kappa}B) signaling pathway. VILI was generated in male C57BL6 mice by performing a tracheostomy and placing the mice on a mechanical ventilator (tidal volume of 30 ml/kg or 10 ml/kg without positive end-expiratory pressure). The ventilator delivered either 2% nitrogen or 2% hydrogen in balanced air. NF{kappa}B activation, as indicated by NF{kappa}B DNA binding, was detected by electrophoretic mobility shift assays and enzyme-linked immunosorbent assay. Hydrogen gas inhalation increased NF{kappa}B DNA binding after 1 h of ventilation and decreased NF{kappa}B DNA binding after 2 h of ventilation, as compared with controls. The early activation of NF{kappa}B during hydrogen treatment was correlated with elevated levels of the antiapoptotic protein Bcl-2 and decreased levels of Bax. Hydrogen inhalation increased oxygen tension, decreased lung edema, and decreased the expression of proinflammatory mediators. Chemical inhibition of early NF{kappa}B activation using SN50 reversed these protective effects. NF{kappa}B activation and an associated increase in the expression of Bcl-2 may contribute, in part, to the

  5. Ventilator-induced Lung Injury

    PubMed Central

    Kneyber, Martin C. J.; Zhang, Haibo; Slutsky, Arthur S.

    2016-01-01

    It is well established that mechanical ventilation can injure the lung, producing an entity known as ventilator-induced lung injury (VILI). There are various forms of VILI, including volutrauma (i.e., injury caused by overdistending the lung), atelectrauma (injury due to repeated opening/closing of lung units), and biotrauma (release of mediators that can induce lung injury or aggravate pre-existing injury, potentially leading to multiple organ failure). Experimental data in the pediatric context are in accord with the importance of VILI, and appear to show age-related susceptibility to VILI, although a conclusive link between use of large Vts and mortality has not been demonstrated in this population. The relevance of VILI in the pediatric intensive care unit population is thus unclear. Given the physiological and biological differences in the respiratory systems of infants, children, and adults, it is difficult to directly extrapolate clinical practice from adults to children. This Critical Care Perspective analyzes the relevance of VILI to the pediatric population, and addresses why pediatric patients might be less susceptible than adults to VILI. PMID:25003705

  6. Rap1 mediates protective effects of iloprost against ventilator-induced lung injury

    PubMed Central

    Birukova, Anna A.; Fu, Panfeng; Xing, Junjie

    2009-01-01

    Prostaglandin I2 (PGI2) has been shown to attenuate vascular constriction, hyperpermeability, inflammation, and acute lung injury. However, molecular mechanisms of PGI2 protective effects on pulmonary endothelial cells (EC) are not well understood. We tested a role of cAMP-activated Epac-Rap1 pathway in the barrier protective effects of PGI2 analog iloprost in the murine model of ventilator-induced lung injury. Mice were treated with iloprost (2 μg/kg) after onset of high tidal volume ventilation (30 ml/kg, 4 h). Bronchoalveolar lavage, histological analysis, and measurements of Evans blue accumulation were performed. In vitro, microvascular EC barrier function was assessed by morphological analysis of agonist-induced gap formation and monitoring of Rho pathway activation and EC permeability. Iloprost reduced bronchoalveolar lavage protein content, neutrophil accumulation, capillary filtration coefficient, and Evans blue albumin extravasation caused by high tidal volume ventilation. Small-interfering RNA-based Rap1 knockdown inhibited protective effects of iloprost. In vitro, iloprost increased barrier properties of lung microvascular endothelium and alleviated thrombin-induced EC barrier disruption. In line with in vivo results, Rap1 depletion attenuated protective effects of iloprost in the thrombin model of EC permeability. These data describe for the first time protective effects for Rap1-dependent signaling against ventilator-induced lung injury and pulmonary endothelial barrier dysfunction. PMID:19850733

  7. Reduced Macular Vascular Density in Myopic Eyes

    PubMed Central

    Fan, Hua; Chen, Hao-Yu; Ma, Hong-Jie; Chang, Zheng; Yin, Hai-Quan; Ng, Danny Siu-Chun; Cheung, Carol Y; Hu, Shan; Xiang, Xiang; Tang, Shi-Bo; Li, Shuang-Nong

    2017-01-01

    Background: Morphological changes of the vasculature system in patients with myopia have been observed by Doppler ultrasound and fundus fluorescein angiography (FFA); however, these studies have limitations. Doppler ultrasound provides low-resolution images which are mainly obtained from visualized large vessels, and FFA is an invasive examination. Optic coherence tomography (OCT) angiography is a noninvasive, high-resolution measurement for vascular density. The purpose of this study was to investigate the change of vascular density in myopic eyes using OCT angiography. Methods: This cross-sectional study includes a total of 91 eyes from 47 participants including control, moderate, and high myopia that were evaluated by OCT angiography. Patients with myopia were recruited from the Refractive Department, Shenzhen Aier Eye Hospital, from August 5, 2015 to April 1, 2016. Emmetropic eyes were from healthy volunteers. The vascular density at macula and optic disc regions, ganglion cell complex (GCC) thickness, and retinal nerve fiber layer (RNFL) thickness were measured. Their relationships with axial length (AL) and refractive error were analyzed. One-way analysis of variance (ANOVA), Pearson's correlation, and generalized estimating equation were used for statistical analysis. Results: Both superficial and deep macular vascular density were highest in control (25.64% ± 3.76% and 37.12% ± 3.66%, respectively), then in moderate myopia (21.15% ± 5.33% and 35.35% ± 5.50%, respectively), and lowest in high myopia group (19.64% ± 3.87% and 32.81% ± 6.29%, respectively) (F = 13.74 and 4.57, respectively; both P < 0.001). Both superficial (β = −0.850 and 0.460, respectively) and deep (β = −0.766 and 0.396, respectively) macular vascular density were associated with AL and spherical equivalent (all P < 0.001). Superficial macular vascular density was associated with GCC thickness (β = 0.244, P = 0.040), independent of spherical equivalent. The vascular density in

  8. Mechanisms of ventilator-induced lung injury in healthy lungs.

    PubMed

    Silva, Pedro Leme; Negrini, Daniela; Rocco, Patricia Rieken Macêdo

    2015-09-01

    Mechanical ventilation is an essential method of patient support, but it may induce lung damage, leading to ventilator-induced lung injury (VILI). VILI is the result of a complex interplay among various mechanical forces that act on lung structures, such as type I and II epithelial cells, endothelial cells, macrophages, peripheral airways, and the extracellular matrix (ECM), during mechanical ventilation. This article discusses ongoing research focusing on mechanisms of VILI in previously healthy lungs, such as in the perioperative period, and the development of new ventilator strategies for surgical patients. Several experimental and clinical studies have been conducted to evaluate the mechanisms of mechanotransduction in each cell type and in the ECM, as well as the role of different ventilator parameters in inducing or preventing VILI. VILI may be attenuated by reducing the tidal volume; however, the use of higher or lower levels of positive end-expiratory pressure (PEEP) and recruitment maneuvers during the perioperative period is a matter of debate. Many questions concerning the mechanisms of VILI in surgical patients remain unanswered. The optimal threshold value of each ventilator parameter to reduce VILI is also unclear. Further experimental and clinical studies are necessary to better evaluate ventilator settings during the perioperative period in different types of surgery. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. VEGF Production by Ly6C+high Monocytes Contributes to Ventilator-Induced Lung Injury

    PubMed Central

    Lin, Chin-Kuo; Li, Jhy-Ming; Chen, Mei-Hsin; Tsai, Mei-Ling; Chang, Chih-Ching

    2016-01-01

    Background Mechanical ventilation is a life-saving procedure for patients with acute respiratory failure, although it may cause pulmonary vascular inflammation and leakage, leading to ventilator-induced lung injury (VILI). Ly6C+high monocytes are involved in the pathogenesis of VILI. In this study, we investigated whether pulmonary infiltrated Ly6C+high monocytes produce vascular endothelial growth factor (VEGF) and contribute to VILI. Methods A clinically relevant two-hit mouse model of VILI, with intravenous lipopolysaccharide (LPS, 20 ng/mouse) immediately before high tidal volume (HTV, 20 mL/kg) ventilation (LPS+HTV), was established. Blood gas and respiratory mechanics were measured to ensure the development of VILI. Flow cytometry and histopathological analyses revealed pulmonary infiltration of leukocytes subsets. Clodronate liposomes were intravenously injected to deplete pulmonary monocytes. In vitro endothelial cell permeability assay with sorted Ly6C+high monocytes condition media assessed the role of Ly6C+high monocytes in vascular permeability. Results LPS+HTV significantly increased total proteins, TNF-α, IL-6, vascular endothelial growth factor (VEGF) and mononuclear cells in the bronchoalveolar lavage fluid (BALF). Pulmonary Ly6C+high monocytes (SSClowCD11b+F4/80+Ly6C+high), but not Ly6C+low monocytes (SSClowCD11b+F4/80+Ly6C+low), were significantly elevated starting at 4 hr. Clodronate liposomes were able to significantly reduce pulmonary Ly6C+high monocytes, and VEGF and total protein in BALF, and restore PaO2/FiO2. There was a strong correlation between pulmonary Ly6C+high monocytes and BALF VEGF (R2 = 0.8791, p<0.001). Moreover, sorted Ly6C+high monocytes were able to produce VEGF, resulting in an increased permeability of endothelial cell monolayer in an in vitro endothelial cell permeability assay. Conclusion VEGF produced by pulmonary infiltrated Ly6C+high monocytes regulates vasculature permeability in a two-hit model of HTV-induced lung

  10. Ventilator-induced diaphragm dysfunction: cause and effect.

    PubMed

    Powers, Scott K; Wiggs, Michael P; Sollanek, Kurt J; Smuder, Ashley J

    2013-09-01

    Mechanical ventilation (MV) is used clinically to maintain gas exchange in patients that require assistance in maintaining adequate alveolar ventilation. Common indications for MV include respiratory failure, heart failure, drug overdose, and surgery. Although MV can be a life-saving intervention for patients suffering from respiratory failure, prolonged MV can promote diaphragmatic atrophy and contractile dysfunction, which is referred to as ventilator-induced diaphragm dysfunction (VIDD). This is significant because VIDD is thought to contribute to problems in weaning patients from the ventilator. Extended time on the ventilator increases health care costs and greatly increases patient morbidity and mortality. Research reveals that only 18-24 h of MV is sufficient to develop VIDD in both laboratory animals and humans. Studies using animal models reveal that MV-induced diaphragmatic atrophy occurs due to increased diaphragmatic protein breakdown and decreased protein synthesis. Recent investigations have identified calpain, caspase-3, autophagy, and the ubiquitin-proteasome system as key proteases that participate in MV-induced diaphragmatic proteolysis. The challenge for the future is to define the MV-induced signaling pathways that promote the loss of diaphragm protein and depress diaphragm contractility. Indeed, forthcoming studies that delineate the signaling mechanisms responsible for VIDD will provide the knowledge necessary for the development of a pharmacological approach that can prevent VIDD and reduce the incidence of weaning problems.

  11. Ventilator-induced lung injury in preterm infants

    PubMed Central

    Carvalho, Clarissa Gutierrez; Silveira, Rita C; Procianoy, Renato Soibelmann

    2013-01-01

    In preterm infants, the need for intubation and mechanical ventilation is associated with ventilator-induced lung injuries and subsequent bronchopulmonary dysplasia. The aim of the present review was to improve the understanding of the mechanisms of injury that involve cytokine-mediated inflammation to contribute to the development of new preventive strategies. Relevant articles were retrieved from the PubMed database using the search terms "ventilator-induced lung injury preterm", "continuous positive airway pressure", "preterm", and "bronchopulmonary dysplasia". The resulting data and other relevant information were divided into several topics to ensure a thorough, critical view of ventilation-induced lung injury and its consequences in preterm infants. The role of pro-inflammatory cytokines (particularly interleukins 6 and 8 and tumor necrosis factor alpha) as mediators of lung injury was assessed. Evidence from studies conducted with animals and human newborns is described. This evidence shows that brief periods of mechanical ventilation is sufficient to induce the release of pro-inflammatory cytokines. Other forms of mechanical and non-invasive ventilation were also analyzed as protective alternatives to conventional mechanical ventilation. It was concluded that non-invasive ventilation, intubation followed by early surfactant administration and quick extubation for nasal continuous positive airway pressure, and strategies that regulate tidal volume and avoid volutrauma (such as volume guarantee ventilation) protect against ventilator-induced lung injury in preterm infants. PMID:24553514

  12. Nitric oxide synthase 3 contributes to ventilator-induced lung injury

    PubMed Central

    Vaporidi, Katerina; Francis, Roland C.; Bloch, Kenneth D.

    2010-01-01

    Nitric oxide synthase (NOS) depletion or inhibition reduces ventilator-induced lung injury (VILI), but the responsible mechanisms remain incompletely defined. The aim of this study was to elucidate the role of endothelial NOS, NOS3, in the pathogenesis of VILI in an in vivo mouse model. Wild-type and NOS3-deficient mice were ventilated with high-tidal volume (HVT; 40 ml/kg) for 4 h, with and without adding NO to the inhaled gas. Additional wild-type mice were pretreated with tetrahydrobiopterin and ascorbic acid, agents that can prevent NOS-generated superoxide production. Arterial blood gas tensions, histology, and lung mechanics were evaluated after 4 h of HVT ventilation. The concentration of protein, IgM, cytokines, malondialdehyde, and 8-isoprostane were measured in bronchoalveolar lavage fluid (BALF). Myeloperoxidase activity, total and oxidized glutathione levels, and NOS-derived superoxide production were measured in lung tissue homogenates. HVT ventilation induced VILI in wild-type mice, as reflected by decreased lung compliance, increased concentrations of protein and cytokines in BALF, and oxidative stress. All indices of VILI were ameliorated in NOS3-deficient mice. Augmenting pulmonary NO levels by breathing NO during mechanical ventilation did not increase lung injury in NOS3-deficient mice. HVT ventilation increased NOS-inhibitable superoxide production in lung extracts from wild-type mice but not in those from NOS3-deficient mice. Administration of tetrahydrobiopterin and ascorbic acid ameliorated VILI in wild-type mice. Our results indicate that NOS3 contributes to ventilator-induced lung injury via increased production of superoxide. PMID:20453164

  13. Moving Beyond JUPITER: Will Inhibiting Inflammation Reduce Vascular Event Rates?

    PubMed Central

    Ridker, Paul M

    2013-01-01

    The recent JUPITER trial demonstrated that potent statin therapy reduces by 50 percent the risk of heart attack and stroke among men and women with low levels of LDL-cholesterol who are at increased vascular risk due to elevated levels of CRP, a biomarker of low-grade systemic inflammation. In JUPITER, both absolute risk and the absolute risk reduction with statin therapy in JUPITER were related to the level of CRP whereas no such relationship was observed for LDL-C. Further, on-treatment levels of CRP and LDL-C were independently associated with residual risk, and the genetic determinants of statin-induced CRP reduction differed from the genetic determinants of statin-induced LDL reduction. Despite these data, it is impossible in any statin trial to establish whether the clinical benefits of treatment are due to LDL-reduction alone, to inflammation inhibition, or to a combination of both processes To address the hypothesis that lowering inflammation will lower vascular event rates, two large-scale placebo controlled trials using targeted anti-inflammatory agents for the secondary prevention of myocardial infarction have been initiated. The first trial, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) is evaluating whether interleukin-1β (IL-1β) inhibition as compared to placebo can reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable coronary artery disease patients who remain at high vascular risk due to persistent elevations of hsCRP (≥2 mg/L) despite contemporary secondary prevention strategies. The second trial, the Cardiovascular Inflammation Reduction Trial (CIRT) has been funded by the NHLBI and will evaluate whether low dose methotrexate (target dose 20 mg/week) as compared to placebo will reduce major vascular events among a group of post-myocardial infarction patients with either diabetes or metabolic syndrome, groups known to have high risk on the basis of a persistent pro

  14. Ventilation-induced lung injury is not exacerbated by growth restriction in preterm lambs.

    PubMed

    Allison, Beth J; Hooper, Stuart B; Coia, Elise; Zahra, Valerie A; Jenkin, Graham; Malhotra, Atul; Sehgal, Arvind; Kluckow, Martin; Gill, Andrew W; Sozo, Foula; Miller, Suzanne L; Polglase, Graeme R

    2016-02-01

    Intrauterine growth restriction (IUGR) and preterm birth are frequent comorbidities and, combined, increase the risk of adverse respiratory outcomes compared with that in appropriately grown (AG) infants. Potential underlying reasons for this increased respiratory morbidity in IUGR infants compared with AG infants include altered fetal lung development, fetal lung inflammation, increased respiratory requirements, and/or increased ventilation-induced lung injury. IUGR was surgically induced in preterm fetal sheep (0.7 gestation) by ligation of a single umbilical artery. Four weeks later, preterm lambs were euthanized at delivery or delivered and ventilated for 2 h before euthanasia. Ventilator requirements, lung inflammation, early markers of lung injury, and morphological changes in lung parenchymal and vascular structure and surfactant composition were analyzed. IUGR preterm lambs weighed 30% less than AG preterm lambs, with increased brain-to-body weight ratio, indicating brain sparing. IUGR did not induce lung inflammation or injury or alter lung parenchymal and vascular structure compared with AG fetuses. IUGR and AG lambs had similar oxygenation and respiratory requirements after birth and had significant, but similar, increases in proinflammatory cytokine expression, lung injury markers, gene expression, and surfactant phosphatidylcholine species compared with unventilated controls. IUGR does not induce pulmonary structural changes in our model. Furthermore, IUGR and AG preterm lambs have similar ventilator requirements in the immediate postnatal period. This study suggests that increased morbidity and mortality in IUGR infants is not due to altered lung tissue or vascular structure, or to an altered response to early ventilation.

  15. Effects of body temperature on ventilator-induced lung injury.

    PubMed

    Akinci, Ozkan I; Celik, Mehmet; Mutlu, Gökhan M; Martino, Janice M; Tugrul, Simru; Ozcan, Perihan E; Yilmazbayhan, Dilek; Yeldandi, Anjana V; Turkoz, Kemal H; Kiran, Bayram; Telci, Lütfi; Cakar, Nahit

    2005-03-01

    To evaluate the effects of body temperature on ventilator-induced lung injury. Thirty-four male Sprague-Dawley rats were randomized into 6 groups based on their body temperature (normothermia, 37 +/- 1 degrees C; hypothermia, 31 +/- 1 degrees C; hyperthermia, 41 +/- 1 degrees C). Ventilator-induced lung injury was achieved by ventilating for 1 hour with pressure-controlled ventilation mode set at peak inspiratory pressure (PIP) of 30 cmH2O (high pressure, or HP) and positive end-expiratory pressure (PEEP) of 0 cmH2O. In control subjects, PIP was set at 14 cmH2O (low pressure, or LP) and PEEP set at 0 cmH2O. Systemic chemokine and cytokine (tumor necrosis factor alpha , interleukin 1 beta , interleukin 6, and monocyte chemoattractant protein 1) levels were measured. The lungs were assessed for histological changes. Serum chemokines and cytokines were significantly elevated in the hyperthermia HP group compared with all 3 groups, LP (control), normothermia HP, and hypothermia HP. Oxygenation was better but not statistically significant in hypothermia HP compared with other HP groups. Cumulative mean histology scores were higher in hyperthermia HP and normothermia HP groups compared with control and normothermia HP groups. Concomitant hyperthermia increased systemic inflammatory response during HP ventilation. Although hypothermia decreased local inflammation in the lung, it did not completely attenuate systemic inflammatory response associated with HP ventilation.

  16. Nuclear factor-κB signaling contributes to mechanical ventilation-induced diaphragm weakness*.

    PubMed

    Smuder, Ashley J; Hudson, Matthew B; Nelson, W Bradley; Kavazis, Andreas N; Powers, Scott K

    2012-03-01

    Although mechanical ventilation is a life-saving measure for patients in respiratory failure, prolonged mechanical ventilation results in diaphragmatic weakness attributable to fiber atrophy and contractile dysfunction. Therefore, identifying the signaling pathways responsible for mechanical ventilation-induced diaphragmatic weakness is important. In this context, it is established that oxidative stress is required for mechanical ventilation-induced diaphragmatic weakness to occur. Numerous redox-sensitive signaling pathways exist in muscle including the transcription factor nuclear factor-κB. Although it has been suggested that nuclear factor-κB contributes to proteolytic signaling in inactivity-induced atrophy in locomotor muscles, the role that nuclear factor-κB plays in mechanical ventilation-induced diaphragmatic weakness is unknown. We tested the hypothesis that nuclear factor-κB activation plays a key signaling role in mechanical ventilation-induced diaphragmatic weakness and that oxidative stress is required for nuclear factor-κB activation. Cause and effect was determined by independently treating mechanically ventilated animals with either a specific nuclear factor-κB inhibitor (SN50) or a clinically relevant antioxidant (curcumin). Inhibition of nuclear factor-κB activity partially attenuated both mechanical ventilation-induced diaphragmatic atrophy and contractile dysfunction. Further, treatment with the antioxidant curcumin prevented mechanical ventilation-induced activation of nuclear factor-κB in the diaphragm and rescued the diaphragm from both mechanical ventilation-induced atrophy and contractile dysfunction. Collectively, these findings support the hypothesis that nuclear factor-κB activation plays a significant signaling role in mechanical ventilation-induced diaphragmatic weakness and that oxidative stress is an upstream activator of nuclear factor-κB. Finally, our results suggest that prevention of mechanical ventilation-induced

  17. Cyr61 silencing reduces vascularization and dissemination of osteosarcoma tumors.

    PubMed

    Habel, N; Vilalta, M; Bawa, O; Opolon, P; Blanco, J; Fromigué, O

    2015-06-11

    Osteosarcoma is the most prevalent primary pediatric cancer-related bone disease. These tumors frequently develop resistance to chemotherapy and are highly metastatic, leading to poor outcome. Thus, there is a need for new therapeutic strategies that can prevent cell dissemination. We previously showed that CYR61/CCN1 expression in osteosarcoma cells is correlated to aggressiveness both in vitro and in vivo in mouse models, as well as in patients. In this study, we found that CYR61 is a critical contributor to the vascularization of primary tumor. We demonstrate that silencing CYR61, using lentiviral transduction, leads to a significant reduction in expression level of pro-angiogenic markers such as VEGF, FGF2, PECAM and angiopoietins concomitantly to an increased expression of major anti-angiogenic markers such as thrombospondin-1 and SPARC. Matrix metalloproteinase-2 family member expression, a key pathway in osteosarcoma metastatic capacity was also downregulated when CYR61 was downregulated in osteosarcoma cells. Using a metastatic murine model, we show that CYR61 silencing in osteosarcoma cells results in reduced tumor vasculature and slows tumor growth compared with control. We also find that microvessel density correlates with lung metastasis occurrence and that CYR61 silencing in osteosarcoma cells limits the number of metastases. Taken together, our data indicate that CYR61 silencing can blunt the malignant behavior of osteosarcoma tumor cells by limiting primary tumor growth and dissemination process.

  18. Ibuprofen Protects Ventilator-Induced Lung Injury by Downregulating Rho-Kinase Activity in Rats

    PubMed Central

    Lin, Chien-Huang; Chou, Hsiu-Chu

    2014-01-01

    Background. Ventilator-induced lung injury-(VILI-) induced endothelial permeability is regulated through the Rho-dependent signaling pathway. Ibuprofen inhibits Rho activation in animal models of spinal-cord injury and Alzheimer's disease. The study aims to investigate ibuprofen effects on high tidal volume associated VILI. Methods. Twenty-eight adult male Sprague-Dawley rats were randomized to receive a ventilation strategy with three different interventions for 2 h: (1) a high-volume zero-positive end-expiratory pressure (PEEP) (HVZP) group; (2) an HVZP + ibuprofen 15 mg/kg group; and (3) an HVZP + ibuprofen 30 mg/kg group. A fourth group without ventilation served as the control group. Rho-kinase activity was determined by ratio of phosphorylated ezrin, radixin, and moesin (p-ERM), substrates of Rho-kinase, to total ERM. VILI was characterized by increased pulmonary protein leak, wet-to-dry weight ratio, cytokines level, and Rho guanine nucleotide exchange factor (GEF-H1), RhoA activity, p-ERM/total ERM, and p-myosin light chain (MLC) protein expression. Results. Ibuprofen pretreatment significantly reduced the HVZP ventilation-induced increase in pulmonary protein leak, wet-to-dry weight ratio, bronchoalveolar lavage fluid interleukin-6 and RANTES levels, and lung GEF-H1, RhoA activity, p-ERM/total ERM, and p-MLC protein expression. Conclusion. Ibuprofen attenuated high tidal volume induced pulmonary endothelial hyperpermeability. This protective effect was associated with a reduced Rho-kinase activity. PMID:25019086

  19. Globular adiponectin reduces vascular calcification via inhibition of ER-stress-mediated smooth muscle cell apoptosis.

    PubMed

    Lu, Yan; Bian, Yunfei; Wang, Yueru; Bai, Rui; Wang, Jiapu; Xiao, Chuanshi

    2015-01-01

    This study aims to explore the mechanism of globular adiponectin inhibiting vascular calcification. We established drug-induced rat vascular calcification model, globular adiponectin was given to observe the effect of globular Adiponectin on the degree of calcification. The markers of vascular calcification and apoptosis were also investigated. Meanwhile, the in vitro effect of globular Adiponectin on vascular calcification was also evaluated using primary cultured rat vascular smooth muscle cells. We found that globular adiponectin could inhibit drug-induced rat vascular calcification significantly in vivo. The apoptosis of vascular smooth muscle cells was also reduced. The possible mechanism could be the down-regulation of endoplasmic reticulum stress by globular adiponectin. Experiments in primary cultured vascular smooth muscle cells also confirmed that globular adiponectin could reduce cell apoptosis to suppress vascular calcification via inhibition of endoplasmic reticulum stress. This study confirmed that globular adiponectin could suppress vascular calcification; one of the mechanisms could be inhibition of endoplasmic reticulum stress to reduce cell apoptosis. It could provide an effective method in the therapy of vascular calcification-associated diseases.

  20. Globular adiponectin reduces vascular calcification via inhibition of ER-stress-mediated smooth muscle cell apoptosis

    PubMed Central

    Lu, Yan; Bian, Yunfei; Wang, Yueru; Bai, Rui; Wang, Jiapu; Xiao, Chuanshi

    2015-01-01

    Objective: This study aims to explore the mechanism of globular adiponectin inhibiting vascular calcification. Methods: We established drug-induced rat vascular calcification model, globular adiponectin was given to observe the effect of globular Adiponectin on the degree of calcification. The markers of vascular calcification and apoptosis were also investigated. Meanwhile, the in vitro effect of globular Adiponectin on vascular calcification was also evaluated using primary cultured rat vascular smooth muscle cells. Results: We found that globular adiponectin could inhibit drug-induced rat vascular calcification significantly in vivo. The apoptosis of vascular smooth muscle cells was also reduced. The possible mechanism could be the down-regulation of endoplasmic reticulum stress by globular adiponectin. Experiments in primary cultured vascular smooth muscle cells also confirmed that globular adiponectin could reduce cell apoptosis to suppress vascular calcification via inhibition of endoplasmic reticulum stress. Conclusions: This study confirmed that globular adiponectin could suppress vascular calcification; one of the mechanisms could be inhibition of endoplasmic reticulum stress to reduce cell apoptosis. It could provide an effective method in the therapy of vascular calcification-associated diseases. PMID:26045760

  1. AT1 receptor blocker losartan protects against mechanical ventilation-induced diaphragmatic dysfunction

    PubMed Central

    Kwon, Oh Sung; Smuder, Ashley J.; Wiggs, Michael P.; Hall, Stephanie E.; Sollanek, Kurt J.; Morton, Aaron B.; Talbert, Erin E.; Toklu, Hale Z.; Tumer, Nihal

    2015-01-01

    Mechanical ventilation is a life-saving intervention for patients in respiratory failure. Unfortunately, prolonged ventilator support results in diaphragmatic atrophy and contractile dysfunction leading to diaphragm weakness, which is predicted to contribute to problems in weaning patients from the ventilator. While it is established that ventilator-induced oxidative stress is required for the development of ventilator-induced diaphragm weakness, the signaling pathway(s) that trigger oxidant production remain unknown. However, recent evidence reveals that increased plasma levels of angiotensin II (ANG II) result in oxidative stress and atrophy in limb skeletal muscles. Using a well-established animal model of mechanical ventilation, we tested the hypothesis that increased circulating levels of ANG II are required for both ventilator-induced diaphragmatic oxidative stress and diaphragm weakness. Cause and effect was determined by administering an angiotensin-converting enzyme inhibitor (enalapril) to prevent ventilator-induced increases in plasma ANG II levels, and the ANG II type 1 receptor antagonist (losartan) was provided to prevent the activation of ANG II type 1 receptors. Enalapril prevented the increase in plasma ANG II levels but did not protect against ventilator-induced diaphragmatic oxidative stress or diaphragm weakness. In contrast, losartan attenuated both ventilator-induced oxidative stress and diaphragm weakness. These findings indicate that circulating ANG II is not essential for the development of ventilator-induced diaphragm weakness but that activation of ANG II type 1 receptors appears to be a requirement for ventilator-induced diaphragm weakness. Importantly, these experiments provide the first evidence that the Food and Drug Administration-approved drug losartan may have clinical benefits to protect against ventilator-induced diaphragm weakness in humans. PMID:26359481

  2. AT1 receptor blocker losartan protects against mechanical ventilation-induced diaphragmatic dysfunction.

    PubMed

    Kwon, Oh Sung; Smuder, Ashley J; Wiggs, Michael P; Hall, Stephanie E; Sollanek, Kurt J; Morton, Aaron B; Talbert, Erin E; Toklu, Hale Z; Tumer, Nihal; Powers, Scott K

    2015-11-15

    Mechanical ventilation is a life-saving intervention for patients in respiratory failure. Unfortunately, prolonged ventilator support results in diaphragmatic atrophy and contractile dysfunction leading to diaphragm weakness, which is predicted to contribute to problems in weaning patients from the ventilator. While it is established that ventilator-induced oxidative stress is required for the development of ventilator-induced diaphragm weakness, the signaling pathway(s) that trigger oxidant production remain unknown. However, recent evidence reveals that increased plasma levels of angiotensin II (ANG II) result in oxidative stress and atrophy in limb skeletal muscles. Using a well-established animal model of mechanical ventilation, we tested the hypothesis that increased circulating levels of ANG II are required for both ventilator-induced diaphragmatic oxidative stress and diaphragm weakness. Cause and effect was determined by administering an angiotensin-converting enzyme inhibitor (enalapril) to prevent ventilator-induced increases in plasma ANG II levels, and the ANG II type 1 receptor antagonist (losartan) was provided to prevent the activation of ANG II type 1 receptors. Enalapril prevented the increase in plasma ANG II levels but did not protect against ventilator-induced diaphragmatic oxidative stress or diaphragm weakness. In contrast, losartan attenuated both ventilator-induced oxidative stress and diaphragm weakness. These findings indicate that circulating ANG II is not essential for the development of ventilator-induced diaphragm weakness but that activation of ANG II type 1 receptors appears to be a requirement for ventilator-induced diaphragm weakness. Importantly, these experiments provide the first evidence that the Food and Drug Administration-approved drug losartan may have clinical benefits to protect against ventilator-induced diaphragm weakness in humans.

  3. Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm weakness.

    PubMed

    Powers, Scott K; Hudson, Matthew B; Nelson, W Bradley; Talbert, Erin E; Min, Kisuk; Szeto, Hazel H; Kavazis, Andreas N; Smuder, Ashley J

    2011-07-01

    Mechanical ventilation is a life-saving intervention used to provide adequate pulmonary ventilation in patients suffering from respiratory failure. However, prolonged mechanical ventilation is associated with significant diaphragmatic weakness resulting from both myofiber atrophy and contractile dysfunction. Although several signaling pathways contribute to diaphragm weakness during mechanical ventilation, it is established that oxidative stress is required for diaphragmatic weakness to occur. Therefore, identifying the site(s) of mechanical ventilation- induced reactive oxygen species production in the diaphragm is important. These experiments tested the hypothesis that elevated mitochondrial reactive oxygen species emission is required for mechanical ventilation-induced oxidative stress, atrophy, and contractile dysfunction in the diaphragm. Cause and effect was determined by preventing mechanical ventilation-induced mitochondrial reactive oxygen species emission in the diaphragm of rats using a novel mitochondria-targeted antioxidant (SS-31). None. Compared to mechanically ventilated animals treated with saline, animals treated with SS-31 were protected against mechanical ventilation-induced mitochondrial dysfunction, oxidative stress, and protease activation in the diaphragm. Importantly, treatment of animals with the mitochondrial antioxidant also protected the diaphragm against mechanical ventilation-induced myofiber atrophy and contractile dysfunction. These results reveal that prevention of mechanical ventilation-induced increases in diaphragmatic mitochondrial reactive oxygen species emission protects the diaphragm from mechanical ventilation-induced diaphragmatic weakness. This important new finding indicates that mitochondria are a primary source of reactive oxygen species production in the diaphragm during prolonged mechanical ventilation. These results could lead to the development of a therapeutic intervention to impede mechanical ventilation-induced

  4. Nicotinamide Exacerbates Hypoxemia in Ventilator-Induced Lung Injury Independent of Neutrophil Infiltration

    PubMed Central

    Jones, Heather D.; Yoo, Jeena; Crother, Timothy R.; Kyme, Pierre; Ben-Shlomo, Anat; Khalafi, Ramtin; Tseng, Ching W.; Parks, William C.; Arditi, Moshe

    2015-01-01

    Background Ventilator-induced lung injury is a form of acute lung injury that develops in critically ill patients on mechanical ventilation and has a high degree of mortality. Nicotinamide phosphoribosyltransferase is an enzyme that is highly upregulated in ventilator-induced lung injury and exacerbates the injury when given exogenously. Nicotinamide (vitamin B3) directly inhibits downstream pathways activated by Nicotinamide phosphoribosyltransferase and is protective in other models of acute lung injury. Methods We administered nicotinamide i.p. to mice undergoing mechanical ventilation with high tidal volumes to study the effects of nicotinamide on ventilator-induced lung injury. Measures of injury included oxygen saturations and bronchoalveolar lavage neutrophil counts, protein, and cytokine levels. We also measured expression of nicotinamide phosophoribosyltransferase, and its downstream effectors Sirt1 and Cebpa, Cebpb, Cebpe. We assessed the effect of nicotinamide on the production of nitric oxide during ventilator-induced lung injury. We also studied the effects of ventilator-induced lung injury in mice deficient in C/EBPε. Results Nicotinamide treatment significantly inhibited neutrophil infiltration into the lungs during ventilator-induced lung injury, but did not affect protein leakage or cytokine production. Surprisingly, mice treated with nicotinamide developed significantly worse hypoxemia during mechanical ventilation. This effect was not linked to increases in nitric oxide production or alterations in expression of Nicotinamide phosphoribosyl transferase, Sirt1, or Cebpa and Cebpb. Cebpe mRNA levels were decreased with either nicotinamide treatment or mechanical ventilation, but mice lacking C/EBPε developed the same degree of hypoxemia and ventilator-induced lung injury as wild-type mice. Conclusions Nicotinamide treatment during VILI inhibits neutrophil infiltration of the lungs consistent with a strong anti-inflammatory effect, but

  5. Mechanical Power and Development of Ventilator-induced Lung Injury.

    PubMed

    Cressoni, Massimo; Gotti, Miriam; Chiurazzi, Chiara; Massari, Dario; Algieri, Ilaria; Amini, Martina; Cammaroto, Antonio; Brioni, Matteo; Montaruli, Claudia; Nikolla, Klodiana; Guanziroli, Mariateresa; Dondossola, Daniele; Gatti, Stefano; Valerio, Vincenza; Vergani, Giordano Luca; Pugni, Paola; Cadringher, Paolo; Gagliano, Nicoletta; Gattinoni, Luciano

    2016-05-01

    The ventilator works mechanically on the lung parenchyma. The authors set out to obtain the proof of concept that ventilator-induced lung injury (VILI) depends on the mechanical power applied to the lung. Mechanical power was defined as the function of transpulmonary pressure, tidal volume (TV), and respiratory rate. Three piglets were ventilated with a mechanical power known to be lethal (TV, 38 ml/kg; plateau pressure, 27 cm H2O; and respiratory rate, 15 breaths/min). Other groups (three piglets each) were ventilated with the same TV per kilogram and transpulmonary pressure but at the respiratory rates of 12, 9, 6, and 3 breaths/min. The authors identified a mechanical power threshold for VILI and did nine additional experiments at the respiratory rate of 35 breaths/min and mechanical power below (TV 11 ml/kg) and above (TV 22 ml/kg) the threshold. In the 15 experiments to detect the threshold for VILI, up to a mechanical power of approximately 12 J/min (respiratory rate, 9 breaths/min), the computed tomography scans showed mostly isolated densities, whereas at the mechanical power above approximately 12 J/min, all piglets developed whole-lung edema. In the nine confirmatory experiments, the five piglets ventilated above the power threshold developed VILI, but the four piglets ventilated below did not. By grouping all 24 piglets, the authors found a significant relationship between the mechanical power applied to the lung and the increase in lung weight (r = 0.41, P = 0.001) and lung elastance (r = 0.33, P < 0.01) and decrease in PaO2/FIO2 (r = 0.40, P < 0.001) at the end of the study. In piglets, VILI develops if a mechanical power threshold is exceeded.

  6. Effect of theophylline on ventilator-induced diaphragmatic dysfunction.

    PubMed

    Kim, Won-Young; Park, So Hee; Kim, Won Young; Huh, Jin Won; Hong, Sang-Bum; Koh, Younsuck; Lim, Chae-Man

    2016-06-01

    To evaluate the effect of theophylline in patients with ventilator-induced diaphragmatic dysfunction (VIDD). Patients who required mechanical ventilation at least 72 hours, met the criteria for a spontaneous breathing trial, and had evidence of VIDD by ultrasonography were included in the study. Of the 40 patients, 21 received theophylline and 19 did not. Clinical characteristics were similar in the 2 groups. Assessment of VIDD showed no between-group differences in baseline diaphragmatic excursion (DE) of both hemidiaphragms. Changes in DE from baseline to 72 hours (ΔDE) were significantly higher in the theophylline group than in the nontheophylline group in the right (3.5 ± 4.5 mm vs 0.4 ± 2.1 mm; P = .004) and left (3.2 ± 5.1 mm vs 0.1 ± 4.0 mm; P = .03) hemidiaphragms and in the total DE of both diaphragms (6.9 ± 9.1 mm vs 0.5 ± 5.7 mm; P = .02). In the theophylline group, theophylline was effective for the diaphragms with VIDD, whereas it was not effective for the diaphragms without VIDD. ΔDE in the right (rs = -0.49, P = .006) hemidiaphragm and total Δ DE in both diaphragms (rs = -0.46, P = .01) correlated negatively with weaning time. Theophylline significantly improved diaphragmatic movements in patients with VIDD. Our results warrant a larger study to determine whether theophylline use has benefits during weaning from mechanical ventilation. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Conservative fluid management prevents age-associated ventilator induced mortality.

    PubMed

    Herbert, Joseph A; Valentine, Michael S; Saravanan, Nivi; Schneck, Matthew B; Pidaparti, Ramana; Fowler, Alpha A; Reynolds, Angela M; Heise, Rebecca L

    2016-08-01

    Approximately 800 thousand patients require mechanical ventilation in the United States annually with an in-hospital mortality rate of over 30%. The majority of patients requiring mechanical ventilation are over the age of 65 and advanced age is known to increase the severity of ventilator-induced lung injury (VILI) and in-hospital mortality rates. However, the mechanisms which predispose aging ventilator patients to increased mortality rates are not fully understood. Ventilation with conservative fluid management decreases mortality rates in acute respiratory distress patients, but to date there has been no investigation of the effect of conservative fluid management on VILI and ventilator associated mortality rates. We hypothesized that age-associated increases in susceptibility and incidence of pulmonary edema strongly promote age-related increases in ventilator associated mortality. 2month old and 20month old male C57BL6 mice were mechanically ventilated with either high tidal volume (HVT) or low tidal volume (LVT) for up to 4h with either liberal or conservative fluid support. During ventilation, lung compliance, total lung capacity, and hysteresis curves were quantified. Following ventilation, bronchoalveolar lavage fluid was analyzed for total protein content and inflammatory cell infiltration. Wet to dry ratios were used to directly measure edema in excised lungs. Lung histology was performed to quantify alveolar barrier damage/destruction. Age matched non-ventilated mice were used as controls. At 4h, both advanced age and HVT ventilation significantly increased markers of inflammation and injury, degraded pulmonary mechanics, and decreased survival rates. Conservative fluid support significantly diminished pulmonary edema and improved pulmonary mechanics by 1h in advanced age HVT subjects. In 4h ventilations, conservative fluid support significantly diminished pulmonary edema, improved lung mechanics, and resulted in significantly lower mortality rates in

  8. Conservative Fluid Management Prevents Age-Associated Ventilator Induced Mortality

    PubMed Central

    Herbert, Joseph A.; Valentine, Michael S.; Saravanan, Nivi; Schneck, Matthew B.; Pidaparti, Ramana; Fowler, Alpha A.; Reynolds, Angela M.; Heise, Rebecca L.

    2017-01-01

    Background Approximately 800 thousand patients require mechanical ventilation in the United States annually with an in-hospital mortality rate of over 30%. The majority of patients requiring mechanical ventilation are over the age of 65 and advanced age is known to increase the severity of ventilator-induced lung injury (VILI) and in-hosptial mortality rates. However, the mechanisms which predispose aging ventilator patients to increased mortality rates are not fully understood. Ventilation with conservative fluid management decreases mortality rates in acute respiratory distress patients, but to date there has been no investigation of the effect of conservative fluid management on VILI and ventilator associated mortality rates. We hypothesized that age-associated increases in susceptibility and incidence of pulmonary edema strongly promote age-related increases in ventilator associated mortality. Methods 2 month old and 20 month old male C57BL6 mice were mechanically ventilated with either high tidal volume (HVT) or low tidal volume (LVT) for up to 4 hours with either liberal or conservative fluid support. During ventilation, lung compliance, total lung capacity, and hysteresis curves were quantified. Following ventilation, bronchoalveolar lavage fluid was analyzed for total protein content and inflammatory cell infiltration. Wet to dry ratios were used to directly measure edema in excised lungs. Lung histology was performed to quantify alveolar barrier damage/destruction. Age matched non-ventilated mice were used as controls. Results At 4hrs, both advanced age and HVT ventilation significantly increased markers of inflammation and injury, degraded pulmonary mechanics, and decreased survival rates. Conservative fluid support significantly diminished pulmonary edema and improved pulmonary mechanics by 1hr in advanced age HVT subjects. In 4hr ventilations, conservative fluid support significantly diminished pulmonary edema, improved lung mechanics, and resulted in

  9. Rice bran enzymatic extract restores endothelial function and vascular contractility in obese rats by reducing vascular inflammation and oxidative stress.

    PubMed

    Justo, Maria Luisa; Candiracci, Manila; Dantas, Ana Paula; de Sotomayor, Maria Alvarez; Parrado, Juan; Vila, Elisabet; Herrera, Maria Dolores; Rodriguez-Rodriguez, Rosalia

    2013-08-01

    Rice bran enzymatic extract (RBEE) used in this study has shown beneficial activities against dyslipidemia, hyperinsulinemia and hypertension. Our aim was to investigate the effects of a diet supplemented with RBEE in vascular impairment developed in obese Zucker rats and to evaluate the main mechanisms mediating this action. Obese Zucker rats were fed a 1% and 5% RBEE-supplemented diet (O1% and O5%). Obese and their lean littermates fed a standard diet were used as controls (OC and LC, respectively). Vascular function was evaluated in aortic rings in organ baths. The role of nitric oxide (NO) was investigated by using NO synthase (NOS) inhibitors. Aortic expression of endothelial NOS (eNOS), inducible NOS (iNOS), tumor necrosis factor (TNF)-α and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits and superoxide production in arterial wall were determined. Endothelial dysfunction and vascular hyperreactivity to phenylephrine in obese rats were ameliorated by RBEE treatment, particularly with 1% RBEE. Up-regulation of eNOS protein expression in RBEE-treated aortas should contribute to this activity. RBEE attenuated vascular inflammation by reducing aortic iNOS and TNF-α expression. Aortas from RBEE-treated groups showed a significant decrease of superoxide production and down-regulation of NADPH oxidase subunits. RBEE treatment restored endothelial function and vascular contractility in obese Zucker rats through a reduction of vascular inflammation and oxidative stress. These results show the nutraceutical potential of RBEE to prevent obesity-related vascular complications. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Inhibition of forkhead boxO-specific transcription prevents mechanical ventilation-induced diaphragm dysfunction.

    PubMed

    Smuder, Ashley J; Sollanek, Kurt J; Min, Kisuk; Nelson, W Bradley; Powers, Scott K

    2015-05-01

    Mechanical ventilation is a lifesaving measure for patients with respiratory failure. However, prolonged mechanical ventilation results in diaphragm weakness, which contributes to problems in weaning from the ventilator. Therefore, identifying the signaling pathways responsible for mechanical ventilation-induced diaphragm weakness is essential to developing effective countermeasures to combat this important problem. In this regard, the forkhead boxO family of transcription factors is activated in the diaphragm during mechanical ventilation, and forkhead boxO-specific transcription can lead to enhanced proteolysis and muscle protein breakdown. Currently, the role that forkhead boxO activation plays in the development of mechanical ventilation-induced diaphragm weakness remains unknown. This study tested the hypothesis that mechanical ventilation-induced increases in forkhead boxO signaling contribute to ventilator-induced diaphragm weakness. University research laboratory. Young adult female Sprague-Dawley rats. Cause and effect was determined by inhibiting the activation of forkhead boxO in the rat diaphragm through the use of a dominant-negative forkhead boxO adeno-associated virus vector delivered directly to the diaphragm. Our results demonstrate that prolonged (12 hr) mechanical ventilation results in a significant decrease in both diaphragm muscle fiber size and diaphragm-specific force production. However, mechanically ventilated animals treated with dominant-negative forkhead boxO showed a significant attenuation of both diaphragm atrophy and contractile dysfunction. In addition, inhibiting forkhead boxO transcription attenuated the mechanical ventilation-induced activation of the ubiquitin-proteasome system, the autophagy/lysosomal system, and caspase-3. Forkhead boxO is necessary for the activation of key proteolytic systems essential for mechanical ventilation-induced diaphragm atrophy and contractile dysfunction. Collectively, these results suggest that

  11. Chemerin reduces vascular nitric oxide/cGMP signalling in rat aorta: a link to vascular dysfunction in obesity?

    PubMed

    Neves, Karla Bianca; Lobato, Núbia S; Lopes, Rhéure Alves Moreira; Filgueira, Fernando P; Zanotto, Camila Ziliotto; Oliveira, Ana Maria; Tostes, Rita C

    2014-07-01

    The adipokine chemerin has been implicated in cardiovascular complications associated with obesity and the metabolic syndrome. Chemerin has direct effects on the vasculature, augmenting vascular responses to contractile stimuli. As NO/cGMP signalling plays a role in vascular dysfunction associated with obesity and the metabolic syndrome, we hypothesized that chemerin induces vascular dysfunction by decreasing NO/cGMP signalling. Aortic rings from male Wistar rats (10-12 weeks of age) were incubated with chemerin (0.5 or 5 ng/ml for 1 h) or vehicle and isometric tension was recorded. Vasorelaxation in response to ACh (acetylcholine), SNP (sodium nitroprusside) and BAY 412272 [an sGC (soluble guanylate cyclase) stimulator] were decreased in chemerin-treated vessels. The NOS (NO synthase) cofactor BH4 (tetrahydrobiopterin), an O2- (superoxide anion) scavenger (tiron) and a SOD (superoxide dismutase) mimetic (tempol) abolished the effects of chemerin on ACh-induced vasodilation. eNOS (endothelial NOS) phosphorylation, determined by Western blotting, was increased in chemerin-treated vessels; however, the enzyme was mainly in the monomeric form, with decreased eNOS dimer/monomer ratio. Chemerin decreased the mRNA levels of the rate-limiting enzyme for BH4 biosynthesis GTP cyclohydrolase I. Chemerin-incubated vessels displayed decreased NO production, along with increased ROS (reactive oxygen species) generation. These effects were abrogated by BH4, tempol and L-NAME (NG-nitro-L-arginine methyl ester). sGC protein expression and cGMP levels were decreased in chemerin-incubated vessels. These results demonstrate that chemerin reduces NO production, enhances NO breakdown and also decreases NO-dependent cGMP signalling, thereby reducing vascular relaxation. Potential mechanisms mediating the effects of chemerin in the vasculature include eNOS uncoupling, increased O2- generation and reduced GC activity.

  12. Physiology in Medicine: Understanding dynamic alveolar physiology to minimize ventilator induced lung injury (VILI).

    PubMed

    Nieman, Gary F; Satalin, Joshua; Kollisch-Singule, Michaela; Andrews, Penny L; Aiash, Hani; Habashi, Nader M; Gatto, Louis A

    2017-04-06

    The acute respiratory distress syndrome (ARDS) remains a serious clinical problem with the main treatment being supportive in the form of mechanical ventilation. However, mechanical ventilation can be a double edge sword, if set improperly can exacerbate the tissue damage caused by ARDS and is known as ventilator induced lung injury (VILI). In order to minimize VILI we must understand the pathophysiologic mechanisms of tissue damage at the alveolar level. In this Physiology in Medicine paper the dynamic physiology of alveolar inflation and deflation during mechanical ventilation will be reviewed. In addition, the pathophysiologic mechanisms of VILI will be reviewed and this knowledge used to suggest an optimal mechanical breath profile (MBP - all airway pressures, volumes, flows, rates and the duration that they are applied at both inspiration and expiration) necessary to minimize VILI. Our review suggests that the current protective ventilation strategy known as the 'Open Lung Strategy' would be the optimal lung protective approach. However, the viscoelastic behavior of dynamic alveolar inflation and deflation has not yet been incorporated into protective mechanical ventilation strategies. Using our knowledge of dynamic alveolar mechanics (i.e the dynamic change in alveolar and alveolar duct size and shape during tidal ventilation) to modify the MBP necessary to minimize VILI will reduce the morbidity and mortality associated with ARDS.

  13. The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction.

    PubMed

    Salah, Heba; Li, Meishan; Cacciani, Nicola; Gastaldello, Stefano; Ogilvie, Hannah; Akkad, Hazem; Namuduri, Arvind Venkat; Morbidoni, Valeria; Artemenko, Konstantin A; Balogh, Gabor; Martinez-Redondo, Vicente; Jannig, Paulo; Hedström, Yvette; Dworkin, Barry; Bergquist, Jonas; Ruas, Jorge; Vigh, Laszlo; Salviati, Leonardo; Larsson, Lars

    2016-08-03

    Ventilation-induced diaphragm dysfunction (VIDD) is a marked decline in diaphragm function in response to mechanical ventilation, which has negative consequences for individual patients' quality of life and for the health care system, but specific treatment strategies are still lacking. We used an experimental intensive care unit (ICU) model, allowing time-resolved studies of diaphragm structure and function in response to long-term mechanical ventilation and the effects of a pharmacological intervention (the chaperone co-inducer BGP-15). The marked loss of diaphragm muscle fiber function in response to mechanical ventilation was caused by posttranslational modifications (PTMs) of myosin. In a rat model, 10 days of BGP-15 treatment greatly improved diaphragm muscle fiber function (by about 100%), although it did not reverse diaphragm atrophy. The treatment also provided protection from myosin PTMs associated with HSP72 induction and PARP-1 inhibition, resulting in improvement of mitochondrial function and content. Thus, BGP-15 may offer an intervention strategy for reducing VIDD in mechanically ventilated ICU patients. Copyright © 2016, American Association for the Advancement of Science.

  14. Induction of cellular antioxidant defense by amifostine improves ventilator-induced lung injury.

    PubMed

    Fu, Panfeng; Murley, Jeffrey S; Grdina, David J; Birukova, Anna A; Birukov, Konstantin G

    2011-12-01

    To test the hypothesis that preconditioning animals with amifostine improves ventilator-induced lung injury via induction of antioxidant defense enzymes. Mechanical ventilation at high tidal volume induces reactive oxygen species production and oxidative stress in the lung, which plays a major role in the pathogenesis of ventilator-induced lung injury. Amifostine attenuates oxidative stress and improves lipopolysaccharide-induced lung injury by acting as a direct scavenger of reactive oxygen and nitrogen species. This study tested effects of chronic amifostine administration on parameters of oxidative stress, lung barrier function, and inflammation associated with ventilator-induced lung injury. Randomized and controlled laboratory investigation in mice and cell culture. University laboratory. C57BL/6J mice. Mice received once-daily dosing with amifostine (10-100 mg/kg, intraperitoneal injection) 3 days consecutively before high tidal volume ventilation (30 mL/kg, 4 hrs) at day 4. Pulmonary endothelial cell cultures were exposed to pathologic cyclic stretching (18% equibiaxial stretch) and thrombin in a previously verified two-hit model of in vitro ventilator-induced lung injury. Three-day amifostine preconditioning before high tidal volume attenuated high tidal volume-induced protein and cell accumulation in the alveolar space judged by bronchoalveolar lavage fluid analysis, decreased Evans Blue dye extravasation into the lung parenchyma, decreased biochemical parameters of high tidal volume-induced tissue oxidative stress, and inhibited high tidal volume-induced activation of redox-sensitive stress kinases and nuclear factor-kappa B inflammatory cascade. These protective effects of amifostine were associated with increased superoxide dismutase 2 expression and increased superoxide dismutase and catalase enzymatic activities in the animal and endothelial cell culture models of ventilator-induced lung injury. Amifostine preconditioning activates lung tissue

  15. IVIG reduced vascular oxidative stress in patients with Kawasaki disease.

    PubMed

    Takatsuki, Shinichi; Ito, Yuka; Takeuchi, Daiji; Hoshida, Hiroshi; Nakayama, Tomotaka; Matsuura, Hiroyuki; Saji, Tsutomu

    2009-07-01

    Oxidative stress (OS) contributes to the acute phase of Kawasaki disease (KD) in a manner that is as yet unknown. In the present study OS in the acute phase of KD was investigated by measuring urinary 8-iso-prostaglandin F2alpha (8-iso-PG) and evaluating its correlation to the efficacy of intravenous immunoglobulin (IVIG) administration. The 62 patients with acute phase of KD were enrolled, as well as 20 healthy children (HC) and 20 with acute febrile illness (FI). Urinary samples were obtained before and after administration of IVIG. The HC and FI groups also had inflammatory markers evaluated at the same time. The 8-iso-PG was significantly elevated in the 62 KD patients (719 +/-335 pg/mg Cr) without IVIG administration compared with those with FI (583 +/-213 pg/mg Cr) as well as HC (443 +/-288 pg/mg Cr) (P<0.01). 40 patients were given 3 different regimens of IVIG: 16 received 2 g/kg for 1 day; 17 received 1 g/kg for 1 day; 7 received 400 mg . kg(-1) . day(-1) for 5 days. All regimens of IVIG reduced the 8-iso-PG level at 7 days after initiation. OS provokes vasculitis in KD, the activation of which was reduced by IVIG. The urinary level of 8-iso-PG is a useful marker of the effectiveness of IVIG in the acute phase of KD.

  16. Dll4 activation of Notch signaling reduces tumor vascularity and inhibits tumor growth

    PubMed Central

    Williams, Cassin Kimmel; la Luz Sierra, Maria de; Bernardo, Marcelino; McCormick, Peter J.; Maric, Dragan; Regino, Celeste; Choyke, Peter; Tosato, Giovanna

    2008-01-01

    Gene targeting experiments have shown that Delta-like 4 (Dll4) is a vascular-specific Notch ligand critical to normal vascular development. Recent studies have demonstrated that inhibition of Dll4/Notch signaling in tumor-bearing mice resulted in excessive, yet nonproductive tumor neovascularization and unexpectedly reduced tumor growth. Because nonfunctional blood vessels have the potential to normalize, we explored the alternative approach of stimulating Notch signaling in the tumor vasculature to inhibit tumor growth. Here we show that retrovirus-induced over-expression of Dll4 in tumor cells activates Notch signaling in cocultured endothelial cells and limits vascular endothelial growth factor (VEGF)–induced endothelial cell growth. Tumors produced in mice by injection of human and murine tumor cells transduced with Dll4 were significantly smaller, less vascularized and more hypoxic than controls, and displayed evidence of Notch activation. In addition, tumor blood perfusion was reduced as documented by vascular imaging. These results demonstrate that Notch activation in the tumor microenvironment reduces tumor neovascularization and blood perfusion, and suggest that Dll4-induced Notch activation may represent an effective therapeutic approach for the treatment of solid tumors. PMID:18577711

  17. Trans Fatty Acids Induce Vascular Inflammation and Reduce Vascular Nitric Oxide Production in Endothelial Cells

    PubMed Central

    Iwata, Naomi G.; Pham, Matilda; Rizzo, Norma O.; Cheng, Andrew M.; Maloney, Ezekiel; Kim, Francis

    2011-01-01

    Intake of trans fatty acids (TFA), which are consumed by eating foods made from partially hydrogenated vegetable oils, is associated with a higher risk of cardiovascular disease. This relation can be explained by many factors including TFA's negative effect on endothelial function and reduced nitric oxide (NO) bioavailability. In this study we investigated the effects of three different TFA (2 common isomers of C18 found in partially hydrogenated vegetable oil and a C18 isomer found from ruminant-derived—dairy products and meat) on endothelial NF-κB activation and nitric oxide (NO) production. Human endothelial cells were treated with increasing concentrations of Elaidic (trans-C18:1 (9 trans)), Linoelaidic (trans-C18:2 (9 trans, 12 trans)), and Transvaccenic (trans-C18:1 (11 trans)) for 3 h. Both Elaidic and Linoelaidic acids were associated with increasing NF-κB activation as measured by IL-6 levels and phosphorylation of IκBα, and impairment of endothelial insulin signaling and NO production, whereas Transvaccenic acid was not associated with these responses. We also measured superoxide production, which has been hypothesized to be necessary in fatty acid-dependent activation of NF-κB. Both Elaidic acid and Linoelaidic acid are associated with increased superoxide production, whereas Transvaccenic acid (which did not induce inflammatory responses) did not increase superoxide production. We observed differential activation of endothelial superoxide production, NF-κB activation, and reduction in NO production by different C18 isomers suggesting that the location and number of trans double bonds effect endothelial NF-κB activation. PMID:22216328

  18. Amelioration of superoxide dismutase on ventilator-induced lung injury by suppressing leukocyte in the lungs and systemic circulation.

    PubMed

    Su, Chien-Ling; Du, Wen-Yuan; Chiang, Ling-Ling; Lin, Yen-Kuang; Lee, Hui-Ling; Chen, Kuan-Hao; Wang, Jiun-; Wang, David

    2013-08-31

    Superoxide dismutase (SOD) is a free radical scavenger and a broad-spectrum antioxidant. Its anti-inflammatory and immunomodulatory effects have recently been noted. We studied the effects of this antioxidant on lung damage, oxidative stress, and inflammation in a model of ventilator-induced lung injury (VILI), using 8- to 12-wk-old Sprange-Dawley rats (n = 40). Animals were randomized and evenly divided into two experimental groups, low tidal volume (V(T)) ventilation (V(T) = 9 ml/kg) and high V(T) ventilation (V(T) = 28 ml/kg). Each group was evenly divided into two subgroups: ten animals were treated with superoxide dismutase (SOD; 10,000 U/kg i.v., 2 h prior to the ventilation) and the rests were treated with vehicle. Lung injury was evaluated by histological examination, and cells counts of red blood cells (RBC) and white blood cells (WBC) in the alveoli and the septal wall thickness in lung tissues and serum lactate dehydrogenase (LDH). The lung permeability was assessed by the wet-to-dry weight ratio (W/D), lung weight to body weight ratio (LW/BW) and protein concentration in broncholavage fluid (BALF). Levels of oxidative stress and lipid peroxidation in the lungs were evaluated by tissue malondialdehyde (MDA) and methylguanidine (MG) in BALF, respectively. SOD pretreatment significantly decreased WBC counts in systemic circulation and in alveoli, and effectively attenuated high V(T) ventilation induced lung injury by reducing hyaline membrane development, septal wall thickness, lung W/D and LW/BW and serum LDH in relation to those of the control. In addition, lung tissues MDA and MG in BALF were also notably reduced.

  19. Anesthetic Propofol Overdose Causes Vascular Hyperpermeability by Reducing Endothelial Glycocalyx and ATP Production

    PubMed Central

    Lin, Ming-Chung; Lin, Chiou-Feng; Li, Chien-Feng; Sun, Ding-Ping; Wang, Li-Yun; Hsing, Chung-Hsi

    2015-01-01

    Prolonged treatment with a large dose of propofol may cause diffuse cellular cytotoxicity; however, the detailed underlying mechanism remains unclear, particularly in vascular endothelial cells. Previous studies showed that a propofol overdose induces endothelial injury and vascular barrier dysfunction. Regarding the important role of endothelial glycocalyx on the maintenance of vascular barrier integrity, we therefore hypothesized that a propofol overdose-induced endothelial barrier dysfunction is caused by impaired endothelial glycocalyx. In vivo, we intraperitoneally injected ICR mice with overdosed propofol, and the results showed that a propofol overdose significantly induced systemic vascular hyperpermeability and reduced the expression of endothelial glycocalyx, syndecan-1, syndecan-4, perlecan mRNA and heparan sulfate (HS) in the vessels of multiple organs. In vitro, a propofol overdose reduced the expression of syndecan-1, syndecan-4, perlecan, glypican-1 mRNA and HS and induced significant decreases in the nicotinamide adenine dinucleotide (NAD+)/NADH ratio and ATP concentrations in human microvascular endothelial cells (HMEC-1). Oligomycin treatment also induced significant decreases in the NAD+/NADH ratio, in ATP concentrations and in syndecan-4, perlecan and glypican-1 mRNA expression in HMEC-1 cells. These results demonstrate that a propofol overdose induces a partially ATP-dependent reduction of endothelial glycocalyx expression and consequently leads to vascular hyperpermeability due to the loss of endothelial barrier functions. PMID:26023717

  20. Prophylactic erythropoietin exacerbates ventilation-induced lung inflammation and injury in preterm lambs.

    PubMed

    Polglase, Graeme R; Barton, Samantha K; Melville, Jacqueline M; Zahra, Valerie; Wallace, Megan J; Siew, Melissa L; Tolcos, Mary; Moss, Timothy J M

    2014-05-01

    Ventilation-induced lung injury (VILI) of preterm neonates probably contributes to the pathogenesis of bronchopulmonary dysplasia (BPD). Erythropoietin (EPO) has been suggested as a therapy for BPD. The aim of this study was to determine whether prophylactic administration of EPO reduces VILI in preterm newborn lambs. Lambs at 126 days of gestation (term is 147 days) were delivered and ventilated with a high tidal volume strategy for 15 min to cause lung injury, then received gentle ventilation until 2 h of age. Lambs were randomized to receive intravenous EPO (5000 IU kg(-1): Vent+EPO; n = 6) or phosphate-buffered saline (Vent; n = 7) soon after birth: unventilated controls (UVC; n = 8) did not receive ventilation or any treatment. Physiological parameters were recorded throughout the experimental procedure. Samples of lung were collected for histological and molecular assessment of inflammation and injury. Samples of liver were collected to assess the systemic acute phase response. Vent+EPO lambs received higher F IO 2, P aO 2 and oxygenation during the first 10 min than Vent lambs. There were no differences in physiological indices beyond this time. Total lung injury score, airway wall thickness, inflammation and haemorrhage were higher in Vent+EPO lambs than in Vent lambs. Lung inflammation and early markers of lung and systemic injury were elevated in ventilated lambs relative to unventilated lambs; EPO administration further increased lung inflammation and markers of lung and systemic injury. Prophylactic EPO exacerbates VILI, which may increase the incidence and severity of long-term respiratory disease. More studies are required before EPO can be used for lung protection in preterm infants.

  1. The effects of exogenous surfactant administration on ventilation-induced inflammation in mouse models of lung injury

    PubMed Central

    2013-01-01

    Background Mechanical ventilation (MV) is an essential supportive therapy for acute lung injury (ALI); however it can also contribute to systemic inflammation. Since pulmonary surfactant has anti-inflammatory properties, the aim of the study was to investigate the effect of exogenous surfactant administration on ventilation-induced systemic inflammation. Methods Mice were randomized to receive an intra-tracheal instillation of a natural exogenous surfactant preparation (bLES, 50 mg/kg) or no treatment as a control. MV was then performed using the isolated and perfused mouse lung (IPML) set up. This model allowed for lung perfusion during MV. In experiment 1, mice were exposed to mechanical ventilation only (tidal volume =20 mL/kg, 2 hours). In experiment 2, hydrochloric acid or air was instilled intra-tracheally four hours before applying exogenous surfactant and ventilation (tidal volume =5 mL/kg, 2 hours). Results For both experiments, exogenous surfactant administration led to increased total and functional surfactant in the treated groups compared to the controls. Exogenous surfactant administration in mice exposed to MV only did not affect peak inspiratory pressure (PIP), lung IL-6 levels and the development of perfusate inflammation compared to non-treated controls. Acid injured mice exposed to conventional MV showed elevated PIP, lung IL-6 and protein levels and greater perfusate inflammation compared to air instilled controls. Instillation of exogenous surfactant did not influence the development of lung injury. Moreover, exogenous surfactant was not effective in reducing the concentration of inflammatory cytokines in the perfusate. Conclusions The data indicates that exogenous surfactant did not mitigate ventilation-induced systemic inflammation in our models. Future studies will focus on altering surfactant composition to improve its immuno-modulating activity. PMID:24256698

  2. Fluoroscopy-guided femoral artery puncture reduces the risk of PCI-related vascular complications.

    PubMed

    Fitts, James; Ver Lee, Peter; Hofmaster, Patricia; Malenka, David

    2008-06-01

    In previous work by the Northern New England Cardiovascular Study Group, risk factors for vascular access site complications in percutaneous coronary intervention (PCI) were identified and a regional effort to reduce these complications was initiated. As part of this effort we considered making a regional recommendation that location of the femoral head as seen on fluoroscopy (fluoro) be used to help determine the site of femoral artery puncture. Therefore, we assessed the use of fluoro to determine whether it actually reduced the rate of vascular complications and shortened length of stay. Data were collected prospectively on 2,651 consecutive PCIs at Eastern Maine Medical Center from 2000 to 2003 including use of fluoro, vascular access site complications (bleeding, pseudoaneurysm formation, hematoma, embolic event or thrombus, A-V fistula), and length of stay. Use of fluoro among eight interventionists was variable: 3 < 20%, 3 35-50%, 2 > 70%. Among all interventions, 48% were performed with fluoro to guide vascular access. The use of fluoro was associated with a significantly lower incidence of pseudoaneurysms (0.3% vs. 1.1%, P = 0.017) and any arterial injury (0.7% vs. 1.9%, P < 0.01). There was no significant difference in bleeding (1.6% vs. 1.8%, P = 0.69). For each physician, there were fewer vascular injuries when fluoro was used. Average length of stay was significantly lower among patients in the fluoro group (2.1 days vs. 2.4, P < 0.01). We conclude that using fluoro to guide vascular access leads to lower complication rates and a shorter length of stay. This approach may become our regional standard of care.

  3. Vascular contractile reactivity in hypotension due to reduced renal reabsorption of Na(+) and restricted dietary Na().

    PubMed

    Alshahrani, Saeed; Rapoport, Robert M; Soleimani, Manoocher

    2017-03-01

    Reduced renal Na(+) reabsorption along with restricted dietary Na(+) depletes intravascular plasma volume which can then result in hypotension. Whether hypotension occurs and the magnitude of hypotension depends in part on compensatory angiotensin II-mediated increased vascular resistance. We investigated whether the ability of vascular resistance to mitigate the hypotension was compromised by decreased contractile reactivity. In vitro reactivity was investigated in aorta from mouse models of reduced renal Na(+) reabsorption and restricted dietary Na(+) associated with considerable hypotension and renin-angiotensin system activation: (1) the Na(+)-Cl(-)-Co-transporter (NCC) knockout (KO) with Na(+) restricted diet (0.1%, 2 weeks) and (2) the relatively more severe pendrin (apical chloride/bicarbonate exchanger) and NCC double KO. Contractile sensitivity to KCl, phenylephrine, and/or U46619 remained unaltered in aorta from both models. Maximal KCl and phenylephrine contraction expressed as force/aorta length from NCC KO with Na(+)-restricted diet remained unaltered, while in pendrin/NCC double KO were reduced to 49 and 64%, respectively. Wet weight of aorta from NCC KO with Na(+)-restricted diet remained unaltered, while pendrin/NCC double KO was reduced to 67%, consistent with decreased medial width determined with Verhoeff-Van Gieson stain. These findings suggest that hypotension associated with severe intravascular volume depletion, as the result of decreased renal Na(+) reabsorption, may in part be due to decreased contractile reactivity as a consequence of reduced vascular hypertrophy.

  4. IL-19 Reduces Ligation-Mediated Neointimal Hyperplasia by Reducing Vascular Smooth Muscle Cell Activation

    PubMed Central

    Ellison, Stephen; Gabunia, Khatuna; Richards, James M.; Kelemen, Sheri E.; England, Ross N.; Rudic, Dan; Azuma, Yasu-Taka; Munroy, M. Alexandra; Eguchi, Satoru; Autieri, Michael V.

    2015-01-01

    We tested the hypothesis that IL-19, a putative member of the type 2 helper T-cell family of anti-inflammatory interleukins, can attenuate intimal hyperplasia and modulate the vascular smooth muscle cell (VSMC) response to injury. Ligated carotid artery of IL-19 knockout (KO) mice demonstrated a significantly higher neointima/intima ratio compared with wild-type (WT) mice (P = 0.04). More important, the increased neointima/intima ratio in the KO could be reversed by injection of 10 ng/g per day recombinant IL-19 into the KO mouse (P = 0.04). VSMCs explanted from IL-19 KO mice proliferated significantly more rapidly than WT. This could be inhibited by addition of IL-19 to KO VSMCs (P = 0.04 and P < 0.01). IL-19 KO VSMCs migrated more rapidly compared with WT (P < 0.01). Interestingly, there was no type 1 helper T-cell polarization in the KO mouse, but there was significantly greater leukocyte infiltrate in the ligated artery in these mice compared with WT. IL-19 KO VSMCs expressed significantly greater levels of inflammatory mRNA, including IL-1β, tumor necrosis factor α, and monocyte chemoattractant protein-1 in response to tumor necrosis factor α stimulation (P < 0.01 for all). KO VSMCs expressed greater adhesion molecule expression and adherence to monocytes. Together, these data indicate that IL-19 is a previously unrecognized counterregulatory factor for VSMCs, and its expression is an important protective mechanism in regulation of vascular restenosis. PMID:24814101

  5. Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury

    SciTech Connect

    Goto, Hiromasa; Nomiyama, Takashi; Mita, Tomoya; Yasunari, Eisuke; Azuma, Kosuke; Komiya, Koji; Arakawa, Masayuki; Jin, Wen Long; Kanazawa, Akio; Kawamori, Ryuzo; Fujitani, Yoshio; Hirose, Takahisa; Watada, Hirotaka

    2011-02-04

    Research highlights: {yields} Exendin-4 reduces neointimal formation after vascular injury in a mouse model. {yields} Exendin-4 dose not alter metabolic parameters in non-diabetic, non-obese mouse model. {yields} Exendin-4 reduces PDGF-induced cell proliferation in cultured SMCs. {yields} Exendin-4 may reduces neointimal formation after vascular injury at least in part through its direct action on SMCs. -- Abstract: Glucagon-like peptide-1 is a hormone secreted by L cells of the small intestine and stimulates glucose-dependent insulin response. Glucagon-like peptide-1 receptor agonists such as exendin-4 are currently used in type 2 diabetes, and considered to have beneficial effects on the cardiovascular system. To further elucidate the effect of glucagon-like peptide-1 receptor agonists on cardiovascular diseases, we investigated the effects of exendin-4 on intimal thickening after endothelial injury. Under continuous infusion of exendin-4 at 24 nmol/kg/day, C57BL/6 mice were subjected to endothelial denudation injury of the femoral artery. Treatment of mice with exendin-4 reduced neointimal formation at 4 weeks after arterial injury without altering body weight or various metabolic parameters. In addition, in vitro studies of isolated murine, rat and human aortic vascular smooth muscle cells showed the expression of GLP-1 receptor. The addition of 10 nM exendin-4 to cultured smooth muscle cells significantly reduced their proliferation induced by platelet-derived growth factor. Our results suggested that exendin-4 reduced intimal thickening after vascular injury at least in part by the suppression of platelet-derived growth factor-induced smooth muscle cells proliferation.

  6. Jujuboside B Reduces Vascular Tension by Increasing Ca2+ Influx and Activating Endothelial Nitric Oxide Synthase.

    PubMed

    Zhao, Yixiu; Zhang, Xin; Li, Jiannan; Bian, Yu; Sheng, Miaomiao; Liu, Bin; Fu, Zidong; Zhang, Yan; Yang, Baofeng

    2016-01-01

    Jujuboside B has been reported to have protective effect on many cardiovascular diseases. However, the effects of Jujuboside B on vascular tension and endothelial function are unknown. The present study investigated the effects of Jujuboside B on reducing vascular tension, protecting endothelial function and the potential mechanisms. The tension of isolated rat thoracic aorta ring was measured by Wire myograph system. The concentration of nitric oxide (NO) and the activity of endothelial nitric oxide synthase (eNOS) in human aortic endothelial cells (HAECs) were determined by Griess reagent method and enzyme-linked immune sorbent assay. The protein levels of eNOS and p-eNOS at Serine-1177 were determined by western blot analysis. Intracellular Ca2+ concentration in HAECs was measured by laser confocal imaging microscopy. Results showed that Jujuboside B reduced the tension of rat thoracic aorta rings with intact endothelium in a dose-dependent manner. L-NAME, KN93, EGTA, SKF96365, iberiotoxin and glibenclamide significantly attenuated Jujuboside B-induced vasodilation in endothelium-intact tissues. In contrast, indometacin and 4-DAMP had no such effects. Jujuboside B also promoted NO generation and increased eNOS activity, which were attenuated by L-NAME, EGTA and SKF96365. Moreover, Jujuboside B increased intracellular Ca2+ concentration dose-dependently, which was inhibited by EGTA and SKF96365. Besides, Jujuboside B induced a rapid Ca2+ influx instantaneously after depleting intracellular Ca2+ store, which was significantly inhibited by SKF96365. In conclusion, this study preliminarily confirmed that Jujuboside B reduced vascular tension endothelium-dependently. The underlying mechanisms involved that Jujuboside B increased extracellular Ca2+ influx through endothelial transient receptor potential cation (TRPC) channels, phosphorylated eNOS and promoted NO generation in vascular endothelial cells. In addition, Jujuboside B-induced vasodilation involved

  7. Jujuboside B Reduces Vascular Tension by Increasing Ca2+ Influx and Activating Endothelial Nitric Oxide Synthase

    PubMed Central

    Zhao, Yixiu; Zhang, Xin; Li, Jiannan; Bian, Yu; Sheng, Miaomiao; Liu, Bin; Fu, Zidong; Zhang, Yan; Yang, Baofeng

    2016-01-01

    Jujuboside B has been reported to have protective effect on many cardiovascular diseases. However, the effects of Jujuboside B on vascular tension and endothelial function are unknown. The present study investigated the effects of Jujuboside B on reducing vascular tension, protecting endothelial function and the potential mechanisms. The tension of isolated rat thoracic aorta ring was measured by Wire myograph system. The concentration of nitric oxide (NO) and the activity of endothelial nitric oxide synthase (eNOS) in human aortic endothelial cells (HAECs) were determined by Griess reagent method and enzyme-linked immune sorbent assay. The protein levels of eNOS and p-eNOS at Serine-1177 were determined by western blot analysis. Intracellular Ca2+ concentration in HAECs was measured by laser confocal imaging microscopy. Results showed that Jujuboside B reduced the tension of rat thoracic aorta rings with intact endothelium in a dose-dependent manner. L-NAME, KN93, EGTA, SKF96365, iberiotoxin and glibenclamide significantly attenuated Jujuboside B-induced vasodilation in endothelium-intact tissues. In contrast, indometacin and 4-DAMP had no such effects. Jujuboside B also promoted NO generation and increased eNOS activity, which were attenuated by L-NAME, EGTA and SKF96365. Moreover, Jujuboside B increased intracellular Ca2+ concentration dose-dependently, which was inhibited by EGTA and SKF96365. Besides, Jujuboside B induced a rapid Ca2+ influx instantaneously after depleting intracellular Ca2+ store, which was significantly inhibited by SKF96365. In conclusion, this study preliminarily confirmed that Jujuboside B reduced vascular tension endothelium-dependently. The underlying mechanisms involved that Jujuboside B increased extracellular Ca2+ influx through endothelial transient receptor potential cation (TRPC) channels, phosphorylated eNOS and promoted NO generation in vascular endothelial cells. In addition, Jujuboside B-induced vasodilation involved

  8. Treatment with polyamine oxidase inhibitor reduces microglial activation and limits vascular injury in ischemic retinopathy

    PubMed Central

    Patel, C.; Xu, Z.; Shosha, E.; Xing, J.; Lucas, R.; Caldwell, R.W.; Caldwell, R.B.; Narayanan, S.P.

    2016-01-01

    Retinal vascular injury is a major cause of vision impairment in ischemic retinopathies. Insults such as hyperoxia, oxidative stress and inflammation contribute to this pathology. Previously, we showed that hyperoxia-induced retinal neurodegeneration is associated with increased polyamine oxidation. Here, we are studying the involvement of polyamine oxidases in hyperoxia-induced injury and death of retinal vascular endothelial cells. Newborn C57BL6/J mice were exposed to hyperoxia (70% O2) from postnatal day (P) 7 to 12 and were treated with the polyamine oxidase inhibitor MDL 72527 or vehicle starting at P6. Mice were sacrificed after different durations of hyperoxia and their retinas were analyzed to determine the effects on vascular injury, microglial cell activation, and inflammatory cytokine profiling. The results of this analysis showed that MDL 72527 treatment significantly reduced hyperoxia-induced retinal vascular injury and enhanced vascular sprouting as compared with the vehicle controls. These protective effects were correlated with significant decreases in microglial activation as well as levels of inflammatory cytokines and chemokines. In order to model the effects of polyamine oxidation in causing microglial activation in vitro, studies were performed using rat brain microvascular endothelial cells treated with conditioned-medium from rat retinal microglia stimulated with hydrogen peroxide. Conditioned-medium from activated microglial cultures induced cell stress signals and cell death in microvascular endothelial cells. These studies demonstrate the involvement of polyamine oxidases in hyperoxia-induced retinal vascular injury and retinal inflammation in ischemic retinopathy, through mechanisms involving cross-talk between endothelial cells and resident retinal microglia. PMID:27239699

  9. A polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy

    PubMed Central

    Crielaard, Bart J; van der Wal, Steffen; Lammers, Twan; Le, Huong Thu; Hennink, Wim E; Schiffelers, Raymond M; Storm, Gert; Fens, Marcel HAM

    2011-01-01

    Colchicinoids are very potent tubulin-binding compounds, which interfere with microtubule formation, giving them strong cytotoxic properties, such as cell mitosis inhibition and induction of microcytoskeleton depolymerization. While this makes them promising vascular disrupting agents (VDAs) in cancer therapy, their dose-limiting toxicity has prevented any clinical application for this purpose. Therefore, colchicinoids are considered attractive lead molecules for the development of novel vascular disrupting nanomedicine. In a previous study, a polymeric colchicinoid prodrug that showed favorable hydrolysis characteristics at physiological conditions was developed. In the current study, this polymeric colchicinoid prodrug was evaluated in vitro and in vivo for its toxicity and vascular disrupting potential. Cell viability studies with human umbilical vein endothelial cells, as an in vitro measure for colchicine activity, reflected the degradation kinetics of the prodrug accordingly. Upon intravenous treatment, in vivo, of B16F10 melanoma-bearing mice with colchicine or with the polymeric colchicinoid prodrug, apparent vascular disruption and consequent tumor necrosis was observed for the prodrug but not for free colchicine at an equivalent dose. Moreover, a five-times-higher dose of the prodrug was well tolerated, indicating reduced toxicity. These findings demonstrate that the polymeric colchicinoid prodrug has a substantially improved efficacy/toxicity ratio compared with that of colchicine, making it a promising VDA for cancer therapy. PMID:22114500

  10. Inhibition of Janus kinase signaling during controlled mechanical ventilation prevents ventilation-induced diaphragm dysfunction.

    PubMed

    Smith, Ira J; Godinez, Guillermo L; Singh, Baljit K; McCaughey, Kelly M; Alcantara, Raniel R; Gururaja, Tarikere; Ho, Melissa S; Nguyen, Henry N; Friera, Annabelle M; White, Kathy A; McLaughlin, John R; Hansen, Derek; Romero, Jason M; Baltgalvis, Kristen A; Claypool, Mark D; Li, Wei; Lang, Wayne; Yam, George C; Gelman, Marina S; Ding, Rongxian; Yung, Stephanie L; Creger, Daniel P; Chen, Yan; Singh, Rajinder; Smuder, Ashley J; Wiggs, Michael P; Kwon, Oh-Sung; Sollanek, Kurt J; Powers, Scott K; Masuda, Esteban S; Taylor, Vanessa C; Payan, Donald G; Kinoshita, Taisei; Kinsella, Todd M

    2014-07-01

    ., Kinoshita, T., Kinsella, T. M. Inhibition of Janus kinase signaling during controlled mechanical ventilation prevents ventilation-induced diaphragm dysfunction.

  11. Inhibition of Janus kinase signaling during controlled mechanical ventilation prevents ventilation-induced diaphragm dysfunction

    PubMed Central

    Smith, Ira J.; Godinez, Guillermo L.; Singh, Baljit K.; McCaughey, Kelly M.; Alcantara, Raniel R.; Gururaja, Tarikere; Ho, Melissa S.; Nguyen, Henry N.; Friera, Annabelle M.; White, Kathy A.; McLaughlin, John R.; Hansen, Derek; Romero, Jason M.; Baltgalvis, Kristen A.; Claypool, Mark D.; Li, Wei; Lang, Wayne; Yam, George C.; Gelman, Marina S.; Ding, Rongxian; Yung, Stephanie L.; Creger, Daniel P.; Chen, Yan; Singh, Rajinder; Smuder, Ashley J.; Wiggs, Michael P.; Kwon, Oh-Sung; Sollanek, Kurt J.; Powers, Scott K.; Masuda, Esteban S.; Taylor, Vanessa C.; Payan, Donald G.; Kinoshita, Taisei; Kinsella, Todd M.

    2014-01-01

    ., Kinoshita, T., Kinsella, T. M. Inhibition of Janus kinase signaling during controlled mechanical ventilation prevents ventilation-induced diaphragm dysfunction. PMID:24671708

  12. Minocycline reduces microgliosis and improves subcortical white matter function in a model of cerebral vascular disease.

    PubMed

    Manso, Yasmina; Holland, Philip R; Kitamura, Akihiro; Szymkowiak, Stefan; Duncombe, Jessica; Hennessy, Edel; Searcy, James L; Marangoni, Martina; Randall, Andrew D; Brown, Jon T; McColl, Barry W; Horsburgh, Karen

    2017-07-19

    Chronic cerebral hypoperfusion is a key mechanism associated with white matter disruption in cerebral vascular disease and dementia. In a mouse model relevant to studying cerebral vascular disease, we have previously shown that cerebral hypoperfusion disrupts axon-glial integrity and the distribution of key paranodal and internodal proteins in subcortical myelinated axons. This disruption of myelinated axons is accompanied by increased microglia and cognitive decline. The aim of the present study was to investigate whether hypoperfusion impairs the functional integrity of white matter, its relation with axon-glial integrity and microglial number, and whether by targeting microglia these effects can be improved. We show that in response to increasing durations of hypoperfusion, the conduction velocity of myelinated fibres in the corpus callosum is progressively reduced and that paranodal and internodal axon-glial integrity is disrupted. The number of microglial cells increases in response to hypoperfusion and correlates with disrupted paranodal and internodal integrity and reduced conduction velocities. Further minocycline, a proposed anti-inflammatory and microglia inhibitor, restores white matter function related to a reduction in the number of microglia. The study suggests that microglial activation contributes to the structural and functional alterations of myelinated axons induced by cerebral hypoperfusion and that dampening microglia numbers/proliferation should be further investigated as potential therapeutic benefit in cerebral vascular disease. © 2017 The Authors GLIA Published by Wiley Periodicals, Inc.

  13. Collagen implant with gentamicin sulphate reduces surgical site infection in vascular surgery: a prospective cohort study.

    PubMed

    Costa Almeida, Carlos Eduardo Perdigão; Reis, Luis; Carvalho, Luis; Costa Almeida, Carlos Manuel

    2014-10-01

    Surgical site infection (SSI) is a common complication after vascular surgery. It may cause exposure of the underlying prosthesis causing graft infection, which may require the removal of the vascular graft, increasing amputation and mortality risks. Graft contamination usually occurs during operative procedure or by direct spread from an infected wound. It is therefore advisable to a strong effort in reducing SSI. Topic antibiotics have not been fully studied in vascular surgery, but collagen implant with gentamicin sulphate has shown to reduce SSI in cardiac surgery, orthopaedics, and general surgery procedures. Sixty (60) non-diabetic and non-obese patients with lower limb ischaemia with indication for femoropopliteal PTFE prosthetic bypass were allocated into 2 groups of 30 patients. A collagen implant impregnated with gentamicin sulphate (Collatamp(®)) was applied in the groin incision adjacent to the prosthesis in one group, and the other was a control group. The same surgical team operated all patients. Szilagyi classification was used. There was no SSI (0% - 0/30) in the collagen implant with gentamicin sulphate group, contrasting with 6 cases (20% - 6/30) of SSI (grade I and II) in the control group (p = 0.024). In-hospital day's data shows a significant difference between the two groups (p = 0.004) with a mean of 5.66 days for implant group and 8.10 days for control group. There was no SSI grade III. Collagen implant with gentamicin sulphate (Collatamp(®)) reduces SSI in the groin incision in ischaemic patients submitted to femoropopliteal PTFE prosthetic bypass. Days of hospitalization are also reduced. Decreasing SSI rate and in-hospital days, this implant may also reduce health care costs. Because this is a small pilot study, a multicentre RCT is necessary for validation. Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

  14. RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction

    PubMed Central

    Hulsmans, Maarten; Courties, Gabriel; Sun, Yuan; Heidt, Timo; Vinegoni, Claudio; Borodovsky, Anna; Fitzgerald, Kevin; Wojtkiewicz, Gregory R.; Iwamoto, Yoshiko; Tricot, Benoit; Khan, Omar F.; Kauffman, Kevin J.; Xing, Yiping; Shaw, Taylor E.; Libby, Peter; Langer, Robert; Weissleder, Ralph; Swirski, Filip K.

    2016-01-01

    Myocardial infarction (MI) leads to a systemic surge of vascular inflammation in mice and humans, resulting in secondary ischemic complications and high mortality. We show that, in ApoE−/− mice with coronary ligation, increased sympathetic tone up-regulates not only hematopoietic leukocyte production but also plaque endothelial expression of adhesion molecules. To counteract the resulting arterial leukocyte recruitment, we developed nanoparticle-based RNA interference (RNAi) that effectively silences five key adhesion molecules. Simultaneously encapsulating small interfering RNA (siRNA)–targeting intercellular cell adhesion molecules 1 and 2 (Icam1 and Icam2), vascular cell adhesion molecule 1 (Vcam1), and E- and P-selectins (Sele and Selp) into polymeric endothelial-avid nanoparticles reduced post-MI neutrophil and monocyte recruitment into atherosclerotic lesions and decreased matrix-degrading plaque protease activity. Five-gene combination RNAi also curtailed leukocyte recruitment to ischemic myocardium. Therefore, targeted multigene silencing may prevent complications after acute MI. PMID:27280687

  15. Peptidylarginine Deiminase Inhibition Reduces Vascular Damage and Modulates Innate Immune Responses in Murine Models of Atherosclerosis

    PubMed Central

    Knight, Jason S.; Luo, Wei; O’Dell, Alexander A.; Yalavarthi, Srilakshmi; Zhao, Wenpu; Subramanian, Venkataraman; Guo, Chiao; Grenn, Robert C.; Thompson, Paul R.; Eitzman, Daniel T.; Kaplan, Mariana J.

    2014-01-01

    Rationale Neutrophil extracellular trap (NET) formation promotes vascular damage, thrombosis, and activation of interferon-α-producing plasmacytoid dendritic cells in diseased arteries. Peptidylarginine deiminase inhibition is a strategy that can decrease in vivo NET formation. Objective To test whether peptidylarginine deiminase inhibition, a novel approach to targeting arterial disease, can reduce vascular damage and inhibit innate immune responses in murine models of atherosclerosis. Methods and Results Apolipoprotein-E (Apoe)−/− mice demonstrated enhanced NET formation, developed autoantibodies to NETs, and expressed high levels of interferon-α in diseased arteries. Apoe−/− mice were treated for 11 weeks with daily injections of Cl-amidine, a peptidylarginine deiminase inhibitor. Peptidylarginine deiminase inhibition blocked NET formation, reduced atherosclerotic lesion area, and delayed time to carotid artery thrombosis in a photochemical injury model. Decreases in atherosclerosis burden were accompanied by reduced recruitment of netting neutrophils and macrophages to arteries, as well as by reduced arterial interferon-α expression. Conclusions Pharmacological interventions that block NET formation can reduce atherosclerosis burden and arterial thrombosis in murine systems. These results support a role for aberrant NET formation in the pathogenesis of atherosclerosis through modulation of innate immune responses. PMID:24425713

  16. Agmatine induces gastric protection against ischemic injury by reducing vascular permeability in rats.

    PubMed

    Al Masri, Abeer A; El Eter, Eman

    2012-05-14

    To investigate the effect of administration of agmatine (AGM) on gastric protection against ischemia reperfusion (I/R) injury. Three groups of rats (6/group); sham, gastric I/R injury, and gastric I/R + AGM (100 mg/kg, i.p. given 15 min prior to gastric ischemia) were recruited. Gastric injury was conducted by ligating celiac artery for 30 min and reperfusion for another 30 min. Gastric tissues were histologically studied and immunostained with angiopoietin 1 (Ang-1) and Ang-2. Vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) were measured in gastric tissue homogenate. To assess whether AKt/phosphatidyl inositol-3-kinase (PI3K) mediated the effect of AGM, an additional group was pretreated with Wortmannin (WM) (inhibitor of Akt/PI3K, 15 μg/kg, i.p.), prior to ischemic injury and AGM treatment, and examined histologically and immunostained. Another set of experiments was run to study vascular permeability of the stomach using Evan's blue dye. AGM markedly reduced Evan's blue dye extravasation (3.58 ± 0.975 μg/stomach vs 1.175 ± 0.374 μg/stomach, P < 0.05), VEGF (36.87 ± 2.71 pg/100 mg protein vs 48.4 ± 6.53 pg/100 mg protein, P < 0.05) and MCP-1 tissue level (29.5 ± 7 pg/100 mg protein vs 41.17 ± 10.4 pg/100 mg protein, P < 0.01). It preserved gastric histology and reduced congestion. Ang-1 and Ang-2 immunostaining were reduced in stomach sections of AGM-treated animals. The administration of WM abolished the protective effects of AGM and extensive hemorrhage and ulcerations were seen. AGM protects the stomach against I/R injury by reducing vascular permeability and inflammation. This protection is possibly mediated by Akt/PI3K.

  17. Short photoperiods reduce vascular endothelial growth factor in the testes of Peromyscus leucopus.

    PubMed

    Young, K A; Nelson, R J

    2000-09-01

    Testicular regression in rodents occurs after short-day exposure. Vascular support is withdrawn during regression, and, presumably, new angiogenesis is inhibited. Blood vessel growth and maintenance are regulated by paracrine factors, including vascular endothelial growth factor (VEGF). Reduced angiogenesis may contribute to the onset of photoperiod-induced regression; i.e., reduction of VEGF protein would be detected early during gonadal atrophy. Alternatively, loss of blood vessel maintenance may reflect reduced testicular volume. If true, VEGF would not be expected to decline until significant regression occurred. To discriminate between these hypotheses, white-footed mice (Peromyscus leucopus) were maintained in either long (LD 16:8) or short (LD 8:16) photoperiod. Immunohistochemical and Western analyses revealed high VEGF expression in Leydig and Sertoli cells in long-day housed males and reduced VEGF expression in short-day housed males. Reductions in VEGF preceded decreases in both seminiferous tubule diameter and spermatogenic activity by 6 wk and reduced testis mass by 8 wk, suggesting that changes in VEGF are not a consequence of gonadal regression and that VEGF may play a critical role in photoperiodic regulation of testicular function.

  18. Connexin43 mimetic peptide reduces vascular leak and retinal ganglion cell death following retinal ischaemia.

    PubMed

    Danesh-Meyer, Helen V; Kerr, Nathan M; Zhang, Jie; Eady, Elizabeth K; O'Carroll, Simon J; Nicholson, Louise F B; Johnson, Cameron S; Green, Colin R

    2012-02-01

    significantly reduced dye leak at 4 and 24 h. In vitro studies on endothelial cells demonstrate that endothelial cell death following hypoxia can be mediated directly by opening of connexin43 hemichannels in endothelial cells. Blocking connexin43 mediated vascular leakage using a connexin43 mimetic peptide led to increased retinal ganglion cell survival at 7 and 21 days to levels of uninjured retinas. Treatment with scrambled peptide did not result in retinal ganglion cell rescue. Pharmacological targeting of connexin43 gap junction protein by transiently blocking gap junction hemichannels following injury provides new opportunities for treatment of central nervous system ischaemia.

  19. Txnip ablation reduces vascular smooth muscle cell inflammation and ameliorates atherosclerosis in apolipoprotein E knockout mice.

    PubMed

    Byon, Chang Hyun; Han, Tieyan; Wu, Judy; Hui, Simon T

    2015-08-01

    Inflammation of vascular smooth muscle cells (VSMC) is intimately linked to atherosclerosis and other vascular inflammatory disease. Thioredoxin interacting protein (Txnip) is a key regulator of cellular sulfhydryl redox and a mediator of inflammasome activation. The goals of the present study were to examine the impact of Txnip ablation on inflammatory response to oxidative stress in VSMC and to determine the effect of Txnip ablation on atherosclerosis in vivo. Using cultured VSMC, we showed that ablation of Txnip reduced cellular oxidative stress and increased protection from oxidative stress when challenged with oxidized phospholipids and hydrogen peroxide. Correspondingly, expression of inflammatory markers and adhesion molecules were diminished in both VSMC and macrophages from Txnip knockout mice. The blunted inflammatory response was associated with a decrease in NF-ĸB nuclear translocation. Loss of Txnip in VSMC also led to a dramatic reduction in macrophage adhesion to VSMC. In vivo data from Txnip-ApoE double knockout mice showed that Txnip ablation led to 49% reduction in atherosclerotic lesion in the aortic root and 71% reduction in the abdominal aorta, compared to control ApoE knockout mice. Our data show that Txnip plays an important role in oxidative inflammatory response and atherosclerotic lesion development in mice. The atheroprotective effect of Txnip ablation implicates that modulation of Txnip expression may serve as a potential target for intervention of atherosclerosis and inflammatory vascular disease. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. A magnesium based phosphate binder reduces vascular calcification without affecting bone in chronic renal failure rats.

    PubMed

    Neven, Ellen; De Schutter, Tineke M; Dams, Geert; Gundlach, Kristina; Steppan, Sonja; Büchel, Janine; Passlick-Deetjen, Jutta; D'Haese, Patrick C; Behets, Geert J

    2014-01-01

    The alternative phosphate binder calcium acetate/magnesium carbonate (CaMg) effectively reduces hyperphosphatemia, the most important inducer of vascular calcification, in chronic renal failure (CRF). In this study, the effect of low dose CaMg on vascular calcification and possible effects of CaMg on bone turnover, a persistent clinical controversy, were evaluated in chronic renal failure rats. Adenine-induced CRF rats were treated daily with 185 mg/kg CaMg or vehicle for 5 weeks. The aortic calcium content and area% calcification were measured to evaluate the effect of CaMg. To study the effect of CaMg on bone remodeling, rats underwent 5/6th nephrectomy combined with either a normal phosphorus diet or a high phosphorus diet to differentiate between possible bone effects resulting from either CaMg-induced phosphate deficiency or a direct effect of Mg. Vehicle or CaMg was administered at doses of 185 and 375 mg/kg/day for 8 weeks. Bone histomorphometry was performed. Aortic calcium content was significantly reduced by 185 mg/kg/day CaMg. CaMg ameliorated features of hyperparathyroid bone disease. In CRF rats on a normal phosphorus diet, the highest CaMg dose caused an increase in osteoid area due to phosphate depletion. The high phosphorus diet combined with the highest CaMg dose prevented the phosphate depletion and thus the rise in osteoid area. CaMg had no effect on osteoblast/osteoclast or dynamic bone parameters, and did not alter bone Mg levels. CaMg at doses that reduce vascular calcification did not show any harmful effect on bone turnover.

  1. Selective head cooling during neonatal seizures prevents postictal cerebral vascular dysfunction without reducing epileptiform activity.

    PubMed

    Harsono, Mimily; Pourcyrous, Massroor; Jolly, Elliott J; de Jongh Curry, Amy; Fedinec, Alexander L; Liu, Jianxiong; Basuroy, Shyamali; Zhuang, Daming; Leffler, Charles W; Parfenova, Helena

    2016-11-01

    Epileptic seizures in neonates cause cerebrovascular injury and impairment of cerebral blood flow (CBF) regulation. In the bicuculline model of seizures in newborn pigs, we tested the hypothesis that selective head cooling prevents deleterious effects of seizures on cerebral vascular functions. Preventive or therapeutic ictal head cooling was achieved by placing two head ice packs during the preictal and/or ictal states, respectively, for the ∼2-h period of seizures. Head cooling lowered the brain and core temperatures to 25.6 ± 0.3 and 33.5 ± 0.1°C, respectively. Head cooling had no anticonvulsant effects, as it did not affect the bicuculline-evoked electroencephalogram parameters, including amplitude, duration, spectral power, and spike frequency distribution. Acute and long-term cerebral vascular effects of seizures in the normothermic and head-cooled groups were tested during the immediate (2-4 h) and delayed (48 h) postictal periods. Seizure-induced cerebral vascular injury during the immediate postictal period was detected as terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive staining of cerebral arterioles and a surge of brain-derived circulating endothelial cells in peripheral blood in the normothermic group, but not in the head-cooled groups. During the delayed postictal period, endothelium-dependent cerebral vasodilator responses were greatly reduced in the normothermic group, indicating impaired CBF regulation. Preventive or therapeutic ictal head cooling mitigated the endothelial injury and greatly reduced loss of postictal cerebral vasodilator functions. Overall, head cooling during seizures is a clinically relevant approach to protecting the neonatal brain by preventing cerebrovascular injury and the loss of the endothelium-dependent control of CBF without reducing epileptiform activity. Copyright © 2016 the American Physiological Society.

  2. A Magnesium Based Phosphate Binder Reduces Vascular Calcification without Affecting Bone in Chronic Renal Failure Rats

    PubMed Central

    Neven, Ellen; De Schutter, Tineke M.; Dams, Geert; Gundlach, Kristina; Steppan, Sonja; Büchel, Janine; Passlick-Deetjen, Jutta; D'Haese, Patrick C.; Behets, Geert J.

    2014-01-01

    The alternative phosphate binder calcium acetate/magnesium carbonate (CaMg) effectively reduces hyperphosphatemia, the most important inducer of vascular calcification, in chronic renal failure (CRF). In this study, the effect of low dose CaMg on vascular calcification and possible effects of CaMg on bone turnover, a persistent clinical controversy, were evaluated in chronic renal failure rats. Adenine-induced CRF rats were treated daily with 185 mg/kg CaMg or vehicle for 5 weeks. The aortic calcium content and area% calcification were measured to evaluate the effect of CaMg. To study the effect of CaMg on bone remodeling, rats underwent 5/6th nephrectomy combined with either a normal phosphorus diet or a high phosphorus diet to differentiate between possible bone effects resulting from either CaMg-induced phosphate deficiency or a direct effect of Mg. Vehicle or CaMg was administered at doses of 185 and 375 mg/kg/day for 8 weeks. Bone histomorphometry was performed. Aortic calcium content was significantly reduced by 185 mg/kg/day CaMg. CaMg ameliorated features of hyperparathyroid bone disease. In CRF rats on a normal phosphorus diet, the highest CaMg dose caused an increase in osteoid area due to phosphate depletion. The high phosphorus diet combined with the highest CaMg dose prevented the phosphate depletion and thus the rise in osteoid area. CaMg had no effect on osteoblast/osteoclast or dynamic bone parameters, and did not alter bone Mg levels. CaMg at doses that reduce vascular calcification did not show any harmful effect on bone turnover. PMID:25229549

  3. Aggressive venous thromboembolism prophylaxis reduces VTE events in vascular surgery patients.

    PubMed

    Durinka, Joel B; Hecht, Todd Eh; Layne, Andrew J; Jackson, Benjamin M; Woo, Edward Y; Fairman, Ronald M; Rohrbach, Jeffery I; Wang, Grace J

    2016-06-01

    Venous thromboembolism (VTE) is a potentially preventable complication following surgery. There is variation with regard to the most effective mode of prophylaxis. We sought to determine if an aggressive approach to VTE prophylaxis would reduce VTE rates on the inpatient vascular surgical service. Vascular inpatients from a single institution from July 2010 to March 2013 were included in the analysis. A protocol for VTE prophylaxis was implemented on the inpatient vascular surgical service in November 2011. This included subcutaneous (SQ) heparin initiation within 24 h of admission unless deemed inappropriate by the attending, as well as intermittent compression devices (ICD) and compression stockings (CS). The rate of VTE was compared prior to and following the intervention. Patients were compared using AHRQ comorbidity categories, APR-DRG severity of illness, insurance status, and principle procedure. T-tests were used to compare continuous variables and chi-square analysis used to compare categorical variables. There were 1483 vascular patients in the pre-intervention group and 1652 patients in the post-intervention group. The rate of pharmacologic prophylaxis was 52.57% pre-intervention compared to 69.33% post-intervention (p < 0.001). The rate of pharmacologic or mechanical prophylaxis was 91.76% pre-intervention compared to 93.10% post-intervention (p = 0.54). The overall rate of VTE prior to the intervention was 1.49% compared to after intervention which was 0.38% (p = 0.033). The DVT rate prior to intervention was 1.09% vs 0.189% after intervention (p = 0.0214). The rate of pulmonary embolism trended towards a significant reduction with the intervention (0.681% vs 0.189%, p = 0.095). There were no statistically significant differences in patient groups based on gender, comorbidity category, severity of illness, or insurance type. The overall rate of VTE was reduced by 75% after the initiation of a standard protocol for pharmacologic

  4. Novel vascular endothelial growth factor blocker improves cellular viability and reduces hypobaric hypoxia-induced vascular leakage and oedema in rat brain.

    PubMed

    Saraswat, Deepika; Nehra, Sarita; Chaudhary, Kamal; CVS, Siva Prasad

    2015-05-01

    Vascular endothelial growth factor (VEGF) is an important cerebral angiogenic and permeability factor under hypoxia. There is a need to find effective molecules that may ameliorate hypoxia-induced cerebral oedema. In silico identification of novel candidate molecules that block VEGF-A site were identified and validated with a Ramachandran plot. The active site residues of VEGF-A were detected by Pocketfinder, CASTp, and DogSiteScorer. Based on in silico data, three VEGF-A blocker (VAB) candidate molecules (VAB1, VAB2, and VAB3) were checked for improvement in cellular viability and regulation of VEGF levels in N2a cells under hypoxia (0.5% O2 ). Additionally, the best candidate molecule's efficacy was assessed in male Sprague-Dawley rats for its ameliorative effect on cerebral oedema and vascular leakage under hypobaric hypoxia 7260 m. All experimental results were compared with the commercially available VEGF blocker sunitinib. Vascular endothelial growth factor-A blocker 1 was found most effective in increasing cellular viability and maintaining normal VEGF levels under hypoxia (0.5% oxygen) in N2a cells. Vascular endothelial growth factor-A blocker 1 effectively restored VEGF levels, decreased cerebral oedema, and reduced vascular leakage under hypobaric hypoxia when compared to sunitinib-treated rats. Vascular endothelial growth factor-A blocker 1 may be a promising candidate molecule for ameliorating hypobaric hypoxia-induced vasogenic oedema by regulating VEGF levels. © 2015 Wiley Publishing Asia Pty Ltd.

  5. Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury.

    PubMed

    Goto, Hiromasa; Nomiyama, Takashi; Mita, Tomoya; Yasunari, Eisuke; Azuma, Kosuke; Komiya, Koji; Arakawa, Masayuki; Jin, Wen Long; Kanazawa, Akio; Kawamori, Ryuzo; Fujitani, Yoshio; Hirose, Takahisa; Watada, Hirotaka

    2011-02-04

    Glucagon-like peptide-1 is a hormone secreted by L cells of the small intestine and stimulates glucose-dependent insulin response. Glucagon-like peptide-1 receptor agonists such as exendin-4 are currently used in type 2 diabetes, and considered to have beneficial effects on the cardiovascular system. To further elucidate the effect of glucagon-like peptide-1 receptor agonists on cardiovascular diseases, we investigated the effects of exendin-4 on intimal thickening after endothelial injury. Under continuous infusion of exendin-4 at 24 nmol/kg/day, C57BL/6 mice were subjected to endothelial denudation injury of the femoral artery. Treatment of mice with exendin-4 reduced neointimal formation at 4weeks after arterial injury without altering body weight or various metabolic parameters. In addition, in vitro studies of isolated murine, rat and human aortic vascular smooth muscle cells showed the expression of GLP-1 receptor. The addition of 10nM exendin-4 to cultured smooth muscle cells significantly reduced their proliferation induced by platelet-derived growth factor. Our results suggested that exendin-4 reduced intimal thickening after vascular injury at least in part by the suppression of platelet-derived growth factor-induced smooth muscle cells proliferation. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. Both acute and prolonged administration of EPO reduce cerebral and systemic vascular conductance in humans.

    PubMed

    Rasmussen, Peter; Kim, Yu-Sok; Krogh-Madsen, Rikke; Lundby, Carsten; Olsen, Niels V; Secher, Niels H; van Lieshout, Johannes J

    2012-03-01

    Administration of erythropoietin (EPO) has been linked to cerebrovascular events. EPO reduces vascular conductance, possibly because of the increase in hematocrit. Whether EPO in itself affects the vasculature remains unknown; here it was evaluated in healthy males by determining systemic and cerebrovascular variables following acute (30,000 IU/d for 3 d; n=8) and chronic (5000 IU/week for 13 wk; n=8) administration of EPO, while the responsiveness of the vasculature was challenged during cycling exercise, with and without hypoxia. Prolonged administration of EPO increased hematocrit from 42.5 ± 3.7 to 47.6 ± 4.1% (P<0.01), whereas hematocrit was unaffected following acute EPO administration. Yet, the two EPO regimes increased arterial pressure similarly (by 8±4 and 7±3 mmHg, respectively; P=0.01) through reduced vascular conductance (by 7±3 and 5±2%; P<0.05). Also, both EPO regimes widened the arterial-to-jugular O(2) differences at rest as well as during normoxic and hypoxic exercise (P<0.01), which indicated reduced cerebral blood flow despite preserved dynamic cerebral autoregulation, and an increase in middle cerebral artery mean blood flow velocity (P<0.05), therefore, reflected vasoconstriction. Thus, administration of EPO to healthy humans lowers systemic and cerebral conductance independent of its effect on hematocrit.

  7. Experimental ventilator-induced lung injury: exacerbation by positive end-expiratory pressure.

    PubMed

    Villar, Jesús; Herrera-Abreu, Maria Teresa; Valladares, Francisco; Muros, Mercedes; Pérez-Méndez, Lina; Flores, Carlos; Kacmarek, Robert M

    2009-06-01

    Previous experimental studies of ventilator-induced lung injury have shown that positive end-expiratory pressure (PEEP) is protective. The authors hypothesized that the application of PEEP during volume-controlled ventilation with a moderately high tidal volume (VT) in previously healthy in vivo rats does not attenuate ventilator-induced lung injury if the peak airway pressure markedly increases during the application of PEEP. Sixty healthy, male Sprague-Dawley rats were anesthetized and randomized to be mechanically ventilated for 4 h at (1) VT of 6 ml/kg, (2) VT of 20 ml/kg, or (3) VT of 20 ml/kg plus 10 cm H2O of PEEP. Peak airway pressures, gas exchange, histologic evaluation, mortality, total lung tissue cytokine gene expression, and serum cytokine concentrations were analyzed. Peak airway pressures exceeded 30 cm H2O with high VT plus PEEP. All lungs ventilated with high VT had perivascular edema and inflammatory infiltrates. In addition, those ventilated with PEEP had small hemorrhages foci. Five animals from the high VT plus PEEP group died (P = 0.020). Animals ventilated with high VT (with or without PEEP) had a substantial increase in serum interleukin-6 (P = 0.0002), and those ventilated with high VT plus PEEP had a 5.5-fold increase in systemic levels of tumor necrosis factor-alpha (P = 0.007). In contrast to previous reports, PEEP exacerbated lung damage and contributed to fatal outcome in an in vivo, mild overdistension model of ventilator-induced lung injury in previously healthy rats. That is, the addition of high PEEP to a constant large VT causes injury in previously healthy animals.

  8. History of Mechanical Ventilation. From Vesalius to Ventilator-induced Lung Injury.

    PubMed

    Slutsky, Arthur S

    2015-05-15

    Mechanical ventilation is a life-saving therapy that catalyzed the development of modern intensive care units. The origins of modern mechanical ventilation can be traced back about five centuries to the seminal work of Andreas Vesalius. This article is a short history of mechanical ventilation, tracing its origins over the centuries to the present day. One of the great advances in ventilatory support over the past few decades has been the development of lung-protective ventilatory strategies, based on our understanding of the iatrogenic consequences of mechanical ventilation such as ventilator-induced lung injury. These strategies have markedly improved clinical outcomes in patients with respiratory failure.

  9. Cinacalcet reduces vascular and soft tissue calcification in secondary hyperparathyroidism (SHPT) in hemodialysis patients.

    PubMed

    Aladrén Regidor, M J

    2009-02-01

    Management of secondary hyperparathyroidism (SHPT) in chronic kidney disease patients on hemodialysis (HD) can be challenging. Conventional treatments can lead to hypercalcemia and hyperphosphatemia, both of which are associated with vascular and soft tissue calcification and increased risk of cardiovascular disease. We report the effect of treatment with the Type II calcimimetic cinacalcet on vascular calcification in a HD patient with SHPT. A 40-year-old male with a 24-year history of kidney failure secondary to mesangial proliferative glomerulonephritis, commenced HD in October 2004 following chronic graft dysfunction. The patient was admitted to hospital with renal insufficiency and metabolic abnormalities. An anatomopathological study showed calcium (Ca) deposits in the alveolar septa, bronchial wall and pulmonary arterioles. Parathyroid methoxy isobutyl isonitrile (MIBI) scintigraphy revealed multiglandular parathyroid disease and an ectopic gland behind the sternal notch. Serum intact parathyroid hormone (iPTH) was repeatedly found to be > or = 2,500 pg/ml, and was accompanied by significant abnormalities in phosphorus (P) and Ca metabolism which were difficult to control. The patient was initially treated with sevelamer, low dose calcium carbonate, a low P and reduced protein diet and high doses of intravenous erythropoietin. In addition, he received HD with a high efficiency membrane for 4.5 hours, 4-times weekly. Treatment with cinacalcet was initiated at 30 mg/day and adjusted to achieve National Kidney Foundation Kidney Disease Outcomes Quality Initiative targets for iPTH, P, Ca and Ca-P product. One year following cinacalcet treatment, a chest x-ray showed a moderate reduction in Ca deposits, a bone X-ray showed a significant reduction in vascular calcifications, and parathyroid MIBI scintigraphy showed a disappearance of ectopic focus and minimal remains of glands. Significant reductions in calcemia were controlled by concomitant modifications to oral

  10. Postpartum Vascular Dysfunction in the Reduced Uteroplacental Perfusion Model of Preeclampsia

    PubMed Central

    Quon, Anita; Davidge, Sandra T.

    2016-01-01

    Preeclampsia is a disorder affecting 2–8% of all pregnancies, characterized by gestational hypertension (≥ 140/90 mmHg) and proteinuria (≥300 mg over 24 hours) diagnosed following the 20th week of pregnancy, and for which there is currently no available treatment. While the precise cause of preeclampsia is unknown, placental ischemia/hypoxia resulting from abnormal trophoblast invasion and maternal endothelial dysfunction are central characteristics. Preeclampsia is a major cause of both maternal and fetal morbidity and mortality in the perinatal period. In addition, women who have experienced preeclampsia are more likely to suffer cardiovascular disease later in life. The cause of this elevation in cardiovascular risk postpartum, however, is unknown. We hypothesize that there may be lasting vascular dysfunction following exposure to reduced uteroplacental perfusion during pregnancy that may contribute to increased cardiovascular risk postpartum. Using the rat reduced utero-placental perfusion pressure (RUPP) model of preeclampsia, blood pressure was assessed in dams at gestational day 20, one and three months postpartum. Mesenteric artery and aortic function were assessed using wire myography. We demonstrated hypertension and increased mesenteric artery responses to phenylephrine at gestational day 20, with the latter due to a decreased contribution of nitric oxide without any change in methylcholine-induced relaxation. At one month postpartum, we demonstrated a small but significant vasoconstrictive phenotype that was due to an underlying loss of basal nitric oxide contribution. At three months postpartum, endothelium-dependent relaxation of the aorta demonstrated sensitivity to oxLDL and mesenteric arteries demonstrated decreased nitric oxide bioavailability with impaired methylcholine-induced relaxation; indicative of an early development of endothelial dysfunction. In summary, we have demonstrated impaired vascular function following exposure to a RUPP

  11. HABP2 is a Novel Regulator of Vascular Integrity

    PubMed Central

    Mambetsariev, N.; Mirzapoiazova, T.; Mambetsariev, B.; Sammani, S.; Lennon, F.E.; Garcia, J.G.N.; Singleton, P.A.

    2010-01-01

    Objective We evaluated the role of the extracellular serine protease, Hyaluronic Acid Binding Protein 2 (HABP2), in vascular barrier regulation. Methods and Results Using immunoblot and immunohistochemical analysis, we observed that lipopolysaccharide (LPS)-induces HABP2 expression in murine lung endothelium in vivo and in human pulmonary microvascular endothelial cell (HPMVEC) in vitro. High molecular weight hyaluronan (HMW-HA, ~1 million Da) decreased HABP2 protein expression in HPMVEC and decreased purified HABP2 enzymatic activity whereas low MW HA (LMW-HA, ~2,500 Da) increased these activities. The effects of LMW-HA on HABP2 activity, but not HMW-HA, were inhibited with a peptide of the polyanion binding domain (PABD) of HABP2. Silencing (siRNA) HABP2 expression augmented HMW-HA-induced EC barrier enhancement and inhibited LPS and LMW-HA-mediated EC barrier disruption, results which were reversed with overexpression of HABP2. Silencing PAR receptors 1 and 3, RhoA or ROCK expression attenuated LPS, LMW-HA and HABP2-mediated EC barrier disruption. Utilizing murine models of acute lung injury, we observed that LPS- and ventilator-induced pulmonary vascular hyper-permeability were significantly reduced with vascular silencing (siRNA) of HABP2. Conclusions HABP2 negatively regulates vascular integrity via activation of PAR receptor/RhoA/ROCK signaling and represents a potentially useful therapeutic target for syndromes of increased vascular permeability. PMID:20042707

  12. Reduced angiotensin II levels cause generalized vascular dysfunction via oxidant stress in hamster cheek pouch arterioles.

    PubMed

    Priestley, Jessica R C; Buelow, Matthew W; McEwen, Scott T; Weinberg, Brian D; Delaney, Melanie; Balus, Sarah F; Hoeppner, Carlyn; Dondlinger, Lynn; Lombard, Julian H

    2013-09-01

    We investigated the effect of suppressing plasma angiotensin II (ANG II) levels on arteriolar relaxation in the hamster cheek pouch. Arteriolar diameters were measured via television microscopy during short-term (3-6days) high salt (HS; 4% NaCl) diet and angiotensin converting enzyme (ACE) inhibition with captopril (100mg/kg/day). ACE inhibition and/or HS diet eliminated endothelium-dependent arteriolar dilation to acetylcholine, endothelium-independent dilation to the NO donor sodium nitroprusside, the prostacyclin analogs carbacyclin and iloprost, and the KATP channel opener cromakalim; and eliminated arteriolar constriction during KATP channel blockade with glibenclamide. Scavenging of superoxide radicals and low dose ANG II infusion (25ng/kg/min, subcutaneous) reduced oxidant stress and restored arteriolar dilation in arterioles of HS-fed hamsters. Vasoconstriction to topically-applied ANG II was unaffected by HS diet while arteriolar responses to elevation of superfusion solution PO2 were unaffected (5% O2, 10% O2) or reduced (21% O2) by HS diet. These findings indicate that sustained exposure to low levels of circulating ANG II leads to widespread dysfunction in endothelium-dependent and independent vascular relaxation mechanisms in cheek pouch arterioles by increasing vascular oxidant stress, but does not potentiate O2- or ANG II-induced constriction of arterioles in the distal microcirculation of normotensive hamsters. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Vascularized tissue to reduce fistula following salvage total laryngectomy: a systematic review.

    PubMed

    Paleri, Vinidh; Drinnan, Mike; van den Brekel, Michiel W M; Hinni, Michael L; Bradley, Patrick J; Wolf, Gregory T; de Bree, Remco; Fagan, Johannes J; Hamoir, Marc; Strojan, Primož; Rodrigo, Juan P; Olsen, Kerry D; Pellitteri, Phillip K; Shaha, Ashok R; Genden, Eric M; Silver, Carl E; Suárez, Carlos; Takes, Robert P; Rinaldo, Alessandra; Ferlito, Alfio

    2014-08-01

    Pharyngocutaneous fistulae (PCF) are known to occur in nearly one-third of patients after salvage total laryngectomy (STL). PCF has severe impact on duration of admission and costs and quality of life and can even cause severe complications such as bleeding, infection and death. Many patients need further surgical procedures. The implications for functional outcome and survival are less clear. Several studies have shown that using vascularized tissue from outside the radiation field reduces the risk of PCFs following STL. This review and meta-analysis aims to identify the evidence base to support this hypothesis. English language literature from 2004 to 2013 REVIEW METHODS: We searched the English language literature for articles published on the subject from 2004 to 2013. Adequate data was available to identify pooled incidence rates from seven articles. The pooled relative risk derived from 591 patients was 0.63 (95% CI: 0.47 to 0.85), indicating that patients who have flap reconstruction/reinforcement reduced their risk of PCF by one-third. This pooled analysis suggests that there is a clear advantage in using vascularized tissue from outside the radiation field in the laryngectomy defect. While some studies show a clear reduction in PCF rates, others suggest that the fistulae that occur are smaller and rarely need repair. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.

  14. Repeated exposure to heat stress results in a diaphragm phenotype that resists ventilator-induced diaphragm dysfunction.

    PubMed

    Yoshihara, Toshinori; Ichinoseki-Sekine, Noriko; Kakigi, Ryo; Tsuzuki, Takamasa; Sugiura, Takao; Powers, Scott K; Naito, Hisashi

    2015-11-01

    Controlled mechanical ventilation (CMV) is a life-saving intervention for patients in respiratory failure. Unfortunately, prolonged mechanical ventilation (MV) results in diaphragmatic atrophy and contractile dysfunction, both of which are predicted to contribute to problems in weaning patients from the ventilator. Therefore, developing a strategy to protect the diaphragm against ventilator-induced weakness is important. We tested the hypothesis that repeated bouts of heat stress result in diaphragm resistance against CMV-induced atrophy and contractile dysfunction. Male Wistar rats were randomly divided into six experimental groups: 1) control; 2) single bout of whole body heat stress; 3) repeated bouts of whole body heat stress; 4) 12 h CMV; 5) single bout of whole body heat stress 24 h before CMV; and 6) repeated bouts of whole body heat stress 1, 3, and 5 days before 12 h of CMV. Our results revealed that repeated bouts of heat stress resulted in increased levels of heat shock protein 72 in the diaphragm and protection against both CMV-induced diaphragmatic atrophy and contractile dysfunction at submaximal stimulation frequencies. The specific mechanisms responsible for this protection remain unclear: this heat stress-induced protection against CMV-induced diaphragmatic atrophy and weakness may be partially due to reduced diaphragmatic oxidative stress, diminished activation of signal transducer/transcriptional activator-3, lower caspase-3 activation, and decreased autophagy in the diaphragm.

  15. Bench-to-bedside review: Damage-associated molecular patterns in the onset of ventilator-induced lung injury

    PubMed Central

    2011-01-01

    Mechanical ventilation (MV) has the potential to worsen pre-existing lung injury or even to initiate lung injury. Moreover, it is thought that injurious MV contributes to the overwhelming inflammatory response seen in patients with acute lung injury or acute respiratory distress syndrome. Ventilator-induced lung injury (VILI) is characterized by increased endothelial and epithelial permeability and pulmonary inflammation, in which the innate immune system plays a key role. A growing body of evidence indicates that endogenous danger molecules, also termed damage-associated molecular patterns (DAMPs), are released upon tissue injury and modulate the inflammatory response. DAMPs activate pattern recognition receptors, may induce the release of proinflammatory cytokines and chemokines, and have been shown to initiate or propagate inflammation in non-infectious conditions. Experimental and clinical studies demonstrate the presence of DAMPs in bronchoalveolar lavage fluid in patients with VILI and the upregulation of pattern recognition receptors in lung tissue by MV. The objective of the present article is to review research in the area of DAMPs, their recognition by the innate immune system, their role in VILI, and the potential utility of blocking DAMP signaling pathways to reduce VILI in the critically ill. PMID:22216838

  16. Linking lung function and inflammatory responses in ventilator-induced lung injury.

    PubMed

    Cannizzaro, Vincenzo; Hantos, Zoltan; Sly, Peter D; Zosky, Graeme R

    2011-01-01

    Despite decades of research, the mechanisms of ventilator-induced lung injury are poorly understood. We used strain-dependent responses to mechanical ventilation in mice to identify associations between mechanical and inflammatory responses in the lung. BALB/c, C57BL/6, and 129/Sv mice were ventilated using a protective [low tidal volume and moderate positive end-expiratory pressure (PEEP) and recruitment maneuvers] or injurious (high tidal volume and zero PEEP) ventilation strategy. Lung mechanics and lung volume were monitored using the forced oscillation technique and plethysmography, respectively. Inflammation was assessed by measuring numbers of inflammatory cells, cytokine (IL-6, IL-1β, and TNF-α) levels, and protein content of the BAL. Principal components factor analysis was used to identify independent associations between lung function and inflammation. Mechanical and inflammatory responses in the lung were dependent on ventilation strategy and mouse strain. Three factors were identified linking 1) pulmonary edema, protein leak, and macrophages, 2) atelectasis, IL-6, and TNF-α, and 3) IL-1β and neutrophils, which were independent of responses in lung mechanics. This approach has allowed us to identify specific inflammatory responses that are independently associated with overstretch of the lung parenchyma and loss of lung volume. These data provide critical insight into the mechanical responses in the lung that drive local inflammation in ventilator-induced lung injury and the basis for future mechanistic studies in this field.

  17. Agmatine induces gastric protection against ischemic injury by reducing vascular permeability in rats

    PubMed Central

    Masri, Abeer A Al; Eter, Eman El

    2012-01-01

    AIM: To investigate the effect of administration of agmatine (AGM) on gastric protection against ischemia reperfusion (I/R) injury. METHODS: Three groups of rats (6/group); sham, gastric I/R injury, and gastric I/R + AGM (100 mg/kg, i.p. given 15 min prior to gastric ischemia) were recruited. Gastric injury was conducted by ligating celiac artery for 30 min and reperfusion for another 30 min. Gastric tissues were histologically studied and immunostained with angiopoietin 1 (Ang-1) and Ang-2. Vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) were measured in gastric tissue homogenate. To assess whether AKt/phosphatidyl inositol-3-kinase (PI3K) mediated the effect of AGM, an additional group was pretreated with Wortmannin (WM) (inhibitor of Akt/PI3K, 15 μg/kg, i.p.), prior to ischemic injury and AGM treatment, and examined histologically and immunostained. Another set of experiments was run to study vascular permeability of the stomach using Evan’s blue dye. RESULTS: AGM markedly reduced Evan’s blue dye extravasation (3.58 ± 0.975 μg/stomach vs 1.175 ± 0.374 μg/stomach, P < 0.05), VEGF (36.87 ± 2.71 pg/100 mg protein vs 48.4 ± 6.53 pg/100 mg protein, P < 0.05) and MCP-1 tissue level (29.5 ± 7 pg/100 mg protein vs 41.17 ± 10.4 pg/100 mg protein, P < 0.01). It preserved gastric histology and reduced congestion. Ang-1 and Ang-2 immunostaining were reduced in stomach sections of AGM-treated animals. The administration of WM abolished the protective effects of AGM and extensive hemorrhage and ulcerations were seen. CONCLUSION: AGM protects the stomach against I/R injury by reducing vascular permeability and inflammation. This protection is possibly mediated by Akt/PI3K. PMID:22611311

  18. Reduced hemodynamic coupling and exercise are associated with vascular stiffening in pulmonary arterial hypertension

    PubMed Central

    Bellofiore, Alessandro; Dinges, Eric; Naeije, Robert; Mkrdichian, Hamorabi; Beussink-Nelson, Lauren; Bailey, Melissa; Cuttica, Michael J.; Sweis, Ranya; Runo, James R.; Keevil, Jon G.; Francois, Christopher J.; Shah, Sanjiv J.; Chesler, Naomi C.

    2016-01-01

    Objective Inadequate right ventricular (RV) and pulmonary arterial (PA) functional responses to exercise are important yet poorly understood features of pulmonary arterial hypertension (PAH). This study combined invasive catheterization with echocardiography to assess RV afterload, RV function and ventricular-vascular coupling in subjects with PAH. Methods Twenty-six subjects with PAH were prospectively recruited to undergo right heart catheterization and Doppler echocardiography at rest and during incremental exercise, and cardiac magnetic resonance imaging (MRI) at rest. Measurements at rest included basic hemodynamics, RV function and coupling efficiency (η). Measurements during incremental exercise included pulmonary vascular resistance (Z0), characteristic impedance (ZC, a measure of proximal PA stiffness) and proximal and distal PA compliance (CPA). Results In PAH patients, the proximal PAs were significantly stiffer at maximum exercise (ZC = 2.31 ± 0.38 vs. 1.33 ± 0.15 mmHg min/ml/m2 at rest; p=0.003) and PA compliance was decreased (CPA = 0.88 ± 0.10 vs. 1.32 ± 0.17 mL/mmHg/m2 at rest; p=0.0002). Z0 did not change with exercise. As a result, the resistance-compliance (RC) time decreased with exercise (1.00 ± 0.07 at vs. 0.67 ± 0.05 s; p<10−6). When patients were grouped according to resting coupling efficiency, those with poorer η exhibited stiffer proximal PAs at rest, a lower maximum exercise level, and more limited CPA reduction at maximum exercise. Conclusions In PAH, exercise causes proximal and distal PA stiffening, which combined with preserved Z0 results in decreased RC time with exercise. Stiff PAs at rest may also contribute to poor hemodynamic coupling, reflecting reduced pulmonary vascular reserve that contributes to limit the maximum exercise level tolerated. PMID:27566296

  19. Breaking dogmas: the plant vascular pathogen Xanthomonas albilineans is able to invade non-vascular tissues despite its reduced genome.

    PubMed

    Mensi, Imène; Vernerey, Marie-Stéphanie; Gargani, Daniel; Nicole, Michel; Rott, Philippe

    2014-02-12

    Xanthomonas albilineans, the causal agent of sugarcane leaf scald, is missing the Hrp type III secretion system that is used by many Gram-negative bacteria to colonize their host. Until now, this pathogen was considered as strictly limited to the xylem of sugarcane. We used confocal laser scanning microscopy, immunocytochemistry and transmission electron microscopy (TEM) to investigate the localization of X. albilineans in diseased sugarcane. Sugarcane plants were inoculated with strains of the pathogen labelled with a green fluorescent protein. Confocal microscopy observations of symptomatic leaves confirmed the presence of the pathogen in the protoxylem and metaxylem; however, X. albilineans was also observed in phloem, parenchyma and bulliform cells of the infected leaves. Similarly, vascular bundles of infected sugarcane stalks were invaded by X. albilineans. Surprisingly, the pathogen was also observed in apparently intact storage cells of the stalk and in intercellular spaces between these cells. Most of these observations made by confocal microscopy were confirmed by TEM. The pathogen exits the xylem following cell wall and middle lamellae degradation, thus creating openings to reach parenchyma cells. This is the first description of a plant pathogenic vascular bacterium invading apparently intact non-vascular plant tissues and multiplying in parenchyma cells.

  20. Breaking dogmas: the plant vascular pathogen Xanthomonas albilineans is able to invade non-vascular tissues despite its reduced genome

    PubMed Central

    Mensi, Imène; Vernerey, Marie-Stéphanie; Gargani, Daniel; Nicole, Michel; Rott, Philippe

    2014-01-01

    Xanthomonas albilineans, the causal agent of sugarcane leaf scald, is missing the Hrp type III secretion system that is used by many Gram-negative bacteria to colonize their host. Until now, this pathogen was considered as strictly limited to the xylem of sugarcane. We used confocal laser scanning microscopy, immunocytochemistry and transmission electron microscopy (TEM) to investigate the localization of X. albilineans in diseased sugarcane. Sugarcane plants were inoculated with strains of the pathogen labelled with a green fluorescent protein. Confocal microscopy observations of symptomatic leaves confirmed the presence of the pathogen in the protoxylem and metaxylem; however, X. albilineans was also observed in phloem, parenchyma and bulliform cells of the infected leaves. Similarly, vascular bundles of infected sugarcane stalks were invaded by X. albilineans. Surprisingly, the pathogen was also observed in apparently intact storage cells of the stalk and in intercellular spaces between these cells. Most of these observations made by confocal microscopy were confirmed by TEM. The pathogen exits the xylem following cell wall and middle lamellae degradation, thus creating openings to reach parenchyma cells. This is the first description of a plant pathogenic vascular bacterium invading apparently intact non-vascular plant tissues and multiplying in parenchyma cells. PMID:24522883

  1. Suspended animation inducer hydrogen sulfide is protective in an in vivo model of ventilator-induced lung injury

    PubMed Central

    Aslami, Hamid; Heinen, André; Roelofs, Joris J. T. H.; Zuurbier, Coert J.; Schultz, Marcus J.

    2010-01-01

    Purpose Acute lung injury is characterized by an exaggerated inflammatory response and a high metabolic demand. Mechanical ventilation can contribute to lung injury, resulting in ventilator-induced lung injury (VILI). A suspended-animation-like state induced by hydrogen sulfide (H2S) protects against hypoxia-induced organ injury. We hypothesized that suspended animation is protective in VILI by reducing metabolism and thereby CO2 production, allowing for a lower respiratory rate while maintaining adequate gas exchange. Alternatively, H2S may reduce inflammation in VILI. Methods In mechanically ventilated rats, VILI was created by application of 25 cmH2O positive inspiratory pressure (PIP) and zero positive end-expiratory pressure (PEEP). Controls were lung-protective mechanically ventilated (13 cmH2O PIP, 5 cmH2O PEEP). H2S donor NaHS was infused continuously; controls received saline. In separate control groups, hypothermia was induced to reproduce the H2S-induced fall in temperature. In VILI groups, respiratory rate was adjusted to maintain normo-pH. Results NaHS dose-dependently and reversibly reduced body temperature, heart rate, and exhaled amount of CO2. In VILI, NaHS reduced markers of pulmonary inflammation and improved oxygenation, an effect which was not observed after induction of deep hypothermia that paralleled the NaHS-induced fall in temperature. Both NaHS and hypothermia allowed for lower respiratory rates while maintaining gas exchange. Conclusions NaHS reversibly induced a hypometabolic state in anesthetized rats and protected from VILI by reducing pulmonary inflammation, an effect that was in part independent of body temperature. Electronic supplementary material The online version of this article (doi:10.1007/s00134-010-2022-2) contains supplementary material, which is available to authorized users. PMID:20721529

  2. A high-potassium diet reduces infarct size and improves vascular structure in hypertensive rats.

    PubMed

    Dorrance, Anne M; Pollock, David M; Romanko, Olga P; Stepp, David W

    2007-01-01

    High-potassium diets can improve vascular function, yet the effects of potassium supplementation on ischemic stroke have not been studied. We hypothesized that dietary potassium supplementation would reduce ischemic cerebral infarct size by reversing cerebral artery hypertrophy. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were fed diets containing 0.79% potassium (LK) or 2.11% potassium (HK) for 6 wk; Wistar-Kyoto (WKY) rats were fed the LK diet. The HK diet did not reduce blood pressure, as measured by telemetry, in the SHRSP. Cerebral ischemia was induced by middle cerebral artery (MCA) occlusion. The resultant infarct was smaller in the HK-SHRSP than in the LK-SHRSP: 55.1 +/- 6.3 vs. 71.4 +/- 2.4% of the hemisphere infarcted (P < 0.05). Infarcts were smaller in WKY rats (33.5 +/- 4.8%) than in LK-SHRSP or HK-SHRSP. The vessel wall of MCAs from LK-SHRSP was hypertrophied compared with WKY rats; this was reversed in HK-SHRSP. RT-PCR analysis of the cerebral vessels showed that expression of platelet-derived growth factor receptors-alpha and -beta, epidermal growth factor receptor, and collagen I and III was increased in the vessels from LK-SHRSP compared with WKY rats and reduced in HK-SHRSP. These results suggest that potassium supplementation provides neuroprotection in a model of ischemic stroke independent of blood pressure and possibly through changes in vascular structure.

  3. Reduced vascular smooth muscle BK channel current underlies heart failure-induced vasoconstriction in mice

    PubMed Central

    Wan, Elaine; Kushner, Jared S.; Zakharov, Sergey; Nui, Xiao-wei; Chudasama, Neelesh; Kelly, Christopher; Waase, Marc; Doshi, Darshan; Liu, Guoxia; Iwata, Shinichi; Shiomi, Takayuki; Katchman, Alexander; D'Armiento, Jeanine; Homma, Shunichi; Marx, Steven O.

    2013-01-01

    Excessively increased peripheral vasoconstriction is a hallmark of heart failure (HF). Here, we show that in mice with systolic HF post–myocardial infarction, the myogenic tone of third-order mesenteric resistance vessels is increased, the vascular smooth muscle (VSM) membrane potential is depolarized by ∼20 mV, and vessel wall intracellular [Ca2+] is elevated relative to that in sham-operated control mice. Despite the increased [Ca2+], the frequency and amplitude of spontaneous transient outward currents (STOCs), mediated by large conductance, Ca2+-activated BK channels, were reduced by nearly 80% (P<0.01) and 25% (P<0.05), respectively, in HF. The expression of the BK α and β1 subunits was reduced in HF mice compared to controls (65 and 82% lower, respectively, P<0.01). Consistent with the importance of a reduction in BK channel expression and function in mediating the HF-induced increase in myogenic tone are two further findings: a blunting of paxilline-induced increase in myogenic tone in HF mice compared to controls (0.9 vs. 10.9%, respectively), and that HF does not alter the increased myogenic tone of BK β1-null mice. These findings identify electrical dysregulation within VSM, specifically the reduction of BK currents, as a key molecular mechanism sensitizing resistance vessels to pressure-induced vasoconstriction in systolic HF.—Wan, E., Kushner, J. S., Zakharov, S., Nui, X-W., Chudasama, N., Kelly, C., Waase, M., Doshi, D., Liu, G., Iwata, S., Shiomi, T., Katchman, A., D'Armiento, J., Homma, S., Marx, S. O. Reduced vascular smooth muscle BK channel current underlies heart failure-induced vasoconstriction in mice. PMID:23325318

  4. RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction.

    PubMed

    Sager, Hendrik B; Dutta, Partha; Dahlman, James E; Hulsmans, Maarten; Courties, Gabriel; Sun, Yuan; Heidt, Timo; Vinegoni, Claudio; Borodovsky, Anna; Fitzgerald, Kevin; Wojtkiewicz, Gregory R; Iwamoto, Yoshiko; Tricot, Benoit; Khan, Omar F; Kauffman, Kevin J; Xing, Yiping; Shaw, Taylor E; Libby, Peter; Langer, Robert; Weissleder, Ralph; Swirski, Filip K; Anderson, Daniel G; Nahrendorf, Matthias

    2016-06-08

    Myocardial infarction (MI) leads to a systemic surge of vascular inflammation in mice and humans, resulting in secondary ischemic complications and high mortality. We show that, in ApoE(-/-) mice with coronary ligation, increased sympathetic tone up-regulates not only hematopoietic leukocyte production but also plaque endothelial expression of adhesion molecules. To counteract the resulting arterial leukocyte recruitment, we developed nanoparticle-based RNA interference (RNAi) that effectively silences five key adhesion molecules. Simultaneously encapsulating small interfering RNA (siRNA)-targeting intercellular cell adhesion molecules 1 and 2 (Icam1 and Icam2), vascular cell adhesion molecule 1 (Vcam1), and E- and P-selectins (Sele and Selp) into polymeric endothelial-avid nanoparticles reduced post-MI neutrophil and monocyte recruitment into atherosclerotic lesions and decreased matrix-degrading plaque protease activity. Five-gene combination RNAi also curtailed leukocyte recruitment to ischemic myocardium. Therefore, targeted multigene silencing may prevent complications after acute MI. Copyright © 2016, American Association for the Advancement of Science.

  5. P-Selectin Targeted Dexamethasone-Loaded Lipid Nanoemulsions: A Novel Therapy to Reduce Vascular Inflammation

    PubMed Central

    Simion, Viorel; Constantinescu, Cristina Ana; Stan, Daniela; Deleanu, Mariana; Tucureanu, Monica Madalina; Butoi, Elena; Manduteanu, Ileana; Simionescu, Maya

    2016-01-01

    Inflammation is a common process associated with numerous vascular pathologies. We hypothesized that targeting the inflamed endothelium by coupling a peptide with high affinity for P-selectin to the surface of dexamethasone-loaded lipid nanoemulsions will highly increase their specific binding to activated endothelial cells (EC) and reduce the cell activation. We developed and characterized dexamethasone-loaded lipid nanoemulsions directed towards P-selectin (PLN-Dex) and monitored their anti-inflammatory effects in vitro using cultured EC (EA.hy926 cells) and in vivo using a mouse model of acute inflammation [lipopolysaccharides (LPS) intravenously administered in C57BL/6 mice]. We found that PLN-Dex bound specifically to the surface of activated EC are efficiently internalized by EC and reduced the expression of proinflammatory genes, thus preventing the monocyte adhesion and transmigration to/through activated EC. Given intravenously in mice with acute inflammation, PLN-Dex accumulated at a significant high level in the lungs (compared to nontargeted nanoemulsions) and significantly reduced mRNA expression level of key proinflammatory cytokines such as IL-1β, IL-6, and MCP-1. In conclusion, the newly developed nanoformulation, PLN-Dex, is functional in vitro and in vivo, reducing selectively the endothelium activation and the consequent monocyte infiltration and diminishing significantly the lungs' inflammation, in a mouse model of acute inflammation. PMID:27703301

  6. NDRG1 overexpressing gliomas are characterized by reduced tumor vascularization and resistance to antiangiogenic treatment.

    PubMed

    Broggini, Thomas; Wüstner, Marie; Harms, Christoph; Stange, Lena; Blaes, Jonas; Thomé, Carina; Harms, Ulrike; Mueller, Susanne; Weiler, Markus; Wick, Wolfgang; Vajkoczy, Peter; Czabanka, Marcus

    2016-10-01

    Hypoxia-regulated molecules play an important role in vascular resistance to antiangiogenic treatment. N-myc downstream-regulated-gene 1 (NDRG1) is significantly upregulated during hypoxia in glioma. It was the aim of the present study to analyze the role of NDRG1 on glioma angiogenesis and on antiangiogenic treatment. Orthotopically implanted NDRG1 glioma showed reduced tumor growth and vessel density compared to controls. RT-PCR gene array analysis revealed a 30-fold TNFSF15 increase in NDRG1 tumors. Consequently, the supernatant from NDRG1 transfected U87MG glioma cells resulted in reduced HUVEC proliferation, migration and angiogenic response in tube formation assays in vitro. This effect was provoked by increased TNFSF15 promoter activity in NDRG1 cells. Mutations in NF-κB and AP-1 promoter response elements suppressed TNFSF15 promoter activity. Moreover, U87MG glioma NDRG1 knockdown supernatant contained multiple proangiogenic proteins and increased HUVEC spheroid sprouting. Sunitinib treatment of orhotopically implanted mice reduced tumor volume and vessel density in controls; in NDRG1 overexpressing cells no reduction of tumor volume or vessel density was observed. NDRG1 overexpression leads to reduced tumor growth and angiogenesis in experimental glioma via upregulation of TNFSF15. In NDRG1 overexpressing glioma antiangiogenic treatment does not yield a therapeutic response.

  7. The Effect of Two Weeks Preoperative Finasteride Therapy in Reducing Prostate Vascularity.

    PubMed

    Khwaja, Muhammad Athar; Nawaz, Gul; Muhammad, Shujah; Jamil, Muhammad Imran; Faisal, Muhammad; Akhter, Saeed

    2016-03-01

    To determine the effect of two weeks preoperative finasteride therapy in reducing prostate vascularity in terms of mean microvessel density (MVD) and expression of VEGF in prostate urothelium among patients of BPH by comparing with controls. Randomized controlled trial. Shifa International Hospital, Islamabad, from January 2013 to January 2014. A total of 80 patients of Benign Prostatic Hyperplasia (BPH) planned for Trans-Urethral Resection of Prostate (TURP) having prostate size of more than 40 grams on trans-abdominal ultrasonography was randomized into two groups, each group having 40 patients. The finasteride group (Group A) was prescribed oral 5 mg of finasteride daily for 2 weeks before surgery. The control group (Group B) did not receive any agent. After 2 weeks, TURP was performed and prostate samples were sent for histopathological determination of MVD and expression of VEGF. The mean age of patients was 66.21 ±10.08 years, ranging from 48 to 86 years. The mean prostate gland size was comparable in both groups (55 ±10.7 vs. 58.1 ±10.8 grams, p=0.21). Mean MVD in finasteride group (20.25 ±10.3) was significantly lower as compared to control group (48.9 ±22.6, p < 0.001). Similarly expression of VEGF was also significantly lower in finasteride group (30%) as compared to control group (65%) [p= 0.0017]. Mean MVD had a significant weak correlation with the size of prostate gland on Pearson correlation test (2-tailed) with r = 0.222. Finasteride reduces microvessel density and hence prostate vascularity with only 2-week therapy and the mean MVD is clearly correlated with size of prostate.

  8. Phosphate restriction significantly reduces mortality in uremic rats with established vascular calcification.

    PubMed

    Finch, Jane L; Lee, Duk H; Liapis, Helen; Ritter, Cindy; Zhang, Sarah; Suarez, Edu; Ferder, Leon; Slatopolsky, Eduardo

    2013-12-01

    The role of hyperphosphatemia in the pathogenesis of secondary hyperparathyroidism, cardiovascular disease, and progression of renal failure is widely known. Here we studied effects of dietary phosphate restriction on mortality and vascular calcification in uremic rats. Control and uremic rats were fed a high-phosphate diet and at 3 months a portion of rats of each group were killed. Serum phosphate and the calcium phosphate product increased in uremic rats, as did aortic calcium. Of the rats, 56% had positive aortic staining for calcium (von Kossa), RUNX2, and osteopontin. The remaining uremic rats were continued on diets containing high phosphate without and with sevelamer, or low phosphate, and after 3 more months they were killed. Serum phosphate was highest in uremic rats on high phosphate. Serum PTH and FGF-23 were markedly lower in rats on low phosphate. Mortality on high phosphate was 71.4%, with sevelamer reducing this to 37.5% and phosphate restriction to 5.9%. Positive aortic staining for von Kossa, RUNX2, and osteopontin was increased, but phosphate restriction inhibited this. Kidneys from low-phosphate and sevelamer-treated uremic rats had less interstitial fibrosis, glomerulosclerosis, and inflammation than those of uremic rats on high phosphate. Importantly, kidneys from rats on low phosphate showed improvement over kidneys from high-phosphate rats at 3 months. Left ventricles from rats on low phosphate had less perivascular fibrosis and smaller cardiomyocyte size compared to rats on high phosphate. Thus, intensive phosphate restriction significantly reduces mortality in uremic rats with severe vascular calcification.

  9. The role of ventilation-induced surfactant dysfunction and atelectasis in causing acute respiratory distress syndrome.

    PubMed

    Albert, Richard K

    2012-04-01

    This Pulmonary Perspective describes a new pathophysiologic scenario by which the acute respiratory distress syndrome (ARDS) might develop, summarizes the literature on which this new scenario is based, and discusses the resulting implications with respect to patient management. Rather than ARDS occurring as a result of the inflammatory response associated with predisposing risk factors, the proposed scenario theorizes that the initiating problem is atelectasis that develops as a result of a surfactant abnormality that is caused by spontaneous or mechanical ventilation, together with our current approaches to patient positioning and sedation. The proposed pathophysiology implies that ventilation-induced lung injury occurs before, and causes, ARDS (rather than developing after the fact and only serving to magnify the existing injury) and that some instances of ARDS are iatrogenic. If the proposed scenario is correct, it also implies that at least some instances of ARDS might be prevented by implementing a number of simple, safe modifications in patient care.

  10. Increased vascular thromboxane generation impairs dilation of skeletal muscle arterioles of obese Zucker rats with reduced oxygen tension.

    PubMed

    Goodwill, Adam G; James, Milinda E; Frisbee, Jefferson C

    2008-10-01

    This study determined if altered vascular prostacyclin (PGI(2)) and/or thromboxane A(2) (TxA(2)) production with reduced Po(2) contributes to impaired hypoxic dilation of skeletal muscle resistance arterioles of obese Zucker rats (OZRs) versus lean Zucker rats (LZRs). Mechanical responses were assessed in isolated gracilis muscle arterioles following reductions in Po(2) under control conditions and following pharmacological interventions inhibiting arachidonic acid metabolism and nitric oxide synthase and alleviating elevated vascular oxidant stress. The production of arachidonic acid metabolites was assessed using pooled arteries from OZRs and LZRs in response to reduced Po(2). Hypoxic dilation, endothelium-dependent in both strains, was attenuated in OZRs versus LZRs. Nitric oxide synthase inhibition had no significant impact on hypoxic dilation in either strain. Cyclooxygenase inhibition dramatically reduced hypoxic dilation in LZRs and abolished responses in OZRs. Treatment of arterioles from OZRs with polyethylene glycol-superoxide dismutase improved hypoxic dilation, and this improvement was entirely cyclooxygenase dependent. Vascular PGI(2) production with reduced Po(2) was similar between strains, although TxA(2) production was increased in OZRs, a difference that was attenuated by treatment of vessels from OZRs with polyethylene glycol-superoxide dismutase. Both blockade of PGH(2)/TxA(2) receptors and inhibition of thromboxane synthase increased hypoxic dilation in OZR arterioles. These results suggest that a contributing mechanism underlying impaired hypoxic dilation of skeletal muscle arterioles of OZRs may be an increased vascular production of TxA(2), which competes against the vasodilator influences of PGI(2). These results also suggest that the elevated vascular oxidant stress inherent in metabolic syndrome may contribute to the increased vascular TxA(2) production and may blunt vascular sensitivity to PGI(2).

  11. Melatonin reduces oxidative stress and improves vascular function in pulmonary hypertensive newborn sheep.

    PubMed

    Torres, Flavio; González-Candia, Alejandro; Montt, Camilo; Ebensperger, Germán; Chubretovic, Magdalena; Serón-Ferré, María; Reyes, Roberto V; Llanos, Aníbal J; Herrera, Emilio A

    2015-04-01

    Pulmonary hypertension of the newborn (PHN) constitutes a critical condition with severe cardiovascular and neurological consequences. One of its main causes is hypoxia during gestation, and thus, it is a public health concern in populations living above 2500 m. Although some mechanisms are recognized, the pathophysiological facts that lead to PHN are not fully understood, which explains the lack of an effective treatment. Oxidative stress is one of the proposed mechanisms inducing pulmonary vascular dysfunction and PHN. Therefore, we assessed whether melatonin, a potent antioxidant, improves pulmonary vascular function. Twelve newborn sheep were gestated, born, and raised at 3600 meters. At 3 days old, lambs were catheterized and daily cardiovascular measurements were recorded. Lambs were divided into two groups, one received daily vehicle as control and another received daily melatonin (1 mg/kg/d), for 8 days. At 11 days old, lung tissue and small pulmonary arteries (SPA) were collected. Melatonin decreased pulmonary pressure and resistance for the first 3 days of treatment. Further, melatonin significantly improved the vasodilator function of SPA, enhancing the endothelial- and muscular-dependent pathways. This was associated with an enhanced nitric oxide-dependent and nitric oxide independent vasodilator components and with increased nitric oxide bioavailability in lung tissue. Further, melatonin reduced the pulmonary oxidative stress markers and increased enzymatic and nonenzymatic antioxidant capacity. Finally, these effects were associated with an increase of lumen diameter and a mild decrease in the wall of the pulmonary arteries. These outcomes support the use of melatonin as an adjuvant in the treatment for PHN. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Aerobic interval training reduces vascular resistances during submaximal exercise in obese metabolic syndrome individuals.

    PubMed

    Mora-Rodriguez, Ricardo; Fernandez-Elias, V E; Morales-Palomo, F; Pallares, J G; Ramirez-Jimenez, M; Ortega, J F

    2017-08-12

    The aim of this study was to determine the effects of high-intensity aerobic interval training (AIT) on exercise hemodynamics in metabolic syndrome (MetS) volunteers. Thirty-eight, MetS participants were randomly assigned to a training (TRAIN) or to a non-training control (CONT) group. TRAIN consisted of stationary interval cycling alternating bouts at 70-90% of maximal heart rate during 45 min day(-1) for 6 months. CONT maintained baseline physical activity and no changes in cardiovascular function or MetS factors were detected. In contrast, TRAIN increased cardiorespiratory fitness (14% in VO2PEAK; 95% CI 9-18%) and improved metabolic syndrome (-42% in Z score; 95% CI 83-1%). After TRAIN, the workload that elicited a VO2 of 1500 ml min(-1) increased 15% (95% CI 5-25%; P < 0.001). After TRAIN when subjects pedaled at an identical submaximal rate of oxygen consumption, cardiac output increased by 8% (95% CI 4-11%; P < 0.01) and stroke volume by 10% (95% CI, 6-14%; P < 0.005) being above the CONT group values at that time point. TRAIN reduced submaximal exercise heart rate (109 ± 15-106 ± 13 beats min(-1); P < 0.05), diastolic blood pressure (83 ± 8-75 ± 8 mmHg; P < 0.001) and systemic vascular resistances (P < 0.01) below CONT values. Double product was reduced only after TRAIN (18.2 ± 3.2-17.4 ± 2.4 bt min(-1) mmHg 10(-3); P < 0.05). The data suggest that intense aerobic interval training improves hemodynamics during submaximal exercise in MetS patients. Specifically, it reduces diastolic blood pressure, systemic vascular resistances, and the double product. The reduction in double product, suggests decreased myocardial oxygen demands which could prevent the occurrence of adverse cardiovascular events during exercise in this population. CLINICALTRIALS. NCT03019796.

  13. Cabergoline reduces cell viability in non functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion.

    PubMed

    Gagliano, Teresa; Filieri, Carlo; Minoia, Mariella; Buratto, Mattia; Tagliati, Federico; Ambrosio, Maria Rosaria; Lapparelli, Marcello; Zoli, Matteo; Frank, Giorgio; degli Uberti, Ettore; Zatelli, Maria Chiara

    2013-03-01

    Dopamine (DA) therapy of non-functioning pituitary adenomas (NFA) can result in tumor stabilization and shrinkage. However, the mechanism of action is still unknown. Previous evidence showed that DA can inhibit pituitary vascular endothelial growth factor expression (VEGF), that may be involved in pituitary tumor growth. The aim of our study was to clarify whether VEGF secretion modulation might mediate the effects of DA agonists on cell proliferation in human NFA. We assessed DA receptor subtype 2 (DR2) expression in 20 NFA primary cultures, where we also investigated the effects of a selective DR2 agonist, cabergoline (Cab), on VEGF secretion and on cell viability. All NFA samples expressed α-subunit and DR2 was expressed in 11 samples. In DR2 expressing tumors, Cab significantly reduced cell viability (-25%; P < 0.05) and VEGF secretion (-20%; P < 0.05). These effects were counteracted by treatment with the DA antagonist sulpiride. Cab antiproliferative effects were blocked by VEGF. Our data demonstrate that Cab, via DR2, inhibits cell viability also by reducing VEGF secretion in a selected group of NFA, supporting that DA agonists can be useful in the medical therapy of DR2 expressing NFA.

  14. Vascular risk and Aβ interact to reduce cortical thickness in AD vulnerable brain regions

    PubMed Central

    Reed, Bruce R.; Madison, Cindee M.; Wirth, Miranka; Marchant, Natalie L.; Kriger, Stephen; Mack, Wendy J.; Sanossian, Nerses; DeCarli, Charles; Chui, Helena C.; Weiner, Michael W.; Jagust, William J.

    2014-01-01

    Objective: The objective of this study was to define whether vascular risk factors interact with β-amyloid (Aβ) in producing changes in brain structure that could underlie the increased risk of Alzheimer disease (AD). Methods: Sixty-six cognitively normal and mildly impaired older individuals with a wide range of vascular risk factors were included in this study. The presence of Aβ was assessed using [11C]Pittsburgh compound B–PET imaging, and cortical thickness was measured using 3-tesla MRI. Vascular risk was measured with the Framingham Coronary Risk Profile Index. Results: Individuals with high levels of vascular risk factors have thinner frontotemporal cortex independent of Aβ. These frontotemporal regions are also affected in individuals with Aβ deposition, but the latter show additional thinning in parietal cortices. Aβ and vascular risk were found to interact in posterior (especially in parietal) brain regions, where Aβ has its greatest effect. In this way, the negative effect of Aβ in posterior regions is increased by the presence of vascular risk. Conclusion: Aβ and vascular risk interact to enhance cortical thinning in posterior brain regions that are particularly vulnerable to AD. These findings give insight concerning the mechanisms whereby vascular risk increases the likelihood of developing AD and supports the therapeutic intervention of controlling vascular risk for the prevention of AD. PMID:24907234

  15. The effect of low level laser therapy on ventilator-induced lung injury in mice (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Szabari, Margit V.; Miller, Alyssa J.; Hariri, Lida P.; Hamblin, Michael R.; Musch, Guido; Stroh, Helene; Suter, Melissa J.

    2016-03-01

    Although mechanical ventilation (MV) is necessary to support gas exchange in critically ill patients, it can contribute to the development of lung injury and multiple organ dysfunction. It is known that high tidal volume (Vt) MV can cause ventilator-induced lung injury (VILI) in healthy lungs and increase the mortality of patients with Acute Respiratory Distress Syndrome. Low level laser therapy (LLLT) has demonstrated to have anti-inflammatory effects. We investigated whether LLLT could alleviate inflammation from injurious MV in mice. Adult mice were assigned to 2 groups: VILI+LLLT group (3 h of injurious MV: Vt=25-30 ml/kg, respiratory rate (RR)=50/min, positive end-expiratory pressure (PEEP)=0 cmH20, followed by 3 h of protective MV: Vt=9 ml/kg, RR=140/min, PEEP=2 cmH20) and VILI+no LLLT group. LLLT was applied during the first 30 min of the MV (810 nm LED system, 5 J/cm2, 1 cm above the chest). Respiratory impedance was measured in vivo with forced oscillation technique and lung mechanics were calculated by fitting the constant phase model. At the end of the MV, bronchoalveolar lavage (BAL) was performed and inflammatory cells counted. Lungs were removed en-bloc and fixed for histological evaluation. We hypothesize that LLLT can reduce lung injury and inflammation from VILI. This therapy could be translated into clinical practice, where it can potentially improve outcomes in patients requiring mechanical ventilation in the operating room or in the intensive care units.

  16. Metabolic rate and vascular function are reduced in women with a family history of type 2 diabetes mellitus.

    PubMed

    Olive, Jennifer L; Ballard, Kevin D; Miller, James J; Milliner, Beth A

    2008-06-01

    Metabolic and vascular abnormalities have been found in individuals with type 2 diabetes mellitus (T2D). Family history is often associated with increased risk of the development of T2D. We sought to determine if young, sedentary, insulin-sensitive individuals with a family history of T2D (FH+) have a reduced resting energy expenditure (REE) and vascular endothelial function compared with individuals who have no family history of T2D (FH-). The REE was determined in 18 FH+ individuals and 15 FH- individuals using indirect open-circuit calorimetry. Vascular endothelial function was measured via flow-mediated dilation (FMD) of the brachial artery. C-reactive protein and interleukin-6 were also measured to look at vascular inflammation. Body composition was measured via bioelectrical impedance analysis to determine fat-free mass and fat mass for each individual. Insulin resistance was calculated using the homeostasis model assessment equation and fasting insulin and glucose concentrations. Subjects (n = 42) were approximately 26 years old and had normal fasting serum insulin or glucose concentrations. The REE normalized for body weight (kilocalories per day per kilogram body weight) was significantly reduced in the FH+ women compared with FH- women (P < .001) but not in the men. The FMD was significantly reduced (34.3%) in the FH+ group compared with the FH- in women (P = .002). However, no between-group difference in FMD was present in male subjects (P = .376). Young, healthy, insulin-sensitive women with a family history of T2D have reduced whole-body metabolic rate and vascular endothelial function compared with those with no family history of disease. These differences in whole-body metabolic rate and vascular endothelial function were not present in male subjects.

  17. Association between interferon use and reduced metabolic and vascular complications among patients with hepatitis C.

    PubMed

    Chirikov, Viktor V; Shaya, Fadia T; Howell, Charles D

    2014-11-01

    We examined whether interferon treatment is associated with reduced metabolic/vascular complications in hepatitis C virus patients. The study had historical prospective cohort design using Maryland Medicaid administrative data (2006-2009). The end point was the incidence rate of mild, severe and combined mild/severe events from the Diabetes Complications Severity Index (DCSI). Interferon-treated and -untreated hepatitis C virus patients were matched on baseline covariates. Using multivariate counting process Cox regressions, we modeled the association between interferon receipt of at least 24 weeks and DCSI events incidence rate. Treated whites had similar rate of mild DCSI events, significantly 64% (p < 0.01) lower rate of severe DCSI events, and overall 29% (p = 0.14) lower rate of mild/severe DCSI events, compared with untreated whites. Compared with untreated blacks, treated blacks had a similar rate of DSCI events. Future studies should confirm our findings and should include important clinical variables such as viral genotype, virologic count and achieving sustained virologic response.

  18. Pioglitazone treatment increases COX-2-derived prostacyclin production and reduces oxidative stress in hypertensive rats: role in vascular function.

    PubMed

    Hernanz, Raquel; Martín, Ángela; Pérez-Girón, Jose V; Palacios, Roberto; Briones, Ana M; Miguel, Marta; Salaices, Mercedes; Alonso, María J

    2012-06-01

    PPARγ agonists, glitazones, have cardioprotective and anti-inflammatory actions associated with gene transcription interference. In this study, we determined whether chronic treatment of adult spontaneously hypertensive rats (SHR) with pioglitazone alters BP and vascular structure and function, and the possible mechanisms involved. Mesenteric resistance arteries from untreated or pioglitazone-treated (2.5 mg·kg⁻¹ ·day⁻¹ , 28 days) SHR and normotensive [Wistar Kyoto (WKY)] rats were used. Vascular structure was studied by pressure myography, vascular function by wire myography, protein expression by Western blot and immunohistochemistry, mRNA levels by RT-PCR, prostanoid levels by commercial kits and reactive oxygen species (ROS) production by dihydroethidium-emitted fluorescence. In SHR, pioglitazone did not modify either BP or vascular structural and mechanical alterations or phenylephrine-induced contraction, but it increased vascular COX-2 levels, prostacyclin (PGI₂) production and the inhibitory effects of NS 398, SQ 29,548 and tranylcypromine on phenylephrine responses. The contractile phase of the iloprost response, which was reduced by SQ 29,548, was greater in pioglitazone-treated and pioglitazone-untreated SHR than WKY. In addition, pioglitazone abolished the increased vascular ROS production, NOX-1 levels and the inhibitory effect of apocynin and allopurinol on phenylephrine contraction, whereas it did not modify eNOS expression but restored the potentiating effect of N-nitro-L-arginine methyl ester on phenylephrine responses. Although pioglitazone did not reduce BP in SHR, it increased COX-2-derived PGI₂ production, reduced oxidative stress, and increased NO bioavailability, which are all involved in vasoconstrictor responses in resistance arteries. These effects would contribute to the cardioprotective effect of glitazones reported in several pathologies. © 2012 The Authors. British Journal of Pharmacology © 2012 The British

  19. Pioglitazone treatment increases COX-2-derived prostacyclin production and reduces oxidative stress in hypertensive rats: role in vascular function

    PubMed Central

    Hernanz, Raquel; Martín, Ángela; Pérez-Girón, Jose V; Palacios, Roberto; Briones, Ana M; Miguel, Marta; Salaices, Mercedes; Alonso, María J

    2012-01-01

    BACKGROUND AND PURPOSE PPARγ agonists, glitazones, have cardioprotective and anti-inflammatory actions associated with gene transcription interference. In this study, we determined whether chronic treatment of adult spontaneously hypertensive rats (SHR) with pioglitazone alters BP and vascular structure and function, and the possible mechanisms involved. EXPERIMENTAL APPROACH Mesenteric resistance arteries from untreated or pioglitazone-treated (2.5 mg·kg−1·day−1, 28 days) SHR and normotensive [Wistar Kyoto (WKY)] rats were used. Vascular structure was studied by pressure myography, vascular function by wire myography, protein expression by Western blot and immunohistochemistry, mRNA levels by RT-PCR, prostanoid levels by commercial kits and reactive oxygen species (ROS) production by dihydroethidium-emitted fluorescence. KEY RESULTS In SHR, pioglitazone did not modify either BP or vascular structural and mechanical alterations or phenylephrine-induced contraction, but it increased vascular COX-2 levels, prostacyclin (PGI2) production and the inhibitory effects of NS 398, SQ 29,548 and tranylcypromine on phenylephrine responses. The contractile phase of the iloprost response, which was reduced by SQ 29,548, was greater in pioglitazone-treated and pioglitazone-untreated SHR than WKY. In addition, pioglitazone abolished the increased vascular ROS production, NOX-1 levels and the inhibitory effect of apocynin and allopurinol on phenylephrine contraction, whereas it did not modify eNOS expression but restored the potentiating effect of N-nitro-L-arginine methyl ester on phenylephrine responses. CONCLUSIONS AND IMPLICATIONS Although pioglitazone did not reduce BP in SHR, it increased COX-2-derived PGI2 production, reduced oxidative stress, and increased NO bioavailability, which are all involved in vasoconstrictor responses in resistance arteries. These effects would contribute to the cardioprotective effect of glitazones reported in several pathologies. PMID

  20. Moderate GSK-3β inhibition improves neovascular architecture, reduces vascular leakage, and reduces retinal hypoxia in a model of ischemic retinopathy.

    PubMed

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

    2010-09-01

    In ischemic retinopathies, unrelieved hypoxia induces the formation of architecturally abnormal, leaky blood vessels that damage retina and ultimately can cause blindness. Because these newly formed blood vessels are functionally defective, they fail to alleviate underlying hypoxia, resulting in more pathological neovascularization and more damage to retina. With an established model of ischemic retinopathy, we investigated inhibition of glycogen synthase kinase-3β (GSK-3β) as a means for improving the architecture and functionality of pathological blood vessels in retina. In vitro, hypoxia increased GSK-3β activity in retinal endothelial cells, reduced β-catenin, and correspondingly impaired integrity of cell/cell junctions. Conversely, GSK-3β inhibitors restored β-catenin, improved cell/cell junctions, and enhanced the formation of capillary cords in three-dimensional collagen matrix. In vivo, GSK-3β inhibitors, at appropriately moderate doses, strongly reduced abnormal vascular tufts, reduced abnormal vascular leakage, and improved vascular coverage and perfusion during the proliferative phase of ischemia-driven retinal neovascularization. Most importantly, these improvements in neovasculature were accompanied by marked reduction in retinal hypoxia, relative to controls. Thus, GSK-3β inhibitors offer a promising strategy for alleviating retinal hypoxia by correcting key vascular defects typically associated with ischemia-driven neovascularization.

  1. Low-Dose Dextromethorphan, a NADPH Oxidase Inhibitor, Reduces Blood Pressure and Enhances Vascular Protection in Experimental Hypertension

    PubMed Central

    Wu, Tao-Cheng; Chao, Chih-Yu; Lin, Shing-Jong; Chen, Jaw-Wen

    2012-01-01

    Background Vascular oxidative stress may be increased with age and aggravate endothelial dysfunction and vascular injury in hypertension. This study aimed to investigate the effects of dextromethorphan (DM), a NADPH oxidase inhibitor, either alone or in combination treatment, on blood pressure (BP) and vascular protection in aged spontaneous hypertensive rats (SHRs). Methodology/Principal Findings Eighteen-week-old WKY rats and SHRs were housed for 2 weeks. SHRs were randomly assigned to one of the 12 groups: untreated; DM monotherapy with 1, 5 or 25 mg/kg/day; amlodipine (AM, a calcium channel blocker) monotherapy with 1 or 5 mg/kg/day; and combination therapy of DM 1, 5 or 25 mg/kg/day with AM 1 or 5 mg/kg/day individually for 4 weeks. The in vitro effects of DM were also examined. In SHRs, AM monotherapy dose-dependently reduced arterial systolic BP. DM in various doses significantly and similarly reduced arterial systolic BP. Combination of DM with AM gave additive effects on BP reduction. DM, either alone or in combination with AM, improved aortic endothelial function indicated by ex vivo acetylcholine-induced relaxation. The combination of low-dose DM with AM gave most significant inhibition on aortic wall thickness in SHRs. Plasma total antioxidant status was significantly increased by all the therapies except for the combination of high-dose DM with high-dose AM. Serum nitrite and nitrate level was significantly reduced by AM but not by DM or the combination of DM with AM. Furthermore, in vitro treatment with DM reduced angiotensin II-induced reactive oxygen species and NADPH oxidase activation in human aortic endothelial cells. Conclusions/Significance Treatment of DM reduced BP and enhanced vascular protection probably by inhibiting vascular NADPH oxidase in aged hypertensive animals with or without AM treatment. It provides the potential rationale to a novel combination treatment with low-dose DM and AM in clinical hypertension. PMID:23049937

  2. Reduced contribution of endothelin to the regulation of systemic and pulmonary vascular tone in severe familial hypercholesterolaemia

    PubMed Central

    Bender, Shawn B; de Beer, Vincent J; Tharp, Darla L; van Deel, Elza D; Bowles, Douglas K; Duncker, Dirk J; Laughlin, M Harold; Merkus, Daphne

    2014-01-01

    Vascular dysfunction has been associated with familial hypercholesterolaemia (FH), a severe form of hyperlipidaemia. We recently demonstrated that swine with FH exhibit reduced exercise-induced systemic, but not pulmonary, vasodilatation involving reduced nitric oxide (NO) bioavailability. Since NO normally limits endothelin (ET) action, we examined the hypothesis that reduced systemic vasodilatation during exercise in FH swine results from increased ET-mediated vasoconstriction. Systemic and pulmonary vascular responses to exercise were examined in chronically instrumented normal and FH swine in the absence and presence of the ETA/B receptor antagonist tezosentan. Intrinsic reactivity to ET was further assessed in skeletal muscle arterioles. FH swine exhibited ∼9-fold elevation in total plasma cholesterol versus normal swine. Similar to our recent findings, systemic, not pulmonary, vasodilatation during exercise was reduced in FH swine. Blockade of ET receptors caused marked systemic vasodilatation at rest and during exercise in normal swine that was significantly reduced in FH swine. The reduced role of ET in FH swine in vivo was not the result of decreased arteriolar ET responsiveness, as responsiveness was increased in isolated arterioles. Smooth muscle ET receptor protein content was unaltered by FH. However, circulating plasma ET levels were reduced in FH swine. ET receptor antagonism caused pulmonary vasodilatation at rest and during exercise in normal, but not FH, swine. Therefore, contrary to our hypothesis, FH swine exhibit a generalised reduction in the role of ET in regulating vascular tone in vivo probably resulting from reduced ET production. This may represent a unique vascular consequence of severe familial hypercholesterolaemia. PMID:24421352

  3. Reduced contribution of endothelin to the regulation of systemic and pulmonary vascular tone in severe familial hypercholesterolaemia.

    PubMed

    Bender, Shawn B; de Beer, Vincent J; Tharp, Darla L; van Deel, Elza D; Bowles, Douglas K; Duncker, Dirk J; Laughlin, M Harold; Merkus, Daphne

    2014-04-15

    Vascular dysfunction has been associated with familial hypercholesterolaemia (FH), a severe form of hyperlipidaemia. We recently demonstrated that swine with FH exhibit reduced exercise-induced systemic, but not pulmonary, vasodilatation involving reduced nitric oxide (NO) bioavailability. Since NO normally limits endothelin (ET) action, we examined the hypothesis that reduced systemic vasodilatation during exercise in FH swine results from increased ET-mediated vasoconstriction. Systemic and pulmonary vascular responses to exercise were examined in chronically instrumented normal and FH swine in the absence and presence of the ETA/B receptor antagonist tezosentan. Intrinsic reactivity to ET was further assessed in skeletal muscle arterioles. FH swine exhibited ∼9-fold elevation in total plasma cholesterol versus normal swine. Similar to our recent findings, systemic, not pulmonary, vasodilatation during exercise was reduced in FH swine. Blockade of ET receptors caused marked systemic vasodilatation at rest and during exercise in normal swine that was significantly reduced in FH swine. The reduced role of ET in FH swine in vivo was not the result of decreased arteriolar ET responsiveness, as responsiveness was increased in isolated arterioles. Smooth muscle ET receptor protein content was unaltered by FH. However, circulating plasma ET levels were reduced in FH swine. ET receptor antagonism caused pulmonary vasodilatation at rest and during exercise in normal, but not FH, swine. Therefore, contrary to our hypothesis, FH swine exhibit a generalised reduction in the role of ET in regulating vascular tone in vivo probably resulting from reduced ET production. This may represent a unique vascular consequence of severe familial hypercholesterolaemia.

  4. Inhibition of Epac1 suppresses mitochondrial fission and reduces neointima formation induced by vascular injury

    PubMed Central

    Wang, Hui; Robichaux, William G.; Wang, Ziqing; Mei, Fang C.; Cai, Ming; Du, Guangwei; Chen, Ju; Cheng, Xiaodong

    2016-01-01

    Vascular smooth muscle cell (VSMC) activation in response to injury plays an important role in the development of vascular proliferative diseases, including restenosis and atherosclerosis. The aims of this study were to ascertain the physiological functions of exchange proteins directly activated by cAMP isoform 1 (Epac1) in VSMC and to evaluate the potential of Epac1 as therapeutic targets for neointima formation during vascular remodeling. In a mouse carotid artery ligation model, genetic knockdown of the Epac1 gene led to a significant reduction in neointima obstruction in response to vascular injury. Pharmacologic inhibition of Epac1 with an Epac specific inhibitor, ESI-09, phenocopied the effects of Epac1 null by suppressing neointima formation and proliferative VSMC accumulation in neointima area. Mechanistically, Epac1 deficient VSMCs exhibited lower level of PI3K/AKT signaling and dampened response to PDGF-induced mitochondrial fission and reactive oxygen species levels. Our studies indicate that Epac1 plays important roles in promoting VSMC proliferation and phenotypic switch in response to vascular injury, therefore, representing a therapeutic target for vascular proliferative diseases. PMID:27830723

  5. Intravenous neutralization of vascular endothelial growth factor reduces vascular function/permeability of the ovary and prevents development of OHSS-like symptoms in rhesus monkeys.

    PubMed

    Bishop, C V; Lee, D M; Slayden, O D; Li, X

    2017-07-06

    Ovarian hyperstimulation syndrome (OHSS) is a disorder associated with elevated serum VEGFA following chorionic gonadotropin (hCG) exposure in controlled ovarian stimulation (COS) cycles in women. In this study, we tested the effect of intravenous VEGFA neutralization on OHSS-like symptoms and vascular function in rhesus macaques during COS cycles. Monkeys (n = 8) were treated with 3 COS protocols and assigned randomly to groups as follows: 1) COS alone (Control, n = 5); 2) COS + VEGF mAb Avastin 19 ± 5 h before hCG (Avastin pre-hCG; n = 6); 3) COS + Avastin 3-4 days post-hCG (Avastin post-hCG; n = 4); 4) COS + Simulated Early Pregnancy (SEP n = 3); or 5) COS + SEP + Avastin (SEP + Avastin n = 3). Follicles were aspirated 36 h post-hCG, fluid was collected from one follicle for analysis of steroid and vascular hormone content. Remaining follicles were aspirated, and luteinized granulosa cells (LGCs) cultured for 24 h. Ovarian/uterine vascular flow (VF) and blood volume (BV) were analyzed by contrast enhanced ultrasound (CEUS) before hCG bolus and 6-8 days post-hCG bolus/time of peak SEP response. Ovarian permeability to albumin was analyzed by Dynamic Contrast Enhanced-MRI (DCE-MRI) post-hCG. Abdominal fluid was present in 4/5 Control, 2/6 Avastin pre-hCG, and 3/4 Avastin post-hCG females. Neutralization of VEGFA before hCG reduced ovarian VF, BV, and permeability to albumin (P < 0.05), while only ovarian VF and permeability were reduced in Avastin-post hCG group (P < 0.05). There was no effect of Avastin on ovarian vascular function during COS + SEP. VEGF levels in follicular fluid were reduced 78-fold by Avastin pre-hCG, and LGCs exposed to Avastin in vivo also released 4-fold less VEGF into culture media (P < 0.05). Culture medium of LGCs exposed to VEGFA neutralization in vivo had lower levels of P4 and ANGPT1, and an increased ratio of ANGPT2/1 (P < 0.05). Uterine VF was reduced by SEP + Avastin in the basalis

  6. Does growth restriction increase the vulnerability to acute ventilation-induced brain injury in newborn lambs? Implications for future health and disease.

    PubMed

    Allison, B J; Hooper, S B; Coia, E; Jenkin, G; Malhotra, A; Zahra, V; Sehgal, A; Kluckow, M; Gill, A W; Yawno, T; Polglase, G R; Castillo-Melendez, M; Miller, S L

    2017-10-01

    Fetal growth restriction (FGR) and preterm birth are frequent co-morbidities, both are independent risks for brain injury. However, few studies have examined the mechanisms by which preterm FGR increases the risk of adverse neurological outcomes. We aimed to determine the effects of prematurity and mechanical ventilation (VENT) on the brain of FGR and appropriately grown (AG, control) lambs. We hypothesized that FGR preterm lambs are more vulnerable to ventilation-induced acute brain injury. FGR was surgically induced in fetal sheep (0.7 gestation) by ligation of a single umbilical artery. After 4 weeks, preterm lambs were euthanized at delivery or delivered and ventilated for 2 h before euthanasia. Brains and cerebrospinal fluid (CSF) were collected for analysis of molecular and structural indices of early brain injury. FGRVENT lambs had increased oxidative cell damage and brain injury marker S100B levels compared with all other groups. Mechanical ventilation increased inflammatory marker IL-8 within the brain of FGRVENT and AGVENT lambs. Abnormalities in the neurovascular unit and increased blood-brain barrier permeability were observed in FGRVENT lambs, as well as an altered density of vascular tight junctions markers. FGR and AG preterm lambs have different responses to acute injurious mechanical ventilation, changes which appear to have been developmentally programmed in utero.

  7. Arterial cutdown reduces complications after brachial access for peripheral vascular intervention.

    PubMed

    Kret, Marcus R; Dalman, Ronald L; Kalish, Jeffrey; Mell, Matthew

    2016-07-01

    Factors influencing risk for brachial access site complications after peripheral vascular intervention are poorly understood. We queried the Society for Vascular Surgery Vascular Quality Initiative to identify unique demographic and technical risks for such complications. The Vascular Quality Initiative peripheral vascular intervention data files from years 2010 to 2014 were analyzed to compare puncture site complication rates and associations encountered with either brachial or femoral arterial access for peripheral vascular intervention. Procedures requiring multiple access sites were excluded. Complications were defined as wound hematoma or access vessel stenosis/occlusion. Univariate and hierarchical logistic regression was used to identify independent factors associated with site complications after brachial access. Of 44,634 eligible peripheral vascular intervention procedures, 732 (1.6%) were performed through brachial access. Brachial access was associated with an increased complication rate compared with femoral access (9.0% vs 3.3%; P < .001), including more hematomas (7.2% vs 3.0%; P < .001) and access site stenosis/occlusion (2.1% vs 0.4%; P < .001). On univariate analysis, factors associated with brachial access complications included age, female gender, and sheath size. Complications occurred less frequently after arterial cutdown (4.1%) compared with either ultrasound-guided (11.8%) or fluoroscopically guided percutaneous access (7.3%; P = .07 across all variables). Neither surgeons' overall peripheral vascular intervention experience nor prior experience with brachial access predicted likelihood of adverse events. By multivariate analysis, male gender (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.28-0.84; P < .01) and arterial cutdown (OR, 0.25; 95% CI, 0.07-0.87; P = .04) were associated with significantly decreased risk for access complications. Larger sheath sizes (>5F) were associated with increased risk of complications (OR

  8. Genetic Targets of Hydrogen Sulfide in Ventilator-Induced Lung Injury – A Microarray Study

    PubMed Central

    Spassov, Sashko; Pfeifer, Dietmar; Strosing, Karl; Ryter, Stefan; Hummel, Matthias; Faller, Simone; Hoetzel, Alexander

    2014-01-01

    Recently, we have shown that inhalation of hydrogen sulfide (H2S) protects against ventilator-induced lung injury (VILI). In the present study, we aimed to determine the underlying molecular mechanisms of H2S-dependent lung protection by analyzing gene expression profiles in mice. C57BL/6 mice were subjected to spontaneous breathing or mechanical ventilation in the absence or presence of H2S (80 parts per million). Gene expression profiles were determined by microarray, sqRT-PCR and Western Blot analyses. The association of Atf3 in protection against VILI was confirmed with a Vivo-Morpholino knockout model. Mechanical ventilation caused a significant lung inflammation and damage that was prevented in the presence of H2S. Mechanical ventilation favoured the expression of genes involved in inflammation, leukocyte activation and chemotaxis. In contrast, ventilation with H2S activated genes involved in extracellular matrix remodelling, angiogenesis, inhibition of apoptosis, and inflammation. Amongst others, H2S administration induced Atf3, an anti-inflammatory and anti-apoptotic regulator. Morpholino mediated reduction of Atf3 resulted in elevated lung injury despite the presence of H2S. In conclusion, lung protection by H2S during mechanical ventilation is associated with down-regulation of genes related to oxidative stress and inflammation and up-regulation of anti-apoptotic and anti-inflammatory genes. Here we show that Atf3 is clearly involved in H2S mediated protection. PMID:25025333

  9. Targeting Heat Shock Proteins Mitigates Ventilator Induced Diaphragm Muscle Dysfunction in an Age-Dependent Manner

    PubMed Central

    Ogilvie, Hannah; Cacciani, Nicola; Akkad, Hazem; Larsson, Lars

    2016-01-01

    Intensive care unit (ICU) patients are often overtly subjected to mechanical ventilation and immobilization, which leads to impaired limb and respiratory muscle function. The latter, termed ventilator-induced diaphragm dysfunction (VIDD) has recently been related to compromised heat shock protein (Hsp) activation. The administration of a pharmacological drug BGP-15 acting as a Hsp chaperone co-inducer has been found to partially alleviate VIDD in young rats. Considering that the mean age in the ICU is increasing, we aimed to explore whether the beneficial functional effects are also present in old rats. For that, we exposed young (7–8 months) and old (28–32 months) rats to 5-day controlled mechanical ventilation and immobilization with or without systemic BGP-15 administration. We then dissected diaphragm muscles, membrane–permeabilized bundles and evaluated the contractile function at single fiber level. Results confirmed that administration of BGP-15 restored the force-generating capacity of isolated muscle cells from young rats in conjunction with an increased expression of Hsp72. On the other hand, our results highlighted that old rats did not positively respond to the BGP-15 treatment. Therefore, it is of crucial importance to comprehend in more depth the effect of VIDD on diaphragm function and ascertain any further age-related differences. PMID:27729867

  10. Detrimental role of the airway mucin Muc5ac during ventilator-induced lung injury

    PubMed Central

    Koeppen, M; McNamee, EN; Brodsky, KS; Aherne, CM; Faigle, M; Downey, GP; Colgan, SP; Evans, CM; Schwartz, DA; Eltzschig, HK

    2013-01-01

    Acute lung injury (ALI) is associated with high morbidity and mortality in critically ill patients. At present, the functional contribution of airway mucins to ALI is unknown. We hypothesized that excessive mucus production could be detrimental during lung injury. Initial transcriptional profiling of airway mucins revealed a selective and robust induction of MUC5AC upon cyclic mechanical stretch exposure of pulmonary epithelia (Calu-3). Additional studies confirmed time- and stretch-dose-dependent induction of MUC5AC transcript or protein during cyclic mechanical stretch exposure in vitro or during ventilator-induced lung injury in vivo. Patients suffering from ALI showed a 58-fold increase in MUC5AC protein in their bronchoalveolar lavage. Studies of the MUC5AC promoter implicated nuclear factor κB in Muc5ac induction during ALI. Moreover, mice with gene-targeted deletion of Muc5ac−/− experience attenuated lung inflammation and pulmonary edema during injurious ventilation. We observed that neutrophil trafficking into the lungs of Muc5ac−/− mice was selectively attenuated. This implicates that endogenous Muc5ac production enhances pulmonary neutrophil trafficking during lung injury. Together, these studies reveal a detrimental role for endogenous Muc5ac production during ALI and suggest pharmacological strategies to dampen mucin production in the treatment of lung injury. PMID:23187315

  11. Bixin protects mice against ventilation-induced lung injury in an NRF2-dependent manner

    PubMed Central

    Tao, Shasha; Rojo de la Vega, Montserrat; Quijada, Hector; Wondrak, Georg T.; Wang, Ting; Garcia, Joe G. N.; Zhang, Donna D.

    2016-01-01

    Mechanical ventilation (MV) is a therapeutic intervention widely used in the clinic to assist patients that have difficulty breathing due to lung edema, trauma, or general anesthesia. However, MV causes ventilator-induced lung injury (VILI), a condition characterized by increased permeability of the alveolar-capillary barrier that results in edema, hemorrhage, and neutrophil infiltration, leading to exacerbated lung inflammation and oxidative stress. This study explored the feasibility of using bixin, a canonical NRF2 inducer identified during the current study, to ameliorate lung damage in a murine VILI model. In vitro, bixin was found to activate the NRF2 signaling pathway through blockage of ubiquitylation and degradation of NRF2 in a KEAP1-C151 dependent manner; intraperitoneal (IP) injection of bixin led to pulmonary upregulation of the NRF2 response in vivo. Remarkably, IP administration of bixin restored normal lung morphology and attenuated inflammatory response and oxidative DNA damage following MV. This observed beneficial effect of bixin derived from induction of the NRF2 cytoprotective response since it was only observed in Nrf2+/+ but not in Nrf2−/− mice. This is the first study providing proof-of-concept that NRF2 activators can be developed into pharmacological agents for clinical use to prevent patients from lung injury during MV treatment. PMID:26729554

  12. The effect of theophylline on the prevention of mechanical ventilation-induced diaphragm atrophy in rats.

    PubMed

    Aydin, Nihal Bakirkalay; Teke, Turgut; Toy, Hatice; Uzun, Kursat

    2014-01-01

    Movement disorders and atrophy occur in the diaphragm, the most important muscle of respiration, because of mechanical ventilation (MV). In this animal model, we aimed to evaluate the effect of intravenous theophylline administration on the prevention of mechanical ventilation-induced diaphragmatic atrophy. In our study, 30 healthy male Sprague-dawley rats were used. They were divided into 3 equal groups. Group 1: the control group (no MV); group 2: the placebo group that received MV; Group 3: the theophylline group composed of rats that received both MV and theophylline therapy. In all 3 groups, the diaphragmatic atrophy was evaluated histopathologically. In the histopathological examination, no macroscopic thickening and microscopic atrophy were observed in the diaphragm in the control group. In the placebo group (group 2), macroscopically definite thickening was observed in all rats, and microscopically, heavy (+++) atrophy was observed. In the theophylline group (group 3), there was no atrophy in one rat. In 8 rats, light (+), and in 1 rat medium (++) atrophy was observed. In our study, it was shown that atrophy occurred in the diaphragms of rats after MV, and the atrophy was decreased after theophylline administration.

  13. The JAK–STAT Pathway Is Critical in Ventilator-Induced Diaphragm Dysfunction

    PubMed Central

    Tang, Huibin; Smith, Ira J; Hussain, Sabah NA; Goldberg, Peter; Lee, Myung; Sugiarto, Sista; Godinez, Guillermo L; Singh, Baljit K; Payan, Donald G; Rando, Thomas A; Kinsella, Todd M; Shrager, Joseph B

    2014-01-01

    Mechanical ventilation (MV) is one of the lynchpins of modern intensive-care medicine and is life saving in many critically ill patients. Continuous ventilator support, however, results in ventilation-induced diaphragm dysfunction (VIDD) that likely prolongs patients’ need for MV and thereby leads to major associated complications and avoidable intensive care unit (ICU) deaths. Oxidative stress is a key pathogenic event in the development of VIDD, but its regulation remains largely undefined. We report here that the JAK–STAT pathway is activated in MV in the human diaphragm, as evidenced by significantly increased phosphorylation of JAK and STAT. Blockage of the JAK–STAT pathway by a JAK inhibitor in a rat MV model prevents diaphragm muscle contractile dysfunction (by ~85%, p < 0.01). We further demonstrate that activated STAT3 compromises mitochondrial function and induces oxidative stress in vivo, and, interestingly, that oxidative stress also activates JAK–STAT. Inhibition of JAK–STAT prevents oxidative stress-induced protein oxidation and polyubiquitination and recovers mitochondrial function in cultured muscle cells. Therefore, in ventilated diaphragm muscle, activation of JAK–STAT is critical in regulating oxidative stress and is thereby central to the downstream pathogenesis of clinical VIDD. These findings establish the molecular basis for the therapeutic promise of JAK–STAT inhibitors in ventilated ICU patients. PMID:25286450

  14. The JAK-STAT pathway is critical in ventilator-induced diaphragm dysfunction.

    PubMed

    Tang, Huibin; Smith, Ira J; Hussain, Sabah N A; Goldberg, Peter; Lee, Myung; Sugiarto, Sista; Godinez, Guillermo L; Singh, Baljit K; Payan, Donald G; Rando, Thomas A; Kinsella, Todd M; Shrager, Joseph B

    2015-02-19

    Mechanical ventilation (MV) is one of the lynchpins of modern intensive-care medicine and is life saving in many critically ill patients. Continuous ventilator support, however, results in ventilation-induced diaphragm dysfunction (VIDD) that likely prolongs patients' need for MV and thereby leads to major associated complications and avoidable intensive care unit (ICU) deaths. Oxidative stress is a key pathogenic event in the development of VIDD, but its regulation remains largely undefined. We report here that the JAK-STAT pathway is activated in MV in the human diaphragm, as evidenced by significantly increased phosphorylation of JAK and STAT. Blockage of the JAK-STAT pathway by a JAK inhibitor in a rat MV model prevents diaphragm muscle contractile dysfunction (by ~85%, p < 0.01). We further demonstrate that activated STAT3 compromises mitochondrial function and induces oxidative stress in vivo, and, interestingly, that oxidative stress also activates JAK-STAT. Inhibition of JAK-STAT prevents oxidative stress-induced protein oxidation and polyubiquitination and recovers mitochondrial function in cultured muscle cells. Therefore, in ventilated diaphragm muscle, activation of JAK-STAT is critical in regulating oxidative stress and is thereby central to the downstream pathogenesis of clinical VIDD. These findings establish the molecular basis for the therapeutic promise of JAK-STAT inhibitors in ventilated ICU patients.

  15. Targeting Heat Shock Proteins Mitigates Ventilator Induced Diaphragm Muscle Dysfunction in an Age-Dependent Manner.

    PubMed

    Ogilvie, Hannah; Cacciani, Nicola; Akkad, Hazem; Larsson, Lars

    2016-01-01

    Intensive care unit (ICU) patients are often overtly subjected to mechanical ventilation and immobilization, which leads to impaired limb and respiratory muscle function. The latter, termed ventilator-induced diaphragm dysfunction (VIDD) has recently been related to compromised heat shock protein (Hsp) activation. The administration of a pharmacological drug BGP-15 acting as a Hsp chaperone co-inducer has been found to partially alleviate VIDD in young rats. Considering that the mean age in the ICU is increasing, we aimed to explore whether the beneficial functional effects are also present in old rats. For that, we exposed young (7-8 months) and old (28-32 months) rats to 5-day controlled mechanical ventilation and immobilization with or without systemic BGP-15 administration. We then dissected diaphragm muscles, membrane-permeabilized bundles and evaluated the contractile function at single fiber level. Results confirmed that administration of BGP-15 restored the force-generating capacity of isolated muscle cells from young rats in conjunction with an increased expression of Hsp72. On the other hand, our results highlighted that old rats did not positively respond to the BGP-15 treatment. Therefore, it is of crucial importance to comprehend in more depth the effect of VIDD on diaphragm function and ascertain any further age-related differences.

  16. Hepatic overexpression of the prodomain of furin lessens progression of atherosclerosis and reduces vascular remodeling in response to injury.

    PubMed

    Lei, Xia; Basu, Debapriya; Li, Zhiqiang; Zhang, Maoxiang; Rudic, R Dan; Jiang, Xian-Cheng; Jin, Weijun

    2014-09-01

    Atherosclerosis is a complex disease, involving elevated LDL-c, lipid accumulation in the blood vessel wall, foam cell formation and vascular dysfunction. Lowering plasma LDL-c is the cornerstone of current management of cardiovascular disease. However, new approaches which reduce plasma LDL-c and lessen the pathological vascular remodeling occurring in the disease should also have therapeutic value. Previously, we found that overexpression of profurin, the 83-amino acid prodomain of the proprotein convertase furin, lowered plasma HDL levels in wild-type mice. The question that remained was whether it had effects on apolipoprotein B (ApoB)-containing lipoproteins. Adenovirus mediated overexpression of hepatic profurin in Ldlr(-/-)mice and wild-type mice were used to evaluate effects of profurin on ApoB-containing lipoproteins, atherosclerosis and vascular remodeling. Hepatic profurin overexpression resulted in a significant reduction in atherosclerotic lesion development in Ldlr(-/-)mice and a robust reduction in plasma LDL-c. Metabolic studies revealed lower secretion of ApoB and triglycerides in VLDL particles. Mechanistic studies showed that in the presence of profurin, hepatic ApoB, mainly ApoB100, was degraded by proteasomes. There was no effect on ApoB mRNA expression. Importantly, short-term hepatic profurin overexpression did not result in hepatic lipid accumulation. Blood vessel wall thickening caused by either wire-induced femoral artery injury or common carotid artery ligation was reduced. Profurin expression inhibited proliferation and migration in vascular smooth muscle cells in vitro. These results indicate that a profurin-based therapy has the potential to treat atherosclerosis by improving metabolic lipid profiles and reducing both atherosclerotic lesion development and pathological vascular remodeling. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  17. Aerobic exercise reduces oxidative stress and improves vascular changes of small mesenteric and coronary arteries in hypertension

    PubMed Central

    Roque, Fernanda R; Briones, Ana M; García-Redondo, Ana B; Galán, María; Martínez-Revelles, Sonia; Avendaño, Maria S; Cachofeiro, Victoria; Fernandes, Tiago; Vassallo, Dalton V; Oliveira, Edilamar M; Salaices, Mercedes

    2013-01-01

    Background and Purpose Regular physical activity is an effective non-pharmacological therapy for prevention and control of hypertension. We investigated the effects of aerobic exercise training in vascular remodelling and in the mechanical and functional alterations of coronary and small mesenteric arteries from spontaneously hypertensive rats (SHR). Experimental Approach Normotensive Wistar Kyoto (WKY), SHR and SHR trained on a treadmill for 12 weeks were used to evaluate vascular structural, mechanical and functional properties. Key Results Exercise did not affect lumen diameter, wall thickness and wall/lumen ratio but reduced vascular stiffness of coronary and mesenteric arteries from SHR. Exercise also reduced collagen deposition and normalized altered internal elastic lamina organization and expression of MMP-9 in mesenteric arteries from SHR. Exercise did not affect contractile responses of coronary arteries but improved the endothelium-dependent relaxation in SHR. In mesenteric arteries, training normalized the increased contractile responses induced by U46619 and by high concentrations of acetylcholine. In vessels from SHR, exercise normalized the effects of the NADPH oxidase inhibitor apocynin and the NOS inhibitor l-NAME in vasodilator or vasoconstrictor responses, normalized the increased O2− production and the reduced Cu/Zn superoxide dismutase expression and increased NO production. Conclusions and Implications Exercise training of SHR improves endothelial function and vascular stiffness in coronary and small mesenteric arteries. This might be related to the concomitant decrease of oxidative stress and increase of NO bioavailability. Such effects demonstrate the beneficial effects of exercise on the vascular system and could contribute to a reduction in blood pressure. PMID:22994554

  18. Microparticle Shedding by Erythrocytes, Monocytes and Vascular Smooth Muscular Cells Is Reduced by Aspirin in Diabetic Patients.

    PubMed

    Chiva-Blanch, Gemma; Suades, Rosa; Padró, Teresa; Vilahur, Gemma; Peña, Esther; Ybarra, Juan; Pou, Jose M; Badimon, Lina

    2016-07-01

    Diabetes mellitus is associated with an enhanced risk for cardiovascular disease and its prevalence is increasing. Diabetes induces metabolic stress on blood and vascular cells, promoting platelet activation and vascular dysfunction. The level of vascular cell activation can be measured by the number and phenotype of microparticles found in the circulation. The aim of this study was to investigate the effect of a platelet-inhibitory dose of aspirin on the number and type of microparticles shed to the circulation. Forty-three diabetic patients were enrolled in the study and received a daily dose of 100mg of aspirin for 10 days to cover the average platelet life-span in the circulation. Before and after the intervention period, circulating microparticles were characterized and quantified by flow cytometry. Type 1 diabetic patients had about twice the number of tissue factor-positive circulating microparticles (derived both from platelets and monocytes) and endothelial-derived E-selectin positive microparticles than type 2 diabetic patients. Aspirin therapy significantly inhibited platelets since cyclooxygenase 1 derived thromboxane generation levels were reduced by 99%. Microparticles derived from erythrocytes, activated monocytes, and smooth muscle cells were significantly reduced after 10 days of aspirin administration. These results indicate that: a) vascular and blood cells in type 1 diabetic patients are exposed to more sustained stress shown by their specific microparticle origin and levels; b) aspirin therapy inhibits vascular wall cell activation and microparticle shedding, and c) the effects of aspirin are similar in type 1 and 2 diabetes. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  19. Choosing the frequency of deep inflation in mice: balancing recruitment against ventilator-induced lung injury.

    PubMed

    Allen, Gilman B; Suratt, Benjamin T; Rinaldi, Lisa; Petty, Joseph M; Bates, Jason H T

    2006-10-01

    Low tidal volume (Vt) ventilation is protective against ventilator-induced lung injury but can promote development of atelectasis. Periodic deep inflation (DI) can open the lung, but if delivered too frequently may cause damage via repeated overdistention. We therefore examined the effects of varying DI frequency on lung mechanics, gas exchange, and biomarkers of injury in mice. C57BL/6 males were mechanically ventilated with positive end-expiratory pressure (PEEP) of 2 cmH2O for 2 h. One high Vt group received a DI with each breath (HV). Low Vt groups received 2 DIs after each hour of ventilation (LV) or 2 DIs every minute (LVDI). Control groups included a nonventilated surgical sham and a group receiving high Vt with zero PEEP (HVZP). Respiratory impedance was measured every 4 min, from which tissue elastance (H) and damping (G) were derived. G and H rose progressively during LV and HVZP, but returned to baseline after hourly DI during LV. During LVDI and HV, G and H remained low and gas exchange was superior to that of LV. Bronchoalveolar lavage fluid protein was elevated in HV and HVZP but was not different between LV and LVDI. Lung tissue IL-6 and IL-1beta levels were elevated in HVZP and lower in LVDI compared with LV. We conclude that frequent DI can safely improve gas exchange and lung mechanics and may confer protection from biotrauma. Differences between LVDI and HV suggest that an optimal frequency range of DI exists, within which the benefits of maintaining an open lung outweigh injury incurred from overdistention.

  20. Magnetic resonance imaging provides sensitive in vivo assessment of experimental ventilator-induced lung injury

    PubMed Central

    Kuethe, Dean O.; Filipczak, Piotr T.; Hix, Jeremy M.; Gigliotti, Andrew P.; Estépar, Raúl San José; Washko, George R.; Baron, Rebecca M.

    2016-01-01

    Animal models play a critical role in the study of acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI). One limitation has been the lack of a suitable method for serial assessment of acute lung injury (ALI) in vivo. In this study, we demonstrate the sensitivity of magnetic resonance imaging (MRI) to assess ALI in real time in rat models of VILI. Sprague-Dawley rats were untreated or treated with intratracheal lipopolysaccharide or PBS. After 48 h, animals were mechanically ventilated for up to 15 h to induce VILI. Free induction decay (FID)-projection images were made hourly. Image data were collected continuously for 30 min and divided into 13 phases of the ventilatory cycle to make cinematic images. Interleaved measurements of respiratory mechanics were performed using a flexiVent ventilator. The degree of lung infiltration was quantified in serial images throughout the progression or resolution of VILI. MRI detected VILI significantly earlier (3.8 ± 1.6 h) than it was detected by altered lung mechanics (9.5 ± 3.9 h, P = 0.0156). Animals with VILI had a significant increase in the Index of Infiltration (P = 0.0027), and early regional lung infiltrates detected by MRI correlated with edema and inflammatory lung injury on histopathology. We were also able to visualize and quantify regression of VILI in real time upon institution of protective mechanical ventilation. Magnetic resonance lung imaging can be utilized to investigate mechanisms underlying the development and propagation of ALI, and to test the therapeutic effects of new treatments and ventilator strategies on the resolution of ALI. PMID:27288491

  1. Role of intrinsic aerobic capacity and ventilator-induced diaphragm dysfunction

    PubMed Central

    Sollanek, Kurt J.; Smuder, Ashley J.; Wiggs, Michael P.; Morton, Aaron B.; Koch, Lauren G.; Britton, Steven L.

    2015-01-01

    Prolonged mechanical ventilation (MV) leads to rapid diaphragmatic atrophy and contractile dysfunction, which is collectively termed “ventilator-induced diaphragm dysfunction” (VIDD). Interestingly, endurance exercise training prior to MV has been shown to protect against VIDD. Further, recent evidence reveals that sedentary animals selectively bred to possess a high aerobic capacity possess a similar skeletal muscle phenotype to muscles from endurance trained animals. Therefore, we tested the hypothesis that animals with a high intrinsic aerobic capacity would naturally be afforded protection against VIDD. To this end, animals were selectively bred over 33 generations to create two divergent strains, differing in aerobic capacity: high-capacity runners (HCR) and low-capacity runners (LCR). Both groups of animals were subjected to 12 h of MV and compared with nonventilated control animals within the same strains. As expected, contrasted to LCR animals, the diaphragm muscle from the HCR animals contained higher levels of oxidative enzymes (e.g., citrate synthase) and antioxidant enzymes (e.g., superoxide dismutase and catalase). Nonetheless, compared with nonventilated controls, prolonged MV resulted in significant diaphragmatic atrophy and impaired diaphragm contractile function in both the HCR and LCR animals, and the magnitude of VIDD did not differ between strains. In conclusion, these data demonstrate that possession of a high intrinsic aerobic capacity alone does not afford protection against VIDD. Importantly, these results suggest that endurance exercise training differentially alters the diaphragm phenotype to resist VIDD. Interestingly, levels of heat shock protein 72 did not differ between strains, thus potentially representing an important area of difference between animals with intrinsically high aerobic capacity and exercise-trained animals. PMID:25571991

  2. Clinical review: Ventilator-induced diaphragmatic dysfunction - human studies confirm animal model findings!

    PubMed Central

    2011-01-01

    Diaphragmatic function is a major determinant of the ability to successfully wean patients from mechanical ventilation. However, the use of controlled mechanical ventilation in animal models results in a major reduction of diaphragmatic force-generating capacity together with structural injury and atrophy of diaphragm muscle fibers, a condition termed ventilator-induced diaphragmatic dysfunction (VIDD). Increased oxidative stress and exaggerated proteolysis in the diaphragm have been linked to the development of VIDD in animal models, but much less is known about the extent to which these phenomena occur in humans undergoing mechanical ventilation in the ICU. In the present review, we first briefly summarize the large body of evidence demonstrating the existence of VIDD in animal models, and outline the major cellular mechanisms that have been implicated in this process. We then relate these findings to very recently published data in critically ill patients, which have thus far been found to exhibit a remarkable degree of similarity with the animal model data. Hence, the human studies to date have indicated that mechanical ventilation is associated with increased oxidative stress, atrophy, and injury of diaphragmatic muscle fibers along with a rapid loss of diaphragmatic force production. These changes are, to a large extent, directly proportional to the duration of mechanical ventilation. In the context of these human data, we also review the methods that can be used in the clinical setting to diagnose and/or monitor the development of VIDD in critically ill patients. Finally, we discuss the potential for using different mechanical ventilation strategies and pharmacological approaches to prevent and/or to treat VIDD and suggest promising avenues for future research in this area. PMID:21457528

  3. Effects of sevoflurane on ventilator induced lung injury in a healthy lung experimental model.

    PubMed

    Romero, A; Moreno, A; García, J; Sánchez, C; Santos, M; García, J

    2016-01-01

    Ventilator-induced lung injury (VILI) causes a systemic inflammatory response in tissues, with an increase in IL-1, IL-6 and TNF-α in blood and tissues. Cytoprotective effects of sevoflurane in different experimental models are well known, and this protective effect can also be observed in VILI. The objective of this study was to assess the effects of sevoflurane in VILI. A prospective, randomized, controlled study was designed. Twenty female rats were studied. The animals were mechanically ventilated, without sevoflurane in the control group and sevoflurane 3% in the treated group (SEV group). VILI was induced applying a maximal inspiratory pressure of 35 cmH2O for 20 min without any positive end-expiratory pressure for 20 min (INJURY time). The animals were then ventilated 30 min with a maximal inspiratory pressure of 12 cmH2O and 3 cmH2O positive end-expiratory pressure (time 30 min POST-INJURY), at which time the animals were euthanized and pathological and biomarkers studies were performed. Heart rate, invasive blood pressure, pH, PaO2, and PaCO2 were recorded. The lung wet-to-dry weight ratio was used as an index of lung edema. No differences were found in the blood gas analysis parameters or heart rate between the 2 groups. Blood pressure was statistically higher in the control group, but still within the normal clinical range. The percentage of pulmonary edema and concentrations of TNF-α and IL-6 in lung tissue in the SEV group were lower than in the control group. Sevoflurane attenuates VILI in a previous healthy lung in an experimental subclinical model in rats. Copyright © 2015 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

  4. Reduced methylation of the thromboxane synthase gene is correlated with its increased vascular expression in preeclampsia.

    PubMed

    Mousa, Ahmad A; Strauss, Jerome F; Walsh, Scott W

    2012-06-01

    Preeclampsia is characterized by increased thromboxane and decreased prostacyclin levels, which predate symptoms, and can explain some of the clinical manifestations of preeclampsia, including hypertension and thrombosis. In this study, we examined DNA methylation of the promoter region of the thromboxane synthase gene (TBXAS1) and the expression of thromboxane synthase in systemic blood vessels of normal pregnant and preeclamptic women. Thromboxane synthase is responsible for the synthesis of thromboxane A(2), a potent vasoconstrictor and activator of platelets. We also examined the effect of experimentally induced DNA hypomethylation on the expression of thromboxane synthase in a neutrophil-like cell line (HL-60 cells) and in cultured vascular smooth muscle and endothelial cells. We found that DNA methylation of the TBXAS1 promoter was decreased and thromboxane synthase expression was increased in omental arteries of preeclamptic women as compared with normal pregnant women. Increased thromboxane synthase expression was observed in vascular smooth muscles cells, endothelial cells, and infiltrating neutrophils. Experimentally induced DNA hypomethylation only increased expression of thromboxane synthase in the neutrophil-like cell line, whereas tumor necrosis factor-α, a neutrophil product, increased its expression in cultured vascular smooth muscle cells. Our study suggests that epigenetic mechanisms and release of tumor necrosis factor-α by infiltrating neutrophils could contribute to the increased expression of thromboxane synthase in maternal systemic blood vessels, contributing to the hypertension and coagulation abnormalities associated with preeclampsia.

  5. Reduced subclinical carotid vascular disease and arterial stiffness in vegetarian men: The CARVOS Study.

    PubMed

    Acosta-Navarro, Julio; Antoniazzi, Luiza; Oki, Adriana Midori; Bonfim, Maria Carlos; Hong, Valeria; Acosta-Cardenas, Pedro; Strunz, Celia; Brunoro, Eleonora; Miname, Marcio Hiroshi; Filho, Wilson Salgado; Bortolotto, Luiz Aparecido; Santos, Raul D

    2017-03-01

    Dietary habits play an important role in the development of atherosclerosis, the most important cause of morbidity and mortality in the world. The objective of this study was to verify if vegetarian (VEG) diet could be related a better profile of subclinical vascular disease evaluated by arterial stiffness and functional and structural properties of carotid arteries, compared to omnivorous (OMN) diet. In this cross-sectional study, 44 VEG and 44 OMN apparently healthy men ≥35years of age, in order to not have confounding risk factors of subclinical atherosclerosis, were assessed for anthropometric data, blood pressure, blood lipids, glucose, C reactive protein (CRP), and arterial stiffness determined by carotid-femoral pulse wave velocity (PWV). Also, carotid intima-media thickness (c-IMT) and distensibility were evaluated. VEG men had lower body mass index, systolic and diastolic blood pressures, fasting serum total cholesterol, LDL and non-HDL-cholesterol, apolipoprotein B, glucose and glycated hemoglobin values in comparison with OMN individuals (all p values <0.05). Markers of vascular structure and function were different between VEG and OMN: PWV 7.1±0.8m/s vs. 7.7±0.9m/s (p<0.001); c-IMT 593±94 vs. 661±128μm (p=0.003); and relative carotid distensibility 6.39±1.7 vs. 5.72±1.8% (p=0.042), respectively. After a multivariate linear regression analysis, a VEG diet was independently and negatively associated with PWV (p value 0.005). A VEG diet is associated with a more favorable cardiovascular diseases biomarker profile and better vascular structural and functional parameters. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Role of Strain Rate in the Pathogenesis of Ventilator-Induced Lung Edema.

    PubMed

    Protti, Alessandro; Maraffi, Tommaso; Milesi, Marta; Votta, Emiliano; Santini, Alessandro; Pugni, Paola; Andreis, Davide T; Nicosia, Francesco; Zannin, Emanuela; Gatti, Stefano; Vaira, Valentina; Ferrero, Stefano; Gattinoni, Luciano

    2016-09-01

    Lungs behave as viscoelastic polymers. Harms of mechanical ventilation could then depend on not only amplitude (strain) but also velocity (strain rate) of lung deformation. Herein, we tested this hypothesis. Laboratory investigation. Animal unit. Thirty healthy piglets. Two groups of animals were ventilated for 54 hours with matched lung strains (ratio between tidal volume and functional residual capacity) but different lung strain rates (ratio between strain and inspiratory time). Individual strains ranged between 0.6 and 3.5 in both groups. Piglets ventilated with low strain rates had an inspiratory-to-expiratory time ratio of 1:2-1:3. Those ventilated with high strain rates had much lower inspiratory-to-expiratory time ratios (down to 1:9). Respiratory rate was always 15 breaths/min. Lung viscoelastic behavior, with ventilator setting required per protocol, was "quantified" as dynamic respiratory system hysteresis (pressure-volume loop [in Joules]) and stress relaxation (airway pressure drop during an end-inspiratory pause [in cm H2O]). Primary outcome was the occurrence of pulmonary edema within 54 hours. On average, the two study groups were ventilated with well-matched strains (2.1 ± 0.9 vs 2.1 ± 0.9; p = 0.864) but different strain rates (1.8 ± 0.8 vs 4.6 ± 1.5 s; p < 0.001), dynamic respiratory system hysteresis (0.6 ± 0.3 vs 1.4 ± 0.8 J; p = 0.001), and stress relaxation (3.1 ± 0.9 vs 5.0 ± 2.3 cm H2O; p = 0.008). The prevalence of pulmonary edema was 20% among piglets ventilated with low strain rates and 73% among those ventilated with high strain rates (p = 0.010). High strain rate is a risk factor for ventilator-induced pulmonary edema, possibly because it amplifies lung viscoelastic behavior.

  7. Negative pressure ventilation and positive pressure ventilation promote comparable levels of ventilator-induced diaphragmatic dysfunction in rats.

    PubMed

    Bruells, Christian S; Smuder, Ashley J; Reiss, Lucy K; Hudson, Matthew B; Nelson, William Bradley; Wiggs, Michael P; Sollanek, Kurt J; Rossaint, Rolf; Uhlig, Stefan; Powers, Scott K

    2013-09-01

    Mechanical ventilation is a life-saving intervention for patients with respiratory failure. Unfortunately, a major complication associated with prolonged mechanical ventilation is ventilator-induced diaphragmatic atrophy and contractile dysfunction, termed ventilator-induced diaphragmatic dysfunction (VIDD). Emerging evidence suggests that positive pressure ventilation (PPV) promotes lung damage (ventilator-induced lung injury [VILI]), resulting in the release of signaling molecules that foster atrophic signaling in the diaphragm and the resultant VIDD. Although a recent report suggests that negative pressure ventilation (NPV) results in less VILI than PPV, it is unknown whether NPV can protect against VIDD. Therefore, the authors tested the hypothesis that compared with PPV, NPV will result in a lower level of VIDD. Adult rats were randomly assigned to one of three experimental groups (n = 8 each): (1) acutely anesthetized control (CON), (2) 12 h of PPV, and (3) 12 h of NPV. Dependent measures included indices of VILI, diaphragmatic muscle fiber cross-sectional area, diaphragm contractile properties, and the activity of key proteases in the diaphragm. Our results reveal that no differences existed in the degree of VILI between PPV and NPV animals as evidenced by VILI histological scores (CON = 0.082 ± 0.001; PPV = 0.22 ± 0.04; NPV = 0.25 ± 0.02; mean ± SEM). Both PPV and NPV resulted in VIDD. Importantly, no differences existed between PPV and NPV animals in diaphragmatic fiber cross-sectional area, contractile properties, and the activation of proteases. These results demonstrate that NPV and PPV result in similar levels of VILI and that NPV and PPV promote comparable levels of VIDD in rats.

  8. Src inhibitor reduces permeability without disturbing vascularization and prevents bone destruction in steroid-associated osteonecrotic lesions in rabbits.

    PubMed

    He, Yi-Xin; Liu, Jin; Guo, Baosheng; Wang, Yi-Xiang; Pan, Xiaohua; Li, Defang; Tang, Tao; Chen, Yang; Peng, Songlin; Bian, Zhaoxiang; Liang, Zicai; Zhang, Bao-Ting; Lu, Aiping; Zhang, Ge

    2015-03-09

    To examine the therapeutic effect of Src inhibitor on the VEGF mediating vascular hyperpermeability and bone destruction within steroid-associated osteonecrotic lesions in rabbits. Rabbits with high risk for progress to destructive repair in steroid-associated osteonecrosis were selected according to our published protocol. The selected rabbits were systemically administrated with either Anti-VEGF antibody (Anti-VEGF Group) or Src inhibitor (Src-Inhibition Group) or VEGF (VEGF-Supplement Group) or a combination of VEGF and Src inhibitor (Supplement &Inhibition Group) or control vehicle (Control Group) for 4 weeks. At 0, 2 and 4 weeks after administration, in vivo dynamic MRI, micro-CT based-angiography, histomorphometry and immunoblotting were employed to evaluate the vascular and skeletal events in different groups. The incidence of the destructive repair in the Anti-VEGF Group, Src-Inhibition Group and Supplement &Inhibition Group was all significantly lower than that in the Control Group. The angiogenesis was promoted in VEGF-Supplement Group, Src-Inhibition Group and Supplement &Inhibition Group, while the hyperpermeability was inhibited in Anti-VEGF Group, Src-Inhibition Group and Supplement &Inhibition Group. The trabecular structure was improved in Src-Inhibition Group and Supplement &Inhibition Group. Src inhibitor could reduce permeability without disturbing vascularization and prevent destructive repair in steroid-associated osteonecrosis.

  9. Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension.

    PubMed

    de Mendonça, Lucas; Felix, Nathane S; Blanco, Natália G; Da Silva, Jaqueline S; Ferreira, Tatiana P; Abreu, Soraia C; Cruz, Fernanda F; Rocha, Nazareth; Silva, Patrícia M; Martins, Vanessa; Capelozzi, Vera L; Zapata-Sudo, Gizele; Rocco, Patricia R M; Silva, Pedro L

    2017-10-03

    Experimental research has reported beneficial effects of mesenchymal stromal cell (MSC) therapy in pulmonary arterial hypertension (PAH). However, these studies either were based on prophylactic protocols or assessed basic remodeling features without evaluating possible mechanisms. We analyzed the effects of MSC therapy on lung vascular remodeling and hemodynamics and its possible mechanisms of action in monocrotaline (MCT)-induced PAH. Twenty-eight Wistar rats were randomly divided into two groups. In the PAH group, animals received MCT 60 mg/kg intraperitoneally, while a control group received saline (SAL) instead. On day 14, both groups were further randomized to receive 10(5) adipose-derived MSCs or SAL intravenously (n = 7/group). On day 28, right ventricular systolic pressure (RVSP) and the gene expression of mediators associated with apoptosis, inflammation, fibrosis, Smad-1 levels, cell proliferation, and endothelial-mesenchymal transition were determined. In addition, lung histology (smooth muscle cell proliferation and plexiform-like injuries), CD68(+) and CD163(+) macrophages, and plasma levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) were evaluated. In the PAH group, adipose-derived MSCs, compared to SAL, reduced mean RVSP (29 ± 1 vs 39 ± 2 mmHg, p < 0.001), lung tissue collagen fiber content, smooth muscle cell proliferation, CD68(+) macrophages, interleukin-6 expression, and the antiapoptotic mediators Bcl-2 and survivin. Conversely, expression of the proapoptotic mediator procaspase-3 and plasma VEGF increased, with no changes in PDGF. In the pulmonary artery, MSCs dampened the endothelial-mesenchymal transition. In MCT-induced PAH, MSC therapy reduced lung vascular remodeling, thus improving hemodynamics. These beneficial effects were associated with increased levels of proapoptotic markers, mesenchymal-to-endothelial transition, reduced cell proliferation markers, and inflammation

  10. Batroxobin protects against spinal cord injury in rats by promoting the expression of vascular endothelial growth factor to reduce apoptosis

    PubMed Central

    YU, HUI; LIN, BIN; HE, YONGZHI; ZHANG, WENBIN; XU, YANG

    2015-01-01

    The host response to spinal cord injury (SCI) can lead to an ischemic environment that can induce cell death. Therapeutic interventions using neurotrophic factors have focused on the prevention of such reactions in order to reduce this cell death. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor. We hypothesized in this study that batroxobin would exhibit protective effects following SCI by promoting the expression of VEGF to reduce the levels of apoptosis in a rat model of SCI. Ninety adult female Sprague Dawley rats were divided randomly into sham injury (group I), SCI (group II) and batroxobin treatment (group III) groups. The Basso-Bettie-Bresnahan (BBB) scores, number of apoptotic cells and expression of VEGF were assessed at 1, 3, 5, 7, 14 and 28 days post-injury. The BBB scores were significantly improved in group III compared with those in group II between days 5 and 28 post-injury (P<0.05). At each time-point subsequent to the injury, the number of apoptotic cells in group III was reduced compared with that in group II. Compared with group II, treatment with batroxobin significantly increased the expression of VEGF from day 3 until 2 weeks post-SCI (P<0.05), while no significant difference was observed at day 28. These data suggest that batroxobin has multiple beneficial effects on SCI, indicating a potential clinical application. PMID:26136870

  11. Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD.

    PubMed

    Labonté, Eric D; Carreras, Christopher W; Leadbetter, Michael R; Kozuka, Kenji; Kohler, Jill; Koo-McCoy, Samantha; He, Limin; Dy, Edward; Black, Deborah; Zhong, Ziyang; Langsetmo, Ingrid; Spencer, Andrew G; Bell, Noah; Deshpande, Desiree; Navre, Marc; Lewis, Jason G; Jacobs, Jeffrey W; Charmot, Dominique

    2015-05-01

    In CKD, phosphate retention arising from diminished GFR is a key early step in a pathologic cascade leading to hyperthyroidism, metabolic bone disease, vascular calcification, and cardiovascular mortality. Tenapanor, a minimally systemically available inhibitor of the intestinal sodium-hydrogen exchanger 3, is being evaluated in clinical trials for its potential to (1) lower gastrointestinal sodium absorption, (2) improve fluid overload-related symptoms, such as hypertension and proteinuria, in patients with CKD, and (3) reduce interdialytic weight gain and intradialytic hypotension in ESRD. Here, we report the effects of tenapanor on dietary phosphorous absorption. Oral administration of tenapanor or other intestinal sodium-hydrogen exchanger 3 inhibitors increased fecal phosphorus, decreased urine phosphorus excretion, and reduced [(33)P]orthophosphate uptake in rats. In a rat model of CKD and vascular calcification, tenapanor reduced sodium and phosphorus absorption and significantly decreased ectopic calcification, serum creatinine and serum phosphorus levels, circulating phosphaturic hormone fibroblast growth factor-23 levels, and heart mass. These results indicate that tenapanor is an effective inhibitor of dietary phosphorus absorption and suggest a new approach to phosphate management in renal disease and associated mineral disorders. Copyright © 2015 by the American Society of Nephrology.

  12. Magnesium reduces calcification in bovine vascular smooth muscle cells in a dose-dependent manner

    PubMed Central

    Peter, Mirjam E.; Sevinc Ok, Ebru; Celenk, Fatma Gul; Yilmaz, Mumtaz; Steppan, Sonja; Asci, Gulay; Ok, Ercan; Passlick-Deetjen, Jutta

    2012-01-01

    Background. Vascular calcification (VC), mainly due to elevated phosphate levels, is one major problem in patients suffering from chronic kidney disease. In clinical studies, an inverse relationship between serum magnesium and VC has been reported. However, there is only few information about the influence of magnesium on calcification on a cellular level available. Therefore, we investigated the effect of magnesium on calcification induced by β-glycerophosphate (BGP) in bovine vascular smooth muscle cells (BVSMCs). Methods. BVSMCs were incubated with calcification media for 14 days while simultaneously increasing the magnesium concentration. Calcium deposition, transdifferentiation of cells and apoptosis were measured applying quantification of calcium, von Kossa and Alizarin red staining, real-time reverse transcription–polymerase chain reaction and annexin V staining, respectively. Results. Calcium deposition in the cells dramatically increased with addition of BGP and could be mostly prevented by co-incubation with magnesium. Higher magnesium levels led to inhibition of BGP-induced alkaline phosphatase activity as well as to a decreased expression of genes associated with the process of transdifferentiation of BVSMCs into osteoblast-like cells. Furthermore, estimated calcium entry into the cells decreased with increasing magnesium concentrations in the media. In addition, higher magnesium concentrations prevented cell damage (apoptosis) induced by BGP as well as progression of already established calcification. Conclusions. Higher magnesium levels prevented BVSMC calcification, inhibited expression of osteogenic proteins, apoptosis and further progression of already established calcification. Thus, magnesium is influencing molecular processes associated with VC and may have the potential to play a role for VC also in clinical situations. PMID:21750166

  13. Reduced Cardiovascular Mortality Associated with Early Vascular Access Placement in Elderly Patients with Chronic Kidney Disease

    PubMed Central

    Lee, Timmy; Thamer, Mae; Zhang, Qian; Zhang, Yi; Allon, Michael

    2016-01-01

    Background Elderly patients with cardiovascular comorbidities are more likely to die before progressing to needing hemodialysis, so deferring their pre-dialysis vascular access (VA) surgery has been suggested. However, recent declines in cardiovascular mortality in the U.S. population may have changed this consideration. We assessed whether there has been a parallel decrease in cardiovascular co-morbidity in elderly chronic kidney disease (CKD) patients undergoing pre-dialysis access surgery, and whether this impacted clinical outcomes after access creation and cardiovascular events after hemodialysis initiation. Methods We identified 3,418 elderly patients undergoing pre-dialysis VA creation from 2004-2009, divided them into 3 time cohorts (2004-05, 2006-07 and 2008-09), and assessed their clinical outcomes during 2 years of follow-up. Results There was a progressive decrease in patients with history of peripheral vascular disease (66.5 to 59.7%, p<0.005), heart failure (47.0 to 35.8%, p<0.005), and myocardial infarction (6.5 to 3.3%, p<0.001) from 2004-2009. Death before hemodialysis decreased from 17.5 to 12.6%, survival without hemodialysis increased from 14.5 to 19.0%, and hemodialysis initiation remained constant at ~68% (p<0.001). The incidence of death or cardiovascular event in the first year of hemodialysis decreased from 2004-05 to 2008-09 (HR=0.83, 95% CI, 0.69-0.99; p=0.04). Conclusion In the context of a changing population from 2004-09, a progressive decrease in cardiovascular comorbidities in elderly CKD patients undergoing pre-dialysis VA surgery was associated with a decrease in death before hemodialysis and cardiovascular events after starting hemodialysis. These insights should be translated into more thoughtful consideration of which elderly patients should undergo pre-dialysis access surgery. PMID:27166150

  14. Effects of MMP-9 inhibition by doxycycline on proteome of lungs in high tidal volume mechanical ventilation-induced acute lung injury

    PubMed Central

    2010-01-01

    Background Although mechanical ventilation (MV) is a major supportive therapy for patients with acute respiratory distress syndrome, it may result in side effects including lung injury. In this study we hypothesize that MMP-9 inhibition by doxycycline might reduce MV-related lung damage. Using a proteomic approach we identified the pulmonary proteins altered in high volume ventilation-induced lung injury (VILI). Forty Wistar rats were randomized to an orally pretreated with doxycycline group (n = 20) or to a placebo group (n = 20) each of which was followed by instrumentation prior to either low or high tidal volume mechanical ventilation. Afterwards, animals were euthanized and lungs were harvested for subsequent analyses. Results Mechanical function and gas exchange parameters improved following treatment with doxycycline in the high volume ventilated group as compared to the placebo group. Nine pulmonary proteins have shown significant changes between the two biochemically analysed (high volume ventilated) groups. Treatment with doxycycline resulted in a decrease of pulmonary MMP-9 activity as well as in an increase in the levels of soluble receptor for advanced glycation endproduct, apoliporotein A-I, peroxiredoxin II, four molecular forms of albumin and two unnamed proteins. Using the pharmacoproteomic approach we have shown that treatment with doxycycline leads to an increase in levels of several proteins, which could potentially be part of a defense mechanism. Conclusion Administration of doxycycline might be a significant supportive therapeutic strategy in prevention of VILI. PMID:20205825

  15. The protective effect of dopamine on ventilator-induced lung injury via the inhibition of NLRP3 inflammasome.

    PubMed

    Yang, Xiaomei; Sun, Xiaotong; Chen, Hongli; Xi, Guangmin; Hou, Yonghao; Wu, Jianbo; Liu, Dejie; Wang, Huanliang; Hou, Yuedong; Yu, Jingui

    2017-04-01

    Dopamine (DA), a neurotransmitter, was previously shown to have anti-inflammatory effects. However, its role in ventilator-induced lung injury (VILI) has not been explicitly demonstrated. This study aimed to investigate the therapeutic efficacy and molecular mechanisms of dopamine in VILI. Rats were treated with dopamine during mechanical ventilation. Afterwards, the influence of dopamine on histological changes, pulmonary edema, the lung wet/dry (W/D) ratio, myeloperoxidase (MPO) activity, polymorphonuclear(PMN)counts, inflammatory cytokine levels, and NLRP3 inflammasome protein expression were examined. Our results showed that dopamine significantly attenuated lung tissue injury, the lung W/D ratio, MPO activity and neutrophil infiltration. Moreover, it inhibited inflammatory cytokine levels in the Bronchoalveolar lavage fluid (BAL). In addition, dopamine significantly inhibited ventilation-induced NLRP3 activation. Our experimental findings demonstrate that dopamine exerted protective effects in VILI by alleviating the inflammatory response through inhibition of NLRP3 signaling pathways. The present study indicated that dopamine could be a potential effective therapeutic strategy for the treatment of VILI. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Attenuation of Lipopolysaccharide-Induced Lung Vascular Stiffening by Lipoxin Reduces Lung Inflammation

    PubMed Central

    Meng, Fanyong; Mambetsariev, Isa; Tian, Yufeng; Beckham, Yvonne; Meliton, Angelo; Leff, Alan; Gardel, Margaret L.; Allen, Michael J.; Birukov, Konstantin G.

    2015-01-01

    Reversible changes in lung microstructure accompany lung inflammation, although alterations in tissue micromechanics and their impact on inflammation remain unknown. This study investigated changes in extracellular matrix (ECM) remodeling and tissue stiffness in a model of LPS-induced inflammation and examined the role of lipoxin analog 15-epi-lipoxin A4 (eLXA4) in the reduction of stiffness-dependent exacerbation of the inflammatory process. Atomic force microscopy measurements of live lung slices were used to directly measure local tissue stiffness changes induced by intratracheal injection of LPS. Effects of LPS on ECM properties and inflammatory response were evaluated in an animal model of LPS-induced lung injury, live lung tissue slices, and pulmonary endothelial cell (EC) culture. In vivo, LPS increased perivascular stiffness in lung slices monitored by atomic force microscopy and stimulated expression of ECM proteins fibronectin, collagen I, and ECM crosslinker enzyme, lysyl oxidase. Increased stiffness and ECM remodeling escalated LPS-induced VCAM1 and ICAM1 expression and IL-8 production by lung ECs. Stiffness-dependent exacerbation of inflammatory signaling was confirmed in pulmonary ECs grown on substrates with high and low stiffness. eLXA4 inhibited LPS-increased stiffness in lung cross sections, attenuated stiffness-dependent enhancement of EC inflammatory activation, and restored lung compliance in vivo. This study shows that increased local vascular stiffness exacerbates lung inflammation. Attenuation of local stiffening of lung vasculature represents a novel mechanism of lipoxin antiinflammatory action. PMID:24992633

  17. Alkylglycerols reduce serum complement and plasma vascular endothelial growth factor in obese individuals.

    PubMed

    Parri, A; Fitó, Montserrat; Torres, C F; Muñoz-Aguayo, D; Schröder, H; Cano, J F; Vázquez, L; Reglero, G; Covas, María-Isabel

    2016-06-01

    Alkylglycerols (AKGs), isolated or present in shark liver oil have anti-inflammatory properties. Complement 3 (C3) and 4 (C4) participate in lipid metabolism and in obesity, contributing to the metabolic syndrome and to the low-grade inflammation associated with obesity. In a randomized, controlled, crossover study, 26 non-diabetes obese individuals were assigned two preparations with low (LAC, 10 mg AKGs) and high (HAC, 20 mg AKGs) AKG content. Intervention periods were of 3 weeks preceded by 2-week washout periods in which shark liver oil was avoided. Cholesterol, C3, C4, and vascular endothelial growth factor (VEGF) decreased in a linear trend (P < 0.01) from baseline (control) to LAC and HAC. Values after HAC were significantly lower (P < 0.05) versus both baseline and after LAC. No adverse effects were observed or reported. Data from this pilot study open a promising field for the study of the beneficial effects of AKGs on cardiovascular risk factors in obese individuals.

  18. Short-term calorie restriction reverses vascular endothelial dysfunction in old mice by increasing nitric oxide and reducing oxidative stress.

    PubMed

    Rippe, Catarina; Lesniewski, Lisa; Connell, Melanie; LaRocca, Thomas; Donato, Anthony; Seals, Douglas

    2010-06-01

    To determine if short-term calorie restriction reverses vascular endothelial dysfunction in old mice, old (O, n = 30) and young (Y, n = 10) male B6D2F1 mice were fed ad libitum (AL) or calorie restricted (CR, approximately 30%) for 8 weeks. Ex vivo carotid artery endothelium-dependent dilation (EDD) was impaired in old ad libitum (OAL) vs. young ad libitum (YAL) (74 +/- 5 vs. 95 +/- 2% of maximum dilation, P < 0.05), whereas old calorie-restricted (OCR) and YCR did not differ (96 +/- 1 vs. 94 +/- 3%). Impaired EDD in OAL was mediated by reduced nitric oxide (NO) bioavailability associated with decreased endothelial NO synthase expression (aorta) (P < 0.05), both of which were restored in OCR. Nitrotyrosine, a cellular marker of oxidant modification, was markedly elevated in OAL (P < 0.05), whereas OCR was similar to Y. Aortic superoxide production was 150% greater in OAL vs. YAL (P < 0.05), but normalized in OCR, and TEMPOL, a superoxide dismutase (SOD) mimetic that restored EDD in OAL (to 97 +/- 2%), had no effect in Y or OCR. OAL had increased expression and activity of the oxidant enzyme, NADPH oxidase, and its inhibition (apocynin) improved EDD, whereas NADPH oxidase in OCR was similar to Y. Manganese SOD activity and sirtuin1 expression were reduced in OAL (P < 0.05), but restored to Y in OCR. Inflammatory cytokines were greater in OAL vs. YAL (P < 0.05), but unaffected by CR. Carotid artery endothelium-independent dilation did not differ among groups. Short-term CR initiated in old age reverses age-associated vascular endothelial dysfunction by restoring NO bioavailability, reducing oxidative stress (via reduced NADPH oxidase-mediated superoxide production and stimulation of anti-oxidant enzyme activity), and upregulation of sirtuin-1.

  19. Short-term Calorie Restriction Reverses Vascular Endothelial Dysfunction in Old Mice by Increasing Nitric Oxide and Reducing Oxidative Stress

    PubMed Central

    Rippe, Catarina; Lesniewski, Lisa; Connell, Melanie; LaRocca, Thomas; Donato, Anthony; Seals, Douglas

    2010-01-01

    Summary To determine if short-term calorie restriction reverses vascular endothelial dysfunction in old mice, old (O, n=30) and young (Y, n=10) male B6D2F1 mice were fed ad libitum (AL) or calorie restricted (CR, ∼30%) for 8 weeks. Ex vivo carotid artery endothelium-dependent dilation (EDD) was impaired in OAL vs. YAL (74±5 vs. 95±2% of maximum dilation, P<0.05), whereas OCR and YCR did not differ (96±1 vs. 94±3%). Impaired EDD in OAL was mediated by reduced nitric oxide (NO) bioavailability associated with decreased endothelial NO synthase expression (aorta) (P<0.05), both of which were restored in OCR. Nitrotyrosine, a cellular marker of oxidant modification, was markedly elevated in OAL (P<0.05), whereas OCR was similar to Y. Aortic superoxide production was 150% greater in OAL vs. YAL (P<0.05), but normalized in OCR, and TEMPOL, a superoxide dismutase (SOD) mimetic that restored EDD in OAL (to 97±2%), had no effect in Y or OCR. OAL had increased expression and activity of the oxidant enzyme, NADPH oxidase, and its inhibition (apocynin) improved EDD, whereas NADPH oxidase in OCR was similar to Y. Manganese SOD activity and sirtuin1 expression were reduced in OAL (P<0.05), but restored to Y in OCR. Inflammatory cytokines were greater in OAL vs. YAL (P<0.05), but unaffected by CR. Carotid artery endothelium-independent dilation did not differ among groups. Short-term CR initiated in old age reverses age-associated vascular endothelial dysfunction by restoring NO bioavailability and reducing oxidation stress via reduced NADPH oxidase-mediated superoxide production and stimulation of anti-oxidant enzyme activity, and upregulates sirtuin1. PMID:20121721

  20. Reduced diaphyseal strength associated with high intracortical vascular porosity within long bones of children with Osteogenesis Imperfecta

    PubMed Central

    Jameson, John; Smith, Peter; Harris, Gerald

    2015-01-01

    Osteogenesis Imperfecta is a genetic disorder resulting in bone fragility. The mechanisms behind this fragility are not well understood. In addition to characteristic bone mass deficiencies, research suggests that bone material properties are compromised in individuals with this disorder. However, little data exists regarding bone properties beyond the microstructural scale in individuals with this disorder. Specimens were obtained from long bone diaphyses of nine children with osteogenesis imperfecta during routine osteotomy procedures. Small rectangular beams, oriented longitudinally and transversely to the diaphyseal axis, were machined from these specimens and elastic modulus, yield strength, and maximum strength were measured in three-point bending. Intracortical vascular porosity, bone volume fraction, osteocyte lacuna density, and volumetric tissue mineral density were determined by synchrotron micro-computed tomography, and relationships among these mechanical properties and structural parameters were explored. Modulus and strength were on average 64–68% lower in the transverse vs. longitudinal beams (P<0.001, linear mixed model). Vascular porosity ranged between 3–42% of total bone volume. Longitudinal properties were associated negatively with porosity (P≤0.006, linear regressions). Mechanical properties, however, were not associated with osteocyte lacuna density or volumetric tissue mineral density (P≥0.167). Bone properties and structural parameters were not associated significantly with donor age (p≥0.225, linear mixed models). This study presents novel data regarding bone material strength in children with osteogenesis imperfecta. Results confirm that these properties are anisotropic. Elevated vascular porosity was observed in most specimens, and this parameter was associated with reduced bone material strength. These results offer insight towards understanding bone fragility and the role of intracortical porosity on the strength of bone

  1. The soluble guanylyl cyclase inhibitor NS-2028 reduces vascular endothelial growth factor-induced angiogenesis and permeability.

    PubMed

    Morbidelli, Lucia; Pyriochou, Anastasia; Filippi, Sandra; Vasileiadis, Ioannis; Roussos, Charis; Zhou, Zongmin; Loutrari, Heleni; Waltenberger, Johannes; Stössel, Anne; Giannis, Athanassios; Ziche, Marina; Papapetropoulos, Andreas

    2010-03-01

    Nitric oxide (NO) is known to promote vascular endothelial growth factor (VEGF)-stimulated permeability and angiogenesis. However, effector molecules that operate downstream of NO in this pathway remain poorly characterized. Herein, we determined the effect of soluble guanylyl cyclase (sGC) inhibition on VEGF responses in vitro and in vivo. Treatment of endothelial cells (EC) with VEGF stimulated eNOS phosphorylation and cGMP accumulation; pretreatment with the sGC inhibitor 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one (NS-2028) blunted cGMP levels without affecting VEGF-receptor phosphorylation. Incubation of cells with NS-2028 blocked the mitogenic effects of VEGF. In addition, cells in which sGC was inhibited exhibited no migration and sprouting in response to VEGF. To study the mechanisms through which NS-2028 inhibits EC migration, we determined the effects of alterations in cGMP levels on p38 MAPK. Initially, we observed that inhibition of sGC attenuated VEGF-stimulated activation of p38. In contrast, the addition of 8-Br-cGMP to EC stimulated p38 phosphorylation. The addition of cGMP elevating agents (BAY 41-2272, DETA NO and YC-1) enhanced EC migration. To test whether sGC also mediated the angiogenic effects of VEGF in vivo, we used the rabbit cornea assay. Animals receiving NS-2028 orally displayed a reduced angiogenic response to VEGF. As increased vascular permeability occurs prior to new blood vessel formation, we determined the effect of NS-2028 in vascular leakage. Using a modified Miles assay, we observed that NS-2028 attenuated VEGF-induced permeability. Overall, we provide evidence that sGC mediates the angiogenic and permeability-promoting activities of VEGF, indicating the significance of sGC as a downstream effector of VEGF-triggered responses.

  2. Reduced diaphyseal strength associated with high intracortical vascular porosity within long bones of children with osteogenesis imperfecta.

    PubMed

    Albert, Carolyne; Jameson, John; Smith, Peter; Harris, Gerald

    2014-09-01

    Osteogenesis imperfecta is a genetic disorder resulting in bone fragility. The mechanisms behind this fragility are not well understood. In addition to characteristic bone mass deficiencies, research suggests that bone material properties are compromised in individuals with this disorder. However, little data exists regarding bone properties beyond the microstructural scale in individuals with this disorder. Specimens were obtained from long bone diaphyses of nine children with osteogenesis imperfecta during routine osteotomy procedures. Small rectangular beams, oriented longitudinally and transversely to the diaphyseal axis, were machined from these specimens and elastic modulus, yield strength, and maximum strength were measured in three-point bending. Intracortical vascular porosity, bone volume fraction, osteocyte lacuna density, and volumetric tissue mineral density were determined by synchrotron micro-computed tomography, and relationships among these mechanical properties and structural parameters were explored. Modulus and strength were on average 64-68% lower in the transverse vs. longitudinal beams (P<0.001, linear mixed model). Vascular porosity ranged between 3 and 42% of total bone volume. Longitudinal properties were associated negatively with porosity (P≤0.006, linear regressions). Mechanical properties, however, were not associated with osteocyte lacuna density or volumetric tissue mineral density (P≥0.167). Bone properties and structural parameters were not associated significantly with donor age (P≥0.225, linear mixed models). This study presents novel data regarding bone material strength in children with osteogenesis imperfecta. Results confirm that these properties are anisotropic. Elevated vascular porosity was observed in most specimens, and this parameter was associated with reduced bone material strength. These results offer insight toward understanding bone fragility and the role of intracortical porosity on the strength of bone

  3. Low-dose oral sirolimus reduces atherogenesis, vascular inflammation and modulates plaque composition in mice lacking the LDL receptor

    PubMed Central

    Zhao, L; Ding, T; Cyrus, T; Cheng, Y; Tian, H; Ma, M; Falotico, R; Praticò, D

    2009-01-01

    Background and purpose: Chronic proliferative responses of different vascular cell types have been involved in the pathogenesis of atherosclerosis. However, their functional role remains to be established. Sirolimus reduces neointimal proliferation after balloon angioplasty and chronic graft vessel disease. These studies were undertaken to investigate the effects of this anti-proliferative drug on atherogenesis. Experimental approach: Low-density lipoprotein receptor-deficient (LDL r-KO) mice on a cholesterol-rich diet were randomized to receive placebo or sirolimus (0.1; 0.3; or 1 mg·kg−1) in their diet for 8 or 16 weeks. Results: In both studies, plasma levels of the drug increased in a dose-dependent fashion, animals gained weight normally and, among groups, plasma lipids levels did not differ significantly. Compared with placebo, plasma levels of interleukin-6, monocyte chemoattractant protein-1, interferon γ, tumour necrosis factor α and CD40, and their mRNA levels in aortic tissue were significantly reduced in sirolimus-treated mice. This effect resulted in a significant and dose-dependent reduction in atherosclerotic lesions, in both the root and aortic tree. Also these lesions contained less monocyte/macrophages and smooth muscle cells, but more collagen. Conclusions and implications: The present results demonstrated that at low doses, sirolimus was an effective and safe anti-atherogenic agent in the LDL r-KO mice. It attenuated the progression of atherosclerosis and modulated the plaque phenotype by reducing the pro-inflammatory vascular responses typical of the disease. British Journal of Pharmacology (2009) doi:10.1111/j.1476-5381.2008.00080.x PMID:19220291

  4. Renal and vascular glutathione S-transferase mu is not affected by pharmacological intervention to reduce systolic blood pressure.

    PubMed

    Koh-Tan, Han Hui Caline; Graham, Delyth; Hamilton, Carlene A; Nicoll, Gavin; Fields, Laura; McBride, Martin W; Young, Barbara; Dominiczak, Anna F

    2009-08-01

    Our previous studies demonstrated reduced rat glutathione S-transferase mu type 1 (Gstm1) expression in stroke-prone spontaneously hypertensive rats (SHRSPs), when compared with the normotensive Wistar-Kyoto rat. This study investigated the effects of angiotensin II type 1 receptor blocker (ARB) and a diuretic/vasodilator combination on the expression levels of rat Gstm1 and other Gstm isoforms. Antihypertensive treatments of young and mature SHRSPs with an ARB and a diuretic/vasodilator combination improved SBP but did not affect the expression levels of Gstm1. Although Gstm1 is a member of a family of highly homologous genes, with the exception of Gstm2, there was no evidence for compensatory increase in expression of other Gstm isoforms. In contrast, we observed reduced expression of several other Gstm isoforms in untreated SHRSPs. Untreated SHRSPs demonstrated increased renal and vascular oxidative stress, both of which were not significantly affected by the antihypertensive treatments. Untreated SHRSPs scored significantly higher when assessed for renal histopathological damage, and this was improved by antihypertensive treatments. These results suggest that reduced Gstm1 expression in SHRSPs is due to strain-dependent genetic abnormalities, playing a causative role in the development of hypertension, probably through oxidative stress pathway. Renal changes occur as a consequence of increased blood pressure and can be improved when treated with antihypertensive drugs. In silico comparative genome analysis combined with expression studies in rat and human vascular tissue revealed that there are possible four human homologues (GSTM1, GSTM2, GSTM4 and GSTM5) for rat Gstm1.

  5. ACE Inhibitors Potently Reduce Vascular Inflammation, Results of an Open Proof-Of-Concept Study in the Abdominal Aortic Aneurysm

    PubMed Central

    Kortekaas, Kim E.; Meijer, C. Arnoud; Hinnen, Jan Willem; Dalman, Ronald L.; Xu, Baohui; Hamming, Jaap F.; Lindeman, Jan H.

    2014-01-01

    Background Independent of their blood pressure lowering effect, ACE inhibitors are thought to reduce vascular inflammation. The clinical relevance of this effect is unclear with the current knowledge. Abdominal aortic aneurysms (AAA) are characterized by a broad, non-specific inflammatory response, and thus provide a clinical platform to evaluate the anti-inflammatory potential of ACE inhibitors. Methods and Results Eleven patients scheduled for open AAA repair received ramipril (5 mg/day) during 2–4 weeks preceding surgery. Aortic wall samples were collected during surgery, and compared to matched samples obtained from a biobank. An anti-inflammatory potential was evaluated in a comprehensive analysis that included immunohistochemistry, mRNA and protein analysis. A putative effect of ACE inhibitors on AAA growth was tested separately by comparing 18-month growth rate of patients on ACE inhibitors (n = 82) and those not taking ACE inhibitors (n = 204). Ramipril reduces mRNA expression of multiple pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, TNF -α, Interferon-, and MCP-1, as well as aortic wall IL-8 and MCP-1 (P = 0.017 and 0.008, respectively) protein content. The is followed by clear effects on cell activation that included a shift towards anti-inflammatory macrophage (M2) subtype. Evaluation of data from the PHAST cohort did not indicate an effect of ACE inhibitors on 18-month aneurysm progression (mean difference at 18 months: −0.24 mm (95% CI: −0.90–0.45, P = NS). Conclusions ACE inhibition quenches multiple aspects of vascular inflammation in AAA. However, this does not translate into reduced aneurysm growth. Trial Registration Nederlands Trial Register 1345. PMID:25474105

  6. Chronic in vitro shear stress stimulates endothelial cell retention on prosthetic vascular grafts and reduces subsequent in vivo neointimal thickness.

    PubMed

    Dardik, A; Liu, A; Ballermann, B J

    1999-01-01

    . Confluent intimal endothelial cell monolayers also were present 1 week and 3 months after implantation. However, 1 week after implantation, macrophage infiltration was observed beneath the luminal cell monolayer. Three months after the implantation in vivo, subendothelial neointimal cells that contained alpha-smooth muscle actin were present. The thickness of this neointima averaged 41 +/- 12 micrometer and 60 +/- 23 micrometer in endothelial cell-seeded grafts that were pretreated with 25 dyne/cm2 shear stress and 1 dyne/cm2 shear stress, respectively, and 158 +/- 46 micrometer in grafts that were not seeded with endothelial cells. The effect of chronic shear stress on the enhancement of endothelial cell retention in vitro can be exploited to fully endothelialize synthetic vascular grafts, which reduces immediate in vivo graft thrombosis and subsequent neointimal thickness.

  7. Mercury induces proliferation and reduces cell size in vascular smooth muscle cells through MAPK, oxidative stress and cyclooxygenase-2 pathways

    SciTech Connect

    Aguado, Andrea; Galán, María; Zhenyukh, Olha; Wiggers, Giulia A.; Roque, Fernanda R.; Redondo, Santiago; Peçanha, Franck; Martín, Angela; Fortuño, Ana; Cachofeiro, Victoria; Tejerina, Teresa; Salaices, Mercedes; and others

    2013-04-15

    Mercury exposure is known to increase cardiovascular risk but the underlying cellular mechanisms remain undetermined. We analyzed whether chronic exposure to HgCl{sub 2} affects vascular structure and the functional properties of vascular smooth muscle cells (VSMC) through oxidative stress/cyclooxygenase-2 dependent pathways. Mesenteric resistance arteries and aortas from Wistar rats treated with HgCl{sub 2} (first dose 4.6 mg kg{sup −1}, subsequent doses 0.07 mg kg{sup −1} day{sup −1}, 30 days) and cultured aortic VSMC stimulated with HgCl{sub 2} (0.05–5 μg/ml) were used. Treatment of rats with HgCl{sub 2} decreased wall thickness of the resistance and conductance vasculature, increased the number of SMC within the media and decreased SMC nucleus size. In VSMCs, exposure to HgCl{sub 2}: 1) induced a proliferative response and a reduction in cell size; 2) increased superoxide anion production, NADPH oxidase activity, gene and/or protein levels of the NADPH oxidase subunit NOX-1, the EC- and Mn-superoxide dismutases and cyclooxygenase-2 (COX-2); 3) induced activation of ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized the proliferative response and the altered cell size induced by HgCl{sub 2}. Blockade of ERK1/2 and p38 signaling pathways abolished the HgCl{sub 2}-induced Nox1 and COX-2 expression and normalized the alterations induced by mercury in cell proliferation and size. In conclusion, long exposure of VSMC to low doses of mercury activates MAPK signaling pathways that result in activation of inflammatory proteins such as NADPH oxidase and COX-2 that in turn induce proliferation of VSMC and changes in cell size. These findings offer further evidence that mercury might be considered an environmental risk factor for cardiovascular disease. - Highlights: ► Chronic HgCl{sub 2} exposure induces vascular remodeling. ► HgCl{sub 2} induces proliferation and decreased cell size in vascular smooth muscle cells. ► HgCl{sub 2} induces

  8. Fenofibrate Improves Vascular Endothelial Function by Reducing Oxidative Stress While Increasing eNOS in Healthy Normolipidemic Older Adults

    PubMed Central

    Walker, Ashley E; Kaplon, Rachelle E; Lucking, Sara Marian S; Russell-Nowlan, Molly J; Eckel, Robert H; Seals, Douglas R

    2013-01-01

    Vascular endothelial dysfunction develops with aging, as indicated by impaired endothelium-dependent dilation(EDD), and is related to increased cardiovascular disease risk. We hypothesized that short-term treatment with fenofibrate, a lipid-lowering agent with potential pleiotropic effects, would improve EDD in middle-aged and older normolipidemic adults by reducing oxidative stress. Brachial artery flow-mediated dilation (FMD), a measure of EDD, was assessed in 22healthy adults aged 50-77 years before and after 7days of fenofibrate (145 mg/d; n=12/7M) or placebo (n=10/5M). Brachial FMD was unchanged with placebo, but improved after 2 and 7 days of fenofibrate (5.1±0.7 vs. 2d: 6.0±0.7 and 7d: 6.4±0.6 %Δ; both P<0.005). The improvements in FMD after 7 days remained significant (P<0.05) after accounting for modest changes in plasma total and LDL-cholesterol. Endothelium-independent dilation was not affected by fenofibrate or placebo (P>0.05). Infusion (i.v.) of the antioxidant vitamin C improved brachial FMD at baseline in both groups and during placebo treatment (P<0.05), but not after 2 and 7 days of fenofibrate (P>0.05). Fenofibrate treatment also reduced plasma oxidized LDL, a systemic marker of oxidative stress, compared with placebo (P<0.05). In vascular endothelial cells sampled from peripheral veins of the subjects, endothelial nitric oxide synthase (eNOS) protein expression was unchanged with placebo and after 2 days of fenofibrate, but was increased after 7 days of fenofibrate (0.54±0.03 vs. 2d: 0.52±0.04 and 7d: 0.76±0.11 intensity/HUVEC control; P<0.05 7d). Short-term treatment with fenofibrate improves vascular endothelial function in healthy normolipidemic middle-aged/older adults by reducing oxidative stress and induces increases in eNOS. PMID:23108655

  9. Pre-treatment with dexamethasone attenuates experimental ventilator-induced lung injury.

    PubMed

    Reis, Fernando Fonseca Dos; Reboredo, Maycon de Moura; Lucinda, Leda Marília Fonseca; Bianchi, Aydra Mendes Almeida; Rabelo, Maria Aparecida Esteves; Fonseca, Lídia Maria Carneiro da; Oliveira, Júlio César Abreu de; Pinheiro, Bruno Valle

    2016-01-01

    To evaluate the effects that administering dexamethasone before the induction of ventilator-induced lung injury (VILI) has on the temporal evolution of that injury. Wistar rats were allocated to one of three groups: pre-VILI administration of dexamethasone (dexamethasone group); pre-VILI administration of saline (control group); or ventilation only (sham group). The VILI was induced by ventilation at a high tidal volume. Animals in the dexamethasone and control groups were euthanized at 0, 4, 24, and 168 h after VILI induction. We analyzed arterial blood gases, lung edema, cell counts (total and differential) in the BAL fluid, and lung histology. At 0, 4, and 24 h after VILI induction, acute lung injury (ALI) scores were higher in the control group than in the sham group (p < 0.05). Administration of dexamethasone prior to VILI induction decreased the severity of the lung injury. At 4 h and 24 h after induction, the ALI score in the dexamethasone group was not significantly different from that observed for the sham group and was lower than that observed for the control group (p < 0.05). Neutrophil counts in BAL fluid were increased in the control and dexamethasone groups, peaking at 4 h after VILI induction (p < 0.05). However, the neutrophil counts were lower in the dexamethasone group than in the control group at 4 h and 24 h after induction (p < 0.05). Pre-treatment with dexamethasone also prevented the post-induction oxygenation impairment seen in the control group. Administration of dexamethasone prior to VILI induction attenuates the effects of the injury in Wistar rats. The molecular mechanisms of such injury and the possible clinical role of corticosteroids in VILI have yet to be elucidated. Avaliar os efeitos da administração de dexametasona antes da indução de lesão pulmonar induzida por ventilação mecânica (LPIVM) na evolução temporal dessa lesão. Ratos Wistar foram alocados em um dos três grupos: administração de dexametasona pr

  10. RhoA-mediated inhibition of vascular endothelial cell mobility: positive feedback through reduced cytosolic p21 and p27.

    PubMed

    Hsu, Yung-Ho; Chang, Chih-Cheng; Yang, Nian-Jie; Lee, Yi-Hsuan; Juan, Shu-Hui

    2014-10-01

    We previously identified that activation of the aryl hydrocarbon receptor (AhR) by 3-methylcholanthrene (3MC) exerts antiproliferative and antimigratory effects on human umbilical vein endothelial cells (HUVECs) through the upregulation of p21/p27 transcription and RhoA activation. In this study, we investigated the mechanisms of 3MC-mediated downregulation of cytosolic p21/ p27, and the effects of 3MC on RhoA activation and cell migration, in mouse cerebral vascular endothelial cells (MCVECs). Our results indicated that 3MC reduced the phosphorylation of p21/p27 through AhR/RhoA/PTEN-mediated PI3K/Akt inactivation, which reduced cytosolic p21/p27 retention, causing RhoA activation through positive feedback. Downregulation of p21/p27 by siRNA, and cytosolic p21/p27 by the nuclear export blocker leptomycin B, further reduced cell migration in the 3MC-treated cells. Reduced cytosolic p21/p27 expression led to reduced interaction between RhoA and the RhoA inhibitor p190RhoGAP, causing RhoA activation. Treatment with YS-49 activated PI3K/Akt, a downstream target of RhoA, to reduce RhoA/PTEN activation in the 3MC-treated cells, whereas treatment with wortmannin, a PI3K inhibitor, activated RhoA/PTEN. Gain- and loss-of-function analyses revealed that constitutively active (CA) Akt1, but not CA Akt2, inactivated RhoA and stimulated migratory activity. Considering the essential role of RhoA activation in cell migration, we evaluated the potential use of simvastatin, a RhoA inhibitor, as a therapeutic intervention in vivo using matrigel plug formation assays. Our results provide a molecular basis for the therapeutic application of simvastatin to reduce RhoA/PTEN activation, restore cytosolic levels of phosphorylated p21/p27, and induce angiogenic processes.

  11. Vascular stents: Coupling full 3-D with reduced-order structural models

    NASA Astrophysics Data System (ADS)

    Avdeev, I.; Shams, M.

    2010-06-01

    Self-expanding nitinol stents are used to treat peripheral arterial disease. The peripheral arteries are subjected to a combination of mechanical forces such as compression, torsion, bending, and contraction. Most commercially available peripheral self-expanding stents are composed of a series of sub-millimeter V-shaped struts, which are laser-cut from a nitinol tube and surface-treated for better fatigue performance. The numerical stent models must accurately predict location and distribution of local stresses and strains caused by large arterial deformations. Full 3-D finite element non-linear analysis of an entire stent is computationally expensive to the point of being prohibitive, especially for longer stents. Reduced-order models based on beam or shell elements are fairly accurate in capturing global deformations, but are not very helpful in predicting stent failure. We propose a mixed approach that combines the full 3-D model and reduced-order models. Several global-local, full 3-D/reduced-order finite element models of a peripheral self-expanding stent were validated and compared with experimental data. The kinematic constraint method used to couple various elements together was found to be very efficient and easily applicable to commercial FEA codes. The proposed mixed models can be used to accurately predict stent failure based on realistic (patient-specific), non-linear kinematic behavior of peripheral arteries.

  12. Efficacy of zoniporide, an Na/H exchange ion inhibitor, for reducing perioperative cardiovascular events in vascular surgery patients.

    PubMed

    Fleisher, Lee A; Newman, Mark F; St Aubin, Lisa B; Cropp, Anne B; Billing, C Bill; Bonney, Sharon; Mackey, William C; Poldermans, Don; Corbalan, Roman; Pereira, Adamastor H; Coriat, Pierre

    2005-10-01

    To determine whether a novel Na+/H+ exchange ion inhibitor, zoniporide, is associated with reduced perioperative myocardial ischemic injury in high-risk surgery patients. Randomized double-blind placebo-controlled multidose trial. Multicenter worldwide (105 centers) trial. Patients with known or multiple risk factors for coronary artery disease undergoing noncardiac vascular surgery. Four parallel groups received 1 of 3 doses of zoniporide or placebo, delivered as a 60-minute loading dose immediately before surgery, and followed by a continuous intravenous infusion for up to 7 days. A total of 824 subjects were randomized into the study from 105 centers worldwide. Of these, 784 subjects received study drug infusion in the 3-mg/kg/d, 6-mg/kg/d, and 12-mg/kg/d groups and the placebo group, and 769 satisfied the criteria for the primary efficacy analysis population. This is 68% of the planned sample size of 1125 subjects. Anesthetic management and perioperative cardiac medications were at the discretion of the attending anesthesiologists, surgeons, and cardiologists. The proportion of subjects who experienced the composite endpoint event (death, myocardial infarction, congestive heart failure, arrhythmia) by postsurgical day 30 was 18.5% in the 12-mg/kg/d group, compared with 15.7% in the placebo group, resulting in a relative risk (RR) of 1.17% (95% confidence interval [CI], 0.80-1.72; p = NS) favoring placebo. The proportions in the lower 2 zoniporide dose groups were slightly lower than in the placebo group, although the sample size is inadequate to reach any firm conclusions. The results fail to demonstrate the efficacy of zoniporide in reducing the proportion of patients at high risk undergoing noncardiac vascular surgery who experience a composite cardiovascular endpoint, which led the corporate sponsor to stop enrollment early on the basis of a futility analysis of the chance of demonstrating efficacy with a larger sample size.

  13. Apolipoprotein A-I gene transfer exerts immunomodulatory effects and reduces vascular inflammation and fibrosis in ob/ob mice.

    PubMed

    Spillmann, Frank; De Geest, Bart; Muthuramu, Ilayaraja; Amin, Ruhul; Miteva, Kapka; Pieske, Burkert; Tschöpe, Carsten; Van Linthout, Sophie

    2016-01-01

    Obesity is associated with vascular inflammation, fibrosis and reduced high-density lipoproteins (HDL)-cholesterol. We aimed to investigate whether adenoviral gene transfer with human apolipoprotein (apo) A-I (Ad.A-I), the main apo of HDL, could exert immunomodulatory effects and counteract vascular inflammation and fibrosis in ob/ob mice. Ad.A-I transfer was performed in 8 weeks (w) old ob/ob mice, which were sacrificed 7 w later. The aorta was excised for mRNA analysis and the spleen for splenocyte isolation for subsequent flow cytometry and co-culture with murine fibroblasts. HDL was added to mononuclear cells (MNC) and fibroblasts to assess their impact on adhesion capacity and collagen deposition, respectively. Ad.A-I led to a 1.8-fold (p < 0.05) increase in HDL-cholesterol versus control ob/ob mice at the day of sacrifice, which was paralleled by a decrease in aortic TNF-α and VCAM-1 mRNA expression. Pre-culture of MNC with HDL decreased their adhesion to TNF-α-activated HAEC. Ad.A-I exerted immunomodulatory effects as evidenced by a downregulation of aortic NOD2 and NLRP3 mRNA expression and by a 12 %, 6.9 %, and 15 % decrease of the induced proliferation/activity of total splenic MNC, CD4+, and CD8+ cells in ob/ob Ad.A-I versus control ob/ob mice, respectively (p < 0.05). Ad.A-I further reduced aortic collagen I and III mRNA expression by 62 % and 66 %, respectively (p < 0.0005), and abrogated the potential of ob/ob splenocytes to induce the collagen content in murine fibroblasts upon co-culture. Finally, HDL decreased the TGF-ß1-induced collagen deposition of murine fibroblasts in vitro. Apo A-I transfer counteracts vascular inflammation and fibrosis in ob/ob mice.

  14. Deficiency of endothelial CXCR4 reduces reendothelialization and enhances neointimal hyperplasia after vascular injury in atherosclerosis-prone mice.

    PubMed

    Noels, Heidi; Zhou, Baixue; Tilstam, Pathricia V; Theelen, Wendy; Li, Xiaofeng; Pawig, Lukas; Schmitz, Corinna; Akhtar, Shamima; Simsekyilmaz, Sakine; Shagdarsuren, Erdenechimeg; Schober, Andreas; Adams, Ralf H; Bernhagen, Jürgen; Liehn, Elisa A; Döring, Yvonne; Weber, Christian

    2014-06-01

    The Cxcl12/Cxcr4 chemokine ligand/receptor axis mediates the mobilization of smooth muscle cell progenitors, driving injury-induced neointimal hyperplasia. This study aimed to investigate the role of endothelial Cxcr4 in neointima formation. β-Galactosidase staining using bone marrow x kinase (Bmx)-CreER(T2) reporter mice and double immunofluorescence revealed an efficient and endothelial-specific deletion of Cxcr4 in Bmx-CreER(T2+) compared with Bmx-CreER(T2-) Cxcr4-floxed apolipoprotein E-deficient (Apoe(-/-)) mice (referred to as Cxcr4(EC-KO)ApoE(-/-) and Cxcr4(EC-WT) ApoE(-/-), respectively). Endothelial Cxcr4 deficiency significantly increased wire injury-induced neointima formation in carotid arteries from Cxcr4(EC-KO)ApoE(-/-) mice. The lesions displayed a higher number of macrophages, whereas the smooth muscle cell and collagen content were reduced. This was associated with a significant reduction in reendothelialization and endothelial cell proliferation in injured Cxcr4(EC-KO)ApoE(-/-) carotids compared with Cxcr4(EC-WT)ApoE(-/-) controls. Furthermore, stimulation of human aortic endothelial cells with chemokine (C-X-C motif) ligand 12 (CXCL12) significantly enhanced their wound-healing capacity in an in vitro scratch assay, an effect that could be reversed with the CXCR4 antagonist AMD3100. Also, flow cytometric analysis showed a reduced mobilization of Sca1(+)Flk1(+)Cd31(+) and of Lin(-)Sca1(+) progenitors in Cxcr4(EC-KO) ApoE(-/-) mice after vascular injury, although Cxcr4 surface expression was unaltered. No differences could be detected in plasma concentrations of Cxcl12, vascular endothelial growth factor, sphingosine 1-phosphate, or Flt3 (fms-related tyrosine kinase 3) ligand, all cytokines with an established role in progenitor cell mobilization. Nonetheless, double immunofluorescence revealed a significant reduction in local endothelial Cxcl12 staining in injured carotids from Cxcr4(EC-KO)ApoE(-/-) mice. Endothelial Cxcr4 is crucial for

  15. Kallistatin reduces vascular senescence and aging by regulating microRNA-34a-SIRT1 pathway.

    PubMed

    Guo, Youming; Li, Pengfei; Gao, Lin; Zhang, Jingmei; Yang, Zhirong; Bledsoe, Grant; Chang, Eugene; Chao, Lee; Chao, Julie

    2017-08-01

    Kallistatin, an endogenous protein, protects against vascular injury by inhibiting oxidative stress and inflammation in hypertensive rats and enhancing the mobility and function of endothelial progenitor cells (EPCs). We aimed to determine the role and mechanism of kallistatin in vascular senescence and aging using cultured EPCs, streptozotocin (STZ)-induced diabetic mice, and Caenorhabditis elegans (C. elegans). Human kallistatin significantly decreased TNF-α-induced cellular senescence in EPCs, as indicated by reduced senescence-associated β-galactosidase activity and plasminogen activator inhibitor-1 expression, and elevated telomerase activity. Kallistatin blocked TNF-α-induced superoxide levels, NADPH oxidase activity, and microRNA-21 (miR-21) and p16(INK)(4a) synthesis. Kallistatin prevented TNF-α-mediated inhibition of SIRT1, eNOS, and catalase, and directly stimulated the expression of these antioxidant enzymes. Moreover, kallistatin inhibited miR-34a synthesis, whereas miR-34a overexpression abolished kallistatin-induced antioxidant gene expression and antisenescence activity. Kallistatin via its active site inhibited miR-34a, and stimulated SIRT1 and eNOS synthesis in EPCs, which was abolished by genistein, indicating an event mediated by tyrosine kinase. Moreover, kallistatin administration attenuated STZ-induced aortic senescence, oxidative stress, and miR-34a and miR-21 synthesis, and increased SIRT1, eNOS, and catalase levels in diabetic mice. Furthermore, kallistatin treatment reduced superoxide formation and prolonged wild-type C. elegans lifespan under oxidative or heat stress, although kallistatin's protective effect was abolished in miR-34 or sir-2.1 (SIRT1 homolog) mutant C. elegans. Kallistatin inhibited miR-34, but stimulated sir-2.1 and sod-3 synthesis in C. elegans. These in vitro and in vivo studies provide significant insights into the role and mechanism of kallistatin in vascular senescence and aging by regulating miR-34a-SIRT1

  16. Doxycycline, a matrix metalloprotease inhibitor, reduces vascular remodeling and damage after cerebral ischemia in stroke-prone spontaneously hypertensive rats.

    PubMed

    Pires, Paulo W; Rogers, Curt T; McClain, Jonathon L; Garver, Hannah S; Fink, Gregory D; Dorrance, Anne M

    2011-07-01

    Matrix metalloproteases (MMPs) are a family of zinc peptidases involved in extracellular matrix turnover. There is evidence that increased MMP activity is involved in remodeling of resistance vessels in chronic hypertension. Thus we hypothesized that inhibition of MMP activity with doxycycline (DOX) would attenuate vascular remodeling. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with DOX (50 mg·kg(-1)·day(-1) in the drinking water) for 6 wk. Untreated SHRSP were controls. Blood pressure was measured by telemetry during the last week. Middle cerebral artery (MCA) and mesenteric resistance artery (MRA) passive structures were assessed by pressure myography. MMP-2 expression in aortas was measured by Western blot. All results are means ± SE. DOX caused a small increase in mean arterial pressure (SHRSP, 154 ± 1; SHRSP + DOX, 159 ± 3 mmHg; P < 0.001). Active MMP-2 expression was reduced in aorta from SHRSP + DOX (0.21 ± 0.06 vs. 0.49 ± 0.13 arbitrary units; P < 0.05). In the MCA, at 80 mmHg, DOX treatment increased the lumen (273.2 ± 4.7 vs. 238.3 ± 6.3 μm; P < 0.05) and the outer diameter (321 ± 5.3 vs. 290 ± 7.6 μm; P < 0.05) and reduced the wall-to-lumen ratio (0.09 ± 0.002 vs. 0.11 ± 0.003; P < 0.05). Damage after transient cerebral ischemia (transient MCA occlusion) was reduced in SHRSP + DOX (20.7 ± 4 vs. 45.5 ± 5% of hemisphere infarcted; P < 0.05). In the MRA, at 90 mmHg DOX, reduced wall thickness (29 ± 1 vs. 22 ± 1 μm; P < 0.001) and wall-to-lumen ratio (0.08 ± 0.004 vs. 0.11 ± 0.008; P < 0.05) without changing lumen diameter. These results suggest that MMPs are involved in hypertensive vascular remodeling in both the peripheral and cerebral vasculature and that DOX reduced brain damage after cerebral ischemia.

  17. Increasing inspiratory time exacerbates ventilator-induced lung injury during high-pressure/high-volume mechanical ventilation.

    PubMed

    Casetti, Alfredo V; Bartlett, Robert H; Hirschl, Ronald B

    2002-10-01

    Ventilator-induced lung injury may be caused by overdistension of alveoli during high-pressure ventilation. In this study, we examined the effects of increasing inspiratory time on ventilator-induced lung injury. Sprague-Dawley rats were divided into four different groups with ten animals per group. Each group was then ventilated for 30 mins with one of four ventilator strategies. All groups were ventilated with an Fio2 of 1.0 and a positive end-expiratory pressure of 0 cm H2O. Group LoP was the negative control group and was ventilated with low pressures (peak inspiratory pressure = 12 cm H2O, rate = 30, and inspiratory time = 0.5 secs). Groups iT = 0.5, iT = 1.0, and iT = 1.5 were the experimental groups and were ventilated with high pressures (peak inspiratory pressure = 45 cm H2O, rate = 10, and inspiratory times = 0.5 secs, iT = 1.0 sec, and iT = 1.5 secs, respectively). Outcome measures included lung compliance, Pao /Fio ratio, wet/dry lung weight, and dry lung/body weight. Final static lung compliance (p =.0002) and Pao2/Fio2 (p =.001) decreased as inspiratory time increased. Wet/dry lung weights (p <.0001) and dry lung/body weights (p <.0001) increased as inspiratory time increased. Light microscopy revealed evidence of intra-alveolar edema and hemorrhage in the iT = 1.0 and iT = 1.5 animals but not the LoP and iT = 0.5 animals. Increasing inspiratory time during high-pressure/high-volume mechanical ventilation is associated with an increase in variables of lung injury.

  18. Mechanical ventilation modulates TLR4 and IRAK-3 in a non-infectious, ventilator-induced lung injury model.

    PubMed

    Villar, Jesús; Cabrera, Nuria E; Casula, Milena; Flores, Carlos; Valladares, Francisco; Díaz-Flores, Lucio; Muros, Mercedes; Slutsky, Arthur S; Kacmarek, Robert M

    2010-03-03

    Previous experimental studies have shown that injurious mechanical ventilation has a direct effect on pulmonary and systemic immune responses. How these responses are propagated or attenuated is a matter of speculation. The goal of this study was to determine the contribution of mechanical ventilation in the regulation of Toll-like receptor (TLR) signaling and interleukin-1 receptor associated kinase-3 (IRAK-3) during experimental ventilator-induced lung injury. Prospective, randomized, controlled animal study using male, healthy adults Sprague-Dawley rats weighing 300-350 g. Animals were anesthetized and randomized to spontaneous breathing and to two different mechanical ventilation strategies for 4 hours: high tidal volume (VT) (20 ml/kg) and low VT (6 ml/kg). Histological evaluation, TLR2, TLR4, IRAK3 gene expression, IRAK-3 protein levels, inhibitory kappa B alpha (IkappaBalpha), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL6) gene expression in the lungs and TNF-alpha and IL-6 protein serum concentrations were analyzed. High VT mechanical ventilation for 4 hours was associated with a significant increase of TLR4 but not TLR2, a significant decrease of IRAK3 lung gene expression and protein levels, a significant decrease of IkappaBalpha, and a higher lung expression and serum concentrations of pro-inflammatory cytokines. The current study supports an interaction between TLR4 and IRAK-3 signaling pathway for the over-expression and release of pro-inflammatory cytokines during ventilator-induced lung injury. Our study also suggests that injurious mechanical ventilation may elicit an immune response that is similar to that observed during infections.

  19. Mesenchymal stromal cells are more effective than the MSC secretome in diminishing injury and enhancing recovery following ventilator-induced lung injury.

    PubMed

    Hayes, Mairead; Curley, Gerard F; Masterson, Claire; Devaney, James; O'Toole, Daniel; Laffey, John G

    2015-12-01

    The potential for mesenchymal stem cells (MSCs) to reduce the severity of experimental lung injury has been established in several pre-clinical studies. We have recently demonstrated that MSCs, and MSC-secreted factors (secretome), enhance lung repair and regeneration at 48 h following ventilation-induced lung injury (VILI). We wished to determine the potential for MSC therapy to exert beneficial effects in the early recovery phase following VILI when ongoing injury coexists with processes of repair, and to compare the efficacy of MSC therapy to the use of the secretome alone. Male Sprague-Dawley rats were anesthetized, oro-tracheally intubated, and subjected to high stretch mechanical ventilation until lung compliance had declined by 50 % of baseline. Animals were then weaned from mechanical ventilation, and anesthesia discontinued. Once awake and spontaneously ventilating, animals received an intravenous injection of either rodent MSCs (10 million/kg), MSC-conditioned medium, fibroblasts (10 million/kg), or vehicle. Thereafter, the animals were allowed to recover and the extent of lung injury/repair was determined after 4 h. Treatment with MSCs diminished injury and enhanced recovery following VILI to a greater extent compared to MSC-conditioned medium, with fibroblasts proving ineffective. MSCs, but not their conditioned medium, attenuated indices of lung injury including oxygenation, respiratory compliance, and lung edema. Total lung water as assessed by wet:dry ratio, bronchoalveolar lavage total inflammatory cell, neutrophil counts, and alveolar IL-6 concentrations were reduced in the animals that received MSC therapy. The immunomodulating and/or reparative effect of MSCs is evident early after VILI in this model. MSC-conditioned medium was not as effective as the cells themselves in diminishing injury and restoring lung structure and function.

  20. Chronotherapy improves blood pressure control and reduces vascular risk in CKD.

    PubMed

    Hermida, Ramón C; Ayala, Diana E; Smolensky, Michael H; Mojón, Artemio; Fernández, José R; Crespo, Juan J; Moyá, Ana; Ríos, María T; Portaluppi, Francesco

    2013-06-01

    In patients with chronic kidney disease (CKD), the prevalence of increased blood pressure during sleep and blunted sleep-time-relative blood pressure decline (a nondipper pattern) is very high and increases substantially with disease severity. Elevated blood pressure during sleep is the major criterion for the diagnoses of hypertension and inadequate therapeutic ambulatory blood pressure control in these patients. Substantial, clinically meaningful ingestion-time-dependent differences in the safety, efficacy, duration of action and/or effects on the 24 h blood pressure pattern of six different classes of hypertension medications and their combinations have been substantiated. For example, bedtime ingestion of angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers is more effective than morning ingestion in reducing blood pressure during sleep and converting the 24 h blood pressure profile into a dipper pattern. We have identified a progressive reduction in blood pressure during sleep--a novel therapeutic target best achieved by ingestion of one or more hypertension medications at bedtime--as the most significant predictor of decreased cardiovascular risk in patients with and without CKD. Recent findings suggest that in patients with CKD, ambulatory blood pressure monitoring should be used for the diagnosis of hypertension and assessment of cardiovascular disease risk, and that therapeutic strategies given at bedtime rather than on awakening are preferable for the management of hypertension.

  1. Reducing the risk of infection associated with vascular access devices through nanotechnology: a perspective

    PubMed Central

    Zhang, Li; Keogh, Samantha; Rickard, Claire M

    2013-01-01

    Intravascular catheter-related infections are still a major problem in health care and are associated with significant morbidity, mortality, and additional cost. The formation of microbial biofilm on catheters makes these infections particularly complicated, as microbial cells that detach from the biofilm can lead to infection, and because these microorganisms are highly resistant to many antimicrobial agents; thus, catheter removal is often required to successfully treat infection. To reduce the risks of catheter-related infections, many strategies have been applied, such as improvements in aseptic insertion and post-insertion care practices, implantation techniques, and antibiotic coated or impregnated materials. However, despite significant advances in using these methods, it has not been possible to completely eradicate biofilm infections. Currently, nanotechnology approaches seem to be among the most promising for preventing biofilm formation and resultant catheter-related bloodstream infection (especially with multi-resistant bacterial strains). In this review, current knowledge about catheter technology and design, the mechanisms of catheter-related bloodstream infection, and the insertion and care practices performed by medical staff, are discussed, along with novel, achievable approaches to infection prevention, based on nanotechnology. PMID:24293997

  2. Natural antioxidant ice cream acutely reduces oxidative stress and improves vascular function and physical performance in healthy individuals.

    PubMed

    Sanguigni, Valerio; Manco, Melania; Sorge, Roberto; Gnessi, Lucio; Francomano, Davide

    2017-01-01

    The formation of reactive oxygen species (ROS) contributes to the pathogenesis and progression of several diseases. Polyphenols have been shown to be beneficial against ROS. The aim of this study was to evaluate the effects of a natural antioxidant ice cream on oxidative stress, vascular function, and physical performance. In this controlled, single-blind, crossover study, 14 healthy individuals were randomized to consume 100 g of either antioxidant ice cream containing dark cocoa powder and hazelnut and green tea extracts or milk chocolate ice cream (control ice cream). Participants were studied at baseline and 2 h after ingesting ice cream. Serum polyphenols, antioxidant status (ferric-reducing ability of plasma [FRAP]), nitric oxide (NOx) bioavailability, markers of oxidative stress (determination of reactive oxygen metabolites [d-ROMs] and hydrogen peroxide [H2O2]), endothelium function (flow-mediated dilation [FMD] and reactive hyperemia index [RHI]), and exercise tolerance (stress test) were assessed, and the double product was measured. Serum polyphenols (P < 0.001), NOx (P < 0.001), FRAP (P < 0.005), FMD (P < 0.001), and RHI (P < 0.05) increased significantly, oxidative stress decreased (d-Roms, P < 0.001; H2O2, P < 0.001), and the double product (P < 0.001) was improved only after antioxidant ice cream ingestion. No changes were found after control ice cream ingestion. To our knowledge, this is the first study to demonstrate that a natural ice cream rich in polyphenols acutely improved vascular function and physical performance in healthy individuals through a reduction in oxidative stress. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Reduced cerebral oxygen-carbohydrate index during endotracheal intubation in vascular surgical patients.

    PubMed

    Fabricius-Bjerre, Andreas; Overgaard, Anders; Winther-Olesen, Marie; Lönn, Lars; Secher, Niels H; Nielsen, Henning B

    2015-09-01

    Brain activation reduces balance between cerebral consumption of oxygen versus carbohydrate as expressed by the so-called cerebral oxygen-carbohydrate-index (OCI). We evaluated whether preparation for surgery, anaesthesia including tracheal intubation and surgery affect OCI. In patients undergoing aortic surgery, arterial to internal jugular venous (a-v) concentration differences for oxygen versus lactate and glucose were determined from before anaesthesia to when the patient left the recovery room. Intravenous anaesthesia was supplemented with thoracic epidural anaesthesia for open aortic surgery (n = 5) and infiltration with bupivacaine for endovascular procedures (n = 14). The a-v difference for O2 decreased throughout anaesthesia and in the recovery room (1.6 ± 1.9 versus 3.2 ± 0.8 mmol l(-1), mean ± SD), and while a-v glucose decreased during surgery and into the recovery (0.4 ± 0.2 versus 0.7 ± 0.2 mmol l(-1) , P<0.05), a-v lactate did not change significantly (0.03 ± 0.16 versus -0.03 ± 0.09 mmol l(-1)). Thus, OCI decreased from 5.2 ± 1.8 before induction of anaesthesia to 3.2 ± 1.0 following tracheal intubation (P<0.05) because of the decrease in a-v O2 with a recovery for OCI to 4.6 ± 1.4 during surgery and to 5.6 ± 1.7 in the recovery room. In conclusion, preparation for surgery and tracheal intubation decrease OCI that recovers during surgery under the influence of sensory blockade. © 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.

  4. FT011, a Novel Cardiorenal Protective Drug, Reduces Inflammation, Gliosis and Vascular Injury in Rats with Diabetic Retinopathy

    PubMed Central

    Deliyanti, Devy; Zhang, Yuan; Khong, Fay; Berka, David R.; Stapleton, David I.; Kelly, Darren J.; Wilkinson-Berka, Jennifer L.

    2015-01-01

    Diabetic retinopathy features inflammation as well as injury to glial cells and the microvasculature, which are influenced by hypertension and overactivity of the renin-angiotensin system. FT011 is an anti-inflammatory and anti-fibrotic agent that has been reported to attenuate organ damage in diabetic rats with cardiomyopathy and nephropathy. However, the potential therapeutic utility of FT011 for diabetic retinopathy has not been evaluated. We hypothesized that FT011 would attenuate retinopathy in diabetic Ren-2 rats, which exhibit hypertension due to an overactive extra-renal renin-angiotensin system. Diabetic rats were studied for 8 and 32 weeks and received intravitreal injections of FT011 (50 μM) or vehicle (0.9% NaCl). Comparisons were to age-matched controls. In the 8-week study, retinal inflammation was examined by quantitating vascular leukocyte adherence, microglial/macrophage density and the expression of inflammatory mediators. Macroglial Müller cells, which exhibit a pro-inflammatory and pro-angiogenic phenotype in diabetes, were evaluated in the 8-week study as well as in culture following exposure to hyperglycaemia and FT011 (10, 30, 100 μM) for 72 hours. In the 32-week study, severe retinal vasculopathy was examined by quantitating acellular capillaries and extracellular matrix proteins. In diabetic rats, FT011 reduced retinal leukostasis, microglial density and mRNA levels of intercellular adhesion molecule-1 (ICAM-1). In Müller cells, FT011 reduced diabetes-induced gliosis and vascular endothelial growth factor (VEGF) immunolabeling and the hyperglycaemic-induced increase in ICAM-1, monocyte chemoattractant protein-1, CCL20, cytokine-induced neutrophil chemoattractant-1, VEGF and IL-6. Late intervention with FT011 reduced acellular capillaries and the elevated mRNA levels of collagen IV and fibronectin in diabetic rats. In conclusion, the protective effects of FT011 in cardiorenal disease extend to key elements of diabetic retinopathy and

  5. Cotinine reduces depressive-like behavior and hippocampal vascular endothelial growth factor downregulation after forced swim stress in mice.

    PubMed

    Grizzell, J Alex; Mullins, Michelle; Iarkov, Alexandre; Rohani, Adeeb; Charry, Laura C; Echeverria, Valentina

    2014-12-01

    Cotinine, the predominant metabolite of nicotine, appears to act as an antidepressant. We have previously shown that cotinine reduced immobile postures in Porsolt's forced swim (FS) and tail suspension tests while preserving the synaptic density in the hippocampus as well as prefrontal and entorhinal cortices of mice subjected to chronic restraint stress. In this study, we investigated the effect of daily oral cotinine (5 mg/kg) on depressive-like behavior induced by repeated, FS stress for 6 consecutive days in adult, male C57BL/6J mice. The results support our previous report that cotinine administration reduces depressive-like behavior in mice subjected or not to high salience stress. In addition, cotinine enhanced the expression of the vascular endothelial growth factor (VEGF) in the hippocampus of mice subjected to repetitive FS stress. Altogether, the results suggest that cotinine may be an effective antidepressant positively influencing mood through a mechanism involving the preservation of brain homeostasis and the expression of critical growth factors such as VEGF. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

  6. Activation of the Wnt/β-Catenin Signaling Pathway by Mechanical Ventilation Is Associated with Ventilator-Induced Pulmonary Fibrosis in Healthy Lungs

    PubMed Central

    Valladares, Francisco; Casula, Milena; Flores, Carlos; Blanch, Lluís; Quilez, María Elisa; Santana-Rodríguez, Norberto; Kacmarek, Robert M.; Slutsky, Arthur S.

    2011-01-01

    Background Mechanical ventilation (MV) with high tidal volumes (VT) can cause or aggravate lung damage, so-called ventilator induced lung injury (VILI). The relationship between specific mechanical events in the lung and the cellular responses that result in VILI remains incomplete. Since activation of Wnt/β-catenin signaling has been suggested to be central to mechanisms of lung healing and fibrosis, we hypothesized that the Wnt/β-catenin signaling plays a role during VILI. Methodology/Principal Findings Prospective, randomized, controlled animal study using adult, healthy, male Sprague-Dawley rats. Animals (n = 6/group) were randomized to spontaneous breathing or two strategies of MV for 4 hours: low tidal volume (VT) (6 mL/kg) or high VT (20 mL/kg). Histological evaluation of lung tissue, measurements of WNT5A, total β-catenin, non-phospho (Ser33/37/Thr41) β-catenin, matrix metalloproteinase-7 (MMP-7), cyclin D1, vascular endothelial growth factor (VEGF), and axis inhibition protein 2 (AXIN2) protein levels by Western blot, and WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, and AXIN2 immunohistochemical localization in the lungs were analyzed. High-VT MV caused lung inflammation and perivascular edema with cellular infiltrates and collagen deposition. Protein levels of WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, cyclin D1, VEGF, and AXIN2 in the lungs were increased in all ventilated animals although high-VT MV was associated with significantly higher levels of WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, cyclin D1, VEGF, and AXIN2 levels. Conclusions/Significance Our findings demonstrate that the Wnt/β-catenin signaling pathway is modulated very early by MV in lungs without preexistent lung disease, suggesting that activation of this pathway could play an important role in both VILI and lung repair. Modulation of this pathway might represent a therapeutic option for prevention and/or management of VILI. PMID:21935365

  7. Activation of the Wnt/β-catenin signaling pathway by mechanical ventilation is associated with ventilator-induced pulmonary fibrosis in healthy lungs.

    PubMed

    Villar, Jesús; Cabrera, Nuria E; Valladares, Francisco; Casula, Milena; Flores, Carlos; Blanch, Lluís; Quilez, María Elisa; Santana-Rodríguez, Norberto; Kacmarek, Robert M; Slutsky, Arthur S

    2011-01-01

    Mechanical ventilation (MV) with high tidal volumes (V(T)) can cause or aggravate lung damage, so-called ventilator induced lung injury (VILI). The relationship between specific mechanical events in the lung and the cellular responses that result in VILI remains incomplete. Since activation of Wnt/β-catenin signaling has been suggested to be central to mechanisms of lung healing and fibrosis, we hypothesized that the Wnt/β-catenin signaling plays a role during VILI. Prospective, randomized, controlled animal study using adult, healthy, male Sprague-Dawley rats. Animals (n = 6/group) were randomized to spontaneous breathing or two strategies of MV for 4 hours: low tidal volume (V(T)) (6 mL/kg) or high V(T) (20 mL/kg). Histological evaluation of lung tissue, measurements of WNT5A, total β-catenin, non-phospho (Ser33/37/Thr41) β-catenin, matrix metalloproteinase-7 (MMP-7), cyclin D1, vascular endothelial growth factor (VEGF), and axis inhibition protein 2 (AXIN2) protein levels by Western blot, and WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, and AXIN2 immunohistochemical localization in the lungs were analyzed. High-V(T) MV caused lung inflammation and perivascular edema with cellular infiltrates and collagen deposition. Protein levels of WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, cyclin D1, VEGF, and AXIN2 in the lungs were increased in all ventilated animals although high-V(T) MV was associated with significantly higher levels of WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, cyclin D1, VEGF, and AXIN2 levels. Our findings demonstrate that the Wnt/β-catenin signaling pathway is modulated very early by MV in lungs without preexistent lung disease, suggesting that activation of this pathway could play an important role in both VILI and lung repair. Modulation of this pathway might represent a therapeutic option for prevention and/or management of VILI.

  8. Rosuvastatin reduces vascular inflammation and T cell and monocyte activation in HIV-infected subjects on antiretroviral therapy

    PubMed Central

    Funderburg, Nicholas T.; Jiang, Ying; Debanne, Sara M.; Labbato, Danielle; Juchnowski, Steven; Ferrari, Brian; Clagett, Brian; Robinson, Janet; Lederman, Michael M.; McComsey, Grace A.

    2014-01-01

    Background Despite suppressive antiretroviral therapy (ART), increased levels of immune activation persist in HIV-infected subjects. Statins have anti-inflammatory effects and may reduce immune activation in HIV disease. Methods SATURN-HIV is a randomized, double-blind, placebo-controlled trial assessing the effect of rosuvastatin (10mg/daily) on markers of cardiovascular risk and immune activation in ART-treated patients. T cell activation was measured by expression of CD38, HLA-DR, and PD1. Monocyte activation was measured with soluble markers (sCD14 and sCD163) and by enumeration of monocyte subpopulations and tissue factor (TF) expression. Markers of systemic and vascular inflammation and coagulation were also measured. SATURN-HIV is registered on clinicaltrials.gov, Identifier: NCT01218802 Results Rosuvastatin, compared to placebo, reduced sCD14 (−10.4% vs 0.5%p=0.006), Lp-PLA2 (−12.2% vs −1.7% p=0.0007), and IP-10 (−27.5 vs −8.2%, p=0.03) levels after 48 weeks. The proportion of TF+ patrolling (CD14DimCD16+) monocytes was also reduced by rosuvastatin (−41.6%) compared to the placebo (−18.8%, p=0.005). There was also a greater decrease in the proportions of activated (CD38+HLA-DR+) T cells between the arms (−38.1% vs −17.8%, p=0.009 for CD4+ cells and −44.8% vs −27.4%, p=0.003 for CD8+ cells). Conclusions 48 weeks of rosuvastatin treatment reduced significantly several markers of inflammation and lymphocyte and monocyte activation in ART-treated subjects. PMID:25514794

  9. Resveratrol Increases Serum BDNF Concentrations and Reduces Vascular Smooth Muscle Cells Contractility via a NOS-3-Independent Mechanism

    PubMed Central

    Malinowski, Bartosz; Grześk, Elżbieta; Grześk, Grzegorz

    2017-01-01

    Resveratrol is a polyphenol that presents both antineuroinflammatory properties and the ability to interact with NOS-3, what contributes to vasorelaxation. Brain-derived neurotrophic factor (BNDF), a molecule associated with neuroprotection in many neurodegenerative disorders, is considered as an important element of maintaining stable cerebral blood flow. Vascular smooth muscle cells (VSMCs) are considered to be an important element in the pathogenesis of neurodegeneration and a potential preventative target by agents which reduce the contractility of the vessels. Our main objectives were to define the relationship between serum and long-term oral resveratrol administration in the rat model, as well as to assess the effect of resveratrol on phenylephrine- (PHE-) induced contraction of vascular smooth muscle cells (VSMCs). Moreover, we attempt to define the dependence of contraction mechanisms on endothelial NO synthase. Experiments were performed on Wistar rats (n = 17) pretreated with resveratrol (4 weeks; 10 mg/kg p.o.) or placebo. Serum BDNF levels were quantified after 2 and 4 weeks of treatment with ELISA. Contraction force was measured on isolated and perfused tail arteries as the increase of perfusion pressure with a constant flow. Values of serum BNDF in week 0 were 1.18 ± 0.12 ng/mL (treated) and 1.17 ± 0.13 ng/mL (control) (p = ns). After 2 weeks of treatment, BDNF in the treatment group was higher than in controls, 1.52 ± 0.23 ng/mL and 1.24 ± 0.13 ng/mL, respectively. (p = 0.02) Following 4 weeks of treatment, BDNF values were higher in the resveratrol group compared to control 1.64 ± 0.31 ng/mL and 1.32 ± 0.26 ng/mL, respectively (p = 0.031). EC50 values obtained for PHE in resveratrol pretreated arteries were significantly higher than controls (5.33 ± 1.7 × 10−7 M/L versus 4.53 ± 1.2 × 10−8 M/L, p < 0.05). These results show a significant increase in BDNF concentration in the resveratrol pretreated group. The

  10. Resveratrol Increases Serum BDNF Concentrations and Reduces Vascular Smooth Muscle Cells Contractility via a NOS-3-Independent Mechanism.

    PubMed

    Wiciński, Michał; Malinowski, Bartosz; Węclewicz, Mateusz M; Grześk, Elżbieta; Grześk, Grzegorz

    2017-01-01

    Resveratrol is a polyphenol that presents both antineuroinflammatory properties and the ability to interact with NOS-3, what contributes to vasorelaxation. Brain-derived neurotrophic factor (BNDF), a molecule associated with neuroprotection in many neurodegenerative disorders, is considered as an important element of maintaining stable cerebral blood flow. Vascular smooth muscle cells (VSMCs) are considered to be an important element in the pathogenesis of neurodegeneration and a potential preventative target by agents which reduce the contractility of the vessels. Our main objectives were to define the relationship between serum and long-term oral resveratrol administration in the rat model, as well as to assess the effect of resveratrol on phenylephrine- (PHE-) induced contraction of vascular smooth muscle cells (VSMCs). Moreover, we attempt to define the dependence of contraction mechanisms on endothelial NO synthase. Experiments were performed on Wistar rats (n = 17) pretreated with resveratrol (4 weeks; 10 mg/kg p.o.) or placebo. Serum BDNF levels were quantified after 2 and 4 weeks of treatment with ELISA. Contraction force was measured on isolated and perfused tail arteries as the increase of perfusion pressure with a constant flow. Values of serum BNDF in week 0 were 1.18 ± 0.12 ng/mL (treated) and 1.17 ± 0.13 ng/mL (control) (p = ns). After 2 weeks of treatment, BDNF in the treatment group was higher than in controls, 1.52 ± 0.23 ng/mL and 1.24 ± 0.13 ng/mL, respectively. (p = 0.02) Following 4 weeks of treatment, BDNF values were higher in the resveratrol group compared to control 1.64 ± 0.31 ng/mL and 1.32 ± 0.26 ng/mL, respectively (p = 0.031). EC50 values obtained for PHE in resveratrol pretreated arteries were significantly higher than controls (5.33 ± 1.7 × 10(-7 )M/L versus 4.53 ± 1.2 × 10(-8 )M/L, p < 0.05). These results show a significant increase in BDNF concentration in the resveratrol pretreated group. The

  11. Reduced intracellular oxidative metabolism promotes firm adhesion of human polymorphonuclear leukocytes to vascular endothelium under flow conditions.

    PubMed

    Montoya, M C; Luscinskas, F W; del Pozo, M A; Aragonés, J; de Landázuri, M O

    1997-08-01

    The interaction of polymorphonuclear leukocytes (PMN) with the vascular endothelium and their subsequent extravasation to the tissues is a key step during different physiological and pathological processes. In certain of these pathologies the oxygen tension becomes very low, leading to reduced cellular oxidative status. To evaluate the effect of lowering the intracellular redox status in the interaction of PMN with the endothelium, exposure to hypoxic conditions as well as treatment with different antioxidant agents was carried out. PMN exposure to hypoxia enhanced beta2 integrin-dependent adhesion to intercellular adhesion molecule-1-coated surfaces, concomitant with a decrease in the intracellular redox status of the cell. As occurs with hypoxia, treatment with antioxidants produced a decrease in the oxidation state of PMN. These agents enhanced adhesion of PMN to human umbilical vein endothelial cells stimulated with tumor necrosis factor-alpha (TNF-alpha), and this effect was also mediated by beta2 integrins LFA-1 and Mac-1. Adhesion studies under defined laminar flow conditions showed that the antioxidant treatment induced an enhanced adhesion mediated by beta2 integrins with a decrease in the fraction of PMN rolling on TNF-alpha-activated endothelial cells. The up-regulated PMN adhesion was correlated to an increase in the expression and activation of integrin Mac-1, without loss of L-selectin surface expression. Altogether, these results demonstrate that a reduction in the intracellular oxidative state produces an enhanced beta2 integrin-dependent adhesion of PMN to stimulated endothelial cells under conditions of flow.

  12. Identification of Risk Factors for Vascular Thrombosis May Reduce Early Renal Graft Loss: A Review of Recent Literature

    PubMed Central

    Keller, Anna Krarup; Jorgensen, Troels Munch; Jespersen, Bente

    2012-01-01

    Renal graft survival has improved over the past years, mainly owing to better immunosuppression. Vascular thrombosis, though rare, therefore accounts for up to one third of early graft loss. We assess current literature on transplantation, identify thrombosis risk factors, and discuss means of avoiding thrombotic events and saving thrombosed grafts. The incidence of arterial thrombosis was reported to 0.2–7.5% and venous thrombosis 0.1–8.2%, with the highest incidence among children and infants, and the lowest in living donor reports. The most significant risk factors for developing thrombosis were donor-age below 6 or above 60 years, or recipient-age below 5-6 years, per- or postoperative hemodynamic instability, peritoneal dialysis, diabetic nephropathy, a history of thrombosis, deceased donor, or >24 hours cold ischemia. Multiple arteries were not a risk factor, and a right kidney graft was most often reported not to be. Given the thrombosed kidney graft is diagnosed in time, salvage is possible by urgent reoperation and thrombectomy. Despite meticulous attentions to reduce thrombotic risk factors, thrombosis cannot be entirely prevented and means to an early detection of this complication is desirable in order to save the kidneys through prompt reoperation. Microdialysis may be a new tool for this. PMID:22701162

  13. Reducing the data: Analysis of the role of vascular geometry on blood flow patterns in curved vessels

    NASA Astrophysics Data System (ADS)

    Alastruey, Jordi; Siggers, Jennifer H.; Peiffer, Véronique; Doorly, Denis J.; Sherwin, Spencer J.

    2012-03-01

    Three-dimensional simulations of blood flow usually produce such large quantities of data that they are unlikely to be of clinical use unless methods are available to simplify our understanding of the flow dynamics. We present a new method to investigate the mechanisms by which vascular curvature and torsion affect blood flow, and we apply it to the steady-state flow in single bends, helices, double bends, and a rabbit thoracic aorta based on image data. By calculating forces and accelerations in an orthogonal coordinate system following the centreline of each vessel, we obtain the inertial forces (centrifugal, Coriolis, and torsional) explicitly, which directly depend on vascular curvature and torsion. We then analyse the individual roles of the inertial, pressure gradient, and viscous forces on the patterns of primary and secondary velocities, vortical structures, and wall stresses in each cross section. We also consider cross-sectional averages of the in-plane components of these forces, which can be thought of as reducing the dynamics of secondary flows onto the vessel centreline. At Reynolds numbers between 50 and 500, secondary motions in the directions of the local normals and binormals behave as two underdamped oscillators. These oscillate around the fully developed state and are coupled by torsional forces that break the symmetry of the flow. Secondary flows are driven by the centrifugal and torsional forces, and these are counterbalanced by the in-plane pressure gradients generated by the wall reaction. The viscous force primarily opposes the pressure gradient, rather than the inertial forces. In the axial direction, and depending on the secondary motion, the curvature-dependent Coriolis force can either enhance or oppose the bulk of the axial flow, and this shapes the velocity profile. For bends with little or no torsion, the Coriolis force tends to restore flow axisymmetry. The maximum circumferential and axial wall shear stresses along the centreline

  14. Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function.

    PubMed

    Kang, D H; Hughes, J; Mazzali, M; Schreiner, G F; Johnson, R J

    2001-07-01

    Impaired angiogenesis and decreased vascular endothelial growth factor (VEGF) expression were recently documented in the remnant kidney (RK) model of progressive renal failure. VEGF (50 microg/kg, twice daily) was administered to RK rats between weeks 4 and 8 after surgery, and rats were euthanized at week 8 for histologic study. During the administration of VEGF (n = 7) or vehicle (n = 6), systemic BP was comparable in the two groups. VEGF treatment resulted in improved renal function and lower mortality rates, compared with the vehicle-treated group. Renal histologic analyses confirmed a 3.5-fold increase in glomerular endothelial cell proliferation (0.14 +/- 0.03 versus 0.04 +/- 0.02 proliferating endothelial cells/glomerulus, VEGF versus vehicle, P < 0.05), a twofold increase in peritubular capillary endothelial cell proliferation (1.60 +/- 0.30 versus 0.78 +/- 0.17 cells/mm(2), VEGF versus vehicle, P < 0.01), a threefold decrease in peritubular capillary rarefaction (P < 0.01), and a twofold increase in endothelial nitrix oxide synthase expression (P < 0.05) in the VEGF-treated group; an eightfold increase in urinary nitrate/nitrite levels (P < 0.05) was also noted. Although the difference in glomerulosclerosis scores did not reach statistical significance (0.67 +/- 0.42 versus 1.22 +/- 0.63, VEGF versus vehicle; range, 0 to 4; P = NS), VEGF-treated rats exhibited less interstitial collagen type III deposition (9.32 +/- 3.26 versus 17.45 +/- 7.50%, VEGF versus vehicle, P < 0.01) and reduced tubular epithelial cell injury, as manifested by osteopontin expression (5.57 +/- 1.60 versus 9.58 +/- 3.45%, VEGF versus vehicle, P < 0.01). In conclusion, VEGF treatment reduces fibrosis and stabilizes renal function in the RK model. The use of angiogenic factors may represent a new approach to the treatment of kidney disease.

  15. Increased Circulating Endothelial Microparticles Associated with PAK4 Play a Key Role in Ventilation-Induced Lung Injury Process

    PubMed Central

    Pan, Shuming; Fei, Aihua; Jing, Lihong; Zhang, Xiangyu

    2017-01-01

    Inappropriate mechanical ventilation (MV) can result in ventilator-induced lung injury (VILI). Probing mechanisms of VILI and searching for effective methods are current areas of research focus on VILI. The present study aimed to probe into mechanisms of endothelial microparticles (EMPs) in VILI and the protective effects of Tetramethylpyrazine (TMP) against VILI. In this study, C57BL/6 and TLR4KO mouse MV models were used to explore the function of EMPs associated with p21 activated kinases-4 (PAK-4) in VILI. Both the C57BL/6 and TLR4 KO groups were subdivided into a mechanical ventilation (MV) group, a TMP + MV group, and a control group. After four hours of high tidal volume (20 ml/kg) MV, the degree of lung injury and the protective effects of TMP were assessed. VILI inhibited the cytoskeleton-regulating protein of PAK4 and was accompanied by an increased circulating EMP level. The intercellular junction protein of β-catenin was also decreased accompanied by a thickening alveolar wall, increased lung W/D values, and neutrophil infiltration. TMP alleviated VILI via decreasing circulating EMPs, stabilizing intercellular junctions, and alleviating neutrophil infiltration. PMID:28261612

  16. Quantifying the roles of tidal volume and PEEP in the pathogenesis of ventilator-induced lung injury.

    PubMed

    Seah, Adrian S; Grant, Kara A; Aliyeva, Minara; Allen, Gilman B; Bates, Jason H T

    2011-05-01

    Management of patients with acute lung injury (ALI) rests on achieving a balance between the gas exchanging benefits of mechanical ventilation and the exacerbation of tissue damage in the form of ventilator-induced lung injury (VILI). Optimizing this balance requires an injury cost function relating injury progression to the measurable pressures, flows, and volumes delivered during mechanical ventilation. With this in mind, we mechanically ventilated naive, anesthetized, paralyzed mice for 4 h using either a low or high tidal volume (Vt) with either moderate or zero positive end-expiratory pressure (PEEP). The derecruitability of the lung was assessed every 15 min in terms of the degree of increase in lung elastance occurring over 3 min following a recruitment maneuver. Mice could be safely ventilated for 4 h with either a high Vt or zero PEEP, but when both conditions were applied simultaneously the lung became increasingly unstable, demonstrating worsening injury. We were able to mimic these data using a computational model of dynamic recruitment and derecruitment that simulates the effects of progressively increasing surface tension at the air-liquid interface, suggesting that the VILI in our animal model progressed via a vicious cycle of alveolar leak, degradation of surfactant function, and increasing tissue stress. We thus propose that the task of ventilating the injured lung is usefully understood in terms of the Vt-PEEP plane. Within this plane, non-injurious combinations of Vt and PEEP lie within a "safe region", the boundaries of which shrink as VILI develops.

  17. Kinetics of ventilation-induced changes in diaphragmatic metabolism by bilateral phrenic pacing in a piglet model

    PubMed Central

    Breuer, Thomas; Hatam, Nima; Grabiger, Benjamin; Marx, Gernot; Behnke, Bradley J.; Weis, Joachim; Kopp, Ruedger; Gayan-Ramirez, Ghislaine; Zoremba, Norbert; Bruells, Christian S.

    2016-01-01

    Perioperative necessity of deep sedation is inevitably associated with diaphragmatic inactivation. This study investigated 1) the feasibility of a new phrenic nerve stimulation method allowing early diaphragmatic activation even in deep sedation and, 2) metabolic changes within the diaphragm during mechanical ventilation compared to artificial activity. 12 piglets were separated into 2 groups. One group was mechanically ventilated for 12 hrs (CMV) and in the second group both phrenic nerves were stimulated via pacer wires inserted near the phrenic nerves to mimic spontaneous breathing (STIM). Lactate, pyruvate and glucose levels were measured continuously using microdialysis. Oxygen delivery and blood gases were measured during both conditions. Diaphragmatic stimulation generated sufficient tidal volumes in all STIM animals. Diaphragm lactate release increased in CMV transiently whereas in STIM lactate dropped during this same time point (2.6 vs. 0.9 mmol L−1 after 5:20 hrs; p < 0.001). CMV increased diaphragmatic pyruvate (40 vs. 146 μmol L−1 after 5:20 hrs between CMV and STIM; p < 0.0001), but not the lactate/pyruvate ratio. Diaphragmatic stimulation via regular electrodes is feasible to generate sufficient ventilation, even in deep sedation. Mechanical ventilation alters the metabolic state of the diaphragm, which might be one pathophysiologic origin of ventilator-induced diaphragmatic dysfunction. Occurrence of hypoxia was unlikely. PMID:27759115

  18. Reduced vascular responses to soluble guanylyl cyclase but increased sensitivity to sildenafil in female rats with type 2 diabetes.

    PubMed

    Goulopoulou, Styliani; Hannan, Johanna L; Matsumoto, Takayuki; Ogbi, Safia; Ergul, Adviye; Webb, R Clinton

    2015-07-15

    Impaired nitric oxide (NO), soluble guanylyl cyclase (sGC), and cyclic guanosine monophosphate (cGMP) signaling (NO-sGC-cGMP) has been implicated in the pathogenesis of diabetic vascular dysfunction. Efforts to directly target this signaling have led to the development of sGC agonists that activate the heme group of sGC (stimulators) or preferentially activate sGC when the heme is oxidized (activators). In this study, we hypothesized that resistance arteries from female rats with spontaneous type 2 diabetes (Goto-Kakizaki rats, GK) would have reduced vasodilatory responses to heme-dependent sGC activation and increased responses to heme-independent sGC activation compared with control rats (Wistar). Endothelium-dependent and -independent relaxation was assessed in isolated segments from mesenteric resistance arteries (MA) mounted in a wire myograph. GK MA had reduced responses to acetylcholine (pEC50: 7.96 ± 0.06 vs. 7.66 ± 0.05, P < 0.05) and sodium nitroprusside (pEC50: 8.34 ± 0.05 vs. 7.77 ± 0.04, P < 0.05). There were no group differences in 8-bromoguanosine cGMP-induced relaxation and protein kinase G1 expression (P > 0.05). GK MA had attenuated responses to BAY 41-2272 (heme-dependent sGC stimulator; pEC50: 7.56 ± 0.05 vs. 6.93 ± 0.06, P < 0.05) and BAY 58-2667 (heme-independent sGC activator; pEC50: 10.82 ± 0.07 vs. 10.27 ± 0.08, P < 0.05) and increased sensitivity to sildenafil [phosphodiesterase 5 (PDE5) inhibitor; pEC50: 7.89 ± 0.14 vs. 8.25 ± 0.13, P < 0.05]. Isolated resistance arteries from female rats of reproductive age that spontaneously develop type 2 diabetes have increased sensitivity to PDE5 inhibition and reduced responsiveness to sGC activators and stimulators. Copyright © 2015 the American Physiological Society.

  19. Finasteride reduces microvessel density and expression of vascular endothelial growth factor in renal tissue of diabetic rats.

    PubMed

    Tian, He-lin; Zhao, Chao-xian; Wu, Hai-ying; Xu, Zhong-xin; Wei, Li-shun; Zhao, Ru-tong; Jin, Dong-ling

    2015-06-01

    Vascular endothelial growth factor (VEGF) plays a critical role in the pathogenesis of diabetic microvascular complications. Finasteride has been confirmed to decrease VEGF expression in prostate and prostatic suburethral tissue resulting in limiting hematuria from human benign prostatic hyperplasia. The purpose of this study was to evaluate the effects of finasteride on microvessel density (MVD), VEGF protein and mRNA expressions in the renal tissue of diabetic rats. Diabetic rats induced by streptozotocin were intragastrically given finasteride at 30 mg/kg body weight once a day for 4 weeks. Histomorphologic changes in kidney were observed under light microscope. Immunohistochemistry for CD34 and VEGF on kidney sections was performed to assess MVD and VEGF protein expression in glomeruli of rats, respectively. The VEGF mRNA expression in the renal tissue was examined using reverse transcription polymerase chain reaction analysis. The glomerular tuft area, glomerular volume, MVD, VEGF protein expression in glomeruli and VEGF mRNA expression in the renal cortex tissue were significantly increased in diabetic rats and finasteride-treated rats when compared with controls (P < 0.01, P < 0.05). When compared with diabetic rats, the glomerular tuft area, glomerular volume, MVD, VEGF protein expression in glomeruli and VEGF mRNA expression in the renal cortex tissue of finasteride-treated rats were significantly decreased (P < 0.05, P < 0.01). Finasteride reduces the VEGF expression and decreases the MVD in the renal tissue of diabetic rats, suggesting the therapeutic potential of finasteride on diabetic microvascular complications.

  20. Inhibition of SRF/myocardin reduces aortic stiffness by targeting vascular smooth muscle cell stiffening in hypertension

    PubMed Central

    Zhou, Ning; Lee, Jia-Jye; Stoll, Shaunrick; Ma, Ben; Wiener, Robert; Wang, Charles; Costa, Kevin D.; Qiu, Hongyu

    2017-01-01

    Aims Increased aortic stiffness is a fundamental manifestation of hypertension. However, the molecular mechanisms involved remain largely unknown. We tested the hypothesis that abnormal intrinsic vascular smooth muscle cell (VSMC) mechanical properties in large arteries, but not in distal arteries, contribute to the pathogenesis of aortic stiffening in hypertension, mediated by the serum response factor (SRF)/myocardin signalling pathway. Methods and results Four month old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were studied. Using atomic force microscopy, significant VSMC stiffening was observed in the large conducting aorta compared with the distal arteries in SHR (P < 0.001), however, this regional variation was not observed in WKY rats (P > 0.4). The increase of VSMC stiffness was accompanied by a parallel increase in the expression of SRF by 9.8-fold and of myocardin by 10.5-fold in thoracic aortic VSMCs from SHR vs. WKY rats, resulting in a significant increase of downstream stiffness-associated genes (all, P < 0.01 vs. WKY). Inhibition of SRF/myocardin expression selectively attenuated aortic VSMC stiffening, and normalized downstream targets in VSMCs isolated from SHR but not from WKY rats. In vivo, 2 weeks of treatment with SRF/myocardin inhibitor delivered by subcutaneous osmotic minipump significantly reduced aortic stiffness and then blood pressure in SHR but not in WKY rats, although concomitant changes in aortic wall remodelling were not detected during this time frame. Conclusions SRF/myocardin pathway acts as a pivotal mediator of aortic VSMC mechanical properties and plays a central role in the pathological aortic stiffening in hypertension. Attenuation of aortic VSMC stiffening by pharmacological inhibition of SRF/myocardin signalling presents a novel therapeutic strategy for the treatment of hypertension by targeting the cellular contributors to aortic stiffness. PMID:28003268

  1. Reduced-fluence photodynamic therapy and anti-vascular endothelial growth factor for polypoidal choroidal vasculopathy in an Indian population

    PubMed Central

    Sen, Parveen; Bhende, Muna; Sachidanandam, Ramya; Bansal, Nishat; Sharma, Tarun

    2016-01-01

    Aims: The aim was to study the efficacy of combined therapy with reduced-fluence photodynamic therapy (RFPDT) and intravitreal bevacizumab/ranibizumab from the Indian subcontinent. Settings and Design: This was a single-center, retrospective interventional study. Methods: Thirty-five eyes of 34 patients diagnosed with polypoidal choroidal vasculopathy were included. All the patients underwent RFPDT, followed by intravitreal bevacizumab/ranibizumab. Statistical Analysis Used: SPSS software, version 17.0 (SPSS Inc., Chicago, IL, USA) was used to compare the logarithm of the minimal angle of resolution visual acuity at presentation and final follow-up. P < 0.05 was considered statistically significant. Results: Regression of polyps after a single session of RFPDT was seen in five eyes; multiple sessions of treatment were required in thirty eyes. An average number of intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections given were 4 ± 1.9 and average number of PDT sessions were 1.2 ± 0.5. Visual acuity improvement was seen in 21 (60%) eyes (P < 0.001), decrease in visual acuity was seen in 7 (20%) eyes (P = 0.016), and in 7 eyes (20%), vision remained stable. Regression of polypoidal lesions was seen in 80% of cases. No complications of massive subretinal hemorrhage or breakthrough vitreous hemorrhage were noted in our patients. The mean follow-up period was 18 months (range, 12–24 months). Conclusions: RFPDT with anti-VEGF is safe and effective treatment with polyp regression and vision improvement in 80% of cases, without any complication of subretinal hemorrhage/vitreous hemorrhage. PMID:28112132

  2. Maintaining end-expiratory transpulmonary pressure prevents worsening of ventilator-induced lung injury caused by chest wall constriction in surfactant-depleted rats

    PubMed Central

    Loring, Stephen H.; Pecchiari, Matteo; Valle, Patrizia Della; Monaco, Ario; Gentile, Guendalina; D'Angelo, Edgardo

    2014-01-01

    Objective To see whether in acute lung injury (ALI) 1) compression of the lungs caused by thoracoabdominal constriction degrades lung function and worsens ventilator-induced lung injury (VILI), and 2) maintaining end-expiratory transpulmonary pressure (Pl) by increasing positive end-expiratory pressure (PEEP) reduces the deleterious effects of chest wall constriction. Design Experimental study in rats. Setting Physiology laboratory. Interventions ALI was induced in 3 groups of 9 rats by saline lavage. Nine animals immediately sacrificed served as control group. Group L had lavage only, group LC had the chest wall constricted with an elastic binder, and group LCP had the same chest constriction but with PEEP raised to maintain end-expiratory Pl. After lavage, all groups were ventilated with the same pattern for 1½ hr. Measurements and Main Results Pl, measured with an esophageal balloon-catheter, lung volume changes, arterial blood gasses and pH were assessed during mechanical ventilation (MV). Lung wet-to-dry ratio (W/D), albumin, TNF-α, IL-1β, IL-6, IL-10, and MIP-2 in serum and bronchoalveolar lavage fluid (BALF), and serum E-selectin and von Willebrand Factor (vWF) were measured at the end of MV. Lavage caused hypoxemia and acidemia, increased lung resistance and elastance, and decreased end-expiratory lung volume. With prolonged MV, lung mechanics, hypoxemia, and W/D were significantly worse in group LC. Pro-inflammatory cytokines except E-selectin were elevated in serum and BALF in all groups, with significantly greater levels of TNF-α, IL-1β, and IL-6 in group LC, which also exhibited significantly worse bronchiolar injury and greater heterogeneity of airspace expansion at a fixed Pl than other groups. Conclusions Chest wall constriction in ALI reduces lung volume, worsens hypoxemia, and increases pulmonary edema, mechanical abnormalities, pro-inflammatory mediator release, and histological signs of VILI. Maintaining end-expiratory Pl at preconstriction

  3. Newly identified precipitating factors in mechanical ventilation-induced brain damage: implications for treating ICU delirium.

    PubMed

    González-López, Adrián; Albaiceta, Guillermo M; Talbot, Konrad

    2014-06-01

    Delirium is 1.5 to 4.1 times as likely in intensive care unit patients when they are mechanically ventilated. While progress in treatment has occurred, delirium is still a major problem in mechanically ventilated patients. Based on studies of a murine mechanical ventilation model, we summarize evidence here for a novel mechanism by which such ventilation can quickly initiate brain damage likely to cause cognitive deficits expressed as delirium. That mechanism consists of aberrant vagal sensory input driving sustained dopamine D2 receptor (D2R) signaling in the hippocampal formation, which induces apoptosis in that brain area within 90 min without causing hypoxia, oxidative stress, or inflammatory responses. This argues for minimizing the duration and tidal volumes of mechanical ventilation and for more effectively reducing sustained D2R signaling than achieved with haloperidol alone. The latter might be accomplished by reducing D2R cell surface expression and D2R-mediated Akt inhibition by elevating protein expression of dysbindin-1C.

  4. A numerical method of reduced complexity for simulating vascular hemodynamics using coupled 0D lumped and 1D wave propagation models.

    PubMed

    Kroon, Wilco; Huberts, Wouter; Bosboom, Marielle; van de Vosse, Frans

    2012-01-01

    A computational method of reduced complexity is developed for simulating vascular hemodynamics by combination of one-dimensional (1D) wave propagation models for the blood vessels with zero-dimensional (0D) lumped models for the microcirculation. Despite the reduced dimension, current algorithms used to solve the model equations and simulate pressure and flow are rather complex, thereby limiting acceptance in the medical field. This complexity mainly arises from the methods used to combine the 1D and the 0D model equations. In this paper a numerical method is presented that no longer requires additional coupling methods and enables random combinations of 1D and 0D models using pressure as only state variable. The method is applied to a vascular tree consisting of 60 major arteries in the body and the head. Simulated results are realistic. The numerical method is stable and shows good convergence.

  5. Inhibition of Src and forkhead box O1 signaling by induced pluripotent stem-cell therapy attenuates hyperoxia-augmented ventilator-induced diaphragm dysfunction.

    PubMed

    Li, Li-Fu; Chang, Yuh-Lih; Chen, Ning-Hung; Wang, Chien-Ying; Chang, Gwo-Jyh; Lin, Meng-Chih; Chang, Chih-Hao; Huang, Chung-Chi; Chuang, Jen-Hua; Yang, Yi-Pin; Chiou, Shih-Hwa; Liu, Yung-Yang

    2016-07-01

    Mechanical ventilation (MV) with hyperoxia is required for providing life support to patients with acute lung injury (ALI). However, MV may cause diaphragm weakness through muscle injury and atrophy, an effect termed ventilator-induced diaphragm dysfunction (VIDD). Src protein tyrosine kinase and class O of forkhead box 1 (FoxO1) mediate acute inflammatory responses and muscle protein degradation induced by oxidative stress. Induced pluripotent stem cells (iPSCs) have been reported to improve hyperoxia-augmented ALI; however, the mechanisms regulating the interactions among VIDD, hyperoxia, and iPSCs are unclear. In this study, we hypothesized that iPSC therapy can ameliorate hyperoxia-augmented VIDD by suppressing the Src-FoxO1 pathway. Male C57BL/6 mice, either wild-type or Src-deficient, aged between 6 and 8 weeks were exposed to MV (6 or 10 mL/kg) with or without hyperoxia for 2-8 h after the administration of 5 × 10(7) cells/kg Oct4/Sox2/Parp1 mouse iPSCs or iPSC-derived conditioned medium (iPSC-CM). Nonventilated mice were used as controls. MV during hyperoxia aggravated VIDD, as demonstrated by the increases in Src activation, FoxO1 dephosphorylation, malondialdehyde, caspase-3, atrogin-1 and muscle ring finger-1 production, microtubule-associated protein light chain 3-II, disorganized myofibrils, disrupted mitochondria, autophagy, and myonuclear apoptosis; however, MV with hyperoxia reduced mitochondrial cytochrome C, diaphragm muscle fiber size, and contractility (P < 0.05). Hyperoxia-exacerbated VIDD was attenuated in Src-deficient mice and by iPSCs and iPSC-CM (P < 0.05). Our data indicate that iPSC therapy attenuates MV-induced diaphragmatic injury that occurs during hyperoxia-augmented VIDD by inhibiting the Src-FoxO1 signaling pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. [Quantitative comparison of ventilator-induced work during simulated CPAP in eight demand-flow valve ventilators].

    PubMed

    Nishimura, M; Imanaka, H; Taenaka, N; Yoshiya, I; Takezawa, J

    1989-08-01

    The ventilator-induced work during continuous positive airway pressure (CPAP) mode in demand-valve ventilators was evaluated by using a piston pump as a simulator for active breathing. A piston pump delivered and withdrew a stroke volume of 500 ml at rates of 10, 20 and 40 cycle.min-1 with a sinusoidal waveform. A hot-wire flowmeter and a differential pressure transducer were interposed between the pump and ventilators and their signals were fed to a microcomputer to display a pressure-volume loop. The area of the loop was divided into the four parts. Inspiratory work associated with the opening of the demand valve was represented by the area of baseline airway pressure (BPa) during inspiration. The remaining area during inspiration reflected the work done by the ventilators. Expiratory work for overcoming the flow resistance of the expiratory apparatus was represented by the area above BPa during exhalation. The fourth was the area below the baseline during exhalation. The Puritan-Bennett 7200a, the Bear 5, the Siemens Servo 900C, the Hamilton Veolar, the Bird 6400ST, the Engström Erica, the Dräger EV-A, and the CPU-1 were examined at varying CPAP and pressure support levels. Because of demand valve oscillation throughout inspiration, the inspiratory workload of the Bear 5, the Siemens Servo 900C, the Hamilton Veolar, the Bird 6400ST, and the Dräger EV-A could not be calculated. Expiratory flow-resistive work was higher in the Siemens Servo 900C and the Bird 6400ST than the others. The present system can assess the entire performance of ventilators, and may serve to compare ventilators' performance.

  7. Inhibition of programmed cell death impairs in vitro vascular-like structure formation and reduces in vivo angiogenesis.

    PubMed

    Segura, Inmaculada; Serrano, Antonio; De Buitrago, Gonzalo González; González, Manuel A; Abad, Jose Luis; Clavería, Cristina; Gómez, Lucio; Bernad, Antonio; Martínez-A, Carlos; Riese, Hans H

    2002-06-01

    Tissue remodeling during embryonic development and in the adult organism relies on a subtle balance between cell growth and apoptosis. As angiogenesis involves restructuring of preexisting endothelium, we examined the role of apoptosis in new vessel formation. We show that apoptosis occurs before capillary formation but not after vessels have assembled. Using the human umbilical vein endothelial cell (HUVEC) in vitro Matrigel angiogenesis model, we show that vascular-like structure formation requires apoptotic cell death through activation of a caspase-dependent mechanism and mitochondrial cytochrome c release. Vascular-like structure formation was further blocked by caspase inhibitors such as z-VAD or Ac-DEVD-CHO, using HUVEC and human lung microvascular endothelial cells. Overexpression of anti-apoptotic human Bcl-2 or baculovirus p35 genes in HUVEC altered endothelial cell rearrangement during in vitro angiogenesis, causing impaired vessel-like structure formation. Caspase inhibitors blocked VEGF- or bFGF-induced HUVEC angiogenesis on 2- or 3-D collagen gels, respectively, confirming that apoptosis was not the result of nonspecific cell death after seeding on the matrix. In an in vivo angiogenesis assay, caspase inhibitors blocked VEGF-dependent vascular formation at the alignment step, as demonstrated histologically. This evidence indicates that endothelial cell apoptosis may be relevant for precise vascular tissue rearrangement in in vitro and in vivo angiogenesis.

  8. Reduced endothelial NO-cGMP vascular relaxation pathway during TNF-alpha-induced hypertension in pregnant rats.

    PubMed

    Davis, Justin R; Giardina, Jena B; Green, Gachavis M; Alexander, Barbara T; Granger, Joey P; Khalil, Raouf A

    2002-02-01

    Placental ischemia during pregnancy is thought to release cytokines such as tumor necrosis factor-alpha (TNF-alpha), which may contribute to the increased vascular resistance associated with pregnancy-induced hypertension. We have reported that a chronic twofold elevation in plasma TNF-alpha increases blood pressure in pregnant but not in virgin rats; however, the vascular mechanisms are unclear. We tested the hypothesis that increasing plasma TNF-alpha during pregnancy impairs endothelium-dependent vascular relaxation and enhances vascular reactivity. Active stress was measured in aortic strips of virgin and late-pregnant Sprague-Dawley rats untreated or infused with TNF-alpha (200 ng x kg(-1) x day(-1) for 5 days) to increase plasma level twofold. Phenylephrine (Phe) increased active stress to a maximum of 4.2 +/- 0.4 x 10(3) and 9.9 +/- 0.7 x 10(3) N/m2 in control pregnant and TNF-alpha-infused pregnant rats, respectively. Removal of the endothelium enhanced Phe-induced stress in control but not in TNF-alpha-infused pregnant rats. In endothelium-intact strips, ACh caused greater relaxation of Phe contraction in control than in TNF-alpha-infused pregnant rats. Basal and ACh-induced nitrite/nitrate production was less in TNF-alpha-infused than in control pregnant rats. Pretreatment of vascular strips with 100 microM N(G)-nitro-L-arginine methyl ester, to inhibit nitric oxide (NO) synthase, or 1 microM 1H-[1,2,4]oxadiazolo[4,3-]quinoxalin-1-one, to inhibit cGMP production in smooth muscle, inhibited ACh-induced relaxation and enhanced Phe-induced stress in control but not in TNF-alpha-infused pregnant rats. Phe contraction and ACh relaxation were not significantly different between control and TNF-alpha-infused virgin rats. Thus an endothelium-dependent NO-cGMP-mediated vascular relaxation pathway is inhibited in late-pregnant rats infused with TNF-alpha. The results support a role for TNF-alpha as one possible mediator of the increased vascular resistance

  9. Vascular Cures

    MedlinePlus

    ... Contact Us Vascular Disease What is Vascular Disease? Education and Awareness Vascular Diseases Abdominal Aortic Aneurysm Aortic Dissection Arteriovenous Malformation Atherosclerosis Buerger's Disease Carotid Artery Disease ...

  10. Reduced endothelial NO-cGMP-mediated vascular relaxation and hypertension in IL-6-infused pregnant rats.

    PubMed

    Orshal, Julia M; Khalil, Raouf A

    2004-02-01

    Placental ischemia during pregnancy is associated with increased plasma cytokines such as interleukin-6 (IL-6), which may contribute to increased vascular resistance and hypertension of pregnancy. We tested the hypothesis that an increase in plasma IL-6 during pregnancy is associated with impaired endothelium-dependent relaxation, enhanced vascular contraction, and hypertension. Systolic blood pressure was measured in virgin and pregnant Sprague-Dawley rats non-treated or infused with IL-6 (200 ng/kg per day for 5 days). Isometric contraction was measured in isolated aortic strips, and endothelial nitric oxide (NO) synthase (eNOS) was measured in aortic homogenate using Western blots. Blood pressure was greater in IL-6-infused (146+/-3) than in control pregnant rats (117+/-2 mm Hg). In endothelium-intact vascular strips, phenylephrine (Phe) caused greater increase in active stress in IL-6-infused (maximum: 10.6+/-0.6) than in control pregnant rats (maximum: 4.1+/-0.3x10(4) N/m2). Acetylcholine (ACh)-induced relaxation of Phe contraction and vascular eNOS protein and nitrite/nitrate production were less in IL-6-infused than in control pregnant rats. N(omega)-nitro-L-arginine methyl ester (10(-4) mol/L), inhibitor of NOS, or 1H-[1,2,4]oxadiazolo[4,3]-quinoxalin-1-one (10(-5) mol/L), inhibitor of cGMP production in smooth muscle, inhibited ACh-induced relaxation and enhanced Phe-induced stress in control but not IL-6-infused pregnant rats. Endothelium removal enhanced Phe-induced stress in control but not in IL-6-infused pregnant rats. The blood pressure and vascular Phe-induced contraction, ACh relaxation, and eNOS protein were not different between control and IL-6-infused virgin rats. Thus, an endothelium-dependent NO-cGMP-mediated relaxation pathway is inhibited in systemic vessels of pregnant rats infused with IL-6. The results support a role for IL-6 as a possible mediator of the increased vascular resistance during hypertension of pregnancy.

  11. Frequent physical activity may not reduce vascular disease risk as much as moderate activity: large prospective study of women in the United Kingdom.

    PubMed

    Armstrong, Miranda E G; Green, Jane; Reeves, Gillian K; Beral, Valerie; Cairns, Benjamin J

    2015-02-24

    Although physical activity has generally been associated with reduced risk of vascular disease, there is limited evidence about the effects of the frequency and duration of various activities on the incidence of particular types of vascular disease. In 1998, on average, 1.1 million women without prior vascular disease reported their frequency of physical activity and many other personal characteristics. Three years later, they were asked about hours spent walking, cycling, gardening, and housework each week. Women were followed by record linkage to National Health Service cause-specific hospital admissions and death records. Cox regression was used to calculate adjusted relative risks for first vascular events in relation to physical activity. During an average of 9 years follow-up, 49,113 women had a first coronary heart disease event, 17,822 had a first cerebrovascular event, and 14,550 had a first venous thromboembolic event. In comparison with inactive women, those reporting moderate activity had significantly lower risks of all 3 conditions (P<0.001 for each). However, women reporting strenuous physical activity daily had higher risks of coronary heart disease (P=0.002), cerebrovascular disease (P<0.001), and venous thromboembolic events (P<0.001) than those reporting doing such activity 2 to 3 times per week. Risks did not differ between hemorrhagic and ischemic stroke, or between venous thromboembolic events with or without pulmonary embolism. Moderate physical activity is associated with a lower risk of coronary heart disease, venous thromboembolic event, and cerebrovascular disease than inactivity. However, among active women, there is little to suggest progressive reductions in risk of vascular diseases with increasing frequency of activity. © 2015 American Heart Association, Inc.

  12. Spironolactone and hydrochlorothiazide exert antioxidant effects and reduce vascular matrix metalloproteinase-2 activity and expression in a model of renovascular hypertension

    PubMed Central

    Ceron, CS; Castro, MM; Rizzi, E; Montenegro, MF; Fontana, V; Salgado, MCO; Gerlach, RF; Tanus-Santos, JE

    2010-01-01

    Background and purpose: Increased oxidative stress and up-regulation of matrix metalloproteinases (MMPs) may cause structural and functional vascular changes in renovascular hypertension. We examined whether treatment with spironolactone (SPRL), hydrochlorothiazide (HCTZ) or both drugs together modified hypertension-induced changes in arterial blood pressure, aortic remodelling, vascular reactivity, oxidative stress and MMP levels and activity, in a model of renovascular hypertension. Experimental approach: We used the two-kidney,one-clip (2K1C) model of hypertension in Wistar rats. Sham-operated or hypertensive rats were treated with vehicle, SPRL (25 mg·kg−1·day−1), HCTZ (20 mg·kg−1·day−1) or a combination for 8 weeks. Systolic blood pressure was monitored weekly. Aortic rings were isolated to assess endothelium-dependent and -independent relaxations. Morphometry of the vascular wall was carried out in sections of aorta. Aortic NADPH oxidase activity and superoxide production were evaluated. Formation of reactive oxygen species was measured in plasma as thiobarbituric acid-reactive substances. Aortic MMP-2 levels and activity were determined by gelatin and in situ zymography, fluorimetry and immunohistochemistry. Key results: Treatment with SPRL, HCTZ or the combination attenuated 2K1C-induced hypertension, and reversed the endothelial dysfunction in 2K1C rats. Both drugs or the combination reversed vascular aortic remodelling induced by hypertension, attenuated hypertension-induced increases in oxidative stress and reduced MMP-2 levels and activity. Conclusions and implications: SPRL or HCTZ, alone or combined, exerted antioxidant effects, and decreased renovascular hypertension-induced MMP-2 up-regulation, thus improving the vascular dysfunction and remodelling found in this model of hypertension. PMID:20331602

  13. Lowered LDL-C Levels Reduce Later Local Vascular Events after Surgical or Endovascular Treatment of Peripheral Artery Disease

    PubMed Central

    Ishii, Kouji; Takahashi, Junichiro; Kanaoka, Tsuyoshi; Wakamatsu, Yutaka; Gohda, Toshihiro; Matsui, Yoshiro

    2012-01-01

    Purpose: To examine the relationship between incidence of later, local vascular events (restenosis and occlusion) and clinical factors including lipid levels after surgical or endovascular treatment of peripheral artery disease (PAD). Methods: Consecutive 418 PAD lesions (in 308 patients under the age of 70) treated with surgical (n = 188) or endovascular (n = 230) repair for iliac (n = 228) and infrainguinal (n = 190) lesions were retrospectively analyzed. Clinical features and lipid levels were compared between patients who developed vascular events (n = 51; VE group) and those who did not (n = 257; NoVE group). Results: Among assessed factors, post-therapeutic low-density lipoprotein cholesterol (LDL-C) levels (mg/dL) were significantly higher in the VE group (120.4 ± 31.2) than in the NoVE group (108.2 ± 25.1) (P = 0.01). Infrainguinal lesions were more common in the VE than in the NoVE group (P <0.001). Cox hazard analysis indicated that infrainguinal lesions relative to iliac lesions significantly increased the risk of vascular events (hazard ratio (HR) 3.35; 95% CI 1.63–6.90; P = 0.001) and post-therapeutic LDL-C levels <130 (mg/dL) decreased the risk (HR 0.34; 95%CI 0.17–0.67; P = 0.002). Conclusion: Lowered post-therapeutic LDL-C levels can decrease the risk of later, local vascular events after PAD treatment. These results may support the rationale for aggressive lipid-modifying therapy for PAD. PMID:23555508

  14. Overexpression of Mitofusin 2 inhibited oxidized low-density lipoprotein induced vascular smooth muscle cell proliferation and reduced atherosclerotic lesion formation in rabbit

    SciTech Connect

    Guo Yanhong; Chen Kuanghueih; Gao Wei; Li Qian; Chen Li; Wang Guisong Tang Jian

    2007-11-16

    Our previous studies have implies that Mitofusin 2 (Mfn2), which was progressively reduced in arteries from ApoE{sup -/-} mice during the development of atherosclerosis, may take part in pathogenesis of atherosclerosis. In this study, we found that overexpression of Mfn2 inhibited oxidized low-density lipoprotein or serum induced vascular smooth muscle cell proliferation by down-regulation of Akt and ERK phosphorylation. Then we investigated the in vivo role of Mfn2 on the development of atherosclerosis in rabbits using adenovirus expressing Mitofusin 2 gene (AdMfn2). By morphometric analysis we found overexpression of Mfn2 inhibited atherosclerotic lesion formation and intima/media ratio by 66.7% and 74.6%, respectively, compared with control group. These results suggest that local Mfn2 treatment suppresses the development of atherosclerosis in vivo in part by attenuating the smooth muscle cell proliferation induced by lipid deposition and vascular injury.

  15. Plasma-derived human C1-esterase inhibitor does not prevent mechanical ventilation-induced pulmonary complement activation in a rat model of Streptococcus pneumoniae pneumonia.

    PubMed

    de Beer, F M; Aslami, H; Hoeksma, J; van Mierlo, G; Wouters, D; Zeerleder, S; Roelofs, J J T H; Juffermans, N P; Schultz, M J; Lagrand, W K

    2014-11-01

    Mechanical ventilation has the potential to cause lung injury, and the role of complement activation herein is uncertain. We hypothesized that inhibition of the complement cascade by administration of plasma-derived human C1-esterase inhibitor (C1-INH) prevents ventilation-induced pulmonary complement activation, and as such attenuates lung inflammation and lung injury in a rat model of Streptococcus pneumoniae pneumonia. Forty hours after intratracheal challenge with S. pneumoniae causing pneumonia rats were subjected to ventilation with lower tidal volumes and positive end-expiratory pressure (PEEP) or high tidal volumes without PEEP, after an intravenous bolus of C1-INH (200 U/kg) or placebo (saline). After 4 h of ventilation blood, broncho-alveolar lavage fluid and lung tissue were collected. Non-ventilated rats with S. pneumoniae pneumonia served as controls. While ventilation with lower tidal volumes and PEEP slightly amplified pneumonia-induced complement activation in the lungs, ventilation with higher tidal volumes without PEEP augmented local complement activation more strongly. Systemic pre-treatment with C1-INH, however, failed to alter ventilation-induced complement activation with both ventilation strategies. In accordance, lung inflammation and lung injury were not affected by pre-treatment with C1-INH, neither in rats ventilated with lower tidal volumes and PEEP, nor rats ventilated with high tidal volumes without PEEP. Ventilation augments pulmonary complement activation in a rat model of S. pneumoniae pneumonia. Systemic administration of C1-INH, however, does not attenuate ventilation-induced complement activation, lung inflammation, and lung injury.

  16. ApoE suppresses atherosclerosis by reducing lipid accumulation in circulating monocytes and the expression of inflammatory molecules on monocytes and vascular endothelium

    PubMed Central

    Gaudreault, Nathalie; Kumar, Nikit; Posada, Jessica M.; Stephens, Kyle B.; de Mochel, Nabora Soledad Reyes; Eberle, Delphine; Olivas, Victor R.; Kim, Roy Y.; Harms, Matthew J.; Johnson, Amy; Messina, Louis M.; Rapp, Joseph H.; Raffai, Robert L.

    2012-01-01

    Objective We investigated atheroprotective properties of apoE beyond its ability to lower plasma cholesterol. We hypothesized that apoE reduces atherosclerosis by decreasing lipid accumulation in circulating monocytes and the inflammatory state of monocytes and the vascular endothelium. Methods and Results We developed mice with spontaneous hyperlipidemia with and without plasma apoE: Hypomorphic apoE mice deficient in low-density lipoprotein receptor (Apoeh/hLdlr–/–) were compared to Apoe–/–Ldlr–/– mice. Despite 4-fold more plasma apoE than WT mice, Apoeh/hLdlr–/– mice displayed similar plasma cholesterol as Apoe–/–Ldlr–/– mice but developed 4-fold less atherosclerotic lesions by 5 months of age. The aortic arch of Apoeh/hLdlr–/– mice showed decreased endothelial expression of ICAM-1, PECAM-1, and JAM-A. In addition, Apoeh/hLdlr–/– mice had less circulating leukocytes and pro-inflammatory Ly6Chigh monocytes. These monocytes had decreased neutral lipid content and reduced surface expression of ICAM-1, VLA-4, and L-Selectin. Apoeh/hLdlr–/– mice displayed increased levels of apoA1-rich HDL that were potent in promoting cellular cholesterol efflux. Conclusions Our findings suggest that apoE reduces atherosclerosis in the setting of hyperlipidemia by increasing plasma apoA1-HDL that likely contribute to reduce intracellular lipid accumulation and thereby the activation of circulating leukocytes and the vascular endothelium. PMID:22053073

  17. Life-long aerobic exercise preserved baseline cerebral blood flow but reduced vascular reactivity to CO2.

    PubMed

    Thomas, Binu P; Yezhuvath, Uma S; Tseng, Benjamin Y; Liu, Peiying; Levine, Benjamin D; Zhang, Rong; Lu, Hanzhang

    2013-11-01

    To examine the potential benefits of life-long aerobic exercise on brain health, in particular cerebrovascular function. Ten Masters athletes (MA) (seven males, three females; 74.5 ± 5.8 years) and 10 sedentary elderly individuals (SE) (eight males, two females; 75.4 ± 5.6 years) were recruited and baseline cerebral blood flow (CBF) and cerebral vascular reactivity (CVR) to CO2 were measured on a 3T MRI scanner. Nine sedentary young subjects were also recruited to serve as a control group to verify the age effect. When compared to the SE group, MA showed higher CBF in posterior cingulate cortex/precuneus, which are key regions of the default-mode-network and are known to be highly sensitive to age and dementia. CVR in the MA brains were paradoxically lower than that in SE. This effect was present throughout the brain. Within the MA group, individuals with higher VO2max had an even lower CVR, suggesting a dose-response relationship. Life-long aerobic exercise preserved blood supply in the brain's default-mode-network against age-related degradation. On the other hand, its impact on the cerebral vascular system seems to be characterized by a dampening of CO2 reactivity, possibly because of desensitization effects due to a higher lifetime exposure. Copyright © 2013 Wiley Periodicals, Inc.

  18. Multifocal vascular lesions.

    PubMed

    Levin, Laura E; Lauren, Christine T

    2016-09-01

    Multifocal vascular lesions are important to recognize and appropriately diagnose. Generally first noticed on the skin, multifocal vascular lesions may have systemic involvement. Distinguishing among the different types of multifocal vascular lesions is often based on clinical features; however, radiological imaging and/or biopsy are frequently needed to identify distinct features and guide treatment. Knowledge of the systemic associations that can occur with different vascular anomalies may reduce life-threatening complications, such as coagulopathy, bleeding, cardiac compromise, and neurologic sequelae. This review provides a synopsis of the epidemiology, pathogenesis, presentation, workup, and treatment of several well-recognized multifocal vascular tumors and malformations.

  19. Physical Activity: A Viable Way to Reduce the Risks of Mild Cognitive Impairment, Alzheimer's Disease, and Vascular Dementia in Older Adults.

    PubMed

    Gallaway, Patrick J; Miyake, Hiroji; Buchowski, Maciej S; Shimada, Mieko; Yoshitake, Yutaka; Kim, Angela S; Hongu, Nobuko

    2017-02-20

    A recent alarming rise of neurodegenerative diseases in the developed world is one of the major medical issues affecting older adults. In this review, we provide information about the associations of physical activity (PA) with major age-related neurodegenerative diseases and syndromes, including Alzheimer's disease, vascular dementia, and mild cognitive impairment. We also provide evidence of PA's role in reducing the risks of these diseases and helping to improve cognitive outcomes in older adults. Finally, we describe some potential mechanisms by which this protective effect occurs, providing guidelines for future research.

  20. Physical Activity: A Viable Way to Reduce the Risks of Mild Cognitive Impairment, Alzheimer’s Disease, and Vascular Dementia in Older Adults

    PubMed Central

    Gallaway, Patrick J.; Miyake, Hiroji; Buchowski, Maciej S.; Shimada, Mieko; Yoshitake, Yutaka; Kim, Angela S.; Hongu, Nobuko

    2017-01-01

    A recent alarming rise of neurodegenerative diseases in the developed world is one of the major medical issues affecting older adults. In this review, we provide information about the associations of physical activity (PA) with major age-related neurodegenerative diseases and syndromes, including Alzheimer’s disease, vascular dementia, and mild cognitive impairment. We also provide evidence of PA’s role in reducing the risks of these diseases and helping to improve cognitive outcomes in older adults. Finally, we describe some potential mechanisms by which this protective effect occurs, providing guidelines for future research. PMID:28230730

  1. Aerobic exercise and weight loss reduce vascular markers of inflammation and improve insulin sensitivity in obese women.

    PubMed

    Ryan, Alice S; Ge, Shealinna; Blumenthal, Jacob B; Serra, Monica C; Prior, Steven J; Goldberg, Andrew P

    2014-04-01

    To examine the relationships between plasma and tissue markers of systemic and vascular inflammation and obesity and insulin resistance and determine the effects of aerobic exercise training plus weight loss (AEX+WL) and weight loss (WL) alone on these biomarkers. Prospective controlled study. Veterans Affairs Medical Center and University research setting. Overweight and obese sedentary postmenopausal women (N = 77). Six months, 3 d/wk AEX+WL (n = 37) or WL (n = 40). Total-body dual-energy X-ray absorptiometry, abdominal computed tomography, hyperinsulinemic-euglycemic clamps (a criterion standard method of assessing insulin sensitivity), adipose tissue biopsies (n = 28), and blood for homeostasis model assessment-insulin resistance, and soluble forms of intracellular adhesion molecule 1 (sICAM-1) and vascular cell adhesion molecule 1 (sVCAM-1), C-reactive protein (CRP), and serum amyloid A (SAA). Body weight (P < .001), percentage of fat (P < .001), visceral fat (P < .005), triglyceride levels (P < .001), and systolic blood pressure decreased comparably after WL and AEX+WL (P = .04). Maximal oxygen consumption increased 16% after AEX+WL (P < .001). Insulin resistance decreased in both groups (P = .005). Glucose utilization according to the clamp increased 10% (P = .04) with AEX+WL and 8% with WL (P = .07). AEX+WL decreased CRP by 29% (P < .001) and WL by 21% (P = .02). SAA levels decreased twice as much after AEX+WL (-19%, P = .02) as after WL (-9%, P = .08). Plasma sICAM-1 and sVCAM-1 levels did not change, but women with the greatest reduction in plasma sICAM-1 levels had the greatest reductions in fasting glucose (P = .02), insulin (P = .02), and insulin resistance (P = .004). Gluteal ICAM messenger ribonucleic acid levels decreased 27% after AEX+WL (P = .02) and did not change after WL. Obesity and insulin resistance worsen markers of systemic and vascular inflammation. A reduction in plasma sICAM-1 is important to improve insulin sensitivity. CRP, SAA, and

  2. Neuropilin-1 modulates vascular endothelial growth factor-induced poly(ADP-ribose)-polymerase leading to reduced cerebrovascular apoptosis.

    PubMed

    Mey, Lilli; Hörmann, Mareike; Schleicher, Nadine; Reuter, Peter; Dönges, Simone; Kinscherf, Ralf; Gassmann, Max; Gerriets, Tibo; Al-Fakhri, Nadia

    2013-11-01

    Cerebral ischemia is encompassed by cerebrovascular apoptosis, yet the mechanisms behind apoptosis regulation are not fully understood. We previously demonstrated inhibition of endothelial apoptosis by vascular endothelial growth factor (VEGF) through upregulation of poly(ADP-ribose)-polymerase (PARP) expression. However, PARP overactivation through oxidative stress can lead to necrosis. This study tested the hypothesis that neuropilin-1 (NP-1), an alternative VEGF receptor, regulates the response to cerebral ischemia by modulating PARP expression and, in turn, apoptosis inhibition by VEGF. In endothelial cell culture, NP-1 colocalized with VEGF receptor-2 (VEGFR-2) and acted as its coreceptor. This significantly enhanced VEGF-induced PARP mRNA and protein expression demonstrated by receptor-specific inhibitors and VEGF-A isoforms. NP-1 augmented the inhibitory effect of VEGF/VEGFR-2 interaction on apoptosis induced by adhesion inhibition through the αV-integrin inhibitor cRGDfV. NP-1/VEGFR-2 signal transduction involved JNK and Akt. In rat models of permanent and temporary middle cerebral artery occlusion, the ischemic cerebral hemispheres displayed endothelial and neuronal apoptosis next to increased endothelial NP-1 and VEGFR-2 expression compared to non-ischemic cerebral hemispheres, sham-operated or untreated controls. Increased vascular superoxide dismutase-1 and catalase expression as well as decreased glycogen reserves indicated oxidative stress in the ischemic brain. Of note, protein levels of intact PARP remained stable despite pro-apoptotic conditions through increased PARP mRNA production during cerebral ischemia. In conclusion, NP-1 is upregulated in conditions of imminent cerebrovascular apoptosis to reinforce apoptosis inhibition and modulate VEGF-dependent PARP expression and activation. We propose that NP-1 is a key modulator of VEGF maintaining cerebrovascular integrity during ischemia. Modulating the function of NP-1 to target PARP could help to

  3. Plasma-derived human antithrombin attenuates ventilator-induced coagulopathy but not inflammation in a Streptococcus pneumoniae pneumonia model in rats.

    PubMed

    Aslami, H; Haitsma, J J; Hofstra, J J; Florquin, S; Dos Santos, C; Streutker, C; Zhang, H; Levi, M; Slutsky, A S; Schultz, M J

    2012-03-01

    Mechanical ventilation exaggerates pneumonia-associated pulmonary coagulopathy and inflammation. We hypothesized that the administration of plasma-derived human antithrombin (AT), one of the natural inhibitors of coagulation, prevents ventilator-induced pulmonary coagulopathy, inflammation and bacterial outgrowth in a Streptococcus pneumoniae pneumonia model in rats. Forty-eight hours after induction of S. pneumoniae pneumonia rats were subjected to mechanical ventilation (tidal volume 12 mL kg(-1), positive end-expiratory pressure 0 cmH(2)O and inspired oxygen fraction 40%). Rats were randomized to systemic treatment with AT (250 IU administered intravenously (i.v.) before the start of mechanical ventilation) or placebo (saline). Non-ventilated, non-infected rats and non-ventilated rats with pneumonia served as controls. The primary endpoints were pulmonary coagulation and inflammation in bronchoalveolar lavage fluid (BALF). Pneumonia was characterized by local activation of coagulation and inhibition of fibrinolysis, resulting in increased levels of fibrin degradation products and fibrin deposition in the lung. Mechanical ventilation exaggerated pulmonary coagulopathy and inflammation. Systemic administration of AT led to supra-normal BALF levels of AT and decreased ventilator-associated activation of coagulation. AT neither affected pulmonary inflammation nor bacterial outgrowth from the lungs or blood. Plasma-derived human AT attenuates ventilator-induced coagulopathy, but not inflammation and bacterial outgrowth in a S. pneumoniae pneumonia model in rats. © 2012 International Society on Thrombosis and Haemostasis.

  4. Airway Pressure Release Ventilation and High-Frequency Oscillatory Ventilation: Potential Strategies to Treat Severe Hypoxemia and Prevent Ventilator-Induced Lung Injury.

    PubMed

    Facchin, Francesca; Fan, Eddy

    2015-10-01

    Although lifesaving, mechanical ventilation can itself be responsible for damage to lung parenchyma. This ventilator-induced lung injury is especially observed in already injured lungs of patients with ARDS. New ventilatory approaches are needed to safely treat patients with ARDS, and recent studies have suggested the potential utility of open-lung strategies. Airway pressure release ventilation (APRV) and high-frequency oscillatory ventilation (HFOV) are 2 different open-lung strategies that have been proposed to treat refractory hypoxemic respiratory failure while preventing ventilator-induced lung injury. APRV provides increased airway pressure as a potential recruitment mechanism and allows spontaneous breathing, with the potential benefits of decreased sedation, shorter duration of mechanical ventilation, and improvement in cardiac performance. HFOV delivers very small tidal volumes, to prevent volutrauma, at a constant (relatively high) mean airway pressure, thus avoiding atelectrauma. Despite their theoretical benefits, the utility of APRV and HFOV remains unproven and controversial for the routine treatment of ARDS in adult patients. This review is focused on the theoretical and practical aspects of APRV and HFOV, provides an overview of the current evidence, and addresses their possible use in the treatment of ARDS.

  5. Inhibition of the ubiquitin-proteasome pathway does not protect against ventilator-induced accelerated proteolysis or atrophy in the diaphragm.

    PubMed

    Smuder, Ashley J; Nelson, W Bradley; Hudson, Matthew B; Kavazis, Andreas N; Powers, Scott K

    2014-07-01

    Mechanical ventilation (MV) is a life-saving intervention in patients with acute respiratory failure. However, prolonged MV results in ventilator-induced diaphragm dysfunction (VIDD), a condition characterized by both diaphragm fiber atrophy and contractile dysfunction. Previous work has shown that calpain, caspase-3, and the ubiquitin-proteasome pathway (UPP) are all activated in the diaphragm during prolonged MV. However, although it is established that both calpain and caspase-3 are important contributors to VIDD, the role that the UPP plays in the development of VIDD remains unknown. These experiments tested the hypothesis that inhibition of the UPP will protect the diaphragm against VIDD. The authors tested this prediction in an established animal model of MV using a highly specific UPP inhibitor, epoxomicin, to prevent MV-induced activation of the proteasome in the diaphragm (n = 8 per group). The results of this study reveal that inhibition of the UPP did not prevent ventilator-induced diaphragm muscle fiber atrophy and contractile dysfunction during 12 h of MV. Also, inhibition of the UPP does not affect MV-induced increases in calpain and caspase-3 activity in the diaphragm. Finally, administration of the proteasome inhibitor did not protect against the MV-induced increases in the expression of the E3 ligases, muscle ring finger-1 (MuRF1), and atrogin-1/MaFbx. Collectively, these results indicate that proteasome activation does not play a required role in VIDD development during the first 12 h of MV.

  6. Inhibition of the ubiquitin-proteasome pathway does not protect against ventilator-induced accelerated proteolysis or atrophy in the diaphragm

    PubMed Central

    Smuder, Ashley J.; Nelson, W. Bradley; Hudson, Matthew B.; Kavazis, Andreas N.; Powers, Scott K.

    2014-01-01

    Background Mechanical ventilation (MV) is a life-saving intervention in patients with acute respiratory failure. However, prolonged MV results in ventilator-induced diaphragm dysfunction (VIDD), a condition characterized by both diaphragm fiber atrophy and contractile dysfunction. Previous work has shown calpain, caspase-3 and the ubiquitin-proteasome pathway (UPP) are all activated in the diaphragm during prolonged MV. However, while it is established that both calpain and caspase-3 are important contributors to VIDD, the role that the UPP plays in VIDD remains unknown. These experiments tested the hypothesis that inhibition of the UPP will protect the diaphragm against VIDD. Methods We tested this prediction in an established animal model of MV using a highly specific UPP inhibitor, epoxomicin, to prevent MV-induced activation of the proteasome in the diaphragm (n = 8/group). Results Our results reveal that inhibition of the UPP did not prevent ventilator-induced diaphragm muscle fiber atrophy and contractile dysfunction during 12 hours of MV. Also, inhibition of the UPP does not impact MV-induced increases in calpain and caspase-3 activity in the diaphragm. Finally, administration of the proteasome inhibitor did not protect against the MV-induced increases in the expression of the E3 ligases, MuRF1 and atrogin-1/MaFbx. Conclusions Collectively, these results indicate that proteasome activation does not play a required role in VIDD during the first 12 hours of MV. PMID:24681580

  7. MicroRNA126 contributes to granulocyte colony-stimulating factor-induced hematopoietic progenitor cell mobilization by reducing the expression of vascular cell adhesion molecule 1.

    PubMed

    Salvucci, Ombretta; Jiang, Kan; Gasperini, Paola; Maric, Dragan; Zhu, Jinfang; Sakakibara, Shuhei; Espigol-Frigole, Georgina; Wang, Shushang; Tosato, Giovanna

    2012-06-01

    Mobilization of hematopoietic stem/progenitor cells from the bone marrow to the peripheral blood by granulocyte colony-stimulating factor is the primary means to acquire stem cell grafts for hematopoietic cell transplantation. Since hematopoietic stem/progenitor cells represent a minority of all blood cells mobilized by granulocyte colony-stimulating factor, the underlying mechanisms need to be understood in order to develop selective drugs. We analyzed phenotypic, biochemical and genetic changes in bone marrow cell populations from granulocyte colony-stimulating factor-mobilized and control mice, and linked such changes to effective mobilization of hematopoietic stem/progenitor cells. We show that granulocyte colony-stimulating factor indirectly reduces expression of surface vascular cell adhesion molecule 1 on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells by promoting the accumulation of microRNA-126 (miR126)-containing microvescicles in the bone marrow extracellular compartment. We found that hematopoietic stem/progenitor cells, stromal cells and endothelial cells readily incorporate these miR126-loaded microvescicles, and that miR126 represses vascular cell adhesion molecule 1 expression on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells. In line with this, miR126-null mice displayed a reduced mobilization response to granulocyte colony-stimulating factor. Our results implicate miR126 in the regulation of hematopoietic stem/progenitor cell trafficking between the bone marrow and peripheral sites, clarify the role of vascular cell adhesion molecule 1 in granulocyte colony-stimulating factor-mediated mobilization, and have important implications for improved approaches to selective mobilization of hematopoietic stem/progenitor cells.

  8. Increased insulin sensitivity and reduced micro and macro vascular disease induced by 2-deoxy-D-glucose during metabolic syndrome in obese JCR: LA-cp rats

    PubMed Central

    Russell, J C; Proctor, S D

    2007-01-01

    Background and purpose: The metabolic syndrome, characterized by obesity, insulin resistance and dyslipidemia, is a major cause of cardiovascular disease. The origins of the syndrome have been hypothesized to lie in continuous availability of energy dense foods in modern societies. In contrast, human physiology has evolved in an environment of sporadic food supply and frequent food deprivation. Intermittent food restriction in rats has previously been shown to lead to reduction of cardiovascular risk and a greater life span. The non-metabolizable glucose analogue, 2-deoxy-D-glucose (2-DG) is taken up by cells and induces pharmacological inhibition of metabolism of glucose. We hypothesized that intermittent inhibition of glucose metabolism, a metabolic deprivation, may mimic intermittent food deprivation and ameliorate metabolic and pathophysiological aspects of the metabolic syndrome. Experimental approach: Insulin resistant, atherosclerosis-prone JCR:LA-cp rats were treated with 2-DG (0.3% w/w in chow) on an intermittent schedule (2 days treated, one day non-treated, two days treated and two days non-treated) or continuously at a dose to give an equivalent averaged intake. Key results: Intermittent 2-DG-treatment improved insulin sensitivity, which correlated with increased adiponectin concentrations. Further, intermittent treatment (but not continuous treatment) reduced plasma levels of leptin and the inflammatory cytokine IL-1β. Both 2-DG treatments reduced micro-vascular glomerular sclerosis, but only the intermittent schedule improved macro-vascular dysfunction. Conclusions and implications: Our findings are consistent with reduction in severity of the metabolic syndrome and protection against end stage micro- and macro-vascular disease through intermittent metabolic deprivation at a cellular level by inhibition of glucose oxidation with 2-DG. PMID:17375078

  9. Increased insulin sensitivity and reduced micro and macro vascular disease induced by 2-deoxy-D-glucose during metabolic syndrome in obese JCR: LA-cp rats.

    PubMed

    Russell, J C; Proctor, S D

    2007-05-01

    The metabolic syndrome, characterized by obesity, insulin resistance and dyslipidemia, is a major cause of cardiovascular disease. The origins of the syndrome have been hypothesized to lie in continuous availability of energy dense foods in modern societies. In contrast, human physiology has evolved in an environment of sporadic food supply and frequent food deprivation. Intermittent food restriction in rats has previously been shown to lead to reduction of cardiovascular risk and a greater life span. The non-metabolizable glucose analogue, 2-deoxy-D-glucose (2-DG) is taken up by cells and induces pharmacological inhibition of metabolism of glucose. We hypothesized that intermittent inhibition of glucose metabolism, a metabolic deprivation, may mimic intermittent food deprivation and ameliorate metabolic and pathophysiological aspects of the metabolic syndrome. Insulin resistant, atherosclerosis-prone JCR:LA-cp rats were treated with 2-DG (0.3% w/w in chow) on an intermittent schedule (2 days treated, one day non-treated, two days treated and two days non-treated) or continuously at a dose to give an equivalent averaged intake. Intermittent 2-DG-treatment improved insulin sensitivity, which correlated with increased adiponectin concentrations. Further, intermittent treatment (but not continuous treatment) reduced plasma levels of leptin and the inflammatory cytokine IL-1 beta. Both 2-DG treatments reduced micro-vascular glomerular sclerosis, but only the intermittent schedule improved macro-vascular dysfunction. Our findings are consistent with reduction in severity of the metabolic syndrome and protection against end stage micro- and macro-vascular disease through intermittent metabolic deprivation at a cellular level by inhibition of glucose oxidation with 2-DG.

  10. Reduced Efficacy of Anti-Aβ Immunotherapy in a Mouse Model of Amyloid Deposition and Vascular Cognitive Impairment Comorbidity.

    PubMed

    Weekman, Erica M; Sudduth, Tiffany L; Caverly, Carly N; Kopper, Timothy J; Phillips, Oliver W; Powell, Dave K; Wilcock, Donna M

    2016-09-21

    Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia behind Alzheimer's disease (AD). It is estimated that 40% of AD patients also have some form of VCID. One promising therapeutic for AD is anti-Aβ immunotherapy, which uses antibodies against Aβ to clear it from the brain. While successful in clearing Aβ and improving cognition in mice, anti-Aβ immunotherapy failed to reach primary cognitive outcomes in several different clinical trials. We hypothesized that one potential reason the anti-Aβ immunotherapy clinical trials were unsuccessful was due to this high percentage of VCID comorbidity in the AD population. We used our unique model of VCID-amyloid comorbidity to test this hypothesis. We placed 9-month-old wild-type and APP/PS1 mice on either a control diet or a diet that induces hyperhomocysteinemia (HHcy). After being placed on the diet for 3 months, the mice then received intraperotineal injections of either IgG2a control or 3D6 for another 3 months. While we found that treatment of our comorbidity model with 3D6 resulted in decreased total Aβ levels, there was no cognitive benefit of the anti-Aβ immunotherapy in our AD/VCID mice. Further, microhemorrhages were increased by 3D6 in the APP/PS1/control but further increased in an additive fashion when 3D6 was administered to the APP/PS1/HHcy mice. This suggests that the use of anti-Aβ immunotherapy in patients with both AD and VCID would be ineffective on cognitive outcomes. Despite significant mouse model data demonstrating both pathological and cognitive efficacy of anti-Aβ immunotherapy for the treatment of Alzheimer's disease, clinical trial outcomes have been underwhelming, failing to meet any primary endpoints. We show here that vascular cognitive impairment and dementia (VCID) comorbidity eliminates cognitive efficacy of anti-Aβ immunotherapy, despite amyloid clearance. Further, cerebrovascular adverse events of the anti-Aβ immunotherapy are

  11. Antisense versus proopiomelanocortin mRNA reduces vascular risk in a murine model of type-2 diabetes following stress exposure in early post-natal life.

    PubMed

    Loizzo, Alberto; Spampinato, Santi M; Fortuna, Andrea; Vella, Stefano; Fabi, Fulvia; Del Basso, Paola; Campana, Gabriele; Loizzo, Stefano

    2015-02-01

    Mechanisms of vascular complications in type-2 diabetes patients and animal models are matter of debate. We previously demonstrated that a double-stress model applied to male mice during nursing period produces enduring hyperfunction of endogenous opioid and adrenocorticotropin (ACTH)-corticosteroid systems, accompanied by type-2 diabetes-like alterations in adult animals. Administration of the opioid receptor antagonist naloxone, or of an antisense oligodeoxynucleotide versus proopiomelanocortin mRNA, capable to block the pro-opiomelanocortin-derived peptides β-endorphin and ACTH, selectively prevent these alterations. Here, we investigated alterations produced by our stress model on aorta endothelium-dependent relaxation and contractile responses. Mice, stressed during nursing period, showed in the adulthood hormonal and metabolic type-2 diabetes-like alterations, including hyperglycemia, increased body weight and increased plasma ACTH and corticosterone levels. Ex vivo isolated aorta rings, gathered from stressed mice, were less sensitive to noradrenaline-induced contractions versus controls. This effect was blocked by nitric-oxide synthase-inhibitor l-N(G)-nitroarginine added to bath organ solution. Aorta rings relaxation caused by acetylcholine was enhanced in stressed mice versus controls, but following treatment with the nitric-oxide donor sodium nitroprusside, concentration-relaxation curves in aorta from stressed groups were similar to controls. Therefore, vascular response alterations to physiologic-pharmacologic stimuli were apparently due to nitric-oxide hyperfunction-dependent mechanisms. Aorta functional alterations, and plasma stress hormones enhancement, were prevented in mice stressed and treated with antisense oligodeoxinucleotide, addressed to reduce ACTH- and corticosteroid-mediated hyperfunction. This study demonstrates the key role of ACTH-corticosteroid axis hyperfunction for the triggering of vascular conditions in male adult rodents

  12. DELETION OF PROTEIN TYROSINE PHOSPHATASE 1B IMPROVES PERIPHERAL INSULIN RESISTANCE AND VASCULAR FUNCTION IN OBESE, LEPTIN RESISTANT MICE VIA REDUCED OXIDANT TONE

    PubMed Central

    Ali, M. Irfan; Ketsawatsomkron, Pimonrat; Belin de Chantelemele, Eric J.; Mintz, James D.; Muta, Kenjiro; Salet, Christina; Black, Stephen M.; Tremblay, Michel L.; Fulton, David J.; Marrero, Mario B.; Stepp, David W.

    2009-01-01

    Rationale Obesity is a risk factor for cardiovascular dysfunction, yet the underlying factors driving this impaired function remain poorly understood. Insulin resistance is a common pathology in obese patients and has been shown to impair vascular function. Whether insulin resistance or obesity, itself, is causal remains unclear. Objective The current study tested the hypothesis that insulin resistance is the underlying mediator for impaired nitric oxide mediated dilation in obesity by genetic deletion of the insulin-desensitizing enzyme protein tyrosine phosphatase 1B (PTP1B) in db/db mice. Methods and Results The db/db mouse is morbidly obese, insulin resistant and has tissue-specific elevation in PTP1B expression compared to lean controls. In db/db mice, PTP1B deletion improved glucose clearance, dyslipidemia, and insulin receptor signaling in muscle and fat. Hepatic insulin signaling in db/db mice was not improved by deletion of PTP1B, indicating specific amelioration of peripheral insulin resistance. Additionally, obese mice demonstrate an impaired endothelium dependent and independent vasodilation to acetylcholine and sodium nitroprusside, respectively. This impairment, which correlated with increased superoxide in the db/db mice, was corrected by superoxide scavenging. Increased superoxide production was associated with increased expression of NAD(P)H Oxidase 1 and its molecular regulators, Noxo1 and Noxa1. Conclusion Deletion of PTP1B improved both endothelium dependent and independent nitric oxide mediated dilation and reduced superoxide generation in db/db mice. PTP1B deletion did not affect any vascular function in lean mice. Taken together, these data reveal a role for peripheral insulin resistance as the mediator of vascular dysfunction in obesity. PMID:19797171

  13. Reduced Cystathionine γ-Lyase and Increased miR-21 Expression Are Associated with Increased Vascular Resistance in Growth-Restricted Pregnancies

    PubMed Central

    Cindrova-Davies, Tereza; Herrera, Emilio A.; Niu, Youguo; Kingdom, John; Giussani, Dino A.; Burton, Graham J.

    2013-01-01

    Increased vascular impedance in the fetoplacental circulation is associated with fetal hypoxia and growth restriction. We sought to investigate the role of hydrogen sulfide (H2S) in regulating vasomotor tone in the fetoplacental vasculature. H2S is produced endogenously by catalytic activity of cystathionine β-synthase and cystathionine γ-lyase (CSE). Immunohistochemical analysis localized CSE to smooth muscle cells encircling arteries in stem villi. Immunoreactivity was reduced in placentas from pregnancies with severe early-onset growth-restriction and preeclampsia displaying abnormal umbilical artery Doppler waveforms compared with preeclamptic placentas with normal waveforms and controls. These findings were confirmed at the protein and mRNA levels. MicroRNA-21, which negatively regulates CSE expression, was increased in placentas with abnormal Doppler waveforms. Exposure of villus explants to hypoxia-reoxygenation significantly reduced CSE protein and mRNA and increased microRNA-21 expression. No changes were observed in cystathionine β-synthase expression, immunolocalized principally to the trophoblast, in pathologic placentas or in vitro. Finally, perfusion of normal placentas with an H2S donor, after preconstriction with a thromboxane mimetic, resulted in dose-dependent vasorelaxation. Glibenclamide and NG-nitro-l-arginine methyl ester partially blocked the effect, indicating that H2S acts through ATP-sensitive K+ channels and nitric oxide synthesis. These results demonstrate that H2S is a powerful vasodilator of the placental vasculature and that expression of CSE is reduced in placentas associated with increased vascular resistance. PMID:23410520

  14. Peroxisome proliferator-activated receptor-γ activation reduces cyclooxygenase-2 expression in vascular smooth muscle cells from hypertensive rats by interfering with oxidative stress.

    PubMed

    Martín, Angela; Pérez-Girón, José V; Hernanz, Raquel; Palacios, Roberto; Briones, Ana M; Fortuño, Ana; Zalba, Guillermo; Salaices, Mercedes; Alonso, María J

    2012-02-01

    Hypertension is associated with increased plasma inflammatory markers such as cytokines and increased vascular cyclooxygenase-2 (COX-2) expression. The ability of peroxisome proliferator-activated receptor-γ (PPARγ) agonists to reduce oxidative stress seems to contribute to their anti-inflammatory properties. This study analyzes the effect of pioglitazone, a PPARγ agonist, on interleukin-1β-induced COX-2 expression and the role of reactive oxygen species (ROS) on this effect. Vascular smooth muscle cells from hypertensive rats stimulated with interleukin-1β (10 ng/ml, 24 h) were used. Interleukin-1β increased: 1) COX-2 protein and mRNA levels; 2) protein and mRNA levels of the NADPH oxidase subunit NOX-1, NADPH oxidase activity and ROS production; and 3) phosphorylation of inhibitor of nuclear factor kappa B (IκB) kinase (IKK) nuclear expression of the p65 nuclear factor kappa B (NF-κB) subunit and cell proliferation, all of which were reduced by apocynin (30 μmol/l). Interleukin-1β-induced COX-2 expression was reduced by apocynin, tempol (10 μmol/l), catalase (1000 U/ml) and lactacystin (5 μmol/l). Moreover, H2O2 (50 μmol/l, 90 min) induced COX-2 expression, which was reduced by lactacystin. Pioglitazone (10 μmol/l) reduced the effects of interleukin-1β on: 1) COX-2 protein and mRNA levels; 2) NOX-1 protein and mRNA levels, NADPH oxidase activity and ROS production; and 3) p-IKK, p65 expressions and cell proliferation. Pioglitazone also reduced the H2O2-induced COX-2 expression and increased Cu/Zn and Mn-superoxide dismutase protein expression. PPARγ small interfering RNA (5 nmol/l) further increased interleukin-1β-induced COX-2 and NOX-1 mRNA levels. In addition, pioglitazone increased the interleukin-1β-induced PPARγ mRNA levels. PPARγ activation with pioglitazone reduces interleukin-1β-induced COX-2 expression by interference with the redox-sensitive transcription factor NF-κB.

  15. Sulforaphane reduces vascular inflammation in mice and prevents TNF-α-induced monocyte adhesion to primary endothelial cells through interfering with the NF-κB pathway.

    PubMed

    Nallasamy, Palanisamy; Si, Hongwei; Babu, Pon Velayutham Anandh; Pan, Dengke; Fu, Yu; Brooke, Elizabeth A S; Shah, Halley; Zhen, Wei; Zhu, Hong; Liu, Dongmin; Li, Yunbo; Jia, Zhenquan

    2014-08-01

    Sulforaphane, a naturally occurring isothiocyanate present in cruciferous vegetables, has received wide attention for its potential to improve vascular function in vitro. However, its effect in vivo and the molecular mechanism of sulforaphane at physiological concentrations remain unclear. Here, we report that a sulforaphane concentration as low as 0.5 μM significantly inhibited tumor necrosis factor-α (TNF-α)-induced adhesion of monocytes to human umbilical vein endothelial cells, a key event in the pathogenesis of atherosclerosis both in static and under flow conditions. Such physiological concentrations of sulforaphane also significantly suppressed TNF-α-induced production of monocyte chemotactic protein-1 and adhesion molecules including soluble vascular adhesion molecule-1 and soluble E-selectin, key mediators in the regulation of enhanced endothelial cell-monocyte interaction. Furthermore, sulforaphane inhibited TNF-α-induced nuclear factor (NF)-κB transcriptional activity, Inhibitor of NF-κB alpha (IκBα) degradation and subsequent NF-κB p65 nuclear translocation in endothelial cells, suggesting that sulforaphane can inhibit inflammation by suppressing NF-κB signaling. In an animal study, sulforaphane (300 ppm) in a mouse diet significantly abolished TNF-α-increased ex vivo monocyte adhesion and circulating adhesion molecules and chemokines in C57BL/6 mice. Histology showed that sulforaphane treatment significantly prevented the eruption of endothelial lining in the intima layer of the aorta and preserved elastin fibers' delicate organization, as shown by Verhoeff-van Gieson staining. Immunohistochemistry studies showed that sulforaphane treatment also reduced vascular adhesion molecule-1 and monocyte-derived F4/80-positive macrophages in the aorta of TNF-α-treated mice. In conclusion, sulforaphane at physiological concentrations protects against TNF-α-induced vascular endothelial inflammation, in both in vitro and in vivo models. This anti

  16. Common Phenolic Metabolites of Flavonoids, but Not Their Unmetabolized Precursors, Reduce the Secretion of Vascular Cellular Adhesion Molecules by Human Endothelial Cells123

    PubMed Central

    Warner, Emily F; Zhang, Qingzhi; Raheem, K Saki; O’Hagan, David; O’Connell, Maria A; Kay, Colin D

    2016-01-01

    Background: Flavonoids have been implicated in the prevention of cardiovascular disease; however, their mechanisms of action have yet to be elucidated, possibly because most previous in vitro studies have used supraphysiological concentrations of unmetabolized flavonoids, overlooking their more bioavailable phenolic metabolites. Objective: We aimed to explore the effects of phenolic metabolites and their precursor flavonoids at physiologically achievable concentrations, in isolation and combination, on soluble vascular cellular adhesion molecule-1 (sVCAM-1). Method: Fourteen phenolic acid metabolites and 6 flavonoids were screened at 1 μM for their relative effects on sVCAM-1 secretion by human umbilical vein endothelial cells stimulated with tumor necrosis factor alpha (TNF-α). The active metabolites were further studied for their response at different concentrations (0.01 μM–100 μM), structure-activity relationships, and effect on vascular cellular adhesion molecule (VCAM)-1 mRNA expression. In addition, the additive activity of the metabolites and flavonoids was investigated by screening 25 unique mixtures at cumulative equimolar concentrations of 1 μM. Results: Of the 20 compounds screened at 1 μM, inhibition of sVCAM-1 secretion was elicited by 4 phenolic metabolites, of which protocatechuic acid (PCA) was the most active (−17.2%, P = 0.05). Investigations into their responses at different concentrations showed that PCA significantly reduced sVCAM-1 15.2–36.5% between 1 and 100 μM, protocatechuic acid-3-sulfate and isovanillic acid reduced sVCAM-1 levels 12.2–54.7% between 10 and 100 μM, and protocatechuic acid-4-sulfate and isovanillic acid-3-glucuronide reduced sVCAM-1 secretion 27.6% and 42.8%, respectively, only at 100 μM. PCA demonstrated the strongest protein response and was therefore explored for its effect on VCAM-1 mRNA, where 78.4% inhibition was observed only after treatment with 100 μM PCA. Mixtures of the metabolites showed no

  17. Reduced oligomeric and vascular amyloid-beta following immunization of TgCRND8 mice with an Alzheimer's DNA vaccine.

    PubMed

    DaSilva, Kevin A; Brown, Mary E; McLaurin, JoAnne

    2009-02-25

    Immunization with amyloid-beta (Abeta) peptide reduces amyloid load in animal studies and in humans; however clinical trials resulted in the development of a pro-inflammatory cellular response to Abeta. Apoptosis has been employed to stimulate humoral and Th2-biased cellular immune responses. Thus, we sought to investigate whether immunization using a DNA vaccine encoding Abeta in conjunction with an attenuated caspase generates therapeutically effective antibodies. Plasmids encoding Abeta and an attenuated caspase were less effective in reducing amyloid pathology than those encoding Abeta alone. Moreover, use of Abeta with an Arctic mutation (E22G) as an immunogen was less effective than wild-type Abeta in terms of improvements in pathology. Low levels of IgG and IgM were generated in response to immunization with a plasmid encoding wild-type Abeta. These antibodies decreased plaque load by as much as 36+/-8% and insoluble Abeta42 levels by 56+/-3%. Clearance of Abeta was most effective when antibodies were directed against N-terminal epitopes of Abeta. Moreover, immunization reduced CAA by as much as 69+/-12% in TgCRND8 mice. Finally, high-molecular-weight oligomers and Abeta trimers were significantly reduced with immunization. Thus, immunization with a plasmid encoding Abeta alone drives an attenuated immune response that is sufficient to clear amyloid pathology in a mouse model of Alzheimer's disease.

  18. Pretreatment of synthetic vascular grafts with heparin before implantation, a simple technique to reduce the risk of thrombosis.

    PubMed

    Gerrah, Rabin; Sunstrom Pa-C, Rachel E; Hohimer, Alan R

    2015-10-01

    Thrombosis of synthetic grafts commonly used in cardiovascular surgery is a major complication. We examined whether pretreatment of the graft with heparin reduces the risk of early thrombosis. A circuit was assembled to compare two pairs of shunts simultaneously in the same animal. The study shunts were pretreated with heparin. After 2 hours of circulation, clot formation was evaluated by image analysis techniques. The pretreated grafts had fewer blood clots adhered to the surface by direct visual inspection. The image analysis showed 5 vs. 39 clots, 0.01% vs. 1.8% clotted area, and 62 vs. 5630 clot pixel area between the treated and non-treated grafts respectively, p < 0.05. Pretreatment of the synthetic graft with heparin prior to implantation reduces the risk of early clot formation. This simple practice might be helpful to prevent initial thrombosis of the graft and later occlusion. © The Author(s) 2014.

  19. Is There a Role for Preoperative 5 Alpha Reductase Inhibitors in Reducing Prostate Vascularity and Blood Loss?

    PubMed

    Bruha, Matthew; Welliver, Charles

    2017-10-01

    Benign prostatic hyperplasia (BPH) and the related medical problems are a major burden as health care costs and as a cause of patient morbidity. The introduction of medical therapy largely offered an alternative to surgical therapy, and these medications have been linked with multiple positive BPH-related outcomes. With ubiquitous use, however, a variety of adverse side effects and unsupported claims to these medications have been reported both in scientific literature and popular press. The use of 5 alpha reductase inhibitors (5ARIs) to reduce recurrent bleeding due to BPH is a reasonable option for men with recurrent trips to the physician or hospital. After a largely anecdotal report of their use in the preoperative period to reduce bleeding during BPH surgery, there was interest in the use of 5ARIs for this indication considering the effusive bleeding that can occur during BPH-related surgery, a dreaded and not uncommon complication. While the pathophysiology for the use of 5ARI to reduce BPH-related bleeding is sound, the actual clinical outcomes still require scrutiny to determine if the efficacy is both scientifically valid and clinically significant. This report will review the current literature on this topic and make attempts to determine if the use of a 5ARI before BPH-related surgery should be encouraged.

  20. Alagebrium inhibits neointimal hyperplasia and restores distributions of wall shear stress by reducing downstream vascular resistance in obese and diabetic rats

    PubMed Central

    Wang, Hongfeng; Weihrauch, Dorothee; Kersten, Judy R.; Toth, Jeffrey M.; Passerini, Anthony G.; Rajamani, Anita; Schrepfer, Sonja

    2015-01-01

    Mechanisms of restenosis in type 2 diabetes mellitus (T2DM) are incompletely elucidated, but advanced glycation end-product (AGE)-induced vascular remodeling likely contributes. We tested the hypothesis that AGE-related collagen cross-linking (ARCC) leads to increased downstream vascular resistance and altered in-stent hemodynamics, thereby promoting neointimal hyperplasia (NH) in T2DM. We proposed that decreasing ARCC with ALT-711 (Alagebrium) would mitigate this response. Abdominal aortic stents were implanted in Zucker lean (ZL), obese (ZO), and diabetic (ZD) rats. Blood flow, vessel diameter, and wall shear stress (WSS) were calculated after 21 days, and NH was quantified. Arterial segments (aorta, carotid, iliac, femoral, and arterioles) were harvested to detect ARCC and protein expression, including transforming growth factor-β (TGF-β) and receptor for AGEs (RAGE). Downstream resistance was elevated (60%), whereas flow and WSS were significantly decreased (44% and 56%) in ZD vs. ZL rats. NH was increased in ZO but not ZD rats. ALT-711 reduced ARCC and resistance (46%) in ZD rats while decreasing NH and producing similar in-stent WSS across groups. No consistent differences in RAGE or TGF-β expression were observed in arterial segments. ALT-711 modified lectin-type oxidized LDL receptor 1 but not RAGE expression by cells on decellularized matrices. In conclusion, ALT-711 decreased ARCC, increased in-stent flow rate, and reduced NH in ZO and ZD rats through RAGE-independent pathways. The study supports an important role for AGE-induced remodeling within and downstream of stent implantation to promote enhanced NH in T2DM. PMID:26254329

  1. Reduced proliferation of aged human vascular smooth muscle cells--role of oxygen-derived free radicals and BubR1 expression.

    PubMed

    Guntani, Atsushi; Matsumoto, Takuya; Kyuragi, Ryoichi; Iwasa, Kazuomi; Onohara, Toshihiro; Itoh, Hiroyuki; Katusic, Zvonimir S; Maehara, Yoshihiko

    2011-09-01

    Aging is a risk factor for atherosclerosis. Recent studies suggest cell cycle events as well as reactive oxygen species (ROS) contribute to vascular cell dysfunction associated with aging. Mice expressing low levels of the spindle assembly checkpoint protein BubR1 develop aging-associated vascular changes at a young age, including decreased smooth muscle cells and increased reactive oxygen species (ROS) production. This study was designed to determine the effect of aging and production of oxygen-derived free radicals on expression of BubR1. To assess cell proliferation capacity, human aortic smooth muscle cells (hAoSMC) derived from a young group (17-30 y) or an aged group (57-62 y) were cultured, and cell numbers were directly counted in using a Neubauer chamber. RT-PCR assay was used to evaluate BubR1 expression in cultured hAoSMC stimulated with Angiotensin II or H(2)O(2). No significant difference in BubR1 expression or hAoSMC proliferative ability was demonstrated at passage 5, but both were significantly decreased at passage 8 in the aged hAoSMC. Angiotensin II and H(2)O(2) up-regulated BubR1 expression in young hAoSMC, and the up-regulation was abrogated by a p38 MAPK inhibitor or an inhibitor of the NADH/NADPH oxidase. siRNA against BubR1 reduced proliferative activity and increased ROS production in hAoSMC. These findings demonstrate BubR1 mRNA expression decreases along with proliferation in aged hAoSMC. Aging-related loss of BubR1 and subsequent impairment of reactivity to ROS may explain reduced proliferative capacity of aged smooth muscle cells. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. A naturally occurring carotenoid, lutein, reduces PDGF and H2O2 signaling and compromised migration in cultured vascular smooth muscle cells

    PubMed Central

    2012-01-01

    Background Platelet-derived growth factor (PDGF) is a potent stimulator of growth and motility of vascular smooth muscle cells (VSMCs). Abnormalities of PDGF/PDGF receptor (PDGFR) are thought to contribute to vascular diseases and malignancy. We previously showed that a carotenoid, lycopene, can directly bind to PDGF and affect its related functions in VSMCs. In this study we examined the effect of the other naturally occurring carotenoid, lutein, on PDGF signaling and migration in VSMCs. Methods Western blotting was performed to examine PDGF and H2O2 signaling. Flowcytometry was used to determine PDGF binding to VSMCs. Fluorescence microscopy was performed to examine intracellular ROS production. Modified Boyden chamber system (Transwell apparatus) was used for migration assay. Results Lutein reduced PDGF signaling, including phosphorylation of PDGFR-β and its downstream protein kinases/enzymes such as phospholipase C-γ, Akt, and mitogen-activated protein kinases (MAPKs). Although lutein possesses a similar structure to lycopene, it was striking that lutein inhibited PDGF signaling through a different way from lycopene in VSMCs. Unlike lycopene, lutein not only interacted with (bound to) PDGF but also interfered with cellular components. This was evidenced that preincubation of PDGF with lutein and treatment of VSMCs with lutein followed by removing of lutein compromised PDGF-induced signaling. Lutein reduced PDGF-induced intracellular reactive oxygen species (ROS) production and attenuated ROS- (H2O2-) induced ERK1/2 and p38 MAPK activation. A further analysis indicated lutein could inhibit a higher concentration of H2O2-induced PDGFR signaling, which is known to act through an oxidative inhibition of protein tyrosine phosphatase. Finally, we showed that lutein functionally inhibited PDGF-induced VSMC migration, whereas its stereo-isomer zeaxanthin did not, revealing a special action of lutein on VSMCs. Conclusions Our study reveals a differential action

  3. NHE1 knockout reduces blood pressure and arterial media/lumen ratio with no effect on resting pH(i) in the vascular wall.

    PubMed

    Boedtkjer, Ebbe; Damkier, Helle H; Aalkjaer, Christian

    2012-04-15

    Acid–base transport in the vascular wall remains incompletely understood. Here, we investigated (a) implications of Na(+)/H(+) exchanger NHE1 knockout for vascular smooth muscle (VSMC) and endothelial cell (EC) pH(i) regulation, mesenteric artery morphology, vasomotor function and blood pressure regulation, and (b) consequences of sustained EC and VSMC acidification for vasomotor function. Na(+)/H(+) exchange activity was abolished in VSMCs and ECs from NHE1 knockout mice, but with CO(2)/HCO(3)(−) present, steady-state pH(i) was unaffected. Active tension was 30% smaller in arteries from NHE1 knockout than wild-type mice, and media thickness equally reduced. Number of VSMCs per unit artery length was unchanged whereas volume and cross-sectional area of individual VSMCs were reduced. Media stress, force production per VSMC cross-sectional area and VSMC Ca(2+) responses were unaffected. Blood pressure was 25 mmHg lower in NHE1 knockout than wild-type mice. Omission of CO(2)/HCO(3)(−) caused VSMCs and ECs to acidify substantially more in NHE1 knockout (0.3–0.6 pH-units) than wild-type (0.02–0.1 pH units) mice. Removing CO(2)/HCO(3)(−) inhibited acetylcholine-induced NO-mediated relaxations in arteries from NHE1 knockout but not wild-type mice. Without CO(2)/HCO(3)(−), effects of NO synthase and rho kinase inhibition on noradrenaline-induced contractions were smaller in arteries from NHE1 knockout than wild-type mice whereas the EC Ca(2+) response to acetylcholine, VSMC Ca(2+) response to noradrenaline and vasorelaxation to S-nitroso-N-acetylpenicillamine were unaffected. In conclusion, NHE1 mediates the Na(+)/H(+) exchange in ECs and VSMCs. Under physiological conditions, CO(2)/HCO(3)(−)-dependent mechanisms mask the pH(i)-regulatory function of NHE1. NHE1 knockout causes hypotrophy of VSMCs, reduced artery tension and lower blood pressure. At acidic pH(i), NO-mediated vasorelaxation and rho kinase-dependent VSMC Ca(2+) sensitivity are reduced.

  4. Hypoglycemia Reduces Vascular Endothelial Growth Factor A Production by Pancreatic Beta Cells as a Regulator of Beta Cell Mass*

    PubMed Central

    Xiao, Xiangwei; Guo, Ping; Chen, Zean; El-Gohary, Yousef; Wiersch, John; Gaffar, Iljana; Prasadan, Krishna; Shiota, Chiyo; Gittes, George K.

    2013-01-01

    VEGF-A expression in beta cells is critical for pancreatic development, formation of islet-specific vasculature, and Insulin secretion. However, two key questions remain. First, is VEGF-A release from beta cells coupled to VEGF-A production in beta cells? Second, how is the VEGF-A response by beta cells affected by metabolic signals? Here, we show that VEGF-A secretion, but not gene transcription, in either cultured islets or purified pancreatic beta cells, was significantly reduced early on during low glucose conditions. In vivo, a sustained hypoglycemia in mice was induced with Insulin pellets, resulting in a significant reduction in beta cell mass. This loss of beta cell mass could be significantly rescued with continuous delivery of exogenous VEGF-A, which had no effect on beta cell mass in normoglycemic mice. In addition, an increase in apoptotic endothelial cells during hypoglycemia preceded an increase in apoptotic beta cells. Both endothelial and beta cell apoptosis were prevented by exogenous VEGF-A, suggesting a possible causative relationship between reduced VEGF-A and the loss of islet vasculature and beta cells. Furthermore, in none of these experimental groups did beta cell proliferation and islet vessel density change, suggesting a tightly regulated balance between these two cellular compartments. The average islet size decreased in hypoglycemia, which was also prevented by exogenous VEGF-A. Taken together, our data suggest that VEGF-A release in beta cells is independent of VEGF-A synthesis. Beta cell mass can be regulated through modulated release of VEGF-A from beta cells based on physiological need. PMID:23378532

  5. Sulforaphane reduces vascular inflammation in mice and prevents TNF-α-induced monocyte adhesion to primary endothelial cells through interfering with the NF-κB pathway

    PubMed Central

    Nallasamy, Palanisamy; Si, Hongwei; Babu, Pon Velayutham Anandh; Pan, Dengke; Fu, Yu; Brooke, Elizabeth A.S.; Shah, Halley; Zhen, Wei; Zhu, Hong; Liu, Dongmin; Li, Yunbo; Jia, Zhenquan

    2014-01-01

    Sulforaphane, a naturally-occurring isothiocyanate present in cruciferous vegetables, has received wide attention for its potential to improve vascular function in vitro. However, its effect in vivo and the molecular mechanism of sulforaphane at physiological concentrations remain unclear. Here, we report that a sulforaphane concentration as low as 0.5 μM significantly inhibited TNF-α-induced adhesion of monocytes to human umbilical vein endothelial cells (HUVECs), a key event in the pathogenesis of atherosclerosis both in static and under flow conditions. Such physiological concentrations of sulforaphane also significantly suppressed TNF-α-induced production of monocyte chemotactic protein-1 (MCP-1), adhesion molecule sVCAM-1 and sE-Selectin, key mediators in the regulation of enhanced endothelial cell-monocyte interaction. Furthermore, sulforaphane inhibited TNF-α-induced NF-κB transcriptional activity, IκBα degradation and subsequent NF-κB p65 nuclear translocation in endothelial cells, suggesting that sulforaphane can inhibit inflammation by suppressing NF-κB signaling. In an animal study, sulforaphane (300 ppm) in a mouse diet significantly abolished TNF-α-increased ex vivo monocyte adhesion and circulating adhesion molecules and chemokines in C57BL/6 mice. Histology showed that sulforaphane treatment significantly prevented the eruption of endothelial lining in the intima layer of the aorta and preserved elastin fibers’ delicate organization as shown by Verhoeff-van Gieson staining. Immunohistochemistry studies showed that sulforaphane treatment also reduced VCAM-1 and monocytes-derived F4/80-positive macrophages in the aorta of TNF-α-treated mice. In conclusion, sulforaphane at physiological concentrations protects against TNF-α-induced vascular endothelial inflammation, in both in vitro and in vivo models. This anti-inflammatory effect of sulforaphane may be, at least in part, associated with interfering with the NF-κB pathway. PMID:24880493

  6. Vascular Diseases

    MedlinePlus

    The vascular system is the body's network of blood vessels. It includes the arteries, veins and capillaries that carry ... to and from the heart. Problems of the vascular system are common and can be serious. Arteries ...

  7. Magnolol reduced TNF-α-induced vascular cell adhesion molecule-1 expression in endothelial cells via JNK/p38 and NF-κB signaling pathways.

    PubMed

    Liang, Chan-Jung; Lee, Chiang-Wen; Sung, Hsin-Ching; Chen, Yung-Hsiang; Wang, Shu-Huei; Wu, Pei-Jhen; Chiang, Yao-Chang; Tsai, Jaw-Shiun; Wu, Chau-Chung; Li, Chi-Yuan; Chen, Yuh-Lien

    2014-01-01

    Expression of cell adhesion molecules by the endothelium and the attachment of leukocytes to these cells play major roles in inflammation and cardiovascular disorders. Magnolol, a major active component of Magnolia officinalis, has antioxidative and anti-inflammatory properties. In the present study, the effects of magnolol on the expression of vascular cell adhesion molecule-1 (VCAM-1) in human aortic endothelial cells (HAECs) and the related mechanisms were investigated. TNF-α induced VCAM-1 protein expression and mRNA stability were significantly decreased in HAECs pre-treated with magnolol. Magnolol significantly reduced the phosphorylation of ERK, JNK, and p38 in TNF-α-treated HAECs. The decrease in VCAM-1 expression in response to TNF-α treatment was affected by JNK and p38 inhibitors, not by an ERK inhibitor. Magnolol also attenuates NF-κB activation and the translocation of HuR (an RNA binding protein) in TNF-α-stimulated HAECs. The VCAM-1 expression was weaker in the aortas of TNF-α-treated apo-E deficient mice with magnolol treatment. These data demonstrate that magnolol inhibits TNF-α-induced JNK/p38 phosphorylation, HuR translocation, NF-κB activation, and thereby suppresses VCAM-1 expression resulting in reduced leukocyte adhesion. Taken together, these results suggest that magnolol has an anti-inflammatory property and may play an important role in the prevention of atherosclerosis and inflammatory responses.

  8. Anti-vascular endothelial growth factor antibody bevacizumab reduced the risk of anemia associated with chemotherapy-A meta-analysis.

    PubMed

    Sher, Amna; Wu, Shenhong

    2011-10-01

    Vascular endothelial growth factor (VEGF) may play a role in erythropoiesis. We performed a meta-analysis of randomized controlled trials (RCT) to determine the effect of the anti-VEGF antibody bevacizumab on anemia in cancer patients treated with chemotherapy. Databases from PUBMED, the Web of Science, Embase, the Cochrane Library, and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences until May 2010 were searched to identify relevant studies. Eligible studies included prospective RCTs in which the combination of bevacizumab and chemotherapy was compared with chemotherapy alone. Summary incidence rate, relative risk (RR), and 95% confidence interval (CI) were calculated. A total of 6439 patients with a variety of solid tumors were included for analysis from 11 RCTs. Among those patients receiving bevacizumab and chemotherapy, the incidences of all-grade and high-grade (grade 3 and above) anemia were 17.8% (95% CI: 11.1-27.1%) and 2.8% (95% CI: 1.6-5.0%) respectively. In comparison with chemotherapy alone, bevacizumab significantly reduced all-grade (RR, 0.79; 95% CI: 0.66-1.0, p = 0.007) and high-grade anemia (RR, 0.72; 95% CI: 0.57-0.90, p = 0.005). The effect did not vary significantly among bevacizumab doses (p = 0.88), tumor types (p = 0.75) or chemotherapy regimens (p = 0.98). Bevacizumab may significantly reduce the risk of anemia with chemotherapy in cancer patients.

  9. Assessment of Cerebral Blood Flow with Micro-Doppler Vascular Reduces the Risk of Ischemic Stroke During the Clipping of Intracranial Aneurysms.

    PubMed

    Pereira, Benedito J A; Holanda, Vanessa M; Giudicissi-Filho, Miguel; Borba, Luiz Alencar B; de Holanda, Carlos Vanderlei M; de Oliveira, Jean G

    2015-12-01

    To analyze the impact of the introduction of Micro-Doppler vascular (MDV) as a method of cerebral blood flow analysis during microsurgical clipping of intracranial aneurysms to check the partial occlusion of the aneurysm and the occurrence of stenosis by comparing these results with those provided by the postoperative digital subtraction angiography (DSA) scan as well as the occurrence of ischemic infarction on the postoperative computed tomography (CT) images. We reviewed retrospectively the last 50 patients operated on before the introduction of the MDV (group 1) compared with the first 50 patients operated on using this technique (group 2). Nine (18%) of the 50 patients evaluated in the group 1 showed a new hypodensity in the postoperative CT images, whereas only 2 (4%) patients showed infarction in the group 2 (P = 0.02). In addition, in the group 1, 10 (20%) patients presented unexpected findings on DSA images (residual aneurysms, stenosis, and arterial occlusion), whereas in the group 2, those unexpected DSA findings were observed in only 3 (6%) patients (P = 0.023). MDV is an excellent method for cerebral blood flow assessment during the microsurgical clipping of intracranial aneurysms, reducing the unexpected angiographic results (residual aneurysms, stenosis, and arterial occlusion), as well as reducing the incidence of ischemic infarction on postoperative CT images, evidence of the positive impact of this method in the microsurgical treatment of intracranial aneurysms. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Buffered l-ascorbic acid, alone or bound to KMUP-1 or sildenafil, reduces vascular endothelium growth factor and restores endothelium nitric oxide synthase in hypoxic pulmonary artery.

    PubMed

    Wu, Jiunn-Ren; Kao, Li-Pin; Wu, Bin-Nan; Dai, Zen-Kong; Wang, Yi-Ya; Chai, Chee-Yin; Chen, Ing-Jun

    2015-05-01

    Ascorbic acid bound to KMUP-1 and sildenafil were examined for their antioxidant effects on vascular endothelium growth factor (VEGF) and endothelium nitric oxide synthase (eNOS) in hypoxic pulmonary artery (PA). Inhaled KMUP-1 and oral sildenafil released NO from eNOS. The effect of buffered l-ascorbic acid, alone and bound to KMUP-1 or sildenafil, for treating pulmonary arterial hypertension (PAH) is unclear. In this study, the antioxidant capacity of ascorbic acid increased the beneficial effects of KMUP-1 on PAH. KMUP-1A and sildenafil-A (5 mg/kg/d) were administered to hypoxic PAH rats. Pulmonary artery blood pressure, and VEGF, Rho kinase II (ROCK II), eNOS, soluble guanylate cyclase (sGC-α), and protein kinase G expression in lung tissues were measured to link PAH and right ventricular hypertrophy. Hypoxic rats had higher pulmonary artery blood pressure, greater PA medial wall thickness and cardiac weight, and a higher right ventricle/left ventricle + septum [RV/(LV+S)] ratio than normoxic rats. Oral KMUP-1A or sildenafil-A for 21 days in hypoxia prevented the rarefaction of eNOS in immunohistochemistry (IHC), reduced the IHC of VEGF in PAs, restored eNOS/protein kinase G/phosphodiesterase 5A; unaffected sGC-α and inactivated ROCK II expression were also found in lung tissues. In normoxic PA, KMUP-1A/Y27632 (10μM) increased eNOS and reduced ROCK II. ROCK II/reactive oxidative species was increased and eNOS was reduced after long-term hypoxia for 21 days. KMUP-1A or Y27632 blunted ROCK II in short-term hypoxic PA at 24 hours. l-Ascorbic acid + l-sodium ascorbate (40, 80μM) buffer alone directly inhibited the IHC of VEGF in hypoxic PA. Finally, KMUP-1A or sildenafil-A reduced PAH and associated right ventricular hypertrophy.

  11. Metformin in adults with type 1 diabetes: Design and methods of REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL): An international multicentre trial.

    PubMed

    Petrie, John R; Chaturvedi, Nish; Ford, Ian; Hramiak, Irene; Hughes, Alun D; Jenkins, Alicia J; E Klein, Barbara; Klein, Ron; Ooi, Teik Chye; Rossing, Peter; Sattar, Naveed; Stehouwer, Coen D A; Colhoun, Helen M

    2017-04-01

    Cardiovascular (CV) disease is a major cause of reduced life expectancy in type 1 diabetes (T1D). Intensive insulin therapy prevents CV complications but is constrained by hypoglycaemia and weight gain. Adjunct metformin reduces insulin dose requirement and stabilizes weight but there are no data on its cardiovascular effects. We have therefore initiated an international double-blind, randomized, placebo-controlled trial (REMOVAL: REducing with MetfOrmin Vascular Adverse Lesions in type 1 diabetes) to examine whether metformin reduces progression of atherosclerosis in adults with T1D. Individuals ≥40 years of age with T1D for ≥5 years are eligible if they have ≥3 of 10 specified CV risk factors. The enrolment target is 500 participants in 17 international centres. After 12 weeks of single-blind placebo-controlled run-in, participants with ≥ 70% adherence are randomized to metformin or matching placebo for 3 years with insulin titrated towards HbA1c 7.0% (53 mmol/mol). The primary endpoint is progression of averaged mean far wall common carotid intima-media thickness (cIMT) measured by ultrasonography at baseline, 12, 24 and 36 months. This design provides 90% power to detect a mean difference of 0.0167 mm in cIMT progression between treatment arms (α = 0.05), assuming that up to 20% withdraw or discontinue treatment. Other endpoints include HbA1c, weight, LDL cholesterol, insulin requirement, progression of retinopathy, endothelial function and frequency of hypoglycaemia. REMOVAL is the largest clinical trial of adjunct metformin therapy in T1D to date and will provide clinically meaningful information on its potential to impact CV disease and other complications. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

  12. Diet-induced obesity may affect the uterine immune environment in early-mid pregnancy, reducing NK-cell activity and potentially compromising uterine vascularization.

    PubMed

    Parker, V J; Solano, M E; Arck, P C; Douglas, A J

    2014-06-01

    To investigate the effect of obesity in early-mid pregnancy on crucial pregnancy hormones and the uterine immune environment. Obesity impacts reproductive ability, adversely affecting conception and leading to complications in pregnancy. Obesity is often regarded as a stress state and an immune disease, both of which may contribute to pregnancy failure. We previously demonstrated that stress in early pregnancy greatly alters progesterone secretion. As progesterone is an immunomodulator, altered progesterone secretion may adversely modify the maternal immune system. In the current study, we test the hypothesis that obesity during pregnancy adversely alters the uterine immune environment. An obese mouse model was created by feeding C57/BL6 mice on a high-fat (HF)/sugar diet for 12 weeks before pregnancy. Control mice were fed on lower-fat/sugar chow. Mice were mated, and on day 7.5 of pregnancy plasma progesterone and prolactin were measured by immunoassay. Cells from the uterus-draining inguinal lymph nodes were collected for analysis of the uterine immune response by flow cytometry. Diet-induced obesity increased the secretion of progesterone and altered a number of uterine natural killer (NK)- and T-cell responses. These included a marked reduction in the percentage of leucocyte-derived NK cells and reduced expression of interferon-γ (IFN-γ) in the NK cells compared with control mice. Maternal obesity, induced by an HF diet, may lead to a reduction in the expression of IFN-γ in NK cells. NK-cell-derived IFN-γ is reported to be involved in supporting uterine spiral artery remodelling. Thus, obesity in early pregnancy may compromise vascularization by reducing the expression of IFN-γ-positive NK cells. Furthermore, the expression of uterine CD8(+) cells was reduced in the HF diet-fed mice, suggesting obesity may adversely alter the maternal immune adaptation that is essential for effective pregnancy.

  13. Oxalomalate reduces expression and secretion of vascular endothelial growth factor in the retinal pigment epithelium and inhibits angiogenesis: Implications for age-related macular degeneration.

    PubMed

    Kim, Sung Hwan; Kim, Hyunjin; Ku, Hyeong Jun; Park, Jung Hyun; Cha, Hanvit; Lee, Seoyoon; Lee, Jin Hyup; Park, Jeen-Woo

    2016-12-01

    Clinical and experimental observations indicate a critical role for vascular endothelial growth factor (VEGF), secreted by the retinal pigment epithelium (RPE), in pathological angiogenesis and the development of choroidal neovascularization (CNV) in age-related macular degeneration (AMD). RPE-mediated VEGF expression, leading to angiogenesis, is a major signaling mechanism underlying ocular neovascular disease. Inhibiting this signaling pathway with a therapeutic molecule is a promising anti-angiogenic strategy to treat this disease with potentially fewer side effects. Oxalomalate (OMA) is a competitive inhibitor of NADP(+)-dependent isocitrate dehydrogenase (IDH), which plays an important role in cellular signaling pathways regulated by reactive oxygen species (ROS). Here, we have investigated the inhibitory effect of OMA on the expression of VEGF, and the associated underlying mechanism of action, using in vitro and in vivo RPE cell models of AMD. We found that OMA reduced the expression and secretion of VEGF in RPE cells, and consequently inhibited CNV formation. This function of OMA was linked to its capacity to activate the pVHL-mediated HIF-1α degradation in these cells, partly via a ROS-dependent ATM signaling axis, through inhibition of IDH enzymes. These findings reveal a novel role for OMA in inhibiting RPE-derived VEGF expression and angiogenesis, and suggest unique therapeutic strategies for treating pathological angiogenesis and AMD development.

  14. Pioglitazone reduces angiotensin II-induced COX-2 expression through inhibition of ROS production and ET-1 transcription in vascular cells from spontaneously hypertensive rats.

    PubMed

    Pérez-Girón, Jose V; Palacios, Roberto; Martín, Angela; Hernanz, Raquel; Aguado, Andrea; Martínez-Revelles, Sonia; Barrús, María T; Salaices, Mercedes; Alonso, María J

    2014-06-01

    Glitazones have anti-inflammatory properties by interfering with the transcription of proinflammatory genes, such as cyclooxygenase (COX)-2, and with ROS production, which are increased in hypertension. This study analyzed whether pioglitazone modulates COX-2 expression in hypertension by interfering with ROS and endothelin (ET)-1. In vivo, pioglitazone (2.5 mg·kg(-1)·day(-1), 28 days) reduced the greater levels of COX-2, pre-pro-ET-1, and NADPH oxidase (NOX) expression and activity as well as O2 (·-) production found in aortas from spontaneously hypertensive rats (SHRs). ANG II increased COX-2 and pre-pro-ET-1 levels more in cultured vascular smooth muscle cells from hypertensive rats compared with normotensive rats. The ETA receptor antagonist BQ-123 reduced ANG II-induced COX-2 expression in SHR cells. ANG II also increased NOX-1 expression, NOX activity, and superoxide production in SHR cells; the selective NOX-1 inhibitor ML-171 and catalase reduced ANG II-induced COX-2 and ET-1 transcription. ANG II also increased c-Jun transcription and phospho-JNK1/2, phospho-c-Jun, and p65 NF-κB subunit nuclear protein expression. SP-600125 and lactacystin, JNK and NF-κB inhibitors, respectively, reduced ANG II-induced ET-1, COX-2, and NOX-1 levels and NOX activity. Pioglitazone reduced the effects of ANG II on NOX activity, NOX-1, pre-pro-ET-1, COX-2, and c-Jun mRNA levels, JNK activation, and nuclear phospho-c-Jun and p65 expression. In conclusion, ROS production and ET-1 are involved in ANG II-induced COX-2 expression in SHRs, explaining the greater COX-2 expression observed in this strain. Furthermore, pioglitazone inhibits ANG II-induced COX-2 expression likely by interfering with NF-κB and activator protein-1 proinflammatory pathways and downregulating ROS production and ET-1 transcription, thus contributing to the anti-inflammatory properties of glitazones.

  15. Clopidogrel but not aspirin reduces P-selectin expression and formation of platelet-leukocyte aggregates in patients with atherosclerotic vascular disease.

    PubMed

    Klinkhardt, Ute; Bauersachs, Rupert; Adams, Jan; Graff, Jochen; Lindhoff-Last, Edeltraud; Harder, Sebastian

    2003-03-01

    /mL; clopidogrel, 274 ng/mL; combination therapy, 273 ng/mL) but significantly lower than those in untreated patients. This is the first report showing that platelet-leukocyte aggregate formation is enhanced in atherosclerotic vascular disease but was found to be reduced in patients receiving clopidogrel.

  16. Pyrazolo-pyrimidine-derived c-Src inhibitor reduces angiogenesis and survival of squamous carcinoma cells by suppressing vascular endothelial growth factor production and signaling.

    PubMed

    Donnini, Sandra; Monti, Martina; Castagnini, Cinzia; Solito, Raffaella; Botta, Maurizio; Schenone, Silvia; Giachetti, Antonio; Ziche, Marina

    2007-03-01

    Src tyrosine kinase family cooperates with activated growth factor receptors to regulate growth, invasion and metastasis. The authors examined the influence of a novel c-Src inhibitor, 1l, derived from 4-amino-substituted-pyrazolo-pyrimidines, on tumor angiogenesis and on the angiogenic output of squamous carcinoma cells, A431 and SCC-4. The effect of 1l was assessed on growth and microvessel density in A431 tumors and its effect compared with the established c-Src inhibitor PP-1. The effects of c-Src inhibition were investigated on vascular endothelial growth factor (VEGF) expression and activity in tumor cells grown in vivo and in vitro, as well as on VEGF mediated signaling and on endothelial cell functions. Nanomolar concentrations of 1l decreased tumor volume promoted by A431 implanted in nude mice, without affecting in vitro cell tumor survival. This effect was related to 1l inhibition of VEGF production, and secondary to an effect on tumor microvessel density. The rabbit cornea assay confirmed that 1l markedly decreased neovessel growth induced by VEGF. In cultured endothelial cells, 1l inhibited the VEGF-induced phosphorylation on tyr416 of c-Src, resulting in a reduced cell proliferation and invasion. Consistently, 1l dowregulated endothelial nitric oxide synthase, MAPK-extracellular receptor kinase 1-2 (ERK1-2) activity and matrix metalloproteinases (MMP-2/MMP-9), while the tissue inhibitors of metalloproteinases (TIMP2/TIMP-1) were upregulated. These results demonstrate that nM concentrations of c-Src kinase inhibitors (1l and PP-1), by reducing the production of VEGF released by tumor cell and its endothelial cell responses, have a highly selective antiangiogenesis effect, which might be useful in combination therapies.

  17. Activation of α7 nicotinic acetylcholine receptor protects against oxidant stress damage through reducing vascular peroxidase-1 in a JNK signaling-dependent manner in endothelial cells.

    PubMed

    Li, Dong-Jie; Zhao, Ting; Xin, Ru-Juan; Wang, Yuan-Yuan; Fei, Yi-Bo; Shen, Fu-Ming

    2014-01-01

    Alpha7 nicotinic acetylcholine receptor (α7nAChR), a subtype of nAChR regulating neurotransmission in central nervous system, is an essential regulator of cholinergic anti-inflammatory pathway in periphery. The present study was to determine the effects of activation of α7nAChR on oxidant stress-induced injury in endothelial cells. Cultured human umbilical vein endothelial cells were treated with H2O2 (400 µM) or H2O2 plus PNU-282987 (10 µM). Cell viability and membrane integrity were measured. Annexin V + PI assay, immunoblotting of bcl-2, bax and cleaved capase-3, and immunofluorescence of apoptosis inducing factor (AIF) were performed to evaluate apoptosis. Protein expression of vascular peroxidase-1 (VPO-1) and phosphor-JNK were measured by immunoblotting. Activation of α7nAChR by a selective agonist PNU-282987 prevented H2O2-indced decrease of cell viability and increase of lactate dehydrogenase release. Activation of α7nAChR markedly reduced cell apoptosis and intracellular oxidative stress level. Moreover, activation of α7nAChR reduced H2O2-induced VPO-1 protein upregulation and JNK1/2 phosphorylation. The inhibitory effect of α7nAChR activation on VPO-1 was blocked by JNK inhibitor SP600125. In addition, pretreatment of α7nAChR antagonist methyllycaconitine blocked the cytoprotective effect of PNU-282987. These results provide the first evidence that activation of α7nAChR protects against oxidant stress-induced damage by suppressing VPO-1 in a JNK signaling pathway-dependent manner in endothelial cells. © 2014 S. Karger AG, Basel.

  18. Stent coated with antibody against vascular endothelial-cadherin captures endothelial progenitor cells, accelerates re-endothelialization, and reduces neointimal formation.

    PubMed

    Lim, Woo-Hyun; Seo, Won-Woo; Choe, Wonseok; Kang, Chan-Koo; Park, Jonghanne; Cho, Hyun-Ju; Kyeong, San; Hur, Jin; Yang, Han-Mo; Cho, Hyun-Jai; Lee, Yoon-Sik; Kim, Hyo-Soo

    2011-12-01

    In contrast to CD34, vascular endothelial-cadherin (VE-cadherin) is exclusively expressed on the late endothelial progenitor cells (EPC) whereas not on the early or myeloid EPC. Thus, VE-cadherin could be an ideal target surface molecule to capture circulating late EPC. In the present study, we evaluated whether anti-VE-cadherin antibody-coated stents (VE-cad stents) might accelerate endothelial recovery and reduce neointimal formation through the ability of capturing EPC. The stainless steel stents were coated with rabbit polyclonal anti-human VE-cadherin antibodies and exposed to EPC for 30 minutes in vitro. The number of EPC that adhered to the surface of VE-cad stents was significantly higher than bare metal stents (BMS) in vitro, which was obliterated by pretreatment of VE-cad stent with soluble VE-cadherin proteins. We deployed VE-cad stents and BMS in the rabbit right and left iliac arteries, respectively. At 48 hours after stent deployment in vivo, CD-31-positive endothelial cells adhered to VE-cad stent significantly more than to BMS. At 3 days, scanning electron microscopy showed that over 90% surface of VE-cad stents was covered with endothelial cells, which was significantly different from BMS. At 42 days, neointimal area that was filled with smooth muscle cells positive for actin or calponin was significantly smaller in VE-cad stents than in BMS by histological analysis (0.95±0.22 versus 1.34±0.43 mm(2), respectively, P=0.02). Immuno-histochemical analysis revealed that infiltration of inflammatory cells was not significantly different between 2 stents. VE-cad stents captured EPC successfully in vitro, accelerated endothelial recovery on stent, and eventually reduced neointimal formation in vivo.

  19. Curcumin supplementation improves vascular endothelial function in healthy middle-aged and older adults by increasing nitric oxide bioavailability and reducing oxidative stress

    PubMed Central

    Santos-Parker, Jessica R.; Strahler, Talia R.; Bassett, Candace J.; Bispham, Nina Z.; Chonchol, Michel B.; Seals, Douglas R.

    2017-01-01

    We hypothesized that curcumin would improve resistance and conduit artery endothelial function and large elastic artery stiffness in healthy middle-aged and older adults. Thirty-nine healthy men and postmenopausal women (45-74 yrs) were randomized to 12 weeks of curcumin (2000 mg/day Longvida®; n=20) or placebo (n=19) supplementation. Forearm blood flow response to acetylcholine infusions (FBFACh; resistance artery endothelial function) increased 37% following curcumin supplementation (107±13 vs. 84±11 AUC at baseline, P=0.03), but not placebo (P=0.2). Curcumin treatment augmented the acute reduction in FBFACh induced by the nitric oxide synthase inhibitor NG monomethyl-L-arginine (L-NMMA; P=0.03), and reduced the acute increase in FBFACh to the antioxidant vitamin C (P=0.02), whereas placebo had no effect (both P>0.6). Similarly, brachial artery flow-mediated dilation (conduit artery endothelial function) increased 36% in the curcumin group (5.7±0.4 vs. 4.4±0.4% at baseline, P=0.001), with no change in placebo (P=0.1). Neither curcumin nor placebo influenced large elastic artery stiffness (aortic pulse wave velocity or carotid artery compliance) or circulating biomarkers of oxidative stress and inflammation (all P>0.1). In healthy middle-aged and older adults, 12 weeks of curcumin supplementation improves resistance artery endothelial function by increasing vascular nitric oxide bioavailability and reducing oxidative stress, while also improving conduit artery endothelial function. PMID:28070018

  20. Vitamin E supplementation reduces plasma vascular cell adhesion molecule-1 and von Willebrand factor levels and increases nitric oxide concentrations in hypercholesterolemic patients.

    PubMed

    Desideri, Giovambattista; Marinucci, Maria Contina; Tomassoni, Gianluca; Masci, Pier Giorgio; Santucci, Anna; Ferri, Claudio

    2002-06-01

    Up-regulation of vascular cell adhesion molecule-1 (VCAM-1) and reduced nitric oxide (NO) availability represent early characteristics of atherosclerosis. To evaluate whether the antioxidant vitamin E affected the circulating levels of soluble VCAM-1 (sVCAM-1) and the plasma metabolite of NO (nitrite+nitrate) in hypercholesterolemic patients, either vitamin E (either 400 IU or 800 IU/d for 8 wk) or placebo were randomly, double-blindly given to 36 hypercholesterolemic patients and 22 age- and sex-matched controls. At baseline hypercholesterolemic patients showed higher plasma sVCAM-1 (microg.liter(-1)) (591.2 +/- 132.5 vs. 505.0 +/- 65.6, P < 0.007) and lower NO metabolite (microM) levels (15.9 +/- 3.4 vs. 29.2 +/- 5.1, P < 0.0001) than controls. In hypercholesterolemic patients, 8 wk vitamin E (but not placebo) treatment significantly decreased circulating sVCAM-1 levels (400 IU: -148.9 +/- 84.6, P < 0.009; 800 IU: -204.0 +/- 75.7, P < 0.0001; placebo: -4.7 +/- 22.6, NS), whereas it increased NO metabolite concentrations (400 IU: +4.0 +/- 1.7, P < 0.02; 800 IU: +5.5 +/- 0.8, P < 0.0001; placebo: +0.1 +/- 1.1, NS) without affecting circulating low- density lipoprotein levels. Changes in both plasma sVCAM-1 and NO metabolite levels showed a trend to significantly correlate (r = -0.515, P = 0.010; and r = 0.435, P = 0.034, respectively) with changes in vitamin E concentrations induced by vitamin E supplementation. In conclusion, isolated hypercholesterolemia both increased circulating sVCAM-1 and reduced NO metabolite concentrations. Vitamin E supplementation counteracts these alterations, thus representing a potential tool for endothelial protection in hypercholesterolemic patients.

  1. Hydrogen Sulfide Prevents Formation of Reactive Oxygen Species through PI3K/Akt Signaling and Limits Ventilator-Induced Lung Injury

    PubMed Central

    Spassov, Sashko Georgiev; Donus, Rosa; Ihle, Paul Mikael; Engelstaedter, Helen; Hoetzel, Alexander

    2017-01-01

    The development of ventilator-induced lung injury (VILI) is still a major problem in mechanically ventilated patients. Low dose inhalation of hydrogen sulfide (H2S) during mechanical ventilation has been proven to prevent lung damage by limiting inflammatory responses in rodent models. However, the capacity of H2S to affect oxidative processes in VILI and its underlying molecular signaling pathways remains elusive. In the present study we show that ventilation with moderate tidal volumes of 12 ml/kg for 6 h led to an excessive formation of reactive oxygen species (ROS) in mice lungs which was prevented by supplemental inhalation of 80 parts per million of H2S. In addition, phosphorylation of the signaling protein Akt was induced by H2S. In contrast, inhibition of Akt by LY294002 during ventilation reestablished lung damage, neutrophil influx, and proinflammatory cytokine release despite the presence of H2S. Moreover, the ability of H2S to induce the antioxidant glutathione and to prevent ROS production was reversed in the presence of the Akt inhibitor. Here, we provide the first evidence that H2S-mediated Akt activation is a key step in protection against VILI, suggesting that Akt signaling limits not only inflammatory but also detrimental oxidative processes that promote the development of lung injury. PMID:28250891

  2. What Is Vascular Disease?

    MedlinePlus

    ... Donors Corporate Sponsors Donor Privacy Policy What Is Vascular Disease? What Is Vascular Disease? Vascular disease is any abnormal condition of ... steps to prevent vascular disease here. Understanding the Vascular System Your vascular system – the highways of the ...

  3. Arginase inhibition reduces interleukin-1β-stimulated vascular smooth muscle cell proliferation by increasing nitric oxide synthase-dependent nitric oxide production

    SciTech Connect

    Yoon, Jeongyeon; Ryoo, Sungwoo

    2013-06-07

    Highlights: •Arginase inhibition suppressed proliferation of IL-1β-stimulated VSMCs in dose-dependent manner. •NO production from IL-1β-induced iNOS expression was augmented by arginase inhibition, reducing VSMC proliferation. •Incubation with cGMP analogues abolished IL-1β-dependent proliferation of VSMCs. -- Abstract: We investigated whether arginase inhibition suppressed interleukin (IL)-1β-stimulated proliferation in vascular smooth muscle cells (VSMCs) and the possible mechanisms involved. IL-1β stimulation increased VSMC proliferation, while the arginase inhibitor BEC and transfection of the antisense (AS) oligonucleotide against arginase I decreased VSMC proliferation and was associated with increased protein content of the cell cycle regulator p21Waf1/Cip1. IL-1β incubation induced inducible nitric oxide synthase (iNOS) mRNA expression and protein levels in a dose-dependent manner, but did not affect arginase I and II expression. Consistent with this data, IL-1β stimulation resulted in increase in NO production that was significantly augmented by arginase inhibition. The specific iNOS inhibitor 1400W abolished IL-1β-mediated NO production and further accentuated IL-1β-stimulated cell proliferation. Incubation with NO donors GSNO and DETA/NO in the presence of IL-1β abolished VSMCs proliferation and increased p21Waf1/Cip1 protein content. Furthermore, incubation with the cGMP analogue 8-Br-cGMP prevented IL-1β-induced VSMCs proliferation. In conclusion, arginase inhibition augmented iNOS-dependent NO production that resulted in suppression of IL-1β-induced VSMCs proliferation in a cGMP-dependent manner.

  4. Chronic vagus nerve stimulation attenuates vascular endothelial impairments and reduces the inflammatory profile via inhibition of the NF-κB signaling pathway in ovariectomized rats.

    PubMed

    Li, Ping; Liu, Huaipu; Sun, Peng; Wang, Xiaoyu; Wang, Chen; Wang, Ling; Wang, Tinghuai

    2016-02-01

    Vagus nerve stimulation (VNS), a method for activating cholinergic anti-inflammatory pathways, could suppress endothelial activation and minimize tissue injury during inflammation. The aim of this study was to investigate the effects of chronic VNS on endothelial impairments and the inflammatory profile in ovariectomized (OVX) rats. Sprague-Dawley rats (7-8 months old) were randomly assigned to the following four groups: sham-OVX, OVX, OVX+sham-VNS, and OVX+VNS. Throughout the experimental period, the OVX+VNS group received VNS for 3h (20.0 Hz, 1.0 mA, and 10.00 ms pulse width) at the same time every other day. After 12 weeks of VNS, blood samples and thoracic aortas were collected for further analyses. Light microscopy and electron microscopy analyses showed that chronic VNS prevented endothelial swelling, desquamation and even necrosis in the OVX rats. In addition, it obviously improved endothelial function in the OVX rats by restoring the endothelial nitric oxide synthase (e-NOS) and serum endothelin-1 level. Increased expression of cell adhesion molecules (VCAM-1, ICAM-1 and E-selectin) in the thoracic aortas and increases in the levels of circulating cytokines (TNF-α, IL-6, MCP-1, and CINC/KC) were also observed in the OVX rats. Chronic VNS significantly restored these detrimental changes partly by increasing the ACh concentrations in vascular walls and blocking NF-κB pathway activity. The results of this in vivo study have shown that the administration of chronic VNS during, in the early stage of estrogen deficiency, protects OVX rats from endothelial impairments and the inflammatory profile. These findings indicate that activation of the vagus nerve could be a promising supplemental therapy for reducing the risks of suffering from further CVDs in postmenopausal women.

  5. Vascular Disorders

    MedlinePlus

    ... a Hand Surgeon? What is a Hand Therapist? Media Find a Hand Surgeon Home Anatomy Vascular Disorders Email to a friend * required fields From * To * DESCRIPTION Vascular disorders are problems with arteries and veins. Arteries are pipes that bring oxygen-rich blood from the heart to the fingers. Veins ...

  6. Lung stress, strain, and energy load: engineering concepts to understand the mechanism of ventilator-induced lung injury (VILI).

    PubMed

    Nieman, Gary F; Satalin, Joshua; Andrews, Penny; Habashi, Nader M; Gatto, Louis A

    2016-12-01

    It was recently shown that acute respiratory distress syndrome (ARDS) mortality has not been reduced in over 15 years and remains ~40 %, even with protective low tidal volume (LVt) ventilation. Thus, there is a critical need to develop novel ventilation strategies that will protect the lung and reduce ARDS mortality. Protti et al. have begun to analyze the impact of mechanical ventilation on lung tissue using engineering methods in normal pigs ventilated for 54 h. They used these methods to assess the impact of a mechanical breath on dynamic and static global lung strain and energy load. Strain is the change in lung volume in response to an applied stress (i.e., Tidal Volume-Vt). This study has yielded a number of exciting new concepts including the following: (1) Individual mechanical breath parameters (e.g., Vt or Plateau Pressure) are not directly correlated with VILI but rather any combination of parameters that subject the lung to excessive dynamic strain and energy/power load will cause VILI; (2) all strain is not equal; dynamic strain resulting in a dynamic energy load (i.e., kinetic energy) is more damaging to lung tissue than static strain and energy load (i.e., potential energy); and (3) a critical consideration is not just the size of the Vt but the size of the lung that is being ventilated by this Vt. This key concept merits attention since our current protective ventilation strategies are fixated on the priority of keeping the Vt low. If the lung is fully inflated, a large Vt is not necessarily injurious. In conclusion, using engineering concepts to analyze the impact of the mechanical breath on the lung is a novel new approach to investigate VILI mechanisms and to help design the optimally protective breath. Data generated using these methods have challenged some of the current dogma surrounding the mechanisms of VILI and of the components in the mechanical breath necessary for lung protection.

  7. Vascular rings.

    PubMed

    Backer, Carl L; Mongé, Michael C; Popescu, Andrada R; Eltayeb, Osama M; Rastatter, Jeffrey C; Rigsby, Cynthia K

    2016-06-01

    The term vascular ring refers to congenital vascular anomalies of the aortic arch system that compress the esophagus and trachea, causing symptoms related to those two structures. The most common vascular rings are double aortic arch and right aortic arch with left ligamentum. Pulmonary artery sling is rare and these patients need to be carefully evaluated for frequently associated tracheal stenosis. Another cause of tracheal compression occurring only in infants is the innominate artery compression syndrome. In the current era, the diagnosis of a vascular ring is best established by CT imaging that can accurately delineate the anatomy of the vascular ring and associated tracheal pathology. For patients with a right aortic arch there recently has been an increased recognition of a structure called a Kommerell diverticulum which may require resection and transfer of the left subclavian artery to the left carotid artery. A very rare vascular ring is the circumflex aorta that is now treated with the aortic uncrossing operation. Patients with vascular rings should all have an echocardiogram because of the incidence of associated congenital heart disease. We also recommend bronchoscopy to assess for additional tracheal pathology and provide an assessment of the degree of tracheomalacia and bronchomalacia. The outcomes of surgical intervention are excellent and most patients have complete resolution of symptoms over a period of time. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Evaluating the Role of Reduced Oxygen Saturation and Vascular Damage in Traumatic Brain Injury Using Magnetic Resonance Perfusion-Weighted Imaging and Susceptibility-Weighted Imaging and Mapping.

    PubMed

    Kou, Zhifeng; Ye, Yongquan; Haacke, Ewart Mark

    2015-10-01

    The cerebral vasculature, along with neurons and axons, is vulnerable to biomechanical insult during traumatic brain injury (TBI). Trauma-induced vascular injury is still an underinvestigated area in TBI research. Cerebral blood flow and metabolism could be important future treatment targets in neural critical care. Magnetic resonance imaging offers a number of key methods to probe vascular injury and its relationship with traumatic hemorrhage, perfusion deficits, venous blood oxygen saturation changes, and resultant tissue damage. They make it possible to image the hemodynamics of the brain, monitor regional damage, and potentially show changes induced in the brain's function not only acutely but also longitudinally following treatment. These methods have recently been used to show that even mild TBI (mTBI) subjects can have vascular abnormalities, and thus they provide a major step forward in better diagnosing mTBI patients.

  9. Vascular Tumors

    PubMed Central

    Sepulveda, Abel; Buchanan, Edward P.

    2014-01-01

    Vascular anomalies are divided into two main groups: tumors and malformations. Vascular tumors are a large and complex group of lesions, especially for clinicians with none or little experience in this field. In the past, these lesions caused a great deal of confusion because many appear analogous to the naked eye. Thankfully, recent advances in diagnostic techniques have helped the medical community to enhance our comprehension, accurately label, diagnose, and treat these lesions. In this article, we will review the most frequent vascular tumors and provide the reader with the tools to properly label, diagnose, and manage these complex lesions. PMID:25045329

  10. Curcumin inhibits angiotensin II-induced inflammation and proliferation of rat vascular smooth muscle cells by elevating PPAR-γ activity and reducing oxidative stress.

    PubMed

    Li, Hai-Yu; Yang, Mei; Li, Ze; Meng, Zhe

    2017-05-01

    Angiotensin II (AngII)-induced production of inflammatory factors and proliferation in vascular smooth muscle cells (VSMCs) play an important role in the progression of atherosclerotic plaques. Growing evidence has demonstrated that activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) effectively attenuates AngII-induced inflammation and intercellular reactive oxygen species (iROS) production. Curcumin (Cur) inhibits inflammatory responses by enhancing PPAR-γ activity and reducing oxidative stress in various tissues. The aim of the present study was to ascertain whether Cur inhibits AngII-induced inflammation and proliferation, and its underlying molecular mechanism, in VSMCs. Enzyme-linked immunosorbent assay (ELISA) and real-time PCR were used to measure the protein and mRNA expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Nitric oxide (NO) production was measured by Griess reaction. Western blot analysis and a DNA-binding assay were used to measure PPAR-γ activity. iROS production was measured using the DCFH-DA method. In rat VSMCs, Cur attenuated AngII‑induced expression of IL-6 and TNF-α mRNA and protein in a concentration-dependent manner, inhibited NO production by suppressing inducible NO synthase (iNOS) activity, and suppressed proliferation of VSMCs. This was accompanied by increased PPAR-γ expression and activation in Cur-pretreated VSMCs. GW9662, a PPAR-γ antagonist, reversed the anti-inflammatory effect of Cur. Moreover, Cur attenuated AngII-induced oxidative stress by downregulating the expression of p47phox, which is a key subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In conclusion, Cur inhibited the expression of IL-6 and TNF-α, decreased the production of NO, and suppressed the proliferation of VSMCs, by elevating PPAR-γ activity and suppressing oxidative stress, leading to attenuated AngII-induced inflammatory responses in VSMCs.

  11. Vascular Dementia

    MedlinePlus

    ... dementia is a general term describing problems with reasoning, planning, judgment, memory and other thought processes caused ... dementia. Whether a stroke affects your thinking and reasoning depends on your stroke's severity and location. Vascular ...

  12. Ultrasound -- Vascular

    MedlinePlus

    ... ultrasound uses sound waves to evaluate the body’s circulatory system and help identify blockages in the arteries and ... is a useful way of evaluating the body's circulatory system. Vascular ultrasound is performed to: help monitor the ...

  13. Vascular Cures

    MedlinePlus

    ... patient to vascular research and care. It combines digital health tools for people to manage their own health with online education and communities, and improves communication between doctors, patients ...

  14. Ultrasound -- Vascular

    MedlinePlus

    ... ultrasound uses sound waves to evaluate the body’s circulatory system and help identify blockages and detect blood clots. ... is a useful way of evaluating the body's circulatory system. Vascular ultrasound is performed to: help monitor the ...

  15. Effect of a vascular access nurse coordinator to reduce central venous catheter use in incident hemodialysis patients: a quality improvement report.

    PubMed

    Polkinghorne, Kevan Roy; Seneviratne, Mechelle; Kerr, Peter G

    2009-01-01

    Starting hemodialysis therapy with an arteriovenous fistula (AVF) is associated with improved patient survival. Clinical audit showed that less than 50% of our patients started hemodialysis therapy with an AVF. Quality improvement report, prospective before and after study. Tertiary referral hospital with 184 patients starting hemodialysis therapy in 2005 and 2006. Situational analysis showed poor overall coordination of surgical waiting lists. Multifaceted intervention included vascular access nurse coordinator and an algorithm to prioritize surgery. Vascular access used at first hemodialysis treatment in patients with pre-end-stage renal disease in the 12 months before and after the intervention. Proportions of patients starting hemodialysis therapy with an AVF. Overall, 65% of patients started hemodialysis therapy with an AVF; 2%, with an arteriovenous graft; and 33%, with a catheter. The proportion of patients starting hemodialysis therapy with an AVF increased from 56% preimplementation to 75% postimplementation (P = 0.007). After adjustment for age, sex, late referral, cause of renal failure, and presentation type, patients starting dialysis therapy in the implementation phase were twice as likely to start treatment with an AVF (odds ratio, 2.85; P = 0.008). The total number of catheter-days in the implementation phase was half that of the preimplementation phase (2,833 v 4,685 days). Nonrandomized study. Implementation of a multifaceted intervention including a vascular access nurse and an algorithm to prioritize surgery significantly increased the proportion of patients starting dialysis therapy with an AVF by improving the overall coordination of the surgical waiting list.

  16. Antioxidants and vascular health.

    PubMed

    Bielli, Alessandra; Scioli, Maria Giovanna; Mazzaglia, Donatella; Doldo, Elena; Orlandi, Augusto

    2015-12-15

    Oxygen free radicals and other reactive oxygen species (ROS) are common products of normal aerobic cellular metabolism, but high levels of ROS lead to oxidative stress and cellular damage. Increased production of ROS favors vascular dysfunction, inducing altered vascular permeability and inflammation, accompanied by the loss of vascular modulatory function, the imbalance between vasorelaxation and vasoconstriction, and the aberrant expression of inflammatory adhesion molecules. Inflammatory stimuli promote oxidative stress generated from the increased activity of mitochondrial nicotinamide adenine dinucleotide phosphate oxidase, particularly of the Nox4 isoform, with the consequent impairment of mitochondrial β-oxidation. Vascular dysfunction due to the increase in Nox4 activity and ROS overproduction leads to the progression of cardiovascular diseases, diabetes, inflammatory bowel disease, and neurological disorders. Considerable research into the development of effective antioxidant therapies using natural derivatives or new synthetic molecules has been conducted. Antioxidants may prevent cellular damage by reducing ROS overproduction or interfering in reactions that involve ROS. Vitamin E and ascorbic acid are well known as natural antioxidants that counteract lipid peroxidative damage by scavenging oxygen-derived free radicals, thus restoring vascular function. Recently, preliminary studies on natural antioxidants such as goji berries, thymus, rosemary, green tea ginseng, and garlic have been conducted for their efficacy in preventing vascular damage. N-acetyl-cysteine and propionyl-L-carnitine are synthetic compounds that regulate ROS production by replacing endogenous antioxidants in both endothelial and smooth muscle cells. In this review, we consider the molecular mechanisms underlying the generation of oxidative stress-induced vascular dysfunction as well as the beneficial effects of antioxidant therapies.

  17. Vascular ring

    MedlinePlus

    ... Stanton BF, St Geme JW, Schor NF. Other congenital heart and vascular malformations. In: Kliegman RM, Stanton BF, St Geme JW, Schor NF, eds. Nelson Textbook of Pediatrics . 20th ed. Philadelphia, ... AN. Congenital heart disease. In: Mann DL, Zipes DP, Libby ...

  18. What Is Vascular Disease?

    MedlinePlus

    ... Contact Us Vascular Disease What is Vascular Disease? Education and Awareness Vascular Diseases Abdominal Aortic Aneurysm Aortic Dissection Arteriovenous Malformation Atherosclerosis Buerger's Disease Carotid Artery Disease ...

  19. Vascular Disease Foundation

    MedlinePlus

    ... Contact Us Vascular Disease What is Vascular Disease? Education and Awareness Vascular Diseases Abdominal Aortic Aneurysm Aortic Dissection Arteriovenous Malformation Atherosclerosis Buerger's Disease Carotid Artery Disease ...

  20. Topical application of {beta}-radiation to reduce intimal hyperplasia after carotid artery balloon injury in rabbit A possible application for brachytherapy in vascular surgery

    SciTech Connect

    Rosenthal, David; Stevens, Scott L.; Skillern, C.S.; Wellons, Eric D.; Robinson, Keith; Matsuura, John H.; Gannon, Brian J

    2002-03-01

    Purpose: Endovascular brachytherapy for the prevention of intimal hyperplasia (IH) and restenosis after balloon/stent angioplasty has proven effective both in animal preparations and clinical trials. A variety of {beta}-emitting isotopes and catheter-based devices have been developed for the delivery of low-dose radiation in clinical coronary and peripheral trials. No platform, however, has yet been developed for brachytherapy in concert with vascular surgical operations. The purpose of this study was to evaluate the vascular histopathologic response following balloon injury to rabbit carotid arteries with and without topically applied low-dose {beta}-radiation. Methods: The {beta}-emitting isotope strontium-90 (Sr-90) was conjugated onto the matrix of polypropylene (PLYP) mesh. Rabbit carotid arteries were balloon-injured with a no. 2 embolectomy catheter. Six carotid arteries were wrapped with nonradioactive PLYP mesh (controls) and Sr-90 ({approx}90 {mu}Ci) PLYP mesh in order to deliver low-dose radiation to the vessel wall from the external (adventitial) surface. Tissue was harvested at 6 weeks and processed for histologic examination. Results: There was consistent blockade of fibrocellular neointima formation with virtually no neointima present in all treated segments, compared to moderate neointima formation in controls. Medial thinning and smooth muscle cell (SMC) necrosis were also associated with topical brachytherapy. Conclusion: {beta}-Radiation applied by an externally wrapped PLYP mesh labeled with Sr-90 markedly suppressed neointima formation in an animal vascular surgical injury model. Further studies, however, are necessary to determine a suitable isotope and dosage for clinical application.

  1. Pravastatin inhibits fibrinogen- and FDP-induced inflammatory response via reducing the production of IL-6, TNF-α and iNOS in vascular smooth muscle cells.

    PubMed

    Lu, Peipei; Liu, Juntian; Pang, Xiaoming

    2015-10-01

    Atherosclerosis is a chronic inflammatory response of the arterial wall to pro‑atherosclerotic factors. As an inflammatory marker, fibrinogen directly participates in the pathogenesis of atherosclerosis. Our previous study demonstrated that fibrinogen and fibrin degradation products (FDP) produce a pro‑inflammatory effect on vascular smooth muscle cells (VSMCs) through inducing the production of interleukin‑6 (IL‑6), tumor necrosis factor‑α (TNF‑α) and inducible nitric oxide synthase (iNOS). In the present study, the effects of pravastatin on fibrinogen‑ and FDP‑induced expression of IL‑6, TNF‑α and iNOS were observed in VSMCs. The results showed that pravastatin dose‑dependently inhibited fibrinogen‑ and FDP‑stimulated expression of IL‑6, TNF‑α and iNOS in VSMCs at the mRNA and protein level. The maximal inhibition of protein expression of IL‑6, TNF‑α and iNOS was 46.9, 42.7 and 49.2% in fibrinogen‑stimulated VSMCs, and 50.2, 49.8 and 53.6% in FDP‑stimulated VSMCs, respectively. This suggests that pravastatin has the ability to relieve vascular inflammation via inhibiting the generation of IL‑6, TNF‑α and iNOS. The results of the present study may aid in further explaining the beneficial effects of pravastatin on atherosclerosis and related cardiovascular diseases. In addition, they suggest that application of pravastatin may be beneficial for prevention of atherosclerosis formation in hyperfibrinogenemia.

  2. Risk-reducing Apolipoprotein E and Clusterin genotypes protect against the consequences of poor vascular health on executive function performance and change in nondemented older adults.

    PubMed

    McFall, G Peggy; Sapkota, Shraddha; McDermott, Kirstie L; Dixon, Roger A

    2016-06-01

    We examined independent and cumulative effects of 2 Alzheimer's-related genetic polymorphisms, Apolipoprotein E (APOE) and Clusterin (CLU), in relation to the deleterious effects of poor vascular health (pulse pressure [PP]) on executive function (EF) performance and change in nondemented older adults. Using a sample (n = 593; age range = 53-95 years) from the Victoria Longitudinal Study, we applied latent growth modeling to test the effect of PP, as moderated by APOE and CLU, on an EF latent variable. EF was affected by higher levels of PP but differentially less so for carriers of low-risk alleles (APOE ɛ2+; CLU TT) than for moderate- or high-risk alleles (APOE ɛ2-; CLU C+). The cumulative genetic risk of APOE plus CLU provided similar moderation of PP level effects on EF. Future research may focus on how APOE and CLU might provide different but complementary contributions to predicting EF level and change. Vascular health risk in synergistic association with risk-related polymorphisms can elucidate the neurobiological underpinnings of cognitive trajectories in nondemented aging. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Palomid 529, a Novel Small-Molecule Drug, Is a TORC1/TORC2 Inhibitor That Reduces Tumor Growth, Tumor Angiogenesis, and Vascular Permeability

    PubMed Central

    Xue, Qi; Hopkins, Benjamin; Perruzzi, Carole; Udayakumar, Durga; Sherris, David; Benjamin, Laura E.

    2009-01-01

    It has become clear that the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is central for promoting both tumor and tumor stroma and is therefore a major target for anticancer drug development. First- and second-generation rapalogs (prototypical mTOR inhibitors) have shown promise but, due to the complex nature of mTOR signaling, can result in counterproductive feedback signaling to potentiate upstream Akt signaling. We present a novel PI3K/Akt/mTOR inhibitor, Palomid 529 (P529), which inhibits the TORC1 and TORC2 complexes and shows both inhibition of Akt signaling and mTOR signaling similarly in tumor and vasculature. We show that P529 inhibits tumor growth, angiogenesis, and vascular permeability. It retains the beneficial aspects of tumor vascular normalization that rapamycin boasts. However, P529 has the additional benefit of blocking pAktS473 signaling consistent with blocking TORC2 in all cells and thus bypassing feedback loops that lead to increased Akt signaling in some tumor cells. [Cancer Res 2008;68(22):9551–7] PMID:19010932

  4. Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability.

    PubMed

    Xue, Qi; Hopkins, Benjamin; Perruzzi, Carole; Udayakumar, Durga; Sherris, David; Benjamin, Laura E

    2008-11-15

    It has become clear that the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is central for promoting both tumor and tumor stroma and is therefore a major target for anticancer drug development. First- and second-generation rapalogs (prototypical mTOR inhibitors) have shown promise but, due to the complex nature of mTOR signaling, can result in counterproductive feedback signaling to potentiate upstream Akt signaling. We present a novel PI3K/Akt/mTOR inhibitor, Palomid 529 (P529), which inhibits the TORC1 and TORC2 complexes and shows both inhibition of Akt signaling and mTOR signaling similarly in tumor and vasculature. We show that P529 inhibits tumor growth, angiogenesis, and vascular permeability. It retains the beneficial aspects of tumor vascular normalization that rapamycin boasts. However, P529 has the additional benefit of blocking pAktS473 signaling consistent with blocking TORC2 in all cells and thus bypassing feedback loops that lead to increased Akt signaling in some tumor cells.

  5. Systemically delivered adipose stromal vascular fraction cells disseminate to peripheral artery walls and reduce vasomotor tone through a CD11b+ cell-dependent mechanism.

    PubMed

    Morris, Marvin E; Beare, Jason E; Reed, Robert M; Dale, Jacob R; LeBlanc, Amanda J; Kaufman, Christina L; Zheng, Huaiyu; Ng, Chin K; Williams, Stuart K; Hoying, James B

    2015-04-01

    Vasoactivity, an important aspect of tissue healing, is often compromised in disease and tissue injury. Dysfunction in the smaller vasoactive arteries is most impactful, given the role of these vessels in controlling downstream tissue perfusion. The adipose stromal vascular fraction (SVF) is a mix of homeostatic cells shown to promote tissue healing. Our objective was to test the hypothesis that autologous SVF cells therapeutically modulate peripheral artery vasoactivity in syngeneic mouse models of small artery function. Analysis of vasoactivity of saphenous arteries isolated from normal mice 1 week after intravenous injection of freshly isolated SVF cells revealed that pressure-dependent artery vasomotor tone was decreased by the SVF cell isolate, but not one depleted of CD11b(+) cells. Scavenging hydrogen peroxide in the vessel wall abrogated the artery relaxation promoted by the SVF cell isolate. Consistent with a CD11b(+) cell being the relevant cell type, SVF-derived F4/80-positive macrophages were present within the adventitia of the artery wall coincident with vasorelaxation. In a model of artery inflammation mimicking a common disease condition inducing vasoactive dysfunction, the SVF cells potentiated relaxation of saphenous arteries without structurally remodeling the artery via a CD11b(+) cell-dependent manner. Our findings demonstrate that freshly isolated, adipose SVF cells promote vasomotor relaxation in vasoactive arteries via a hydrogen peroxide-dependent mechanism that required CD11b(+) cells (most likely macrophages). Given the significant impact of small artery dysfunction in disease, we predict that the intravenous delivery of this therapeutic cell preparation would significantly improve tissue perfusion, particularly in diseases with diffuse vascular involvement. ©AlphaMed Press.

  6. Systemically Delivered Adipose Stromal Vascular Fraction Cells Disseminate to Peripheral Artery Walls and Reduce Vasomotor Tone Through a CD11b+ Cell-Dependent Mechanism

    PubMed Central

    Morris, Marvin E.; Beare, Jason E.; Reed, Robert M.; Dale, Jacob R.; LeBlanc, Amanda J.; Kaufman, Christina L.; Zheng, Huaiyu; Ng, Chin K.; Williams, Stuart K.

    2015-01-01

    Vasoactivity, an important aspect of tissue healing, is often compromised in disease and tissue injury. Dysfunction in the smaller vasoactive arteries is most impactful, given the role of these vessels in controlling downstream tissue perfusion. The adipose stromal vascular fraction (SVF) is a mix of homeostatic cells shown to promote tissue healing. Our objective was to test the hypothesis that autologous SVF cells therapeutically modulate peripheral artery vasoactivity in syngeneic mouse models of small artery function. Analysis of vasoactivity of saphenous arteries isolated from normal mice 1 week after intravenous injection of freshly isolated SVF cells revealed that pressure-dependent artery vasomotor tone was decreased by the SVF cell isolate, but not one depleted of CD11b+ cells. Scavenging hydrogen peroxide in the vessel wall abrogated the artery relaxation promoted by the SVF cell isolate. Consistent with a CD11b+ cell being the relevant cell type, SVF-derived F4/80-positive macrophages were present within the adventitia of the artery wall coincident with vasorelaxation. In a model of artery inflammation mimicking a common disease condition inducing vasoactive dysfunction, the SVF cells potentiated relaxation of saphenous arteries without structurally remodeling the artery via a CD11b+ cell-dependent manner. Our findings demonstrate that freshly isolated, adipose SVF cells promote vasomotor relaxation in vasoactive arteries via a hydrogen peroxide-dependent mechanism that required CD11b+ cells (most likely macrophages). Given the significant impact of small artery dysfunction in disease, we predict that the intravenous delivery of this therapeutic cell preparation would significantly improve tissue perfusion, particularly in diseases with diffuse vascular involvement. PMID:25722428

  7. Use of an optical technique to evaluate the cerebral vascular effects of alcohol (A): Effects on deoxyhemoglobin (DH) and levels of reduced cytochrome oxidase (rCO)

    SciTech Connect

    Barbour, R.L.; Gebiewold, A.; Altura, B.M. )

    1992-02-26

    The dose-response effects of acute A infusion were studied to examine the suggestion that A can induce stroke-like events as a consequence of cerebral vasospasm. By employing a single sending and receiving fiber, an optical backscatter measurement was employed to monitor the levels in DH and rCO in a closed cranium preparation. Anesthetized rats were prepared by cannulating a branch of the internal carotid artery and subjected to either a bolus infusion (BI) or to a constant infusion (CI) of 5 or 10% A at various rates. Results showed that low BI doses of A typically produced a slight increase in the oxyhemoglobin signal indicating that vasodilation had probably occurred. Higher BI doses, however, produced a prompt and significant reduction in the hemoglobin signal with a rise in rCO suggesting a vasoconstrictor response leading to ischemia, followed by recovery within 3-5 min. CI of A produced a similar cerebral vascular response, in a dose-related manner, but of a more sustained nature. At 30-50% of the BI dose levels, a global blanching of the brain surface occurred; rCO levels increased by 50-90% with a corresponding decline in levels of oxyhemoglobin. Control experiments using identical volumes/flow rates of Ringers solution failed to produce any alterations in the optical spectrum. Overall, these data indicate that, depending on dose, (a) A can induce vasodilatory or vasoconstrictor effects in the intact brain; (b) the more pronounced effects involve vasospasm in the cortical microcirculation leading to global ischemia as determined by elevated levels of rCO and DH; (c) optical measurements permit direct noninvasive assessment of the cerebral vascular effects of substances of abuse.

  8. Portal Vein Embolization Using a Nitinol Plug (Amplatzer Vascular Plug) in Combination with Histoacryl Glue and Iodinized Oil: Adequate Hypertrophy with a Reduced Risk of Nontarget Embolization

    SciTech Connect

    Bent, Clare L. Low, Deborah; Matson, Matthew B.; Renfrew, Ian; Fotheringham, Tim

    2009-05-15

    The purpose of this study was to assess whether portal vein embolization (PVE) using a nitinol vascular plug in combination with histoacryl glue and iodinized oil minimizes the risk of nontarget embolization while obtaining good levels of future liver remnant (FLR) hypertrophy. Between November 2005 and August 2008, 16 patients (8 females, 8 males; mean age, 63 {+-} 3.6 years), each with a small FLR, underwent right ipsilateral transhepatic PVE prior to major hepatectomy. Proximal PVE was initially performed by placement of a nitinol vascular plug, followed by distal embolization using a mixture of histoacryl glue and iodinized oil. Pre- and 6 weeks postprocedural FLR volumes were calculated using computed tomographic imaging. Selection for surgery required an FLR of 0.5% of the patient's body mass. Clinical course and outcome of surgical resection for all patients were recorded. At surgery, the ease of hepatectomy was subjectively assessed in comparison to previous experience following PVE with alternative embolic agents. PVE was successful in all patients. Mean procedure time was 30.4 {+-} 2.5 min. Mean absolute increase in FLR volume was 68.9% {+-} 12.0% (p = 0.00005). There was no evidence of nontarget embolization during the procedure or on subsequent imaging. Nine patients proceeded to extended hepatectomy. Six patients demonstrated disease progression. One patient did not achieve sufficient hypertrophy in relation to body mass to undergo hepatic resection. At surgery, the hepatobiliary surgeons observed less periportal inflammation compared to previous experience with alternative embolic agents, facilitating dissection at extended hepatectomy. In conclusion, ipsilateral transhepatic PVE using a single nitinol plug in combination with histoacryl glue and iodinized oil simplifies the procedure, offering short procedural times with minimal risk of nontarget embolization. Excellent levels of FLR hypertrophy are achieved enabling safe extended hepatectomy.

  9. Renal osteodystrophy and vascular calcification.

    PubMed

    Arcidiacono, T; Paloschi, V; Rainone, F; Terranegra, A; Dogliotti, E; Aloia, A; Soldati, L; Vezzoli, G

    2009-01-01

    Chronic kidney disease (CKD) is characterized by phosphate retention and reduced synthesis of 1.25(OH)2-vitamin D stimulating parathyroid hyperplasia. These changes cause a complex osteopathy, defined as renal osteodystrophy, and vascular calcification. Renal osteodystrophy increases the risk of fracture and causes deformities and disability. Vascular calcification occurs in a large proportion of hemodialysis patients and is a marker of arteriopathy. Calcifying arteriopathy induces arterial stiffness and contributes to the high cardiovascular mortality and morbidity among CKD patients. Vascular calcification results from a process of local bone formation induced by osteoblast-like cells developing in the vascular wall from resident cells. Osteoblast differentiation of resident vascular cells may be mediated by metabolic factors and may be induced by high concentrations of phosphate. Therefore, phosphate retention appears as the most detrimental factor affecting arteries in CKD patients. There is no specific therapy to revert soft tissue calcification, but calcification must be prevented in the early stages of CKD.

  10. ENMD-1198, a novel tubulin-binding agent reduces HIF-1alpha and STAT3 activity in human hepatocellular carcinoma(HCC) cells, and inhibits growth and vascularization in vivo.

    PubMed

    Moser, Christian; Lang, Sven A; Mori, Akira; Hellerbrand, Claus; Schlitt, Hans J; Geissler, Edward K; Fogler, William E; Stoeltzing, Oliver

    2008-07-23

    Hepatocellular carcinoma (HCC) represents a highly vascularized tumor entity and the process of angiogenesis is essential for the growth of HCC. Importantly, the pro-angiogenic transcription factors HIF-1alpha and STAT3 have been implicated in HCC progression, thus representing interesting targets for molecular targeted therapy. We hypothesized that therapeutic inhibition of HIF-1alpha could be achieved by using a novel tubulin-binding agent (ENMD-1198). ENMD-1198 is an analog of 2-methoxyestradiol (2ME2) with antiproliferative and antiangiogenic activity. The human HCC cell lines HUH-7 and HepG2 were used for experiments. Effects of ENMD-1198 on constitutive and inducible (hypoxia, growth factors) activation of signaling cascades, including HIF-1alpha and STAT3, were investigated by Western blotting. Changes in VEGF expression were determined by real-time PCR. Effects of ENMD-1198 on cancer cell migration and invasion were evaluated in in vitro-assays. The growth-inhibitory effects of ENMD-1198 (200 mg/kg/day) were determined in a subcutaneous tumor model (HUH-7). ENMD-1198 inhibited the phosphorylation of MAPK/Erk, PI-3K/Akt and FAK. Moreover, activation of HIF-1alpha and STAT3 was dramatically reduced by ENMD-1198, which resulted in lower VEGF mRNA expression (P < 0.05). In addition, tumor cell migratory and invasive properties were significantly inhibited (P < 0.05, for both). In vivo, treatment with ENMD-1198 led to a significant reduction in tumor growth, tumor vascularization, and numbers of proliferating tumor cells (P < 0.05 for all). The novel microtubule destabilizing agent ENMD-1198 is suitable for inhibiting HIF-1alpha and STAT3 in human HCC cells and leads to reduced tumor growth and vascularization in vivo. Hence, inhibition of HIF-1alpha and STAT3 could prove valuable for therapy of hepatocellular carcinoma.

  11. ENMD-1198, a novel tubulin-binding agent reduces HIF-1alpha and STAT3 activity in human hepatocellular carcinoma(HCC) cells, and inhibits growth and vascularization in vivo

    PubMed Central

    Moser, Christian; Lang, Sven A; Mori, Akira; Hellerbrand, Claus; Schlitt, Hans J; Geissler, Edward K; Fogler, William E; Stoeltzing, Oliver

    2008-01-01

    Background Hepatocellular carcinoma (HCC) represents a highly vascularized tumor entity and the process of angiogenesis is essential for the growth of HCC. Importantly, the pro-angiogenic transcription factors HIF-1α and STAT3 have been implicated in HCC progression, thus representing interesting targets for molecular targeted therapy. We hypothesized that therapeutic inhibition of HIF-1α could be achieved by using a novel tubulin-binding agent (ENMD-1198). ENMD-1198 is an analog of 2-methoxyestradiol (2ME2) with antiproliferative and antiangiogenic activity. Methods The human HCC cell lines HUH-7 and HepG2 were used for experiments. Effects of ENMD-1198 on constitutive and inducible (hypoxia, growth factors) activation of signaling cascades, including HIF-1α and STAT3, were investigated by Western blotting. Changes in VEGF expression were determined by real-time PCR. Effects of ENMD-1198 on cancer cell migration and invasion were evaluated in in vitro-assays. The growth-inhibitory effects of ENMD-1198 (200 mg/kg/day) were determined in a subcutaneous tumor model (HUH-7). Results ENMD-1198 inhibited the phosphorylation of MAPK/Erk, PI-3K/Akt and FAK. Moreover, activation of HIF-1α and STAT3 was dramatically reduced by ENMD-1198, which resulted in lower VEGF mRNA expression (P < 0.05). In addition, tumor cell migratory and invasive properties were significantly inhibited (P < 0.05, for both). In vivo, treatment with ENMD-1198 led to a significant reduction in tumor growth, tumor vascularization, and numbers of proliferating tumor cells (P < 0.05 for all). Conclusion The novel microtubule destabilizing agent ENMD-1198 is suitable for inhibiting HIF-1α and STAT3 in human HCC cells and leads to reduced tumor growth and vascularization in vivo. Hence, inhibition of HIF-1α and STAT3 could prove valuable for therapy of hepatocellular carcinoma. PMID:18651980

  12. Vascular Calcification: Mechanisms of Vascular Smooth Muscle Cell Calcification

    PubMed Central

    Leopold, Jane A.

    2014-01-01

    Vascular calcification is highly prevalent and, when present, is associated with major adverse cardiovascular events. Vascular smooth muscle cells play an integral role in mediating vessel calcification by undergoing differentiation to osteoblast-like cells and generating matrix vesicles that serve as a nidus for calcium-phosphate deposition in the vessel wall. Once believed to be a passive process, it is now recognized that vascular calcification is a complex and highly regulated process that involves activation of cellular signaling pathways, circulating inhibitors of calcification, genetic factors, and hormones. This review will examine several of the key mechanisms linking vascular smooth muscle cells to vessel calcification that may be targeted to reduce vessel wall mineralization and, thereby, reduce cardiovascular risk. PMID:25435520

  13. Menaquinone-7 Supplementation to Reduce Vascular Calcification in Patients with Coronary Artery Disease: Rationale and Study Protocol (VitaK-CAC Trial).

    PubMed

    Vossen, Liv M; Schurgers, Leon J; van Varik, Bernard J; Kietselaer, Bas L J H; Vermeer, Cees; Meeder, Johannes G; Rahel, Braim M; van Cauteren, Yvonne J M; Hoffland, Ge A; Rennenberg, Roger J M W; Reesink, Koen D; de Leeuw, Peter W; Kroon, Abraham A

    2015-10-28

    Coronary artery calcification (CAC) develops early in the pathogenesis of atherosclerosis and is a strong and independent predictor of cardiovascular disease (CVD). Arterial calcification is caused by an imbalance in calcification regulatory mechanisms. An important inhibitor of calcification is vitamin K-dependent matrix Gla protein (MGP). Both preclinical and clinical studies have shown that inhibition of the vitamin K-cycle by vitamin K antagonists (VKA) results in elevated uncarboxylated MGP (ucMGP) and subsequently in extensive arterial calcification. This led us to hypothesize that vitamin K supplementation may slow down the progression of calcification. To test this, we designed the VitaK-CAC trial which analyses effects of menaquinone-7 (MK-7) supplementation on progression of CAC. The trial is a double-blind, randomized, placebo-controlled trial including patients with coronary artery disease (CAD). Patients with a baseline Agatston CAC-score between 50 and 400 will be randomized to an intervention-group (360 microgram MK-7) or a placebo group. Treatment duration will be 24 months. The primary endpoint is the difference in CAC-score progression between both groups. Secondary endpoints include changes in arterial structure and function, and associations with biomarkers. We hypothesize that treatment with MK-7 will slow down or arrest the progression of CAC and that this trial may lead to a treatment option for vascular calcification and subsequent CVD.

  14. ACCRETA COMPLICATING COMPLETE PLACENTA PREVIA IS CHARACTERIZED BY REDUCED SYSTEMIC LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND EPITHELIAL-TO-MESENCHYMAL TRANSITION OF THE INVASIVE TROPHOBLAST

    PubMed Central

    Wehrum, Mark J.; Buhimschi, Irina A.; Salafia, Carolyn; Thung, Stephen; Bahtiyar, Mert O.; Werner, Erica F.; Campbell, Katherine H.; Laky, Christine; Sfakianaki, Anna K.; Zhao, Guomao; Funai, Edmund F.; Buhimschi, Catalin S.

    2011-01-01

    OBJECTIVE To characterize serum angiogenic factor profile of women with complete placenta previa and determine if invasive trophoblast differentiation characteristic of accreta, increta or percreta shares features of epitehelial-mesenchymal-transition (EMT). STUDY DESIGN We analyzed gestational age matched serum samples from 90 pregnant women with either complete placenta previa (n=45) or uncomplicated pregnancies (n=45). Vascular-endothelial-growth-factor (VEGF), placental-growth-factor (PlGF) and soluble fms-like-tyrosine-kinase-1 (sFlt-1) were immunoassayed. VEGF and phosphotyrosine (P-Tyr) immunoreactivity was surveyed in histological specimens relative to expression of vimentin and cytokeratin-7. RESULTS Women with previa and invasive placentation [accreta (n=5); increta (n=6); percreta (n=2)] had lower systemic VEGF (invasive previa: median [IQR]: 0.8[0.02–3.4] vs. control: 6.5[2.7–10.5] pg/mL, P=0.02). VEGF and P-Tyr immunostaining predominated in the invasive extravillous trophoblasts (EVT) which co-expressed vimentin and cytokeratin-7, a EMT feature and tumor-like cell phenotype. CONCLUSIONS Lower systemic free VEGF and a switch of the interstitial EVT to a metastable cell phenotype characterize placenta previa with excessive myometrial invasion. PMID:21316642

  15. Accreta complicating complete placenta previa is characterized by reduced systemic levels of vascular endothelial growth factor and by epithelial-to-mesenchymal transition of the invasive trophoblast.

    PubMed

    Wehrum, Mark J; Buhimschi, Irina A; Salafia, Carolyn; Thung, Stephen; Bahtiyar, Mert O; Werner, Erica F; Campbell, Katherine H; Laky, Christine; Sfakianaki, Anna K; Zhao, Guomao; Funai, Edmund F; Buhimschi, Catalin S

    2011-05-01

    We sought to characterize serum angiogenic factor profile of women with complete placenta previa and determine if invasive trophoblast differentiation characteristic of accreta, increta, or percreta shares features of epithelial-to-mesenchymal transition. We analyzed gestational age-matched serum samples from 90 pregnant women with either complete placenta previa (n = 45) or uncomplicated pregnancies (n = 45). Vascular endothelial growth factor (VEGF), placental growth factor, and soluble form of fms-like-tyrosine-kinase-1 were immunoassayed. VEGF and phosphotyrosine immunoreactivity was surveyed in histological specimens relative to expression of vimentin and cytokeratin-7. Women with previa and invasive placentation (accreta, n = 5; increta, n = 6; percreta, n = 2) had lower systemic VEGF (invasive previa: median 0.8 [0.02-3.4] vs control 6.5 [2.7-10.5] pg/mL, P = .02). VEGF and phosphotyrosine immunostaining predominated in the invasive extravillous trophoblasts that coexpressed vimentin and cytokeratin-7, an epithelial-to-mesenchymal transition feature and tumorlike cell phenotype. Lower systemic free VEGF and a switch of the interstitial extravillous trophoblasts to a metastable cell phenotype characterize placenta previa with excessive myometrial invasion. Published by Mosby, Inc.

  16. Menaquinone-7 Supplementation to Reduce Vascular Calcification in Patients with Coronary Artery Disease: Rationale and Study Protocol (VitaK-CAC Trial)

    PubMed Central

    Vossen, Liv M.; Schurgers, Leon J.; van Varik, Bernard J.; Kietselaer, Bas L. J. H.; Vermeer, Cees; Meeder, Johannes G.; Rahel, Braim M.; van Cauteren, Yvonne J. M.; Hoffland, Ge A.; Rennenberg, Roger J. M. W.; Reesink, Koen D.; de Leeuw, Peter W.; Kroon, Abraham A.

    2015-01-01

    Coronary artery calcification (CAC) develops early in the pathogenesis of atherosclerosis and is a strong and independent predictor of cardiovascular disease (CVD). Arterial calcification is caused by an imbalance in calcification regulatory mechanisms. An important inhibitor of calcification is vitamin K-dependent matrix Gla protein (MGP). Both preclinical and clinical studies have shown that inhibition of the vitamin K-cycle by vitamin K antagonists (VKA) results in elevated uncarboxylated MGP (ucMGP) and subsequently in extensive arterial calcification. This led us to hypothesize that vitamin K supplementation may slow down the progression of calcification. To test this, we designed the VitaK-CAC trial which analyses effects of menaquinone-7 (MK-7) supplementation on progression of CAC. The trial is a double-blind, randomized, placebo-controlled trial including patients with coronary artery disease (CAD). Patients with a baseline Agatston CAC-score between 50 and 400 will be randomized to an intervention-group (360 microgram MK-7) or a placebo group. Treatment duration will be 24 months. The primary endpoint is the difference in CAC-score progression between both groups. Secondary endpoints include changes in arterial structure and function, and associations with biomarkers. We hypothesize that treatment with MK-7 will slow down or arrest the progression of CAC and that this trial may lead to a treatment option for vascular calcification and subsequent CVD. PMID:26516910

  17. Vascular dementia

    PubMed Central

    Korczyn, Amos D; Vakhapova, Veronika; Grinberg, Lea T

    2012-01-01

    The epidemic grow of dementia causes great concern for the society. It is customary to consider Alzheimer’s disease (AD) as the most common cause of dementia, followed by vascular dementia (VaD). This dichotomous view of a neurodegenerative disease as opposed to brain damage caused by extrinsic factors led to separate lines of research in these two entities. Indeed, accumulated data suggest that the two disorders have additive effects and probably interact; however it is still unknown to what degree. Furthermore, epidemiological studies have shown “vascular” risk factors to be associated with AD. Therefore, a clear distinction between AD and VaD cannot be made in most cases, and is furthermore unhelpful. In the absence of efficacious treatment for the neurodegenerative process, special attention must be given to vascular component, even in patients with presumed mixed pathology. Symptomatic treatment of VaD and AD are similar, although the former is less effective. For prevention of dementia it is important to treat aggressively all factors, even in stroke survivors who do not show evidence of cognitive decline,. In this review, we will give a clinical and pathological picture of the processes leading to VaD and discuss it interaction with AD. PMID:22575403

  18. [The impacts of regulating Toll-like receptor 2/nuclear factor-ΚB signal pathway on rats with ventilator-induced lung injury].

    PubMed

    Fu, Ruili; Pan, Linghui; Lin, Fei; Ge, Wanyun; Huang, Cuiyuan; Dai, Huijun

    2014-12-01

    To evaluate the role of Toll-like receptor 2/nuclear factor-ΚB (TLR2/NF-ΚB) signaling pathway pretreatment in ventilator-induced lung injury (VILI). Thirty male Sprague-Dawley (SD) rats were randomly divided into three groups by using random number scale, with 10 rats in each group. Group A: rats were given 200 μL of TLR2 monoclonal antibodies (TLR2mAb, 10 μg/kg) by slow instillation through tracheal catheter, and then ventilated with a high tidal volume (VT) of 40 mL/kg. Group B: ventilated with a normal VT of 8 mL/kg. Group C: rats were tracheally instilled with 10 μg/kg of TLR2mAb devoid of biologic activity, and then ventilated with a high VT of 40 mL/kg. The rats were mechanically ventilated for 4 hours, the lung wet to dry weight ratio (W/D) was calculated. The changes in pathology and ultrastructure in lung tissue were observed with microscope. Enzyme linked immunosorbent assay (ELISA) was performed to determine the concentration of interleukins (IL-1β, IL-6) and tumor necrosis factor-α (TNF-α) in serum and brconchoalveolar lavage fluid (BALF). Real-time fluorescent quantitation reverse transcription-polymerase chain reaction (RT-PCR) was used to assess the mRNA expressions of TLR2, NF-ΚB and myeloid differentiation factor 88 (MyD88) in lung tissue. No obvious pathological changes in lungs were found in group A and group B, and no obvious damages to ultra-microstructure were found in lung macrophages, typeI epithelial cell and typeII epithelial cell. In group C, pathological changes were observed, including pulmonary alveoli fusion, alveoli septum thickening, inflammatory cells infiltration, and damages to ultrastructure of lung macrophage, damage to cell membrane of typeI epithelial cells and type II epithelial cells, vacuoles in cytoplasm, damage to organelle, and even pyknosis and perinuclear cistern thickening. Compared with group C, W/D ratio and mean concentration of inflammatory cytokines in serum and BALF showed a significant decrease in

  19. Pre-dive Whole-Body Vibration Better Reduces Decompression-Induced Vascular Gas Emboli than Oxygenation or a Combination of Both

    PubMed Central

    Balestra, Costantino; Theunissen, Sigrid; Papadopoulou, Virginie; Le Mener, Cedric; Germonpré, Peter; Guerrero, François; Lafère, Pierre

    2016-01-01

    Purpose: Since non-provocative dive profiles are no guarantor of protection against decompression sickness, novel means including pre-dive “preconditioning” interventions, are proposed for its prevention. This study investigated and compared the effect of pre-dive oxygenation, pre-dive whole body vibration or a combination of both on post-dive bubble formation. Methods: Six healthy volunteers performed 6 no-decompression dives each, to a depth of 33 mfw for 20 min (3 control dives without preconditioning and 1 of each preconditioning protocol) with a minimum interval of 1 week between each dive. Post-dive bubbles were counted in the precordium by two-dimensional echocardiography, 30 and 90 min after the dive, with and without knee flexing. Each diver served as his own control. Results: Vascular gas emboli (VGE) were systematically observed before and after knee flexing at each post-dive measurement. Compared to the control dives, we observed a decrease in VGE count of 23.8 ± 7.4% after oxygen breathing (p < 0.05), 84.1 ± 5.6% after vibration (p < 0.001), and 55.1 ± 9.6% after vibration combined with oxygen (p < 0.001). The difference between all preconditioning methods was statistically significant. Conclusions: The precise mechanism that induces the decrease in post-dive VGE and thus makes the diver more resistant to decompression stress is still not known. However, it seems that a pre-dive mechanical reduction of existing gas nuclei might best explain the beneficial effects of this strategy. The apparent non-synergic effect of oxygen and vibration has probably to be understood because of different mechanisms involved. PMID:27965591

  20. Prostaglandin E2 reduces swine myocardial ischemia reperfusion injury via increased endothelial nitric oxide synthase and vascular endothelial growth factor expression levels

    PubMed Central

    Zhou, Ying; Yang, Peng; Li, Aili; Ye, Xiaojun; Ren, Shiyan; Li, Xianlun

    2017-01-01

    Prostaglandin E2 (PGE2) has been demonstrated to attenuate cardiac ischemia-reperfusion (I/R) injury. However, the underlying mechanism of PGE2 in cardiac I/R injury remains unknown. Upregulated expression levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) were reported in acute myocardial infarction (AMI), and were demonstrated to diminish I/R injury. In the current study the involvement of VEGF and eNOS in the myocardial protective effect of PGE2 were investigated in a catheter-based porcine model of AMI. Twenty-two Chinese miniature pigs were randomized into sham-surgery (n=6), control (n=8) and PGE2 (n=8) groups. PGE2 (1 µg/kg) was injected from 10 min prior to left anterior descending occlusion up to 1 h after reperfusion in the PGE2 group. Subsequently, the hemodynamic parameters were evaluated. Thioflavin-S and Evans Blue double staining were performed to evaluate the extent of the myocardial reperfusion area (RA) and no-reflow area (NRA). Immunohistochemical and western blot analysis were used to evaluate protein expression levels of VEGF and eNOS. Left ventricular (LV) systolic pressure significantly improved and LV end-diastolic pressure significantly decreased in the PGE2 group when compared with the control group 2 h after occlusion and 3 h after reperfusion (P<0.05, respectively). The RA and NRA were smaller in the PGE2 group than in the control group (P<0.05, respectively). Furthermore, PGE2 treatment increased the myocardial content of VEGF and eNOS when compared with the control group (P<0.05, respectively). Thus, the results of the present study demonstrate the cardio-protective mechanisms of PGE2, which may protect the heart from I/R injury via enhancement of VEGF and eNOS expression levels. PMID:28357071

  1. Inflammation-associated repression of vasodilator-stimulated phosphoprotein (VASP) reduces alveolar-capillary barrier function during acute lung injury

    PubMed Central

    Henes, Janek; Schmit, Marthe A.; Morote-Garcia, Julio C.; Mirakaj, Valbona; Köhler, David; Glover, Louise; Eldh, Therese; Walter, Ulrich; Karhausen, Jörn; Colgan, Sean P.; Rosenberger, Peter

    2009-01-01

    Acute lung injury (ALI) is an inflammatory disorder associated with reduced alveolar-capillary barrier function, increased pulmonary vascular permeability, and infiltration of leukocytes into the alveolar space. Pulmonary function might be compromised, its most severe form being the acute respiratory distress syndrome. A protein central to physiological barrier properties is vasodilator-stimulated phosphoprotein (VASP). Given the fact that VASP expression is reduced during periods of cellular hypoxia, we investigated the role of VASP during ALI. Initial studies revealed reduced VASP expressional levels through cytokines in vitro. Studies in the putative human VASP promoter identified NF-κB as a key regulator of VASP transcription. This VASP repression results in increased paracellular permeability and migration of neutrophils in vitro. In a model of LPS-induced ALI, VASP−/− mice demonstrated increased pulmonary damage compared with wild-type animals. These findings were confirmed in a second model of ventilator-induced lung injury. Studies employing bone marrow chimeric animals identified tissue-specific repression of VASP as the underlying cause of decreased barrier properties of the alveolar-capillary barrier during ALI. Taken together these studies identify tissue-specific VASP as a central protein in the control of the alveolar-capillary barrier properties during ALI.—Henes, J., Schmit, M. A., Morote-Garcia, J. C., Mirakaj, V., Köhler, D., Glover, L., Eldh, T., Walter, U., Karhausen, J., Colgan, S. P., Rosenberger, P. Inflammation-associated repression of vasodilator-stimulated phosphoprotein (VASP) reduces alveolar-capillary barrier function during acute lung injury. PMID:19690214

  2. Supplementation with alpha-tocopherol or beta-carotene reduces serum concentrations of vascular endothelial growth factor-D, but Not -A or -C, in male smokers.

    PubMed

    Mondul, Alison M; Rager, Helen C; Kopp, William; Virtamo, Jarmo; Albanes, Demetrius

    2011-11-01

    Evidence from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study suggests that vitamin E and β-carotene supplement use may influence the risk of several cancers. Vascular endothelial growth factors (VEGF) are proteins involved in angiogenesis, an important requirement for tumor growth and metastasis. Thus, vitamin E and β-carotene may influence cancer risk through one or more VEGF. The ATBC Study was a randomized, double-blind, placebo-controlled, primary cancer prevention trial in which participants were assigned to 1 of 4 supplementation groups based on a 2 × 2 factorial design: 1) α-tocopherol (vitamin E); 2) β-carotene; 3) both; or 4) placebo. For the present study, 100 cancer-free participants with follow-up serum available were randomly selected from each intervention group. VEGF-A, -C, and -D concentrations were measured by ELISA in serum obtained at baseline and after at least 2 y of supplementation. Differences in change in VEGF levels from baseline to follow-up between intervention groups were assessed using the ANOVA test. Change in VEGF-A and VEGF-C concentrations between baseline and follow-up did not differ by intervention group (P = 0.45 and 0.29, respectively). The decrease in the serum VEGF-D concentration was greater in the men supplemented with α-tocopherol (-9.7 ± 2.5%) or β-carotene (-8.5 ± 2.7%) and tended to be greater in those supplemented with both (-6.8 ± 2.4%) compared to the placebo group, in which there was no change (-0.4 ± 3.0%) (P = 0.03). In this population of male smokers, supplementation with α-tocopherol or β-carotene was associated with a decrease in VEGF-D levels over time. Although the mechanism through which these supplements affect cancer etiolog remains unclear, our results support the hypothesis that vitamin E and β-carotene may influence cancer progression through VEGF-mediated lymphangiogenesis.

  3. Vascular access in oncology patients.

    PubMed

    Gallieni, Maurizio; Pittiruti, Mauro; Biffi, Roberto

    2008-01-01

    Adequate vascular access is of paramount importance in oncology patients. It is important in the initial phase of surgical treatment or chemotherapy, as well as in the chronic management of advanced cancer and in the palliative care setting. We present an overview of the available vascular access devices and of the most relevant issues regarding insertion and management of vascular access. Particular emphasis is given to the use of ultrasound guidance as the preferred technique of insertion, which has dramatically decreased insertion-related complications. Vascular access management has considerably improved after the publication of effective guidelines for the appropriate nursing of the vascular device, which has reduced the risk of late complications, such as catheter-related bloodstream infection. However, many areas of clinical practice are still lacking an evidence-based background, such as the choice of the most appropriate vascular access device in each clinical situation, as well as prevention and treatment of thrombosis. We suggest an approach to the choice of the most appropriate vascular access device for the oncology patient, based on the literature available to date.

  4. GRP78 is a novel receptor initiating a vascular barrier protective response to oxidized phospholipids.

    PubMed

    Birukova, Anna A; Singleton, Patrick A; Gawlak, Grzegorz; Tian, Xinyong; Mirzapoiazova, Tamara; Mambetsariev, Bolot; Dubrovskyi, Oleksii; Oskolkova, Olga V; Bochkov, Valery N; Birukov, Konstantin G

    2014-07-01

    Vascular integrity and the maintenance of blood vessel continuity are fundamental features of the circulatory system maintained through endothelial cell-cell junctions. Defects in the endothelial barrier become an initiating factor in several pathologies, including ischemia/reperfusion, tumor angiogenesis, pulmonary edema, sepsis, and acute lung injury. Better understanding of mechanisms stimulating endothelial barrier enhancement may provide novel therapeutic strategies. We previously reported that oxidized phospholipids (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine [OxPAPC]) promote endothelial cell (EC) barrier enhancement both in vitro and in vivo. This study examines the initiating mechanistic events triggered by OxPAPC to increase vascular integrity. Our data demonstrate that OxPAPC directly binds the cell membrane-localized chaperone protein, GRP78, associated with its cofactor, HTJ-1. OxPAPC binding to plasma membrane-localized GRP78 leads to GRP78 trafficking to caveolin-enriched microdomains (CEMs) on the cell surface and consequent activation of sphingosine 1-phosphate receptor 1, Src and Fyn tyrosine kinases, and Rac1 GTPase, processes essential for cytoskeletal reorganization and EC barrier enhancement. Using animal models of acute lung injury with vascular hyperpermeability, we observed that HTJ-1 knockdown blocked OxPAPC protection from interleukin-6 and ventilator-induced lung injury. Our data indicate for the first time an essential role of GRP78 and HTJ-1 in OxPAPC-mediated CEM dynamics and enhancement of vascular integrity.

  5. Vascular permeability, vascular hyperpermeability and angiogenesis

    PubMed Central

    Nagy, Janice A.; Benjamin, Laura; Zeng, Huiyan; Dvorak, Ann M.

    2008-01-01

    The vascular system has the critical function of supplying tissues with nutrients and clearing waste products. To accomplish these goals, the vasculature must be sufficiently permeable to allow the free, bidirectional passage of small molecules and gases and, to a lesser extent, of plasma proteins. Physiologists and many vascular biologists differ as to the definition of vascular permeability and the proper methodology for its measurement. We review these conflicting views, finding that both provide useful but complementary information. Vascular permeability by any measure is dramatically increased in acute and chronic inflammation, cancer, and wound healing. This hyperpermeability is mediated by acute or chronic exposure to vascular permeabilizing agents, particularly vascular permeability factor/vascular endothelial growth factor (VPF/VEGF, VEGF-A). We demonstrate that three distinctly different types of vascular permeability can be distinguished, based on the different types of microvessels involved, the composition of the extravasate, and the anatomic pathways by which molecules of different size cross-vascular endothelium. These are the basal vascular permeability (BVP) of normal tissues, the acute vascular hyperpermeability (AVH) that occurs in response to a single, brief exposure to VEGF-A or other vascular permeabilizing agents, and the chronic vascular hyperpermeability (CVH) that characterizes pathological angiogenesis. Finally, we list the numerous (at least 25) gene products that different authors have found to affect vascular permeability in variously engineered mice and classify them with respect to their participation, as far as possible, in BVP, AVH and CVH. Further work will be required to elucidate the signaling pathways by which each of these molecules, and others likely to be discovered, mediate the different types of vascular permeability. PMID:18293091

  6. Activation of GLP-1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow.

    PubMed

    Jensen, Elisa P; Poulsen, Steen S; Kissow, Hannelouise; Holstein-Rathlou, Niels-Henrik; Deacon, Carolyn F; Jensen, Boye L; Holst, Jens J; Sorensen, Charlotte M

    2015-04-15

    Glucagon-like peptide (GLP)-1 has a range of extrapancreatic effects, including renal effects. The mechanisms are poorly understood, but GLP-1 receptors have been identified in the kidney. However, the exact cellular localization of the renal receptors is poorly described. The aim of the present study was to localize renal GLP-1 receptors and describe GLP-1-mediated effects on the renal vasculature. We hypothesized that renal GLP-1 receptors are located in the renal microcirculation and that activation of these affects renal autoregulation and increases renal blood flow. In vivo autoradiography using (125)I-labeled GLP-1, (125)I-labeled exendin-4 (GLP-1 analog), and (125)I-labeled exendin 9-39 (GLP-1 receptor antagonist) was performed in rodents to localize specific GLP-1 receptor binding. GLP-1-mediated effects on blood pressure, renal blood flow (RBF), heart rate, renin secretion, urinary flow rate, and Na(+) and K(+) excretion were investigated in anesthetized rats. Effects of GLP-1 on afferent arterioles were investigated in isolated mouse kidneys. Specific binding of (125)I-labeled GLP-1, (125)I-labeled exendin-4, and (125)I-labeled exendin 9-39 was observed in the renal vasculature, including afferent arterioles. Infusion of GLP-1 increased blood pressure, RBF, and urinary flow rate significantly in rats. Heart rate and plasma renin concentrations were unchanged. Exendin 9-39 inhibited the increase in RBF. In isolated murine kidneys, GLP-1 and exendin-4 significantly reduced the autoregulatory response of afferent arterioles in response to stepwise increases in pressure. We conclude that GLP-1 receptors are located in the renal vasculature, including afferent arterioles. Activation of these receptors reduces the autoregulatory response of afferent arterioles to acute pressure increases and increases RBF in normotensive rats. Copyright © 2015 the American Physiological Society.

  7. Impact of a multimodal intervention to reduce bloodstream infections related to vascular catheters in non-ICU wards: a multicentre study.

    PubMed

    Freixas, N; Bella, F; Limón, E; Pujol, M; Almirante, B; Gudiol, F

    2013-09-01

    To determine the impact of a multimodal intervention designed to reduce the incidence of catheter-related bloodstream infections (CRBSIs) outside the ICU, we conducted a prospective, quasi-experimental, before-after intervention study in 11 hospitals participating in the VINCat programme in Catalonia, Spain. The intervention consists of: (i) an evidence-based bundle of practices relating to catheter insertion and maintenance; (ii) a training programme for healthcare workers; (iii) four point-prevalence surveys to track the status of the catheters; and (iv) feedback reports to the staff involved. The study included both central (CVC) and peripheral venous catheters (PVCs). Rates of CRBSI per 1000 patient-days were prospectively measured in 2009 (pre-intervention period) and 2010 (post-intervention period). The analysis included 1 191 843 patient-days in 2009 and 1 173 672 patient-days in 2010. The overall incidence of CRBSI decreased from 0.19 to 0.15 (p 0.04) and the incidence of CRBSI associated with a CVC decreased from 0.14 to 0.10 (p 0.004) after the intervention. The incidence in PVCs remained unchanged. There was a statistically significant improvement in the adequate maintenance of both CVCs and PVCs. Among the CRBSIs originating in PVCs, 61.8% appeared more than 72 h every insertion. There was a lower infection rate in the hospitals with a higher adherence to the recommendation to replace PVCs after 72 h. Our findings suggest that the implementation of intervention programmes similar to ours could have a major impact on patient safety by reducing the incidence of CRBSIs, and that routine replacement of PVCs might additionally prevent a significant number of bloodstream infections. © 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.

  8. Willow bark extract increases antioxidant enzymes and reduces oxidative stress through activation of Nrf2 in vascular endothelial cells and Caenorhabditis elegans.

    PubMed

    Ishikado, Atsushi; Sono, Yoko; Matsumoto, Motonobu; Robida-Stubbs, Stacey; Okuno, Aya; Goto, Masashi; King, George L; Blackwell, T Keith; Makino, Taketoshi

    2013-12-01

    Willow bark extract (WBE) is listed in the European Pharmacopoeia and has been traditionally used for treating fever, pain, and inflammation. Recent studies have demonstrated its clinical usefulness. This study investigated the antioxidative effects of WBE in human umbilical vein endothelial cells (HUVECs) and Caenorhabditis elegans. WBE prevented oxidative-stress-induced cytotoxicity of HUVECs and death of C. elegans. WBE dose-dependently increased mRNA and protein expression levels of the nuclear factor erythroid 2-related factor 2 (Nrf2) target genes heme oxygenase-1, γ-glutamylcysteine ligase modifier and catalytic subunits, and p62 and intracellular glutathione (GSH) in HUVECs. In the nematode C. elegans, WBE increased the expression of the gcs-1::green fluorescent protein reporter, a well-characterized target of the Nrf2 ortholog SKN-1, in a manner that was SKN-1-dependent. WBE increased intranuclear expression and DNA binding of Nrf2 and the activity of an antioxidant response element (ARE) reporter plasmid in HUVECs. WBE-induced expression of Nrf2-regulated genes and increased GSH levels in HUVECs were reduced by Nrf2 and p38 small interfering (si) RNAs and by the p38-specific inhibitor SB203580. Nrf2 siRNA reduced the cytoprotective effect of WBE against oxidative stress in HUVECs. Salicin, a major anti-inflammatory ingredient of WBE, failed to activate ARE-luciferase activity, whereas a salicin-free WBE fraction showed intensive activity. WBE induced antioxidant enzymes and prevented oxidative stress through activation of Nrf2 independent of salicin, providing a new potential explanation for the clinical usefulness of WBE. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. SPARC (secreted protein acidic and rich in cysteine) knockdown protects mice from acute liver injury by reducing vascular endothelial cell damage

    PubMed Central

    Peixoto, E; Atorrasagasti, C; Aquino, JB; Militello, R; Bayo, J; Fiore, E; Piccioni, F; Salvatierra, E; Alaniz, L; García, MG; Bataller, R; Corrales, F; Gidekel, M; Podhajcer, O; Colombo, MI; Mazzolini, G

    2015-01-01

    Secreted protein, acidic and rich in cysteine (SPARC) is involved in many biological process including liver fibrogenesis, but its role in acute liver damage is unknown. To examine the role of SPARC in acute liver injury, we used SPARC knock-out (SPARC−/−) mice. Two models of acute liver damage were used: concanavalin A (Con A) and the agonistic anti-CD95 antibody Jo2. SPARC expression levels were analyzed in liver samples from patients with acute-on-chronic alcoholic hepatitis (AH). SPARC expression is increased on acute-on-chronic AH patients. Knockdown of SPARC decreased hepatic damage in the two models of liver injury. SPARC−/− mice showed a marked reduction in Con A-induced necroinflammation. Infiltration by CD4+ T cells, expression of tumor necrosis factor-α and interleukin-6 and apoptosis were attenuated in SPARC−/− mice. Sinusoidal endothelial cell monolayer was preserved and was less activated in Con A-treated SPARC−/− mice. SPARC knockdown reduced Con A-induced autophagy of cultured human microvascular endothelial cells (HMEC-1). Hepatic transcriptome analysis revealed several gene networks that may have a role in the attenuated liver damaged found in Con A-treated SPARC−/− mice. SPARC has a significant role in the development of Con A-induced severe liver injury. These results suggest that SPARC could represent a therapeutic target in acute liver injury. PMID:25410742

  10. The vascular biology of calcification.

    PubMed

    Shroff, Rukshana C; Shanahan, Catherine M

    2007-01-01

    Vascular calcification is an active, cell-mediated process that results from an imbalance between the promoters and inhibitors of mineralization. The process of vascular calcification shares many similarities with that of skeletal mineralization. However, while skeletal mineralization is a regulated process induced by complex, well-timed developmental cues, vascular calcification is a pathological process, occurring in response to dysregulated/inappropriate environmental cues. Damage inducing agents present in the uremic milieu such as a mineral imbalance, induce vascular smooth muscle cell (VSMC) apoptosis, and vesicle release resulting in mineral nucleation and the deposition of hydroxyapatite. Under normal conditions, inhibitors of soft-tissue mineralization such as matrix gamma-carboxyglutamic acid protein are expressed locally within the vessel wall while others such as fetuin-A are present in the circulation. Down-regulation or perturbation of these proteins leads to a phenotypic transformation of VSMC into osteo/chondrocytic-like cells that have the capacity to modulate the mineralization process. Many aspects of the mechanisms underlying vascular calcification have been defined through in vitro studies and molecular biological techniques; however, there are still unanswered questions, particularly with respect to the relationship between bone and vascular calcification, processes that appear to be inversely related. A better understanding of the complex mechanisms regulating tissue calcification may have therapeutic potential in reducing the cardiovascular disease-associated morbidity and mortality in patients with renal disease.

  11. Vascular aging and geriatric patient.

    PubMed

    Nicita-Mauro, V; Maltese, G; Nicita-Mauro, C; Basile, G

    2007-08-01

    Advancing age is associated with changes in structure and function of different segments of the vascular system and is the dominant risk factor for cardiovascular diseases. The oxidative stress represents a key event of vascular aging, mainly characterized by endothelium dysfunction and reduced arterial elasticity. Age-related changes include intimal and medial thickening, arterial calcification, increased deposition of matrix substances, thus leading to a reduced compliance and increased wall stiffness, that significantly contributes to an increase in systolic blood pressure. Frail elderly patients, because of their complex clinical presentations and needs, require a special approach: the comprehensive geriatric assessment, a multidimensional process intended to determine medical, psychosocial and functional capabilities and problems in order to develop a plan for treatment and continued care. All physicians, and geriatricians in particular, must, therefore, educate their patients to healthy lifestyle to prevent or delay vascular aging, cardiovascular diseases, and to maintain a good quality of life and increase life expectancy.

  12. Vascular development in Arabidopsis.

    PubMed

    Ye, Zheng-Hua; Freshour, Glenn; Hahn, Michael G; Burk, David H; Zhong, Ruiqin

    2002-01-01

    Vascular tissues, xylem and phloem, form a continuous network throughout the plant body for transport of water, minerals, and food. Characterization of Arabidopsis mutants defective in various aspects of vascular formation has demonstrated that Arabidopsis is an ideal system for investigating the molecular mechanisms controlling vascular development. The processes affected in these mutants include initiation or division of procambium or vascular cambium, formation of continuous vascular cell files, differentiation of procambium or vascular cambium into vascular tissues, cell elongation, patterned secondary wall thickening, and biosynthesis of secondary walls. Identification of the genes affected by some of these mutations has revealed essential roles in vascular development for a cytokinin receptor and several factors mediating auxin transport or signaling. Mutational studies have also identified a number of Arabidopsis mutants defective in leaf venation pattern or vascular tissue organization in stems. Genetic evidence suggests that the vascular tissue organization is regulated by the same positional information that determines organ polarity.

  13. Downregulation of Securin by the variant RNF213 R4810K (rs112735431, G>A) reduces angiogenic activity of induced pluripotent stem cell-derived vascular endothelial cells from moyamoya patients

    SciTech Connect

    Hitomi, Toshiaki; Habu, Toshiyuki; Kobayashi, Hatasu; Okuda, Hiroko; Harada, Kouji H.; Osafune, Kenji; Taura, Daisuke; Sone, Masakatsu; Asaka, Isao; Ameku, Tomonaga; Watanabe, Akira; Kasahara, Tomoko; Sudo, Tomomi; Shiota, Fumihiko; Hashikata, Hirokuni; Takagi, Yasushi; Morito, Daisuke; Miyamoto, Susumu; Nakao, Kazuwa; Koizumi, Akio

    2013-08-16

    Highlights: •Angiogenic activities were reduced in iPSECs from MMD patients. •Many mitosis-regulated genes were downregulated in iPSECs from MMD patients. •RNF213 R4810K downregulated Securin and inhibited angiogenic activity. •Securin suppression by siRNA reduced angiogenic activities of iPSECs and HUVECs. -- Abstract: Moyamoya disease (MMD) is a cerebrovascular disease characterized by occlusive lesions in the circle of Willis. The RNF213 R4810K polymorphism increases susceptibility to MMD. Induced pluripotent stem cells (iPSCs) were established from unaffected fibroblast donors with wild-type RNF213 alleles, and from carriers/patients with one or two RNF213 R4810K alleles. Angiogenic activities of iPSC-derived vascular endothelial cells (iPSECs) from patients and carriers were lower (49.0 ± 19.4%) than from wild-type subjects (p < 0.01). Gene expression profiles in iPSECs showed that Securin was down-regulated (p < 0.01) in carriers and patients. Overexpression of RNF213 R4810K downregulated Securin, inhibited angiogenic activity (36.0 ± 16.9%) and proliferation of humanumbilical vein endothelial cells (HUVECs) while overexpression of RNF213 wild type did not. Securin expression was downregulated using RNA interference techniques, which reduced the level of tube formation in iPSECs and HUVECs without inhibition of proliferation. RNF213 R4810K reduced angiogenic activities of iPSECs from patients with MMD, suggesting that it is a promising in vitro model for MMD.

  14. Plant Vascular Biology 2013: vascular trafficking.

    PubMed

    Ursache, Robertas; Heo, Jung-Ok; Helariutta, Ykä

    2014-04-01

    About 200 researchers from around the world attended the Third International Conference on Plant Vascular Biology (PVB 2013) held in July 2013 at the Rantapuisto Conference Center, in Helsinki, Finland (http://www.pvb2013.org). The plant vascular system, which connects every organ in the mature plant, continues to attract the interest of researchers representing a wide range of disciplines, including development, physiology, systems biology, and computational biology. At the meeting, participants discussed the latest research advances in vascular development, long- and short-distance vascular transport and long-distance signalling in plant defence, in addition to providing a context for how these studies intersect with each other. The meeting provided an opportunity for researchers working across a broad range of fields to share ideas and to discuss future directions in the expanding field of vascular biology. In this report, the latest advances in understanding the mechanism of vascular trafficking presented at the meeting have been summarized.

  15. [Surgical treatment of vascular malformations].

    PubMed

    Fernández Alonso, L

    2004-01-01

    In spite of the numerous advances made over the last two decades, the treatment of congenital vascular malformations continues to be one of the greatest enigmas facing modern medicine. There are no clear criteria concerning the indications to be followed, and even less concerning the most appropriate therapeutic procedures for each type of lesion. The results of a strictly surgical approach are discouraging and today it is accepted that congenital vascular malformations should be attended to and treated by multidisciplinary units, combining the efforts of all the specialists involved in its treatment. This paper reviews the general principles of surgical treatment of congenital vascular malformations, without losing sight of the fact that the traditional role of isolated surgery in the treatment of congenital vascular malformations has been replaced by a multidisciplinary approach to this type of lesions, making it possible to integrate embolization, sclerotherapy and surgery to improve the results. The combination of these techniques reduces the risk and complications that existed when they were applied in an isolated form. Thus, surgical treatment should not be considered as an independent tool of treatment but as a therapeutic weapon integrated in the ensemble of measures directed at improving the quality of life of the patient with a congenital vascular malformation.

  16. Daily consumption of grapefruit for 6 weeks reduces urine F2-isoprostanes in overweight adults with high baseline values but has no effect on plasma high-sensitivity C-reactive protein or soluble vascular cellular adhesion molecule 1.

    PubMed

    Dow, Caitlin A; Wertheim, Betsy C; Patil, Bhimanagouda S; Thomson, Cynthia A

    2013-10-01

    Individuals with obesity and metabolic syndrome (MetS) are at increased risk of cardiovascular disease, in part due to heightened inflammatory/oxidative processes. Results from epidemiologic and experimental studies suggest that citrus, and grapefruit in particular, may have a role in promoting vascular health, although clinical trial data are lacking. Here, we evaluated the anti-inflammatory/antioxidant effects of habitual grapefruit consumption in 69 overweight/obese men and women and in a subsample of participants with MetS (n = 29). Participants were randomly assigned to either a grapefruit group in which they consumed a low bioactive diet plus 1.5 grapefruit/d for 6 wk (n = 37, n = 14 with MetS) or to a control condition in which a low bioactive diet devoid of citrus was consumed (n = 32, n = 15 with MetS). Plasma soluble vascular adhesion molecule-1 (sVCAM-1), plasma high-sensitivity C-reactive protein (hsCRP), and urinary F2-isoprostanes were evaluated before and after the intervention phase. F2-isoprostane concentrations were not different in the grapefruit versus control arm after the intervention (12.4 ± 6.4 vs. 15.9 ± 9.0 ng/mg creatinine, P = 0.16), whereas plasma hsCRP concentrations tended to be lower in the grapefruit versus control arm postintervention (2.1 ± 1.5 vs. 2.8 ± 2.0 mg/L, P = 0.09). In adults with MetS, grapefruit consumption tended to result in lower postintervention F2-isoprostane concentrations compared with the control condition (12.0 ± 4.5 vs. 18.3 ± 10.9 ng/mg creatinine, P = 0.06). Furthermore, those with high baseline F2-isoprostane concentrations experienced significant reductions in this biomarker in response to grapefruit consumption (P = 0.021). Change in sVCAM-1 concentrations did not vary by treatment arm nor were there differences between arms postintervention. These results suggest that intake of grapefruit twice daily for 6 wk does not significantly reduce inflammation and oxidative stress, although there is a

  17. Daily Consumption of Grapefruit for 6 Weeks Reduces Urine F2-Isoprostanes in Overweight Adults with High Baseline Values but Has No Effect on Plasma High-Sensitivity C-Reactive Protein or Soluble Vascular Cellular Adhesion Molecule 1123

    PubMed Central

    Dow, Caitlin A.; Wertheim, Betsy C.; Patil, Bhimanagouda S.; Thomson, Cynthia A.

    2013-01-01

    Individuals with obesity and metabolic syndrome (MetS) are at increased risk of cardiovascular disease, in part due to heightened inflammatory/oxidative processes. Results from epidemiologic and experimental studies suggest that citrus, and grapefruit in particular, may have a role in promoting vascular health, although clinical trial data are lacking. Here, we evaluated the anti-inflammatory/antioxidant effects of habitual grapefruit consumption in 69 overweight/obese men and women and in a subsample of participants with MetS (n = 29). Participants were randomly assigned to either a grapefruit group in which they consumed a low bioactive diet plus 1.5 grapefruit/d for 6 wk (n = 37, n = 14 with MetS) or to a control condition in which a low bioactive diet devoid of citrus was consumed (n = 32, n = 15 with MetS). Plasma soluble vascular adhesion molecule-1 (sVCAM-1), plasma high-sensitivity C-reactive protein (hsCRP), and urinary F2-isoprostanes were evaluated before and after the intervention phase. F2-isoprostane concentrations were not different in the grapefruit versus control arm after the intervention (12.4 ± 6.4 vs. 15.9 ± 9.0 ng/mg creatinine, P = 0.16), whereas plasma hsCRP concentrations tended to be lower in the grapefruit versus control arm postintervention (2.1 ± 1.5 vs. 2.8 ± 2.0 mg/L, P = 0.09). In adults with MetS, grapefruit consumption tended to result in lower postintervention F2-isoprostane concentrations compared with the control condition (12.0 ± 4.5 vs. 18.3 ± 10.9 ng/mg creatinine, P = 0.06). Furthermore, those with high baseline F2-isoprostane concentrations experienced significant reductions in this biomarker in response to grapefruit consumption (P = 0.021). Change in sVCAM-1 concentrations did not vary by treatment arm nor were there differences between arms postintervention. These results suggest that intake of grapefruit twice daily for 6 wk does not significantly reduce inflammation and oxidative stress, although there is a

  18. Primary vascular access.

    PubMed

    Gibbons, C P

    2006-05-01

    Primary vascular access is usually achievable by a distal autogenous arterio-venous fistula (AVF). This article describes the approach to vascular access planning, the usual surgical options and the factors affecting patency.

  19. Society for Vascular Medicine

    MedlinePlus

    ... Certification with this new online course from the Society for Vascular Medicine. Learn more. Looking for a ... jobs are listed right now. Copyright © 2016 The Society for Vascular Medicine. All Rights Reserved.

  20. Vascular Access for Hemodialysis

    MedlinePlus

    ... designed for long-term use include the arteriovenous (AV) fistula and the AV graft. A third type of vascular access—the ... term use. What is an arteriovenous fistula? An AV fistula is a connection, made by a vascular ...

  1. Vascular access for hemodialysis.

    PubMed

    Vanholder, R; Ringoir, S

    1994-04-01

    Indwelling central venous catheters were consecutively used as access for acute and chronic hemodialysis, emergency treatment of pulmonary fluid overload, intoxication and electrolyte disturbances, plasmapheresis, and semiacute continuous dialysis strategies, such as continuous arteriovenous hemofiltration (CAVH). Modification in catheter structure also made it possible to use this access for long-term treatment (e.g., surgically insertable catheters [Hickman], soft large-bore catheters for blind insertion). We discuss the remaining open questions in this field: Which is the insertion site of preference (i.e., subclavian, femoral, or deep jugular)? Should we prefer stiff or soft catheters? Should soft catheters be positioned surgically or is blind insertion by nonsurgeons as adequate? Is it necessary to couple catheter insertion to adjuvant techniques, such as echographic guidance, to reduce complications? Is the currently used polymer structure of the catheters acceptable? Should catheter dialysis be used with single or double vascular access?

  2. Vascular restoration therapy and bioresorbable vascular scaffold

    PubMed Central

    Wang, Yunbing; Zhang, Xingdong

    2014-01-01

    This article describes the evolution of minimally invasive intervention technologies for vascular restoration therapy from early-stage balloon angioplasty in 1970s, metallic bare metal stent and metallic drug-eluting stent technologies in 1990s and 2000s, to bioresorbable vascular scaffold (BVS) technology in large-scale development in recent years. The history, the current stage, the challenges and the future of BVS development are discussed in detail as the best available approach for vascular restoration therapy. The criteria of materials selection, design and processing principles of BVS, and the corresponding clinical trial results are also summarized in this article. PMID:26816624

  3. Vascular restoration therapy and bioresorbable vascular scaffold.

    PubMed

    Wang, Yunbing; Zhang, Xingdong

    2014-11-01

    This article describes the evolution of minimally invasive intervention technologies for vascular restoration therapy from early-stage balloon angioplasty in 1970s, metallic bare metal stent and metallic drug-eluting stent technologies in 1990s and 2000s, to bioresorbable vascular scaffold (BVS) technology in large-scale development in recent years. The history, the current stage, the challenges and the future of BVS development are discussed in detail as the best available approach for vascular restoration therapy. The criteria of materials selection, design and processing principles of BVS, and the corresponding clinical trial results are also summarized in this article.

  4. Initiation of vascular development.

    PubMed

    Ohashi-Ito, Kyoko; Fukuda, Hiroo

    2014-06-01

    The initiation of vascular development occurs during embryogenesis and the development of lateral organs, such as lateral roots and leaves. Understanding the mechanism underlying the initiation of vascular development has been an important goal of plant biologists. Auxin flow is a crucial factor involved in the initiation of vascular development. In addition, recent studies have identified key factors that regulate the establishment of vascular initial cells in embryos and roots. In this review, we summarize the recent findings in this field and discuss the initiation of vascular development.

  5. Mechanisms and Clinical Consequences of Vascular Calcification

    PubMed Central

    Zhu, Dongxing; Mackenzie, Neil C. W.; Farquharson, Colin; MacRae, Vicky E.

    2012-01-01

    Vascular calcification has severe clinical consequences and is considered an accurate predictor of future adverse cardiovascular events, including myocardial infarction and stroke. Previously vascular calcification was thought to be a passive process which involved the deposition of calcium and phosphate in arteries and cardiac valves. However, recent studies have shown that vascular calcification is a highly regulated, cell-mediated process similar to bone formation. In this article, we outline the current understanding of key mechanisms governing vascular calcification and highlight the clinical consequences. By understanding better the molecular pathways and genetic circuitry responsible for the pathological mineralization process novel drug targets may be identified and exploited to combat and reduce the detrimental effects of vascular calcification on human health. PMID:22888324

  6. Ultrafast and whole-body cooling with total liquid ventilation induces favorable neurological and cardiac outcomes after cardiac arrest in rabbits.

    PubMed

    Chenoune, M; Lidouren, F; Adam, C; Pons, S; Darbera, L; Bruneval, P; Ghaleh, B; Zini, R; Dubois-Randé, J-L; Carli, P; Vivien, B; Ricard, J-D; Berdeaux, A; Tissier, R

    2011-08-23

    In animal models of cardiac arrest, the benefit afforded by hypothermia is closely linked to the rapidity of the decrease in body temperature after resuscitation. Because total liquid ventilation (TLV) with temperature-controlled perfluorocarbons induces a very rapid and generalized cooling, we aimed to determine whether this could limit the post-cardiac arrest syndrome in a rabbit model. We especially focused on neurological, cardiac, pulmonary, liver and kidney dysfunctions. Anesthetized rabbits were submitted to either 5 or 10 minutes of untreated ventricular fibrillation. After cardiopulmonary resuscitation and resumption of a spontaneous circulation, the animals underwent either normothermic life support (control) or therapeutic hypothermia induced by TLV. The latter procedure decreased esophageal and tympanic temperatures to 32°C to 33°C within only 10 minutes. After rewarming, the animals submitted to TLV exhibited an attenuated neurological dysfunction and decreased mortality 7 days later compared with control. The neuroprotective effect of TLV was confirmed by a significant reduction in brain histological damages. We also observed limitation of myocardial necrosis, along with a decrease in troponin I release and a reduced myocardial caspase 3 activity, with TLV. The beneficial effects of TLV were directly related to the rapidity of hypothermia induction because neither conventional cooling (cold saline infusion plus external cooling) nor normothermic TLV elicited a similar protection. Ultrafast cooling instituted by TLV exerts potent neurological and cardiac protection in an experimental model of cardiac arrest in rabbits. This could be a relevant approach to provide a global and protective hypothermia against the post-cardiac arrest syndrome.

  7. Vascular Closure Device Failure: Frequency and Implications

    PubMed Central

    Bangalore, Sripal; Arora, Nipun; Resnic, Frederic S.

    2011-01-01

    Background Vascular closure devices (VCDs) are effective at reducing the time to ambulation for patients undergoing cardiac catheterization procedures, and in reducing the risk of vascular complications in selected patient cohorts. However, the frequency and consequence of failure of VCDs is not well defined. Methods and Results From a prospective registry of consecutive patients undergoing cardiac catheterization at our center, 9823 patients who received either a collagen-plug (Angio-Seal®) based or a suture-based (Perclose®) VCD were selected for the study. VCD failure was defined as unsuccessful deployment or failure to achieve hemostasis. Major vascular complication was defined as any retroperitoneal hemorrhage, limb ischemia, or any surgical repair. Minor vascular complication was defined as any groin bleeding, hematoma (≥ 5 cm), pseudoaneurysm or arteriovenous fistula. ‘Any’ vascular complication was defined as either a major or minor vascular complication. Among the 9823 patients in the study, VCD failed in 268 (2.7%; 2.3% diagnostic vs. 3.0% PCI; P = 0.029) patients. Patients with VCD failure had significantly increased risk of any (6.7% vs. 1.4%; P < 0.0001), major (1.9% vs. 0.6%; P = 0.006) or minor (6.0% vs. 1.1%; P < 0.0001) vascular complication compared with the group with successful deployment of VCD. The increased risk of vascular complication was unchanged in a propensity score matched cohort. Conclusions In contemporary practice, VCD failure is rare but when it does fail, it is associated with significant increase in the risk of vascular complications. Patients with VCD failure should be closely monitored to prevent vascular complications. PMID:20031773

  8. New concept of vascular calcification and metabolism.

    PubMed

    Nakagami, Hironori; Osako, Mariana K; Morishita, Ryuichi

    2011-01-01

    Vascular calcification is recently considered as one of the major complications and an independent risk factor of cardiovascular diseases. Although vascular calcification was commonly regarded as a passive process of mineral adsorption or precipitation, it tends to be an active process associated with the expression of growth factors, matrix proteins, and other bone-related proteins. There are 2 main types of vascular calcification. Intimal calcification is found in atherosclerotic plaques and is associated with the vascular events such as myocardial infarction. Medial calcification is usually associated with age and chronic kidney disease patients, which leads to increased vascular stiffness and reduced vascular compliance. Interestingly, our vascular calcification model using ApoE deficient mice showed intima calcification at sites of atherosclerotic plaques under high fat diet with ovariectomy. Thus, lipid metabolism is one of the therapeutic targets to prevent intima calcification of aorta. Previously we reported that ezetimibe significantly prevented atherosclerosis through lipid-lowering effects in ApoE-deficient mice. Based on these findings, we speculate that ezetimibe might prevent aortic intima calcification, which may give us the benefits to decrease vascular events.

  9. [Sclerosing treatment of vascular malformations].

    PubMed

    Cabrera, J; Redondo, P

    2004-01-01

    Traditional sclerotherapy with liquid sclerosants has been used for many years in the treatment of venous, lymphatic and low flow vascular malformations; it is efficient only with those vascular malformations of reduced size as a pre or post-operational complement. The use of liquid sclerosants has the limitations of their dilution and progressive inactivation in a great haematic volume, the irregular distribution of the sclerosant on the endothelium, the handling of the sclerosant once injected and its imperceptibility to the echo-Doppler. In their turn, both ethanol and sodium morrhuate - the most habitually employed sclerosants - produce important secondary effects. On the contrary, the use of sclerosants, specifically polidocanol in microfoam form, significantly improves the procedure, since the microfoam displaces the blood instead of mixing and diluting itself in it, thus facilitating an homogeneous distribution of the sclerosant over the endothelial surface. Finally, the echogenicity of the microbubbles, which makes them directly visible, together with their manageable consistency, means that it can be distributed more easily throughout the treated area. We comment on our experience with 50 patients with venous or low flow vascular malformations, treated with this new form of sclerosant. Similarly, the use of OK-432 (picibanil) - as the recommended sclerosant treatment in lymphatic vascular, especially macrocystic, malformations - is reviewed and its protocol given.

  10. [Banks of vascular homografts].

    PubMed

    Polvani, G L; Guarino, A; Pompilio, G; Parolari, A; Piccolo, G; Sala, A; Biglioli, P

    2001-01-01

    We define as Banking of the tissues all the procedures that include the finding, preparation, conservation and distribution of the homograft. The vascular homografts are taken and put into a solution of transportation at +4 degrees C and kept at this temperature till their arrival at the Bank. The following step is the dissection of the homograft which will have to be performed as quickly as possible at most 24 hours after the taking in conditions of maximum sterility. At the Italian Homograft Bank at Centro Cardiologico, the vascular homografts are kept at +4 degrees C for 96 hours on average with antibiotics. After a phase of sterilization at +4 degrees C the tissue is frozen according to a homogeneous and controlled thermic decrease and stored at -150 degrees C/-180 degrees C in fumes of liquid nitrogen till the moment of their employment allowing a long term conservation. The aim of all these procedures of cryopreservation is to keep the structural and functional integrity of cells and tissues. The thermic decrease of the tissues must occur so that to avoid all the damages of the cellular vitality and functionality and especially of the tissue structure in toto. In order to limitate these events some cryoprotector agents are employed because they reduce the concentration of the solutes, the cellular dehydration, the formation of micro-macro crystals. Another step to establish if the homograft is proper is the study of bacteriological and viral aspects. The viral screenings are performed on the donor's blood and the bacteriological tests are performed on the tissue and on the liquids. For each phase of the banking a series of information about the donor and about the tissues are recorded and filed both on paper and database so that to grant always a right conduct of the material.

  11. Azilsartan, an angiotensin II type 1 receptor blocker, restores endothelial function by reducing vascular inflammation and by increasing the phosphorylation ratio Ser1177/Thr497 of endothelial nitric oxide synthase in diabetic mice

    PubMed Central

    2014-01-01

    Background Azilsartan, an angiotensin II type 1 (AT1) receptor blocker (ARB), has a higher affinity for and slower dissociation from AT1 receptors and shows stronger inverse agonism compared to other ARBs. Possible benefits of azilsartan in diabetic vascular dysfunction have not been established. Methods We measured vascular reactivity of aortic rings in male KKAy diabetic mice treated with vehicle, 0.005% azilsartan, or 0.005% candesartan cilexetil for 3 weeks. Expression of markers of inflammation and oxidative stress was measured using semiquantitative RT-PCR in the vascular wall, perivascular fat, and skeletal muscle. Phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and Thr495 was measured using Western blotting, and the ratio of phosphorylation at Ser1177 to phosphorylation at Thr495 was used as a putative indicator of vascular eNOS activity. Results (1) Vascular endothelium–dependent relaxation with acetylcholine in KKAy mice was improved by azilsartan treatment compared to candesartan cilexetil; (2) the ratio of Ser1177/Thr495 phosphorylation of eNOS was impaired in KKAy and was effectively restored by azilsartan; (3) anomalies in the expression levels of monocyte chemotactic protein 1 (MCP1), F4/80, NAD(P)H oxidase (Nox) 2, and Nox4 of the aortic wall and in the expression of TNFα in the perivascular fat were strongly attenuated by azilsartan compared to candesartan cilexetil. Conclusions These results provide evidence that azilsartan prevents endothelial dysfunction in diabetic mice, more potently than does candesartan cilexetil. Azilsartan’s higher affinity for and slower dissociation from AT1 receptors may underlie its efficacy in diabetic vascular dysfunction via a dual effect on uncoupled eNOS and on Nox. PMID:24485356

  12. Azilsartan, an angiotensin II type 1 receptor blocker, restores endothelial function by reducing vascular inflammation and by increasing the phosphorylation ratio Ser(1177)/Thr(497) of endothelial nitric oxide synthase in diabetic mice.

    PubMed

    Matsumoto, Sachiko; Shimabukuro, Michio; Fukuda, Daiju; Soeki, Takeshi; Yamakawa, Ken; Masuzaki, Hiroaki; Sata, Masataka

    2014-01-31

    Azilsartan, an angiotensin II type 1 (AT1) receptor blocker (ARB), has a higher affinity for and slower dissociation from AT1 receptors and shows stronger inverse agonism compared to other ARBs. Possible benefits of azilsartan in diabetic vascular dysfunction have not been established. We measured vascular reactivity of aortic rings in male KKAy diabetic mice treated with vehicle, 0.005% azilsartan, or 0.005% candesartan cilexetil for 3 weeks. Expression of markers of inflammation and oxidative stress was measured using semiquantitative RT-PCR in the vascular wall, perivascular fat, and skeletal muscle. Phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and Thr495 was measured using Western blotting, and the ratio of phosphorylation at Ser1177 to phosphorylation at Thr495 was used as a putative indicator of vascular eNOS activity. (1) Vascular endothelium-dependent relaxation with acetylcholine in KKAy mice was improved by azilsartan treatment compared to candesartan cilexetil; (2) the ratio of Ser1177/Thr495 phosphorylation of eNOS was impaired in KKAy and was effectively restored by azilsartan; (3) anomalies in the expression levels of monocyte chemotactic protein 1 (MCP1), F4/80, NAD(P)H oxidase (Nox) 2, and Nox4 of the aortic wall and in the expression of TNFα in the perivascular fat were strongly attenuated by azilsartan compared to candesartan cilexetil. These results provide evidence that azilsartan prevents endothelial dysfunction in diabetic mice, more potently than does candesartan cilexetil. Azilsartan's higher affinity for and slower dissociation from AT1 receptors may underlie its efficacy in diabetic vascular dysfunction via a dual effect on uncoupled eNOS and on Nox.

  13. Imaging Pediatric Vascular Lesions

    PubMed Central

    Nguyen, Tuyet A.; Krakowski, Andrew C.; Naheedy, John H.; Kruk, Peter G.

    2015-01-01

    Vascular anomalies are commonly encountered in pediatric and dermatology practices. Most of these lesions are benign and easy to diagnose based on history and clinical exam alone. However, in some cases the diagnosis may not be clear. This may be of particular concern given that vascular anomalies may occasionally be associated with an underlying syndrome, congenital disease, or serious, life-threatening condition. Defining the type of vascular lesion early and correctly is particularly important to determine the optimal approach to management and treatment of each patient. The care of pediatric patients often requires collaboration from a multitude of specialties including pediatrics, dermatology, plastic surgery, radiology, ophthalmology, and neurology. Although early characterization of vascular lesions is important, consensus guidelines regarding the evaluation and imaging of vascular anomalies does not exist to date. Here, the authors provide an overview of pediatric vascular lesions, current classification systems for characterizing these lesions, the various imaging modalities available, and recommendations for appropriate imaging evaluation. PMID:26705446

  14. Vascular Cognitive Impairment.

    PubMed

    Dichgans, Martin; Leys, Didier

    2017-02-03

    Cerebrovascular disease typically manifests with stroke, cognitive impairment, or both. Vascular cognitive impairment refers to all forms of cognitive disorder associated with cerebrovascular disease, regardless of the specific mechanisms involved. It encompasses the full range of cognitive deficits from mild cognitive impairment to dementia. In principle, any of the multiple causes of clinical stroke can cause vascular cognitive impairment. Recent work further highlights a role of microinfarcts, microhemorrhages, strategic white matter tracts, loss of microstructural tissue integrity, and secondary neurodegeneration. Vascular brain injury results in loss of structural and functional connectivity and, hence, compromise of functional networks within the brain. Vascular cognitive impairment is common both after stroke and in stroke-free individuals presenting to dementia clinics, and vascular pathology frequently coexists with neurodegenerative pathology, resulting in mixed forms of mild cognitive impairment or dementia. Vascular dementia is now recognized as the second most common form of dementia after Alzheimer's disease, and there is increasing awareness that targeting vascular risk may help to prevent dementia, even of the Alzheimer type. Recent advances in neuroimaging, neuropathology, epidemiology, and genetics have led to a deeper understanding of how vascular disease affects cognition. These new findings provide an opportunity for the present reappraisal of vascular cognitive impairment. We further briefly address current therapeutic concepts.

  15. Pathophysiological consequences of VEGF-induced vascular permeability

    NASA Astrophysics Data System (ADS)

    Weis, Sara M.; Cheresh, David A.

    2005-09-01

    Although vascular endothelial growth factor (VEGF) induces angiogenesis, it also disrupts vascular barrier function in diseased tissues. Accordingly, VEGF expression in cancer and ischaemic disease has unexpected pathophysiological consequences. By uncoupling endothelial cell-cell junctions VEGF causes vascular permeability and oedema, resulting in extensive injury to ischaemic tissues after stroke or myocardial infarction. In cancer, VEGF-mediated disruption of the vascular barrier may potentiate tumour cell extravasation, leading to widespread metastatic disease. Therefore, by blocking the vascular permeability promoting effects of VEGF it may be feasible to reduce tissue injury after ischaemic disease and minimize the invasive properties of circulating tumour cells.

  16. Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury.

    PubMed

    Rizzo, Alicia N; Sammani, Saad; Esquinca, Adilene E; Jacobson, Jeffrey R; Garcia, Joe G N; Letsiou, Eleftheria; Dudek, Steven M

    2015-12-01

    Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), an illness characterized by life-threatening vascular leak, is a significant cause of morbidity and mortality in critically ill patients. Recent preclinical studies and clinical observations have suggested a potential role for the chemotherapeutic agent imatinib in restoring vascular integrity. Our prior work demonstrates differential effects of imatinib in mouse models of ALI, namely attenuation of LPS-induced lung injury but exacerbation of ventilator-induced lung injury (VILI). Because of the critical role of mechanical ventilation in the care of patients with ARDS, in the present study we pursued an assessment of the effectiveness of imatinib in a "two-hit" model of ALI caused by combined LPS and VILI. Imatinib significantly decreased bronchoalveolar lavage protein, total cells, neutrophils, and TNF-α levels in mice exposed to LPS plus VILI, indicating that it attenuates ALI in this clinically relevant model. In subsequent experiments focusing on its protective role in LPS-induced lung injury, imatinib attenuated ALI when given 4 h after LPS, suggesting potential therapeutic effectiveness when given after the onset of injury. Mechanistic studies in mouse lung tissue and human lung endothelial cells revealed that imatinib inhibits LPS-induced NF-κB expression and activation. Overall, these results further characterize the therapeutic potential of imatinib against inflammatory vascular leak.

  17. Vascular smooth muscle function: defining the diabetic vascular phenotype.

    PubMed

    Bruno, Rosa Maria; Ghiadoni, Lorenzo

    2013-10-01

    In this issue of Diabetologia, a meta-analysis performed by Montero and co-authors (Diabetologia doi 10.1007/s00125-013-2974-1 ) demonstrates a significant impairment of vascular smooth muscle (VSM) function in type 2 diabetic patients. Endothelial function and VSM function between type 2 diabetic and healthy individuals were associated, especially in the microcirculation, confirming the hypothesis that unresponsiveness of VSM cells to NO may amplify the consequences of reduced NO availability. This study suggests a novel interpretation for endothelial dysfunction in diabetic patients, indicating VSM cells as key players. Causative mechanisms of VSM dysfunction, which seems to be a feature of the vascular phenotype of type 2 diabetes mellitus, are largely unexplored in humans. Future studies should also address the crucial issue of the prognostic significance of VSM dysfunction in diabetic patients, and possibly in other conditions characterised by high cardiovascular risk.

  18. The dualistic role of vitamin D in vascular calcifications

    PubMed Central

    Razzaque, M. Shawkat

    2011-01-01

    Vitamin D is a multifunctional hormone that can affect many essential biological functions, ranging from the immune regulation to mineral ion metabolism. A close association between altered activity of vitamin D and vascular calcification has been reported in various human diseases, including in patients with atherosclerosis, osteoporosis, and chronic kidney disease (CKD). Vascular calcification is a progressive disorder and is a major determinant of morbidity and mortality of the affected patients. Experimental studies have shown that excessive vitamin D activities can induce vascular calcification, and such vascular pathology can be reversed by reducing vitamin D activities. The human relevance of these experimental studies is not clear, as vitamin D toxicity is relatively rare in the general population. Contrary to the relationship between vitamin D and vascular calcification, in experimental uremic models, low levels of vitamin D were shown to be associated with extensive vascular calcification, a phenomenon that is very similar to the vascular pathology seen in patients with CKD. The current treatment approach of providing vitamin D analogs to patients with CKD often poses a dilemma, as studies linked vitamin D treatment to subsequent vascular calcification. Recent genetic studies, however, have shown that vascular calcification can be prevented by reducing serum phosphate levels, even in the presence of extremely high serum 1,25-dihydroxyvitamin D and calcium levels. This article will briefly summarize the dual effects of vitamin D in vascular calcification and will provide evidence of vitamin D-dependent and -independent vascular calcification. PMID:20962746

  19. Human vascular model with defined stimulation medium - a characterization study.

    PubMed

    Huttala, Outi; Vuorenpää, Hanna; Toimela, Tarja; Uotila, Jukka; Kuokkanen, Hannu; Ylikomi, Timo; Sarkanen, Jertta-Riina; Heinonen, Tuula

    2015-01-01

    The formation of blood vessels is a vital process in embryonic development and in normal physiology. Current vascular modelling is mainly based on animal biology leading to species-to-species variation when extrapolating the results to humans. Although there are a few human cell based vascular models available these assays are insufficiently characterized in terms of culture conditions and developmental stage of vascular structures. Therefore, well characterized vascular models with human relevance are needed for basic research, embryotoxicity testing, development of therapeutic strategies and for tissue engineering. We have previously shown that the in vitro vascular model based on co-culture of human adipose stromal cells (hASC) and human umbilical vein endothelial cells (HUVEC) is able to induce an extensive vascular-like network with high reproducibility. In this work we developed a defined serum-free vascular stimulation medium (VSM) and performed further characterization in terms of cell identity, maturation and structure to obtain a thoroughly characterized in vitro vascular model to replace or reduce corresponding animal experiments. The results showed that the novel vascular stimulation medium induced intact and evenly distributed vascular-like network with morphology of mature vessels. Electron microscopic analysis assured the three-dimensional microstructure of the network containing lumen. Additionally, elevated expressions of the main human angiogenesis-related genes were detected. In conclusion, with the new defined medium the vascular model can be utilized as a characterized test system for chemical testing as well as in creating vascularized tissue models.

  20. [Vascular factors in glaucoma].

    PubMed

    Mottet, B; Aptel, F; Geiser, M; Romanet, J P; Chiquet, C

    2015-12-01

    The exact pathophysiology of glaucoma is not fully understood. Understanding of the vascular pathophysiology of glaucoma requires: knowing the techniques for measuring ocular blood flow and characterizing the topography of vascular disease and the mechanisms involved in this neuropathy. A decreased mean ocular perfusion pressure and a loss of vascular autoregulation are implicated in glaucomatous disease. Early decrease in ocular blood flow has been identified in primary open-angle glaucoma and normal pressure glaucoma, contributing to the progression of optic neuropathy. The vascular damage associated with glaucoma is present in various vascular territories within the eye (from the ophthalmic artery to the retina) and is characterized by a decrease in basal blood flow associated with a dysfunction of vasoregulation.

  1. Rho kinase as a target for cerebral vascular disorders

    PubMed Central

    Bond, Lisa M; Sellers, James R; McKerracher, Lisa

    2015-01-01

    The development of novel pharmaceutical treatments for disorders of the cerebral vasculature is a serious unmet medical need. These vascular disorders are typified by a disruption in the delicate Rho signaling equilibrium within the blood vessel wall. In particular, Rho kinase overactivation in the smooth muscle and endothelial layers of the vessel wall results in cytoskeletal modifications that lead to reduced vascular integrity and abnormal vascular growth. Rho kinase is thus a promising target for the treatment of cerebral vascular disorders. Indeed, preclinical studies indicate that Rho kinase inhibition may reduce the formation/growth/rupture of both intracranial aneurysms and cerebral cavernous malformations. PMID:26062400

  2. Vascular Calcification: an Update on Mechanisms and Challenges in Treatment

    PubMed Central

    Wu, Meiting; Rementer, Cameron; Giachelli, Cecilia M.

    2013-01-01

    Vascular calcification is highly associated with cardiovascular disease mortality, particularly in high risk patients with diabetes and chronic kidney diseases (CKD). In blood vessels, intimal calcification is associated with atherosclerosis, whereas medial calcification is a non-occlusive process which leads to increased vascular stiffness and reduced vascular compliance. In the valves, calcification of the leaflets can change the mechanical properties of the tissue and result in stenosis. For many decades, vascular calcification has been noted as a consequence of aging. Studies now confirm that vascular calcification is an actively regulated process and shares many features with bone development and metabolism. This review provides an update on the mechanisms of vascular calcification including the emerging roles of the RANK/RANKL/OPG triad, osteoclasts and microRNAs. Potential treatments adapted from osteoporosis and CKD treatments that are under investigation for preventing and/or regressing vascular calcification will also be reviewed. PMID:23456027

  3. Impact of Integrated Vascular Residencies on Academic Productivity within Vascular Surgery Divisions.

    PubMed

    Kim, Bradford J; Valsangkar, Nakul P; Liang, Tiffany W; Murphy, Michael P; Zimmers, Teresa A; Bell, Teresa M; Davies, Mark G; Koniaris, Leonidas G

    2017-02-01

    Changing training paradigms in vascular surgery have been introduced to reduce overall training time. Herein, we sought to examine how shortened training for vascular surgeons may have influenced overall divisional academic productivity. Faculty from the top 55 surgery departments were identified according to National Institutes of Health (NIH) funding. Academic metrics of 315 vascular surgery, 1,132 general surgery, and 2,403 other surgical specialties faculty were examined using institutional Web sites, Scopus, and NIH Research Portfolio Online Reporting Tools from September 1, 2014, to January 31, 2015. Individual-level and aggregate numbers of publications, citations, and NIH funding were determined. The mean size of the vascular divisions was 5 faculty. There was no correlation between department size and academic productivity of individual faculty members (R(2) = 0.68, P = 0.2). Overall percentage of vascular surgery faculty with current or former NIH funding was 20%, of which 10.8% had major NIH grants (R01/U01/P01). Vascular surgery faculty associated with integrated vascular training programs demonstrated significantly greater academic productivity. Publications and citations were higher for vascular surgery faculty from institutions with both integrated and traditional training programs (48 of 1,051) compared to those from programs with integrated training alone (37 of 485) or traditional fellowships alone (26 of 439; P < 0.05). In this retrospective examination, academic productivity was improved within vascular surgery divisions with integrated training programs or both program types. These data suggest that the earlier specialization of integrated residencies in addition to increasing dedicated vascular training time may actually help promote research within the field of vascular surgery. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Cartilage oligomeric matrix protein prevents vascular aging and vascular smooth muscle cells senescence.

    PubMed

    Wang, Meili; Fu, Yi; Gao, Cheng; Jia, Yiting; Huang, Yaqian; Liu, Limei; Wang, Xian; Wang, Wengong; Kong, Wei

    2016-09-16

    Aging-related vascular dysfunction contributes to cardiovascular morbidity and mortality. Cartilage oligomeric matrix protein (COMP), a vascular extracellular matrix protein, has been described as a negative regulatory factor for the vascular aging-related processes including atherosclerosis and vascular calcification. However, whether COMP is implicated in the process of vascular aging remains unclear. Here, we identified a novel function of COMP in preventing vascular aging and vascular smooth muscle cells (VSMCs) senescence. Firstly, vascular COMP expression was decreased in three different senescence-accelerated mouse models and was also declining with age. COMP(-/-) mice displayed elevated senescence-associated markers expression, including p53, p21 and p16, in the aortas compared with their wild type (WT) littermates. In accordance, COMP deficiency induced aging-related vascular dysfunction as evidenced by the significantly reduced phenylephrine-induced contraction and increased vascular stiffness as evaluated by pulse wave velocity. The aortic wall of COMP(-/-) mice was susceptible to senescence by displaying senescence-associated β-galactosidase (SA β-gal) activity induced by periadventitial application of CaCl2 to the abdominal aorta. In vitro, COMP knockdown by small interfering (si) RNA led to the elevation of p53, p21 and p16 as well as SA β-gal activity in VSMCs after H2O2 stimulation. VSMCs isolated from COMP(-/-) mice showed elevated senescence-associated markers expression and supplement of COMP adenovirus to COMP-deficient VSMCs greatly rescued cellular senescence. Taken together, these findings revealed the essential role of COMP in retarding the development of vascular aging and VSMC senescence. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Vascular Access in Children

    SciTech Connect

    Krishnamurthy, Ganesh Keller, Marc S.

    2011-02-15

    Establishment of stable vascular access is one of the essential and most challenging procedures in a pediatric hospital. Many clinical specialties provide vascular service in a pediatric hospital. At the top of the 'expert procedural pyramid' is the pediatric interventional radiologist, who is best suited and trained to deliver this service. Growing awareness regarding the safety and high success rate of vascular access using image guidance has led to increased demand from clinicians to provide around-the-clock vascular access service by pediatric interventional radiologists. Hence, the success of a vascular access program, with the pediatric interventional radiologist as the key provider, is challenging, and a coordinated multidisciplinary team effort is essential for success. However, there are few dedicated pediatric interventional radiologists across the globe, and also only a couple of training programs exist for pediatric interventions. This article gives an overview of the technical aspects of pediatric vascular access and provides useful tips for obtaining vascular access in children safely and successfully using image guidance.

  6. Arginase and vascular aging

    PubMed Central

    Santhanam, Lakshmi; Christianson, David W.; Nyhan, Daniel; Berkowitz, Dan E.

    2008-01-01

    Vascular and associated ventricular stiffness is one of the hallmarks of the aging cardiovascular system. Both an increase in reactive oxygen species production and a decrease in nitric oxide (NO) bioavailability contribute to the endothelial dysfunction that underlies this vascular stiffness, independent of other age-related vascular pathologies such as atherosclerosis. The activation/upregulation of arginase appears to be an important contributor to age-related endothelial dysfunction by a mechanism that involves substrate (l-arginine) limitation for NO synthase (NOS) 3 and therefore NO synthesis. Not only does this lead to impaired NO production but also it contributes to the enhanced production of reactive oxygen species by NOS. Although arginase abundance is increased in vascular aging models, it appears that posttranslational modification by S-nitrosylation of the enzyme enhances its activity as well. The S-nitrosylation is mediated by the induction of NOS2 in the endothelium. Furthermore, arginase activation contributes to aging-related vascular changes by mechanisms that are not directly related to changes in NO signaling, including polyamine-dependent vascular smooth muscle proliferation and collagen synthesis. Taken together, arginase may represent an as yet elusive target for the modification of age-related vascular and ventricular stiffness contributing to cardiovascular morbidity and mortality. PMID:18719233

  7. Vascular anomalies in children.

    PubMed

    Weibel, L

    2011-11-01

    Vascular anomalies are divided in two major categories: tumours (such as infantile hemangiomas) and malformations. Hemangiomas are common benign neoplasms that undergo a proliferative phase followed by stabilization and eventual spontaneous involution, whereas vascular malformations are rare structural anomalies representing morphogenetic errors of developing blood vessels and lymphatics. It is important to properly diagnose vascular anomalies early in childhood because of their distinct differences in morbidity, prognosis and need for a multidisciplinary management. We discuss a number of characteristic clinical features as clues for early diagnosis and identification of associated syndromes.

  8. Stromal vascular fraction improves deep partial thickness burn wound healing.

    PubMed

    Atalay, Sibel; Coruh, Atilla; Deniz, Kemal

    2014-11-01

    The practice of early burn wound excision and wound closure by immediate autologous skin or skin substitutes is the preferred treatment in extensive deep partial and full-thickness burns. To date there is no proven definite medical treatment to decrease burn wound size and accelerate burn wound healing in modern clinical practice. Stromal vascular fraction is an autologous mixture that has multiple proven beneficial effects on different kinds of wounds. In our study, we investigated the effects of stromal vascular fraction on deep partial-thickness burn wound healing. In this study, 20 Wistar albino rats were used. Inguinal adipose tissue of the rats was surgically removed and stromal vascular fraction was isolated. Thereafter, deep second-degree burns were performed on the back of the rats by hot water. The rats were divided into two groups in a randomized fashion. The therapy group received stromal vascular fraction, whereas the control group received only physiologic serum by intradermal injection. Assessment of the burn wound healing between the groups was carried out by histopathologic and immuno-histochemical data. Stromal vascular fraction increased vascular endothelial growth factor, proliferating cell nuclear antigen index, and reduced inflammation of the burn wound. Furthermore, vascularization and fibroblastic activity were achieved earlier and observed to be at higher levels in the stromal vascular fraction group. Stromal vascular fraction improves burn wound healing by increasing cell proliferation and vascularization, reducing inflammation, and increasing fibroblastic activity. Copyright © 2014 Elsevier Ltd and ISBI. All rights reserved.

  9. Calcium intake, vascular calcification, and vascular disease.

    PubMed

    Spence, Lisa A; Weaver, Connie M

    2013-01-01

    Recent research has reported a possible link between calcium supplementation and increased risk of cardiovascular disease and its endpoints in healthy, older adults. To evaluate the current evidence regarding the impact of calcium supplementation on cardiovascular disease risk and to address research gaps, the present review was conducted. Systematic reviews and meta-analyses were included, when available, along with original articles. The articles included in the review were obtained from PubMed using the following search terms: calcium intake, calcium supplementation, cardiovascular disease, myocardial infarction, mortality, and vascular calcification. The majority of the studies reviewed demonstrated no statistically significant adverse or beneficial effect of calcium supplementation on cardiovascular disease or its endpoints. While some studies indicate a possible increased risk, there is a lack of consensus on these findings and a need exists to further elucidate a mechanism. More experimental data are necessary to understand the impact of calcium intake, both levels and sources, on vascular calcification and vascular disease. The use of (41)C kinetic modeling in the Ossabaw swine provides an approach for assessing soft tissue calcification in an atherosclerotic and normal state to address research gaps.

  10. Uterine Vascular Lesions

    PubMed Central

    Vijayakumar, Abhishek; Srinivas, Amruthashree; Chandrashekar, Babitha Moogali; Vijayakumar, Avinash

    2013-01-01

    Vascular lesions of the uterus are rare; most reported in the literature are arteriovenous malformations (AVMs). Uterine AVMs can be congenital or acquired. In recent years, there has been an increasing number of reports of acquired vascular lesions of the uterus following pregnancy, abortion, cesarean delivery, and curettage. It can be seen from these reports that there is confusion concerning the terminology of uterine vascular lesions. There is also a lack of diagnostic criteria and management guidelines, which has led to an increased number of unnecessary invasive procedures (eg, angiography, uterine artery embolization, hysterectomy for abnormal vaginal bleeding). This article familiarizes readers with various vascular lesions of the uterus and their management. PMID:24340126

  11. Vascular Malformations: A Review

    PubMed Central

    Cox, Joshua A.; Bartlett, Erica; Lee, Edward I.

    2014-01-01

    Identification and treatment of vascular malformations is a challenging endeavor for physicians, especially given the great concern and anxiety created for patients and their families. The goal of this article is to provide a review of vascular malformations, organized by subtype, including capillary, venous, lymphatic and arteriovenous malformations. Only by developing a clear understanding of the clinical aspects, diagnostic tools, imaging modalities, and options for intervention will appropriate care be provided and results maximized. PMID:25045330

  12. [Complex vascular access].

    PubMed

    Mangiarotti, G; Cesano, G; Thea, A; Hamido, D; Pacitti, A; Segoloni, G P

    1998-03-01

    Availability of a proper vascular access is a basic condition for a proper extracorporeal replacement in end-stage chronic renal failure. However, biological factors, management and other problems, may variously condition their middle-long term survival. Therefore, personal experience of over 25 years has been critically reviewed in order to obtain useful information. In particular "hard" situations necessitating complex procedures have been examined but, if possible, preserving the peripherical vascular features.

  13. Role of Krev Interaction Trapped-1 in Prostacyclin-Induced Protection against Lung Vascular Permeability Induced by Excessive Mechanical Forces and Thrombin Receptor Activating Peptide 6

    PubMed Central

    Meliton, Angelo; Meng, Fanyong; Tian, Yufeng; Shah, Alok A.; Birukova, Anna A.

    2015-01-01

    Mechanisms of vascular endothelial cell (EC) barrier regulation during acute lung injury (ALI) or other pathologies associated with increased vascular leakiness are an active area of research. Adaptor protein krev interaction trapped-1 (KRIT1) participates in angiogenesis, lumen formation, and stabilization of EC adherens junctions (AJs) in mature vasculature. We tested a role of KRIT1 in the regulation of Rho-GTPase signaling induced by mechanical stimulation and barrier dysfunction relevant to ventilator-induced lung injury and investigated KRIT1 involvement in EC barrier protection by prostacyclin (PC). PC stimulated Ras-related protein 1 (Rap1)–dependent association of KRIT1 with vascular endothelial cadherin at AJs, with KRIT1-dependent cortical cytoskeletal remodeling leading to EC barrier enhancement. KRIT1 knockdown exacerbated Rho-GTPase activation and EC barrier disruption induced by pathologic 18% cyclic stretch and thrombin receptor activating peptide (TRAP) 6 and attenuated the protective effects of PC. In the two-hit model of ALI caused by high tidal volume (HTV) mechanical ventilation and TRAP6 injection, KRIT1 functional deficiency in KRIT1+/− mice increased basal lung vascular leak and augmented vascular leak and lung injury caused by exposure to HTV and TRAP6. Down-regulation of KRIT1 also diminished the protective effects of PC against TRAP6/HTV-induced lung injury. These results demonstrate a KRIT1-dependent mechanism of vascular EC barrier control in basal conditions and in the two-hit model of ALI caused by excessive mechanical forces and TRAP6 via negative regulation of Rho activity and enhancement of cell junctions. We also conclude that the stimulation of the Rap1-KRIT1 signaling module is a major mechanism of vascular endothelial barrier protection by PC in the injured lung. PMID:25923142

  14. Resident vascular progenitor cells.

    PubMed

    Torsney, Evelyn; Xu, Qingbo

    2011-02-01

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

  15. Vascular compression syndromes.

    PubMed

    Czihal, Michael; Banafsche, Ramin; Hoffmann, Ulrich; Koeppel, Thomas

    2015-11-01

    Dealing with vascular compression syndromes is one of the most challenging tasks in Vascular Medicine practice. This heterogeneous group of disorders is characterised by external compression of primarily healthy arteries and/or veins as well as accompanying nerval structures, carrying the risk of subsequent structural vessel wall and nerve damage. Vascular compression syndromes may severely impair health-related quality of life in affected individuals who are typically young and otherwise healthy. The diagnostic approach has not been standardised for any of the vascular compression syndromes. Moreover, some degree of positional external compression of blood vessels such as the subclavian and popliteal vessels or the celiac trunk can be found in a significant proportion of healthy individuals. This implies important difficulties in differentiating physiological from pathological findings of clinical examination and diagnostic imaging with provocative manoeuvres. The level of evidence on which treatment decisions regarding surgical decompression with or without revascularisation can be relied on is generally poor, mostly coming from retrospective single centre studies. Proper patient selection is critical in order to avoid overtreatment in patients without a clear association between vascular compression and clinical symptoms. With a focus on the thoracic outlet-syndrome, the median arcuate ligament syndrome and the popliteal entrapment syndrome, the present article gives a selective literature review on compression syndromes from an interdisciplinary vascular point of view.

  16. Combat related vascular trauma.

    PubMed

    Mishwani, Ahmad Hussain; Ghaffar, Abdul; Janjua, Sarfaraz

    2012-04-01

    To determine the frequency and pattern of different types of vascular injuries, their management and surgical complications. Case series. Combined Military Hospital, Peshawar, from August 2008 to August 2010. All patients of vascular injuries were included. Traumatic amputation, amputation for extensive soft tissue, or nerve injury, death due to reasons other than vascular injuries or Mangled Extremity Severity Score (MESS > 7) were excluded from study. Data included patient profile, time and date of admission, place, site, type and mechanism of injury, associated injuries, vital signs, treatment, type of vascular repair and outcome. Decision to operate was mainly based on clinical diagnosis and hand-held Doppler finding. There were 170 vascular injuries in 96 patients; 76.4% were arterial and 23.5% were venous. Gunshot wounds was main cause (54%) and extremities were the commonest site (85%). Arteries were repaired in 87% and veins in 40% cases. Venous interposition graft was the preferred method of repair. The overall limb salvage rate was 95%. Thrombosis and infection of the graft and repair were the main causes of secondary amputation. Haemorrhage, reperfusion injury and infection were the main causes of death. Every effort should be made to repair an injured artery to preserve a limb and life. Tourniquet, prophylactic fasciotomy and vascular shunts play an important role. Management of life threatening injuries, unstable fracture of long bones and debridement before definitive repair of artery is important.

  17. Stroke injury, cognitive impairment and vascular dementia☆

    PubMed Central

    Kalaria, Raj N.; Akinyemi, Rufus; Ihara, Masafumi

    2016-01-01

    The global burden of ischaemic strokes is almost 4-fold greater than haemorrhagic strokes. Current evidence suggests that 25–30% of ischaemic stroke survivors develop immediate or delayed vascular cognitive impairment (VCI) or vascular dementia (VaD). Dementia after stroke injury may encompass all types of cognitive disorders. States of cognitive dysfunction before the index stroke are described under the umbrella of pre-stroke dementia, which may entail vascular changes as well as insidious neurodegenerative processes. Risk factors for cognitive impairment and dementia after stroke are multifactorial including older age, family history, genetic variants, low educational status, vascular comorbidities, prior transient ischaemic attack or recurrent stroke and depressive illness. Neuroimaging determinants of dementia after stroke comprise silent brain infarcts, white matter changes, lacunar infarcts and medial temporal lobe atrophy. Until recently, the neuropathology of dementia after stroke was poorly defined. Most of post-stroke dementia is consistent with VaD involving multiple substrates. Microinfarction, microvascular changes related to blood–brain barrier damage, focal neuronal atrophy and low burden of co-existing neurodegenerative pathology appear key substrates of dementia after stroke injury. The elucidation of mechanisms of dementia after stroke injury will enable establishment of effective strategy for symptomatic relief and prevention. Controlling vascular disease risk factors is essential to reduce the burden of cognitive dysfunction after stroke. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26806700

  18. Vascular Risk Factors: Imaging and Neuropathologic Correlates

    PubMed Central

    Knopman, David S.; Roberts, Rosebud

    2010-01-01

    Cerebrovascular disease plays an important role in cognitive disorders in the elderly. Cerebrovascular disease and Alzheimer’s disease interact on several levels, one important level being the overlap in risk factors. The major vascular risk factors such as diabetes and impaired glycemic control, hypertension, obesity and hyper- or dyslipidemia have been associated both with Alzheimer’s disease and vascular dementia. The purpose of this review is to consider the context in which vascular dementia is diagnosed, place the pathophysiological consequences of cerebrovascular disease on cognition in the context of clinical and pathological Alzheimer’s disease, and then to consider the evidence for the role of major vascular risk factors in late-life cognitive impairment, changes in brain imaging and neuropathological changes. Midlife diabetes mellitus, hypertension and obesity are established risk factors for clinically defined Alzheimer’s disease as well as vascular dementia. The basis for these relationships could either be that the risk factors lead to microvascular brain disease, promote Alzheimer pathology or both. The associations of late-life onset diabetes mellitus, hypertension and obesity with cognitive impairment are either attenuated or reversed. The role of vascular risk factors in midlife should be the focus of public health efforts to reduce the burden of late-life cognitive impairment. PMID:20182020

  19. Vascular Compromise from Soft Tissue Augmentation

    PubMed Central

    Humphrey, Shannon; Carruthers, Jean D.A.; Carruthers, Alastair

    2014-01-01

    The popularity of soft tissue fillers is, in part, due to their favorable side-effect profile. However, serious complications can occur. The authors describe their extensive clinical experience with soft-tissue augmentation and the rare complication of vascular compromise, which can lead to necrosis and scarring. Over a 10-year period between January 2003 and January 2013, the authors observed a total of 12 cases of vascular compromise. Eight patients in their clinical practice showed evidence of vascular compromise out of a total of 14,355 filler injections (0.05%). In addition, four patients treated with an experimental particulate filler had vascular complications. All cases were examined for filler type, location of complication, risk factors, treatment, and outcomes. Although treatment plans differed for each patient in their series, all cases of vascular compromise resolved fully. The authors believe that an office-based protocol for both immediate and ongoing care—including a thorough individualized assessment and treatment plan for each patient—is critical to timely and effective resolution of side effects. They propose key recommendations for the prevention and management of vascular compromise to improve patient outcomes and reduce the risk of permanent complications. PMID:25276276

  20. Drivers of readmissions in vascular surgery patients.

    PubMed

    Glebova, Natalia O; Bronsert, Michael; Hammermeister, Karl E; Nehler, Mark R; Gibula, Douglas R; Malas, Mahmoud B; Black, James H; Henderson, William G

    2016-07-01

    , myocardial infection, and sepsis. Readmissions in vascular surgery patients are mainly driven by postoperative complications identified after discharge. Thus, efforts to reduce vascular readmissions focusing on inpatient hospital data may prove ineffective. Our study suggests that interventions to reduce vascular readmissions should focus on prompt identification of modifiable postdischarge complications. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

  1. Exercise, Vascular Stiffness, and Tissue Transglutaminase

    PubMed Central

    Steppan, Jochen; Sikka, Gautam; Jandu, Simran; Barodka, Viachaslau; Halushka, Marc K.; Flavahan, Nicholas A.; Belkin, Alexey M.; Nyhan, Daniel; Butlin, Mark; Avolio, Alberto; Berkowitz, Dan E.; Santhanam, Lakshmi

    2014-01-01

    Background Vascular aging is closely associated with increased vascular stiffness. It has recently been demonstrated that decreased nitric oxide (NO)‐induced S‐nitrosylation of tissue transglutaminase (TG2) contributes to age‐related vascular stiffness. In the current study, we tested the hypothesis that exercise restores NO signaling and attenuates vascular stiffness by decreasing TG2 activity and cross‐linking in an aging rat model. Methods and Results Rats were subjected to 12 weeks of moderate aerobic exercise. Aging was associated with diminished phosphorylated endothelial nitric oxide synthase and phosphorylated vasodilator‐stimulated phosphoprotein abundance, suggesting reduced NO signaling. TG2 cross‐linking activity was significantly increased in old animals, whereas TG2 abundance remained unchanged. These alterations were attenuated in the exercise cohort. Simultaneous measurement of blood pressure and pulse wave velocity (PWV) demonstrated increased aortic stiffness in old rats, compared to young, at all values of mean arterial pressure (MAP). The PWV‐MAP correlation in the old sedentary and old exercise cohorts was similar. Tensile testing of the vessels showed increased stiffness of the aorta in the old phenotype with a modest restoration of mechanical properties toward the young phenotype with exercise. Conclusions Increased vascular stiffness during aging is associated with decreased TG2 S‐nitrosylation, increased TG2 cross‐linking activity, and increased vascular stiffness likely the result of decreased NO bioavailability. In this study, a brief period of moderate aerobic exercise enhanced NO signaling, attenuated TG cross‐linking activity, and reduced ex vivo tensile properties, but failed to reverse functional vascular stiffness in vivo, as measured by PWV. PMID:24721796

  2. Frequency and Effect of Access-Related Vascular Injury and Subsequent Vascular Intervention After Transcatheter Aortic Valve Replacement.

    PubMed

    Dencker, Ditte; Taudorf, Mikkel; Luk, N H Vincent; Nielsen, Michael B; Kofoed, Klaus F; Schroeder, Torben V; Søndergaard, Lars; Lönn, Lars; De Backer, Ole

    2016-10-15

    Vascular access and closure remain a challenge in transcatheter aortic valve replacement (TAVR). This single-center study aimed to report the incidence, predictive factors, and clinical outcomes of access-related vascular injury and subsequent vascular intervention. During a 30-month period, 365 patients underwent TAVR and 333 patients (94%) were treated by true percutaneous transfemoral approach. Of this latter group, 83 patients (25%) had an access-related vascular injury that was managed by the use of a covered self-expanding stent (n = 49), balloon angioplasty (n = 33), or by surgical intervention (n = 1). In 16 patients (5%), the vascular injury was classified as a major vascular complication. Absence of a preprocedural computed tomography angiography (CTA) of the iliofemoral arteries (OR 2.04, p = 0.007) and female gender (OR 2.18, p = 0.004) were independent predictors of the need for access-related vascular intervention. In addition, a high sheath/common femoral artery ratio as measured on preoperative CTA was associated with a higher rate of post-TAVR vascular intervention. The radiation dose, iodine contrast volume, transfusion need, length of hospitalization, and 30-day mortality were not significantly different between patients with versus without access-related vascular intervention. In conclusion, access-related vascular intervention in patients who underwent transfemoral-TAVR is not uncommon. Female gender and a high sheath/common femoral artery ratio are risk factors for access-related vascular injury, whereas preprocedural planning with CTA of the access vessels may reduce the risk of vascular injury. Importantly, most access-related vascular injuries may be treated by percutaneous techniques with similar clinical outcomes to patients without vascular injuries. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Smoking and vascular risk: are all forms of smoking harmful to all types of vascular disease?

    PubMed

    Katsiki, N; Papadopoulou, S K; Fachantidou, A I; Mikhailidis, D P

    2013-05-01

    Smoking, both active and passive, is an established vascular risk factor. The present narrative review considers the effects of different forms of smoking (i.e. cannabis, cigar, pipe, smokeless tobacco and cigarette) on cardiovascular risk. Furthermore, the impact of smoking on several vascular risk factors [e.g. hypertension, diabetes mellitus (DM), dyslipidaemia and haemostasis] and on vascular diseases such as coronary heart disease (CHD), peripheral arterial disease (PAD), abdominal aortic aneurysms (AAA) and carotid arterial disease, is discussed. The adverse effects of all forms of smoking and the interactions between smoking and established vascular risk factors highlight the importance of smoking cessation in high-risk patients in terms of both primary and secondary vascular disease prevention. Healthcare providers should discourage people (especially the young) from becoming smokers, strongly encourage all vascular patients to stop smoking and support those who decide to quit by pharmaceutical and psychological interventions. In high-risk populations such as patients with CHD, DM and/or PAD, smoking cessation should always be a part of a multifactorial treatment to reduce vascular risk. Copyright © 2013 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

  4. Haemoglobin and vascular function in the human retinal vascular bed.

    PubMed

    Ritt, Martin; Harazny, Joanna M; Schmidt, Stephanie; Raff, Ulrike; Ott, Christian; Michelson, Georg; Schmieder, Roland E

    2013-04-01

    Haemoglobin is a potential nitric oxide (NO) scavenger. Haemoglobin is associated with blood viscosity and the red blood cell free layer width of microvessels that impact on shear stress in the microcirculation. We hypothesized that haemoglobin modulates retinal vascular function. In 139 nondiabetic male patients with haemoglobin levels within the normal range, the vasodilatatory response of retinal capillary blood flow (RCF) to flicker light exposure and the vasoconstrictor response of RCF to infusion of NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA) were assessed. The latter, because of the selective nature of L-NMMA, reflects a parameter of basal NO activity of retinal vasculature. Examinations of retinal parameters were performed noninvasively and in vivo using scanning laser Doppler flowmetry. Patients with haemoglobin greater or equal the median revealed reduced increase of RCF to flicker light exposure (2.83 ± 12 vs. 9.52 ± 14 (%), P adjusted = 0.002), and greater decrease of RCF to L-NMMA infusion (-7.35 ± 13 vs. -0.92 ± 14 (%), P adjusted = 0.008), compared with patients with haemoglobin below the median. Haemoglobin was negatively related to the percentage change of RCF to flicker light exposure (r = -0.249, P = 0.004) and to L-NMMA infusion (r = -0.201, P = 0.018). In multiple linear regression analysis haemoglobin was an independent determinant of the percentage change of RCF to flicker light exposure (model 1: ß = -0.278, P = 0.003 and model 2: ß = -0.283, P = 0.002) and to L-NMMA infusion (model 1: ß = -0.256, P = 0.005 and model 2: ß = -0.269, P = 0.004). Haemoglobin emerged as an independent determinant of vascular function in the human retinal vascular bed.

  5. Comparison of a vascular closure device versus the radial approach to reduce access site complications in non-ST-segment elevation acute coronary syndrome patients: The angio-seal versus the radial approach in acute coronary syndrome trial.

    PubMed

    Andrade, Pedro B; Mattos, Luiz A; Rinaldi, Fábio S; Bienert, Igor C; Barbosa, Robson A; Labrunie, André; Tebet, Marden; Esteves, Vinícius; Abizaid, Alexandre; Sousa, Amanda R

    2017-05-01

    To compare the radial versus femoral approach using Angio-Seal for the incidence of access site complications among non-ST-segment elevation acute coronary syndrome patients undergoing invasive strategy. Arterial access is a major site of complications after invasive coronary procedures. Vascular closure devices provide more comfort to patients decreasing time to hemostasis and need for bed rest. However, the inconsistency of data proving their safety limits their routine adoption as a strategy to prevent vascular complications. Single-center non-inferiority trial where 240 patients were randomized to radial or femoral access using Angio-Seal. The primary objective was the occurrence of complications at the arterial puncture site until 30 days after the procedure. There were no baseline clinical differences between groups, except for a greater prevalence of female patients in the radial group (33.3 vs. 20.0%, P = 0.020). Hemostasis was achieved in the entire radial group with the use of TR Band and in 95% of the procedures in the femoral group with Angio-Seal (P = 0.029). Except for a higher incidence of asymptomatic arterial occlusion in the radial group, there were no differences among the other analyzed outcomes. According to the noninferiority test, the use of Angio-Seal was noninferior to the radial approach, considering the margin of 15% (12.5 vs. 13.3%, difference -0.83%, 95% CI -9.31 - 7.65, P for noninferiority <0.001). Angio-Seal seems noninferior in the incidence of access site complications at 30 days when compared with the radial approach. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  6. Matrix Metalloproteinases and their Inhibitors in Vascular Remodeling and Vascular Disease

    PubMed Central

    Raffetto, Joseph D.; Khalil, Raouf A.

    2008-01-01

    Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade various components of the extracellular matrix (ECM). Members of the MMP family include collagenases, gelatinases, stromelysins, matrilysins and membrane-type MMPs. ProMMPs are cleaved into active forms that promote degradation of ECM proteins. Also, recent evidence suggests direct or indirect effects of MMPs on ion channels in the endothelium and vascular smooth muscle, and on other mechanisms of vascular relaxation/contraction. Endogenous tissue inhibitors of metalloproteinases (TIMPs) reduce excessive proteolytic ECM degradation by MMPs. The balance between MMPs and TIMPs plays a major role in vascular remodeling, angiogenesis, and the uterine and systemic vasodilation during normal pregnancy. An imbalance in the MMPs/TIMPs activity ratio may underlie the pathogenesis of vascular diseases such as abdominal aortic aneurysm, varicose veins, hypertension and preeclampsia. Downregulation of MMPs using genetic manipulations of endogenous TIMPs, or synthetic pharmacological inhibitors such as BB-94 (Batimastat) and doxycycline, and Ro-28-2653, a more specific inhibitor of gelatinases and membrane type 1-MMP, could be beneficial in reducing the MMP-mediated vascular dysfunction and the progressive vessel wall damage associated with vascular disease. PMID:17678629

  7. [Vascularization of hepatoceliular carcinoma].

    PubMed

    Tumanova, U N; Shchegolev, A I

    2015-01-01

    The paper gives the data available in the literature on vascularization of hepatocellular carcinoma (HCC). Sinusoidal capillarization and unpaired arteries are shown to play an important role in the development and progression of HCC. The density of microvessels detected by immunohistochemical techniques is a morphological indicator of the degree of angiogenic processes. Higher-grade HCC is followed by changes in its vascularization and concurrent with a progressive increase in the proportion of blood entering along the hepatic artery. The morphological indicators of microvessel density are recommended to use as addi- tional criteria for determining the prognosis of the disease, designing targeted anti-angiogenic drugs, and evaluating the efficiency of performed therapy.

  8. [Bisphosphonates for vascular calcification].

    PubMed

    Tanaka, Yoshiya; Okada, Yosuke

    2007-03-01

    Recent progress in basic research has revealed certain similarities between processes of bone calcification and calcifications of vascular tissues which contribute to several cardiovascular diseases. Bisphosphonates, which are inhibitors of bone resorption that are widely used to treat osteoporosis, also inhibit cholesterol biosynthesis, differentiation of macrophage to foam cell, differentiation of smooth muscle cells to osteoblast-like cells in certain stimuli during calcification processes of vessels. These findings extend the link between bone remodeling and vascular calcification, opening perspectives toward novel therapeutic strategies, however, current evidence is not conclusive and further research is necessary to confirm these actions in the clinical setting.

  9. Genealogy of training in vascular neurosurgery.

    PubMed

    Chowdhry, Shakeel A; Spetzler, Robert F

    2014-02-01

    Remarkable advances and changes in the landscape of neurovascular disease have occurred recently. Concurrently, a paradigm shift in training and resident education is underway. This crossroad of unique opportunities and pressures necessitates creative change in the training of future vascular neurosurgeons to allow incorporation of surgical advances, new technology, and supplementary treatment modalities in a setting of reduced work hours and increased public scrutiny. This article discusses the changing landscape in neurovascular disease treatment, followed by the recent changes in resident training, and concludes with our view of the future of training in vascular neurosurgery.

  10. Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease.

    PubMed

    Khalil, Raouf A

    2013-12-15

    Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women's Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject's age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Estrogen, Vascular Estrogen Receptor and Hormone Therapy in Postmenopausal Vascular Disease

    PubMed Central

    Khalil, Raouf A.

    2013-01-01

    Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women’s Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject’s age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD. PMID:24099797

  12. Prostacyclin receptor-dependent modulation of pulmonary vascular remodeling.

    PubMed

    Hoshikawa, Y; Voelkel, N F; Gesell, T L; Moore, M D; Morris, K G; Alger, L A; Narumiya, S; Geraci, M W

    2001-07-15

    Prostacyclin (PGI(2)) reduces pulmonary vascular resistance and attenuates vascular smooth muscle cell proliferation through signal transduction following ligand binding to its receptor. Because patients with severe pulmonary hypertension have a reduced PGI(2) receptor (PGI-R) expression in the remodeled pulmonary arterial smooth muscle, we hypothesized that pulmonary vascular remodeling may be modified PGI-R dependently. To test this hypothesis, PGI-R knockout (KO) and wild-type (WT) mice were subjected to a simulated altitude of 17,000 ft or Denver altitude for 3 wk, and right ventricular pressure and lung histology were assessed. The PGI-R KO mice developed more severe pulmonary hypertension and vascular remodeling after chronic hypoxic exposure when compared to the WT mice. Our results indicate that PGI(2) and its receptor play an important role in the regulation of hypoxia-induced pulmonary vascular remodeling, and that the absence of a functional receptor worsens pulmonary hypertension.

  13. Effects of vascularization on cancer nanochemotherapy outcomes

    NASA Astrophysics Data System (ADS)

    Paiva, L. R.; Ferreira, S. C.; Martins, M. L.

    2016-08-01

    Cancer therapy requires anticancer agents capable of efficient and uniform systemic delivery. One promising route to their development is nanotechnology. Here, a previous model for cancer chemotherapy based on a nanosized drug carrier (Paiva et al., 2011) is extended by including tissue vasculature and a three-dimensional growth. We study through computer simulations the therapy against tumors demanding either large or small nutrient supplies growing under different levels of tissue vascularization. Our results indicate that highly vascularized tumors demand more aggressive therapies (larger injected doses administrated at short intervals) than poorly vascularized ones. Furthermore, nanoparticle endocytic rate by tumor cells, not its selectivity, is the major factor that determines the therapeutic success. Finally, our finds indicate that therapies combining cytotoxic agents with antiangiogenic drugs that reduce the abnormal tumor vasculature, instead of angiogenic drugs that normalize it, can lead to successful treatments using feasible endocytic rates and administration intervals.

  14. Nonthrombogenic polymer vascular prosthesis.

    PubMed

    Nojiri, C; Senshu, K; Okano, T

    1995-01-01

    Although many synthetic vascular grafts have been developed and evaluated experimentally or clinically, none of them have met long-term patency when applied as a small diameter vascular substitute. We have recently developed a small caliber vascular graft (3 mm i.d.) using a nonthrombogenic polymer coating. The graft consists of three layered structures: Dacron for the outer layer, polyurethane in the middle layer, and a HEMA/styrene block copolymer (HEMA-st) coating for the inner layer. HEMA-st is an amphiphilic block copolymer composed of 2-hydroxyethyl methacrylate and styrene which has demonstrated improved blood compatibility over existing biomedical polymers in both in vitro and ex vivo experiments. Ten grafts were evaluated in a dog bilateral carotid replacement model. The grafts were electively retrieved at 7, 14, 30, 92, and 372 days after implantation. All grafts were patent without detectable thrombi along the graft length including anastomotic sites. Scanning electron micrographs of retrieved graft lumen showed fairly clean surfaces covered with a homogenous protein-like layer without microthrombi or endothelial cell lining. The thickness of the surface protein layer measured by a transmission electron microscopy was what can be described as monolayer protein adsorption regardless of implantation periods of as much as 372 days. A stable monolayer adsorbed protein layer formed on HEMA-st surfaces demonstrated nonthrombogenic activities in vivo and secure long-term patency of small caliber vascular grafts with the absence of an endothelial cell lining.

  15. Hypercholesterolaemia and vascular dementia.

    PubMed

    Appleton, Jason P; Scutt, Polly; Sprigg, Nikola; Bath, Philip M

    2017-07-15

    Vascular dementia (VaD) is the second commonest cause of dementia. Stroke is the leading cause of disability in adults in developed countries, the second major cause of dementia and the third commonest cause of death. Traditional vascular risk factors-diabetes, hypercholesterolaemia, hypertension and smoking-are implicated as risk factors for VaD. The associations between cholesterol and small vessel disease (SVD), stroke, cognitive impairment and subsequent dementia are complex and as yet not fully understood. Similarly, the effects of lipids and lipid-lowering therapy on preventing or treating dementia remain unclear; the few trials that have assessed lipid-lowering therapy for preventing (two trials) or treating (four trials) dementia found no evidence to support the use of lipid-lowering therapy for these indications. It is appropriate to treat those patients with vascular risk factors that meet criteria for lipid-lowering therapy for the primary and secondary prevention of cardiovascular and cerebrovascular events, and in line with current guidelines. Managing the individual patient in a holistic manner according to his or her own vascular risk profile is recommended. Although the paucity of randomized controlled evidence makes for challenging clinical decision making, it provides multiple opportunities for on-going and future research, as discussed here. © 2017 The Author(s).

  16. Heart and vascular services

    MedlinePlus

    ... may be done to diagnose, monitor or treat diseases of the circulatory and vascular system include: Cardiac CT for calcium scoring Cardiac MRI ... Cardiac rehabilitation is therapy used to prevent heart disease from getting worse. It is usually recommended after major heart-related events such ... Boateng S, Sanborn T. ...

  17. Pathogenesis of Vascular Anomalies

    PubMed Central

    Boon, Laurence M.; Ballieux, Fanny; Vikkula, Miikka

    2010-01-01

    Vascular anomalies are localized defects of vascular development. Most of them occur sporadically, i.e. there is no familial history of lesions, yet in a few cases clear inheritance is observed. These inherited forms are often characterized by multifocal lesions that are mainly small in size and increase in number with patient’s age. On the basis of these inherited forms, molecular genetic studies have unraveled a number of inherited mutations giving direct insight into the pathophysiological cause and the molecular pathways that are implicated. Genetic defects have been identified for hereditary haemorrhagic telangiectasia (HHT), inherited cutaneomucosal venous malformation (VMCM), glomuvenous malformation (GVM), capillary malformation - arteriovenous malformation (CM-AVM), cerebral cavernous malformation (CCM) and some isolated and syndromic forms of primary lymphedema. We focus on these disorders, the implicated mutated genes and the underlying pathogenic mechanisms. We also call attention to the concept of Knudson’s double-hit mechanism to explain incomplete penetrance and the large clinical variation in expressivity of inherited vascular anomalies. This variability renders the making of correct diagnosis of the rare inherited forms difficult. Yet, the identification of the pathophysiological causes and pathways involved in them has had an unprecedented impact on our thinking of their etiopathogenesis, and has opened the doors towards a more refined classification of vascular anomalies. It has also made it possible to develop animal models that can be tested for specific molecular therapies, aimed at alleviating the dysfunctions caused by the aberrant genes and proteins. PMID:21095468

  18. Amputation in vascular disease.

    PubMed Central

    Robinson, K.

    1980-01-01

    The management of vascular amputees in the Roehampton Limb Surgery Unit since its opening in 1975 is outlined and the results in 167 cases presented. Of the 35 patients over the age of 80, 57% were walking independently at the time of their discharge from the unit. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:7377693

  19. Synthetic vascular prostheses.

    PubMed

    Struszczyk, Marcin H; Bednarek, Paweł; Raczyński, Krzysztof

    2002-01-01

    Polyethyleneterephthalate (PET), and to a lesser extent Teflon have become the major synthetic grafting material. Unlike nylon, Ivalon, and Vinyon-N which lose their tensile strength after implantation, PET and Teflon remain essentially unchanged even after long periods. TRICOMED S.A. produces the family of the knitted vascular implants Dallon made from PET fibres including: Dallon, Dallon H, Tricogel. Both Dallon and Dallon H are manufactured in a form of double (external and internal) velour surface using multifilament yarn and having optimal graft design (a variety of sizes and lengths). The velour surface gives the surface a velvety, plush texture, which improves tissue in--growth. Moreover, Dallon H is a unique vascular prostheses showing the increase in the blood susceptibility that is useful for 4 times less blood demand during preclotting as compared with standard prosthesis. Tricogel graft is made of thin-wall prostheses sealed with the porcine gelatin that provides intraoperative tightness (without preclotting) and the optimal healing process. Hydrophilic behavior of the graft is observed as an instant moistening of the surface with patient's blood and as sweating. The blood stream does not dissolve nor washes away the gelatin but causes the gelatin film to swell, which makes a better tightness. The work will describe the properties of manmade vascular grafts as well as their applications in the vascular surgery.

  20. Habitual exercise and vascular ageing

    PubMed Central

    Seals, Douglas R; Walker, Ashley E; Pierce, Gary L; Lesniewski, Lisa A

    2009-01-01

    Age is the major risk factor for cardiovascular diseases (CVD) and this is attributable in part to stiffening of large elastic arteries and development of vascular endothelial dysfunction (e.g. impaired endothelium-dependent dilatation, EDD). In contrast, regular aerobic exercise is associated with reduced risk of CVD. Endurance exercise-trained middle-aged/older adults demonstrate lower large elastic artery stiffness and greater EDD than their sedentary peers. With daily brisk walking, previously sedentary middle-aged/older adults show reduced stiffness and improved EDD. The mechanisms underlying the effects of regular aerobic exercise on large elastic artery stiffness with ageing are largely unknown, but are likely to include changes to the composition of the arterial wall. Enhanced EDD in older adults who exercise is mediated by increased nitric oxide (NO) bioavailability associated with reduced oxidative stress. Arteries from old rodents that perform regular aerobic exercise demonstrate increased expression and activity of endothelial NO synthase, reduced oxidative damage associated with reduced expression and activity of the oxidant enzyme NADPH oxidase, and increased activity of the antioxidant enzyme superoxide dismutase. Aerobic exercise also may protect arteries with ageing by increasing resistance to the effects of other CVD risk factors like LDL-cholesterol. Habitual aerobic exercise is an effective strategy to combat arterial ageing. PMID:19723776

  1. Atherosclerosis, vascular aging and therapeutic strategies.

    PubMed

    Liu, Yue; Chen, Ke-Ji

    2012-02-01

    With the arrival of the era of global population aging, we strive for healthy aging and a healthy senior life rather than simple prolongation of the physical age. For the past 50 years, cardiovascular diseases (CVD) have been the most common cause of death among the elderly people globally. In China, there has been an exponential increase in the incidence of heart disease and stroke in the elderly population. Atherosclerosis is the pathological change in the coronary artery disease, stroke, and peripheral vascular disease. Despite the significant benefit demonstrated, control of classic risk factors alone, such as lifestyle change or drug therapy, was shown to have limitations in reducing the incidence of cardiovascular events. Vascular aging has been shown to be an important independent predictor of CVD events. Interventions targeting vascular aging have emerged as a new paradigm in conjunction with control of risk factors for the prevention of CVD. Vascular aging and atherosclerosis are two distinct pathological changes and difficult to distinguish clinically. Recent research with Chinese medicine (CM) has shown encouraging observations, linking the clinical benefit of delaying vascular aging and treating atherosclerosis. These results demonstrate great potential of CM in the prevention and treatment of CVD.

  2. Vascular wall extracellular matrix proteins and vascular diseases

    PubMed Central

    Xu, Junyan; Shi, Guo-Ping

    2014-01-01

    Extracellular matrix proteins form the basic structure of blood vessels. Along with providing basic structural support to blood vessels, matrix proteins interact with different sets of vascular cells via cell surface integrin or non-integrin receptors. Such interactions induce vascular cell de novo synthesis of new matrix proteins during blood vessel development or remodeling. Under pathological conditions, vascular matrix proteins undergo proteolytic processing, yielding bioactive fragments to influence vascular wall matrix remodeling. Vascular cells also produce alternatively spliced variants that induce vascular cell production of different matrix proteins to interrupt matrix homeostasis, leading to increased blood vessel stiffness; vascular cell migration, proliferation, or death; or vascular wall leakage and rupture. Destruction of vascular matrix proteins leads to vascular cell or blood-borne leukocyte accumulation, proliferation, and neointima formation within the vascular wall; blood vessels prone to uncontrolled enlargement during blood flow diastole; tortuous vein development; and neovascularization from existing pathological tissue microvessels. Here we summarize discoveries related to blood vessel matrix proteins within the past decade from basic and clinical studies in humans and animals — from expression to cross-linking, assembly, and degradation under physiological and vascular pathological conditions, including atherosclerosis, aortic aneurysms, varicose veins, and hypertension. PMID:25045854

  3. Ultrasound for vascular access in pediatric patients.

    PubMed

    Schindler, Ehrenfried; Schears, Gregory J; Hall, Stuart R; Yamamoto, Tomohiro

    2012-10-01

    In pediatric patients vascular access is often more difficult than in adults because of the smaller size of the vessels and the inability of the patient to cooperate without deep sedation or general anesthesia. Therefore Ultrasound has already become an invaluable tool for vascular access, but the full potential of ultrasound has yet to be fully realized. Improvements in image quality and a better understanding of optimal insertion techniques continue to help clinicians safely and efficiently place catheters with fewer complications. The probes used for the vascular access are mainly linear and convex type. Higher- frequency ultrasound provides a vivid image; however, the signals are remarkably attenuated. Therefore, the choice of the probe with appropriate frequency is essential. As blood vessels are relatively easily identified with ultrasound, ultrasound-guided vascular access does not require as sharp images as ultrasound-guided nerve block. For pediatric vascular access, the linear probe with 5-15 MHz, 2-5 cm depth is ideal and adequate for almost all cases. Ultrasound-guided vascular access has two main approaches: 'long-axis' or 'in-plane approach' and 'short-axis' or 'transverse approach'. The long-axis approach visualizes the vessel along the insertion pathway and is commonly used to monitor the entire approach of the needle into the vessel. The short-axis approach is easier to show the positional relationship and depth of target vessels, but it is much harder to follow the needle tip within the tissues. The use of 'real-time' ultrasound has been shown to increase first insertion success, reduce access time, have a higher overall success, and reduce arterial puncture. As the technology continues to improve the use of ultrasound will become as ubiquitous as the lines themselves. © 2012 Blackwell Publishing Ltd.

  4. Leaf hydraulics II: vascularized tissues.

    PubMed

    Rockwell, Fulton E; Holbrook, N Michele; Stroock, Abraham D

    2014-01-07

    Current models of leaf hydration employ an Ohm's law analogy of the leaf as an ideal capacitor, neglecting the resistance to flow between cells, or treat the leaf as a plane sheet with a source of water at fixed potential filling the mid-plane, neglecting the discrete placement of veins as well as their resistance. We develop a model of leaf hydration that considers the average conductance of the vascular network to a representative areole (region bounded by the vascular network), and represent the volume of tissue within the areole as a poroelastic composite of cells and air spaces. Solutions to the 3D flow problem are found by numerical simulation, and these results are then compared to 1D models with exact solutions for a range of leaf geometries, based on a survey of temperate woody plants. We then show that the hydration times given by these solutions are well approximated by a sum of the ideal capacitor and plane sheet times, representing the time for transport through the vasculature and tissue respectively. We then develop scaling factors relating this approximate solution to the 3D model, and examine the dependence of these scaling factors on leaf geometry. Finally, we apply a similar strategy to reduce the dimensions of the steady state problem, in the context of peristomatal transpiration, and consider the relation of transpirational gradients to equilibrium leaf water potential measurements. © 2013 Published by Elsevier Ltd. All rights reserved.

  5. Vascular calcification in patients with chronic kidney disease.

    PubMed

    Nitta, Kosaku

    2011-12-01

    Vascular calcification is very prevalent in patients with chronic kidney disease (CKD). In addition to having more traditional cardiovascular (CV) risk factors, CKD patients also have a number of non-traditional CV risk factors that may play a prominent role in the pathogenesis of vascular calcification. The transformation of vascular smooth muscle cells into osteoblast-like cells seems to be a key element in the pathogenesis of vascular calcification in the presence of calcium (Ca) and phosphorus (P) deposition due to abnormal bone metabolism and impaired renal excretion. Vascular calcification causes increased arterial stiffness, left ventricular hypertrophy, decreased coronary artery perfusion, myocardial ischemia, and increased cardiovascular morbidity and mortality. Although current treatment strategies focus on correcting abnormal Ca, P, parathyroid hormone, or vitamin D levels in CKD, a better understanding of the mechanisms of abnormal tissue calcification may lead to the development of new therapeutic agents that are capable of reducing vascular calcification and improving the CV outcome of CKD patients. This review article summarizes the following: (i) the pathophysiological mechanism responsible for vascular calcification; (ii) the methods of detecting vascular calcification in CKD patients; and (iii) the treatment of vascular calcification in CKD patients. © 2011 The Author. Therapeutic Apheresis and Dialysis © 2011 International Society for Apheresis.

  6. Hemodialysis vascular access dysfunction: a cellular and molecular viewpoint.

    PubMed

    Roy-Chaudhury, Prabir; Sukhatme, Vikas P; Cheung, Alfred K

    2006-04-01

    Hemodialysis vascular access dysfunction is a major cause of morbidity and hospitalization in the hemodialysis population. The major cause of hemodialysis vascular access dysfunction is venous stenosis as a result of neointimal hyperplasia. Despite the magnitude of the clinical problem, however, there has been a paucity of novel therapeutic interventions in this field. This is in marked contrast to a recent plethora of targeted interventions for the treatment of arterial neointimal hyperplasia after coronary angioplasty. The reasons for this are two-fold. First there has been a relative lack of cellular and molecular research that focuses on venous neointimal hyperplasia in the specific setting of hemodialysis vascular access. Second, there have been inadequate efforts by the nephrology community to translate the recent advances in molecular and interventional cardiology into therapies for hemodialysis vascular access. This review therefore (1) briefly examines the different forms of hemodialysis vascular access that are available, (2) describes the pathology and pathogenesis of hemodialysis vascular access dysfunction in both polytetrafluoroethylene grafts and native arteriovenous fistulae, (3) reviews recent concepts about the pathogenesis of vascular stenosis that could potentially be applied in the setting of hemodialysis vascular access dysfunction, (4) summarizes novel experimental and clinical therapies that could potentially be used in the setting of hemodialysis vascular access dysfunction, and, finally, (5) offers some broad guidelines for future innovative translational and clinical research in this area that hopefully will reduce the huge clinical morbidity and economic costs that are associated with this condition.

  7. Advances in Vascular Hyporeactivity After Shock: The Mechanisms and Managements.

    PubMed

    Duan, Chenyang; Yang, Guangming; Li, Tao; Liu, Liangming

    2015-12-01

    Vascular reactivity to vasoconstrictors and vasodilators is greatly reduced after severe trauma, shock, and sepsis or multiple organ dysfunction syndrome. This reduced vascular reactivity severely interferes with the treatment of shock and other critical conditions. In particular, it interferes with the efficacy of vasoactive agents. Consequently, it is very important to elucidate the mechanisms and search for the effective treatment measures. In recent years, a lot of studies focused on the characteristics and the change rules of vascular hyporeactivity and mechanisms following shock. Also, the treatment approaches based on various mechanisms have been a hot pot these years.

  8. Modern advances in vascular trauma.

    PubMed

    Callcut, Rachael A; Mell, Matthew W

    2013-08-01

    Early diagnosis and intervention are paramount for improving the likelihood of a favorable outcome for traumatic vascular injuries. As technology has rapidly diversified, the diagnostic and therapeutic approaches available for vascular injuries have evolved. Mortality and morbidity from vascular injury have declined over the last decade. The use of vascular shunts and tourniquets has become standard of care in military medicine. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Vascular imaging in the elderly.

    PubMed

    Kalva, Sanjeeva P; Mueller, Peter R

    2008-07-01

    Though a myriad of vascular conditions affect the elderly, atherosclerosis remains the most common vascular disorder, followed by venous thromboembolism and varicose veins. In this article, the authors discuss the imaging of atherosclerosis affecting various vascular territories and pay special attention to the elderly population. The authors also discuss imaging findings of segmental arterial mediolysis, giant cell arteritis, and venous thromboembolism.

  10. Association of Serum Phosphate and Related Factors in ESRD-Related Vascular Calcification

    PubMed Central

    Zheng, Cai-Mei; Lu, Kuo-Cheng; Wu, Chia-Chao; Hsu, Yung-Ho; Lin, Yuh-Feng

    2011-01-01

    Vascular calcification is common in ESRD patients and is important in increasing mortality from cardiovascular complications in these patients. Hyperphosphatemia related to chronic kidney disease is increasingly known as major stimulus for vascular calcification. Hyperphosphatemia and vascular calcification become popular discussion among nephrologist environment more than five decades, and many researches have been evolved. Risk factors for calcification are nowadays focused for the therapeutic prevention of vascular calcification with the hope of reducing cardiovascular complications. PMID:21660259

  11. Aspirin for vascular dementia

    PubMed Central

    Rands, Gianetta; Orrell, Martin

    2014-01-01

    Background Aspirin is widely prescribed for patients with a diagnosis of vascular dementia. In a survey of UK geriatricians and psychiatrists 80% of patients with clinical diagnoses of vascular dementia were prescribed aspirin. However, a number of queries remain unanswered. Is there convincing evidence that aspirin benefits patients with vascular dementia? Does aspirin affect cognition and behaviour, or improve prognosis? Does the risk of cerebral or gastric haemorrhage outweigh any benefit? Objectives To assess the randomised trial evidence for efficacy and safety of aspirin in the treatment of vascular dementia. Search methods We searched ALOIS: the Cochrane Dementia and Cognitive Improvement Group’s Specialized Register on 12 March 2012 using the terms: aspirin OR “acetylsalicylic acid”. ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. In addition, relevant websites were searched and some journals were handsearched. Specialists in the field were approached for unpublished material and any publications found were searched for additional references. Selection criteria Randomised controlled trials investigating the effect of aspirin for vascular dementia were eligible for inclusion. Data collection and analysis Retrieved studies were analysed independently by both review authors. Methodology and results were critically appraised and outcomes scanned included cognition, behavioural change, mortality and institutionalisation. Main results No trials were eligible for inclusion in this review. Authors’ conclusions The most recent search for references to relevant research was carried out in March 2012. No trials were found for inclusion in this systematic review. Low-dose aspirin is frequently used as ‘treatment as normal’ in control groups and as a baseline treatment in pharmacological trials. There is still no good evidence that

  12. The Vascular Depression Hypothesis: Mechanisms Linking Vascular Disease with Depression

    PubMed Central

    Taylor, Warren D.; Aizenstein, Howard J.; Alexopoulos, George S.

    2013-01-01

    The ‘Vascular Depression’ hypothesis posits that cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes. This hypothesis stimulated much research that has improved our understanding of the complex relationships between late-life depression (LLD), vascular risk factors, and cognition. Succinctly, there are well-established relationships between late-life depression, vascular risk factors, and cerebral hyperintensities, the radiological hallmark of vascular depression. Cognitive dysfunction is common in late-life depression, particularly executive dysfunction, a finding predictive of poor antidepressant response. Over time, progression of hyperintensities and cognitive deficits predicts a poor course of depression and may reflect underlying worsening of vascular disease. This work laid the foundation for examining the mechanisms by which vascular disease influences brain circuits and influences the development and course of depression. We review data testing the vascular depression hypothesis with a focus on identifying potential underlying vascular mechanisms. We propose a disconnection hypothesis, wherein focal vascular damage and white matter lesion location is a crucial factor influencing neural connectivity that contributes to clinical symptomatology. We also propose inflammatory and hypoperfusion hypotheses, concepts that link underlying vascular processes with adverse effects on brain function that influence the development of depression. Testing such hypotheses will not only inform the relationship between vascular disease and depression but also provide guidance on the potential repurposing of pharmacological agents that may improve late-life depression outcomes. PMID:23439482

  13. Vascular endothelial growth factor gene-transferred bone marrow stromal cells engineered with a herpes simplex virus type 1 vector can improve neurological deficits and reduce infarction volume in rat brain ischemia.

    PubMed

    Miki, Yoshihito; Nonoguchi, Naosuke; Ikeda, Naokado; Coffin, Robert S; Kuroiwa, Toshihiko; Miyatake, Shin-ichi

    2007-09-01

    Several reports recently suggested that vascular endothelial growth factor (VEGF) may have a therapeutic benefit against experimental cerebral infarction animal models. In addition, bone marrow stromal cells (BMSCs) are known to have therapeutic potency in improving neurological deficits after occlusive cerebrovascular diseases. In the present study, we evaluated the hypothesis that intracerebral transplantation of VEGF gene-transferred BMSCs could provide a greater therapeutic effect than intracerebral transplantation of native (non-gene-transformed) BMSCs by using a transient middle cerebral artery occlusion (MCAO) rat model. Adult Wistar rats (Japan SLC, Inc., Hamamatsu, Japan) were anesthetized. VEGF gene-transferred BMSCs engineered with a replication-deficient herpes simplex virus type 1 1764/4-/pR19-hVEGF165 vector, native BMSCs, or phosphate-buffered saline were administered intracerebrally 24 hours after transient MCAO. All animals underwent behavioral testing for 28 days, and the infarction volume was determined 14 days after MCAO. The brain water contents in the ipsilateral and contralateral hemispheres of the MCAO were measured 2 and 7 days after the MCAO. Fourteen days after MCAO, immunohistochemical staining for VEGF was performed. The group receiving VEGF-modified BMSCs demonstrated significant functional recovery compared with those receiving native BMSCs. Fourteen days after the MCAO, there was a significantly lower infarct volume without aggravating cerebral edema in the group treated with VEGF gene-modified BMSCs compared with the control groups. The transplanted VEGF gene-modified BMSCs strongly expressed VEGF protein for at least 14 days. Our data suggest that the intracerebral transplantation of VEGF gene-transferred BMSCs may provide a more potent autologous cell transplantation therapy for stroke than the transplantation of native BMSCs alone.

  14. Plant Vascular Biology 2010

    SciTech Connect

    Ding, Biao

    2014-11-17

    This grant supported the Second International Conference on Plant Vascular Biology (PVB 2010) held July 24-28, 2010 on the campus of Ohio State University, Columbus, Ohio. Biao Ding (Ohio State University; OSU) and David Hannapel (Iowa State University; ISU) served as co-chairs of this conference. Biao Ding served as the local organizer. PVB is defined broadly here to include studies on the biogenesis, structure and function of transport systems in plants, under conditions of normal plant growth and development as well as of plant interactions with pathogens. The transport systems cover broadly the xylem, phloem, plasmodesmata and vascular cell membranes. The PVB concept has emerged in recent years to emphasize the integrative nature of the transport systems and approaches to investigate them.

  15. Pelvic Vascular Malformations

    PubMed Central

    Christenson, Brian M.; Gipson, Matthew G.; Smith, Mitchell T.

    2013-01-01

    Vascular malformations (VMs) comprise a wide spectrum of lesions that are classified by content and flow characteristics. These lesions, occurring in both focal and diffuse forms, can involve any organ and tissue plane and can cause significant morbidity in both children and adults. Since treatment strategy depends on the type of malformation, correct diagnosis and classification of a vascular lesion are crucial. Slow-flow VMs (venous and lymphatic malformations) are often treated by sclerotherapy, whereas fast-flow lesions (arteriovenous malformations) are generally managed with embolization. In addition, some cases of VMs are best treated surgically. This review will present an overview of VMs in the female pelvis as well as a discussion of endovascular therapeutic techniques. PMID:24436563

  16. [Vascular endothelial Barrier Function].

    PubMed

    Ivanov, A N; Puchinyan, D M; Norkin, I A

    2015-01-01

    Endothelium is an important regulator of selective permeability of the vascular wall for different molecules and cells. This review summarizes current data on endothelial barrier function. Endothelial glycocalyx structure, its function and role in the molecular transport and leukocytes migration across the endothelial barrier are discussed. The mechanisms of transcellular transport of macromolecules and cell migration through endothelial cells are reviewed. Special section of this article addresses the structure and function of tight and adherens endothelial junction, as well as their importance for the regulation of paracellular transport across the endothelial barrier. Particular attention is paid to the signaling mechanism of endothelial barrier function regulation and the factors that influence on the vascular permeability.

  17. Vascular trauma historical notes.

    PubMed

    Rich, Norman M

    2011-03-01

    This article provides a brief historical review of treatment of vascular trauma. Although methods for ligation came into use in the second century, this knowledge was lost during the Dark Ages and did not come back until the Renaissance. Many advances in vascular surgery occurred during the Balkan Wars, World War I, and World War II, although without antibiotics and blood banking, the philosophy of life over limb still ruled. Documenting and repairing both arteries and veins became more common during the Korean and Vietnam conflicts. Increased documentation has revealed that the current conflicts have resulted in more arterial injuries than in previous wars, likely because of improved body armor, improvised explosive device attacks, tourniquet use, and improved medical evacuation time. This brief review emphasizes the great value of mentorship and the legacy of the management of arterial and venous injuries to be passed on.

  18. Brain Vascular Imaging Techniques

    PubMed Central

    Laviña, Bàrbara

    2016-01-01

    Recent major improvements in a number of imaging techniques now allow for the study of the brain in ways that could not be considered previously. Researchers today have well-developed tools to specifically examine the dynamic nature of the blood vessels in the brain during development and adulthood; as well as to observe the vascular responses in disease situations in vivo. This review offers a concise summary and brief historical reference of different imaging techniques and how these tools can be applied to study the brain vasculature and the blood-brain barrier integrity in both healthy and disease states. Moreover, it offers an overview on available transgenic animal models to study vascular biology and a description of useful online brain atlases. PMID:28042833

  19. Modeling Cerebral Vascular Injury

    DTIC Science & Technology

    2016-01-01

    Using a pressure gradient to drive the blood flow, and the external pressure induced by a blast wave through the surrounding brain elements, an...unlimited. 13. SUPPLEMENTARY NOTES 14. ABSTRACT Many numerical models for the brain do not include the vascular structures within the brain and thus...are incapable of predicting damage to the cerebral vasculature. The presence of the vasculature within the brain produces a reinforcing effect and

  20. Vascular Cambium Development

    PubMed Central

    Nieminen, Kaisa; Blomster, Tiina; Helariutta, Ykä; Mähönen, Ari Pekka

    2015-01-01

    Secondary phloem and xylem tissues are produced through the activity of vascular cambium, the cylindrical secondary meristem which arises among the primary plant tissues. Most dicotyledonous species undergo secondary development, among them Arabidopsis. Despite its small size and herbaceous nature, Arabidopsis displays prominent secondary growth in several organs, including the root, hypocotyl and shoot. Together with the vast genetic resources and molecular research methods available for it, this has made Arabidopsis a versatile and accessible model organism for studying cambial development and wood formation. In this review, we discuss and compare the development and function of the vascular cambium in the Arabidopsis root, hypocotyl, and shoot. We describe the current understanding of the molecular regulation of vascular cambium and compare it to the function of primary meristems. We conclude with a look at the future prospects of cambium research, including opportunities provided by phenotyping and modelling approaches, complemented by studies of natural variation and comparative genetic studies in perennial and woody plant species. PMID:26078728

  1. Vascular Lumen Formation

    PubMed Central

    Lammert, Eckhard; Axnick, Jennifer

    2012-01-01

    The vascular system developed early in evolution. It is required in large multicellular organisms for the transport of nutrients, oxygen, and waste products to and from tissues. The vascular system is composed of hollow tubes, which have a high level of complexity in vertebrates. Vasculogenesis describes the de novo formation of blood vessels, e.g., aorta formation in vertebrate embryogenesis. In contrast, angiogenesis is the formation of blood vessels from preexisting ones, e.g., sprouting of intersomitic blood vessels from the aorta. Importantly, the lumen of all blood vessels in vertebrates is lined and formed by endothelial cells. In both vasculogenesis and angiogenesis, lumen formation takes place in a cord of endothelial cells. It involves a complex molecular mechanism composed of endothelial cell repulsion at the cell–cell contacts within the endothelial cell cords, junctional rearrangement, and endothelial cell shape change. As the vascular system also participates in the course of many diseases, such as cancer, stroke, and myocardial infarction, it is important to understand and make use of the molecular mechanisms of blood vessel formation to better understand and manipulate the pathomechanisms involved. PMID:22474612

  2. Retinal Vascular Changes are a Marker for Cerebral Vascular Diseases.

    PubMed

    Moss, Heather E

    2015-07-01

    The retinal circulation is a potential marker of cerebral vascular disease because it shares origin and drainage with the intracranial circulation and because it can be directly visualized using ophthalmoscopy. Cross-sectional and cohort studies have demonstrated associations between chronic retinal and cerebral vascular disease, acute retinal and cerebral vascular disease, and chronic retinal vascular disease and acute cerebral vascular disease. In particular, certain qualitative features of retinopathy, retinal artery occlusion, and increased retinal vein caliber are associated with concurrent and future cerebrovascular events. These associations persist after accounting for confounding variables known to be disease-causing in both circulations, which supports the potential use of retinal vasculature findings to stratify individuals with regards to cerebral vascular disease risk.

  3. Delivery of Polymeric Nanoparticles to Target Vascular Diseases

    PubMed Central

    Agyare, Edward; Kandimalla, Karunyna

    2015-01-01

    Current advances in nanotechnology have paved the way for the early detection, prevention and treatment of various diseases such as vascular disorders and cancer. These advances have provided novel approaches or modalities of incorporating or adsorbing therapeutic, biosensor and targeting agents into/on nanoparticles. With significant progress, nanomedicine for vascular therapy has shown significant advantages over traditional medicine because of its ability to selectively target the disease site and reduce adverse side effects. Targeted delivery of nanoparticles to vascular endothelial cells or the vascular wall provides an effective and more efficient way for early detection and/or treatment of vascular diseases such as atherosclerosis, thrombosis and Cerebrovascular Amyloid Angiopathy (CAA). Clinical applications of biocompatible and biodegradable polymers in areas such as vascular graft, implantable drug delivery, stent devices and tissue engineering scaffolds have advanced the candidature of polymers as potential nano-carriers for vascular-targeted delivery of diagnostic agents and drugs. This review focuses on the basic aspects of the vasculature and its associated diseases and relates them to polymeric nanoparticle-based strategies for targeting therapeutic agents to diseased vascular site. PMID:26069867

  4. PECAM-1 is necessary for flow-induced vascular remodeling

    PubMed Central

    Chen, Zhongming; Tzima, Ellie

    2009-01-01

    OBJECTIVE Vascular remodeling is a physiological process that occurs in response to long-term changes in hemodynamic conditions, but may also contribute to the pathophysiology of intima-media thickening (IMT) and vascular disease. Shear stress detection by the endothelium is thought to be an important determinant of vascular remodeling. Previous work showed that Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a component of a mechanosensory complex that mediates endothelial cell (EC) responses to shear stress. METHODS AND RESULTS We tested the hypothesis that PECAM-1 contributes to vascular remodeling by analyzing the response to partial carotid artery ligation in PECAM-1 knockout mice and wild-type littermates. PECAM-1 deficiency resulted in impaired vascular remodeling and significantly reduced IMT in areas of low flow. Inward remodeling was associated with PECAM-1-dependent NFκB activation, surface adhesion molecule expression and leukocyte infiltration as well as Akt activation and vascular cell proliferation. CONCLUSIONS PECAM-1 plays a crucial role in the activation of the NFκB and Akt pathways and inflammatory cell accumulation during vascular remodeling and IMT. Elucidation of some of the signals that drive vascular remodeling represent pharmacologically tractable targets for the treatment of restenosis after balloon angioplasty or stent placement. PMID:19390054

  5. An integrated approach for vascular health: a call to action.

    PubMed

    O'Neill, Blair J; Rana, Shadab N; Bowman, Vincent

    2015-01-01

    Vascular diseases such as stroke, myocardial infarction, most causes of heart failure, dementia, peripheral arterial disease, certain kidney, and many lung and eye conditions are a result of disorders in the blood vessels (large and small) throughout the entire human body. Vascular diseases are the leading cause of preventable death and disability in Canada. Most vascular diseases share common risk factors (high blood pressure, diabetes, dyslipidemia, and obesity), which can be influenced by modifiable health behaviours such as unhealthy diet, smoking, lack of physical activity, and stress. Ninety percent of Canadians face an increased risk, which could be modified by managing these health behaviours and risk factors. Canada's aging population, combined with alarming trends in obesity, physical inactivity, high blood pressure, and diabetes are expected to further increase the social and economic effect of vascular diseases in the coming decades, unless there are major changes in health policy. Even more concerning is the increase in vascular risk factors among Canada's youth, and ethnically diverse populations. Vascular diseases affect not only the patient, but also place burdens on their spouses, families, friends, and communities. Tremendous potential exists to reduce the effects of vascular diseases through healthy public policy, supporting Canadians to make healthy lifestyle changes, and coordinating efforts across the continuum of care in a patient-focused manner. Vascular health requires partnerships for action across many sectors including government, health care practitioners, academia, not-for-profit organizations, and the private sector. The health sector alone cannot solve this problem.

  6. Vinpocetine Attenuates the Osteoblastic Differentiation of Vascular Smooth Muscle Cells

    PubMed Central

    Chen, Xiu-Juan; Wang, Na; Yi, Peng-Fei; Song, Min; Zhang, Bo; Wang, Yu-Zhong; Liang, Qiu-Hua

    2016-01-01

    Vascular calcification is an active process of osteoblastic differentiation of vascular smooth muscle cells; however, its definite mechanism remains unknown. Vinpocetine, a derivative of the alkaloid vincamine, has been demonstrated to inhibit the high glucose-induced proliferation of vascular smooth muscle cells; however, it remains unknown whether vinpocetine can affect the osteoblastic differentiation of vascular smooth muscle cells. We hereby investigated the effect of vinpocetine on vascular calcification using a beta-glycerophosphate-induced cell model. Our results showed that vinpocetine significantly reduced the osteoblast-like phenotypes of vascular smooth muscle cells including ALP activity, osteocalcin, collagen type I, Runx2 and BMP-2 expression as well as the formation of mineralized nodule. Vinpocetine, binding to translocation protein, induced phosphorylation of extracellular signal-related kinase and Akt and thus inhibited the translocation of nuclear factor-kappa B into the nucleus. Silencing of translocator protein significantly attenuated the inhibitory effect of vinpocetine on osteoblastic differentiation of vascular smooth muscle cells. Taken together, vinpocetine may be a promising candidate for the clinical therapy of vascular calcification. PMID:27589055

  7. Genetic Pathways of Vascular Calcification

    PubMed Central

    Bowman, Marion A. Hofmann; McNally, Elizabeth M.

    2012-01-01

    Vascular calcification is an independent risk factor for cardiovascular disease. Arterial calcification of the aorta, coronary, carotid and peripheral arteries becomes more prevalent with age. Genomewide association studies have identified regions of the genome linked to vascular calcification, and these same regions are linked to myocardial infarction risk. The 9p21 region linked to vascular disease and inflammation also associates with vascular calcification. In addition to these common variants, rare genetic defects can serve as primary triggers of accelerated and premature calcification. Infancy-associated calcific disorders are caused by loss of function mutations in ENPP1 an enzyme that produces extracellular pyrophosphate. Adult onset vascular calcification is linked to mutations NTE5, another enzyme that regulates extracellular phosphate metabolism. Common conditions that secondarily enhance vascular calcification include atherosclerosis, metabolic dysfunction, diabetes, and impaired renal clearance. Oxidative stress and vascular inflammation, along with biophysical properties, converge with these predisposing factors to promote soft tissue mineralization. Vascular calcification is accompanied by an osteogenic profile, and this osteogenic conversion is seen within the vascular smooth muscle itself as well as the matrix. Herein we will review the genetic causes of medial calcification in the smooth muscle layer, focusing on recent discoveries of gene mutations that regulate extracellular matrix phosphate production and the role of S100 proteins as promoters of vascular calcification. PMID:23040839

  8. Secondhand Smoking Is Associated With Vascular Inflammation

    PubMed Central

    Adams, Tessa; Wan, Elaine; Wei, Ying; Wahab, Romina; Castagna, Francesco; Wang, Gang; Emin, Memet; Russo, Cesare; Homma, Shunichi; Le Jemtel, Thierry H.

    2015-01-01

    BACKGROUND: The relative risk for cardiovascular diseases in passive smokers is similar to that of active smokers despite almost a 100-fold lower dose of inhaled cigarette smoke. However, the mechanisms underlying the surprising susceptibility of the vascular tissue to the toxins in secondhand smoke (SHS) have not been directly investigated. The aim of this study was to investigate directly vascular endothelial cell function in passive smokers. METHODS: Using a minimally invasive method of endothelial biopsy, we investigated directly the vascular endothelium in 23 healthy passive smokers, 25 healthy active smokers, and 23 healthy control subjects who had never smoked and had no regular exposure to SHS. Endothelial nitric oxide synthase (eNOS) function (expression of basal eNOS and activated eNOS [phosphorylated eNOS at serine1177 (P-eNOS)]) and expression of markers of inflammation (nuclear factor-κB [NF-κB]) and oxidative stress (nitrotyrosine) were assessed in freshly harvested venous endothelial cells by quantitative immunofluorescence. RESULTS: Expression of eNOS and P-eNOS was similarly reduced and expression of NF-κB was similarly increased in passive and active smokers compared with control subjects. Expression of nitrotyrosine was greater in active smokers than control subjects and similar in passive and active smokers. Brachial artery flow-mediated dilation was similarly reduced in passive and active smokers compared with control subjects, consistent with reduced endothelial NO bioavailability. CONCLUSIONS: Secondhand smoking increases vascular endothelial inflammation and reduces active eNOS to a similar extent as active cigarette smoking, indicating direct toxic effects of SHS on the vasculature. PMID:25742439

  9. Double-filter identification of vascular-expressed genes using Arabidopsis plants with vascular hypertrophy and hypotrophy.

    PubMed

    Ckurshumova, Wenzislava; Scarpella, Enrico; Goldstein, Rochelle S; Berleth, Thomas

    2011-08-01

    Genes expressed in vascular tissues have been identified by several strategies, usually with a focus on mature vascular cells. In this study, we explored the possibility of using two opposite types of altered tissue compositions in combination with a double-filter selection to identify genes with a high probability of vascular expression in early organ primordia. Specifically, we generated full-transcriptome microarray profiles of plants with (a) genetically strongly reduced and (b) pharmacologically vastly increased vascular tissues and identified a reproducible cohort of 158 transcripts that fulfilled the dual requirement of being underrepresented in (a) and overrepresented in (b). In order to assess the predictive value of our identification scheme for vascular gene expression, we determined the expression patterns of genes in two unbiased subsamples. First, we assessed the expression patterns of all twenty annotated transcription factor genes from the cohort of 158 genes and found that seventeen of the twenty genes were preferentially expressed in leaf vascular cells. Remarkably, fifteen of these seventeen vascular genes were clearly expressed already very early in leaf vein development. Twelve genes with published leaf expression patterns served as a second subsample to monitor the representation of vascular genes in our cohort. Of those twelve genes, eleven were preferentially expressed in leaf vascular tissues. Based on these results we propose that our compendium of 158 genes represents a sample that is highly enriched for genes expressed in vascular tissues and that our approach is particularly suited to detect genes expressed in vascular cell lineages at early stages of their inception.

  10. [Estrogens and vascular thrombosis].

    PubMed

    Colmou, A

    1982-09-01

    The incidence of thromboses among young women has increased with widespread use of oral contraceptives (OCs) due to the significant thromboembolic risk of estrogen. Estrogens intervene at the vascular, platelet, and plasma levels as a function of hormonal variations in the menstrual cycle, increasing the aggregability of the platelets and thrombocytes, accelerating the formation of clots, and decreasing the amount of antithrombin III. Estrogens are used in medicine to treat breast and prostate cancers and in gynecology to treat dysmenorrhea, during the menopause, and in contraception. Smoking, cardiovascular disease and hypertension, hypercholesterolemia, and diabetes are contraindicators to estrogen use. Thrombosis refers to blockage of a blood vessel by a clot or thrombus. Before estrogens are prescribed, a history of phlebitis, obesity, hyperlipidemia, or significant varicosities should be ruled out. A history of venous thrombosis, hyperlipoproteinemia, breast nodules, serious liver condition, allergies to progesterone, and some ocular diseases of vascular origin definitively rule out treatment with estrogens. A family history of infarct, embolism, diabetes, cancer, or vascular accidents at a young age signals a need for greater patient surveillance. All patients receiving estrogens should be carefully observed for signs of hypertension, hypercholesterolemia, hypercoagulability, or diabetes. Nurses have a role to play in carefully eliciting the patient's history of smoking, personal and family medical problems, and previous and current laboratory results, as well as in informing the patients of the risks and possible side effects of OCs, especially for those who smoke. Nurses should educate patients receiving estrogens, especially those with histories of circulatory problems, to avoid standing in 1 position for prolonged periods, avoid heat which is a vasodilator, avoid obesity, excercise regularly, wear appropriate footgear, and follow other good health

  11. Nanoengineering of therapeutics for retinal vascular disease.

    PubMed

    Gahlaut, Nivriti; Suarez, Sandra; Uddin, Md Imam; Gordon, Andrew Y; Evans, Stephanie M; Jayagopal, Ashwath

    2015-09-01

    Retinal vascular diseases, including diabetic retinopathy, neovascular age related macular degeneration, and retinal vein occlusion, are leading causes of blindness in the Western world. These diseases share several common disease mechanisms, including vascular endothelial growth factor (VEGF) signaling, hypoxia, and inflammation, which provide opportunities for common therapeutic strategies. Treatment of these diseases using laser therapy, anti-VEGF injections, and/or steroids has significantly improved clinical outcomes. However, these strategies do not address the underlying root causes of pathology, and may have deleterious side effects. Furthermore, many patients continue to progress toward legal blindness despite receiving regular therapy. Nanomedicine, the engineering of therapeutics at the 1-100 nm scale, is a promising approach for improving clinical management of retinal vascular diseases. Nanomedicine-based technologies have the potential to revolutionize the treatment of ophthalmology, through enabling sustained release of drugs over several months, reducing side effects due to specific targeting of dysfunctional cells, and interfacing with currently "undruggable" targets. We will discuss emerging nanomedicine-based applications for the treatment of complications associated with retinal vascular diseases, including angiogenesis and inflammation.

  12. Endothelial cell dynamics in vascular remodelling.

    PubMed

    Barbacena, Pedro; Carvalho, Joana R; Franco, Claudio A

    2016-01-01

    In this ESCHM 2016 conference talk report, we summarise two recently published original articles Franco et al. PLoS Biology 2015 and Franco et al. eLIFE 2016. The vascular network undergoes extensive vessel remodelling to become fully functional. Is it well established that blood flow is a main driver for vascular remodelling. It has also been proposed that vessel pruning is a central process within physiological vessel remodelling. However, despite its central function, the cellular and molecular mechanisms regulating vessel regression, and their interaction with blood flow patterns, remain largely unexplained. We investigated the cellular process governing developmental vascular remodelling in mouse and zebrafish. We established that polarised reorganization of endothelial cells is at the core of vessel regression, representing vessel anastomosis in reverse. Moreover, we established for the first time an axial polarity map for all endothelial cells together with an in silico method for the computation of the haemodynamic forces in the murine retinal vasculature. Using network-level analysis and microfluidics, we showed that endothelial non-canonical Wnt signalling regulates endothelial sensitivity to shear forces. Loss of Wnt5a/11 renders endothelial cells more sensitive to shear, resulting in axial polarisation at lower shear stress levels. Collectively our data suggest that non-canonical Wnt signalling stabilizes forming vascular networks by reducing endothelial shear sensitivity, thus keeping vessels open under low flow conditions that prevail in the primitive plexus.

  13. Distinct vascular conduction with cortical spreading depression.

    PubMed

    Brennan, Kevin C; Beltrán-Parrazal, Luis; López-Valdés, Hector E; Theriot, Jeremy; Toga, Arthur W; Charles, Andrew C

    2007-06-01

    Cortical spreading depression (CSD) is associated with significant vasodilatation and vasoconstriction, but the relationship between the cortical parenchymal and vascular phenomena remains poorly understood. We used optical intrinsic signal (OIS) imaging and electrophysiology to simultaneously examine the vascular and parenchymal changes that occur with CSD in anesthetized mice and rats. CSD was associated with a propagated multiphasic change in optical reflectance, with correlated negative DC shift in field potential. Dilatation of cortical surface arterioles propagated with a significantly greater intrinsic velocity than the parenchymal CSD wavefront measured by OIS and electrophysiology. Dilatation traveled in a circuitous pattern along individual arterioles, indicating specific vascular conduction as opposed to concentric propagation of a parenchymal signal. Arteriolar dilatation propagated into areas beyond the spread of parenchymal OIS and electrophysiological changes of CSD. Conversely, vasomotor activity could be experimentally dissociated from the parenchymal CSD wave. Frequent repetitive CSD evoked by continuous stimulation was associated with a reduced or absent arteriolar response despite preserved parenchymal OIS and electrophysiological changes. Similarly, dimethylsulfoxide at high concentrations (10%) inhibited arteriolar reactivity despite preserved parenchymal OIS and electrophysiological changes. These results suggest a mechanism, intrinsic to the vasculature, for propagation of vasodilatation associated with CSD. Distinct vascular conduction could be important for the pathogenesis of conditions that involve CSD, including migraine, stroke, and traumatic brain injury.

  14. Protein Kinase C Inhibitors as Modulators of Vascular Function and Their Application in Vascular Disease

    PubMed Central

    Khalil, Raouf A.

    2013-01-01

    Blood pressure (BP) is regulated by multiple neuronal, hormonal, renal and vascular control mechanisms. Changes in signaling mechanisms in the endothelium, vascular smooth muscle (VSM) and extracellular matrix cause alterations in vascular tone and blood vessel remodeling and may lead to persistent increases in vascular resistance and hypertension (HTN). In VSM, activation of surface receptors by vasoconstrictor stimuli causes an increase in intracellular free Ca2+ concentration ([Ca2+]i), which forms a complex with calmodulin, activates myosin light chain (MLC) kinase and leads to MLC phosphorylation, actin-myosin interaction and VSM contraction. Vasoconstrictor agonists could also increase the production of diacylglycerol which activates protein kinase C (PKC). PKC is a family of Ca2+-dependent and Ca2+-independent isozymes that have different distributions in various blood vessels, and undergo translocation from the cytosol to the plasma membrane, cytoskeleton or the nucleus during cell activation. In VSM, PKC translocation to the cell surface may trigger a cascade of biochemical events leading to activation of mitogen-activated protein kinase (MAPK) and MAPK kinase (MEK), a pathway that ultimately increases the myofilament force sensitivity to [Ca2+]i, and enhances actin-myosin interaction and VSM contraction. PKC translocation to the nucleus may induce transactivation of various genes and promote VSM growth and proliferation. PKC could also affect endothelium-derived relaxing and contracting factors as well as matrix metalloproteinases (MMPs) in the extracellular matrix further affecting vascular reactivity and remodeling. In addition to vasoactive factors, reactive oxygen species, inflammatory cytokines and other metabolic factors could affect PKC activity. Increased PKC expression and activity have been observed in vascular disease and in certain forms of experimental and human HTN. Targeting of vascular PKC using PKC inhibitors may function in concert with

  15. Protein Kinase C Inhibitors as Modulators of Vascular Function and their Application in Vascular Disease.

    PubMed

    Khalil, Raouf A

    2013-01-01

    Blood pressure (BP) is regulated by multiple neuronal, hormonal, renal and vascular control mechanisms. Changes in signaling mechanisms in the endothelium, vascular smooth muscle (VSM) and extracellular matrix cause alterations in vascular tone and blood vessel remodeling and may lead to persistent increases in vascular resistance and hypertension (HTN). In VSM, activation of surface receptors by vasoconstrictor stimuli causes an increase in intracellular free Ca(2+) concentration ([Ca(2+)]i), which forms a complex with calmodulin, activates myosin light chain (MLC) kinase and leads to MLC phosphorylation, actin-myosin interaction and VSM contraction. Vasoconstrictor agonists could also increase the production of diacylglycerol which activates protein kinase C (PKC). PKC is a family of Ca(2+)-dependent and Ca(2+)-independent isozymes that have different distributions in various blood vessels, and undergo translocation from the cytosol to the plasma membrane, cytoskeleton or the nucleus during cell activation. In VSM, PKC translocation to the cell surface may trigger a cascade of biochemical events leading to activation of mitogen-activated protein kinase (MAPK) and MAPK kinase (MEK), a pathway that ultimately increases the myofilament force sensitivity to [Ca(2+)]i, and enhances actin-myosin interaction and VSM contraction. PKC translocation to the nucleus may induce transactivation of various genes and promote VSM growth and proliferation. PKC could also affect endothelium-derived relaxing and contracting factors as well as matrix metalloproteinase (MMPs) in the extracellular matrix further affecting vascular reactivity and remodeling. In addition to vasoactive factors, reactive oxygen species, inflammatory cytokines and other metabolic factors could affect PKC activity. Increased PKC expression and activity have been observed in vascular disease and in certain forms of experimental and human HTN. Targeting of vascular PKC using PKC inhibitors may function in

  16. [Cervical vascular penetrating trauma].

    PubMed

    Etl, S; Hafer, G; Mundinger, A

    2000-01-01

    The case of a 25 year old male with a stab wound of common carotid artery and the internal jugular vein is reported. He was admitted in severe hemorrhagic shock and immediately treated successfully by arterial reconstruction by means of a venous patch. Mild, declining neurological deficits correlated in magnetic resonance imaging with disturbances in the perfusion area of the medial cerebral artery. A survey of the literature shows that the fast repair of the carotid artery is clearly to be given preference to ligature. First can be executed successfully in exceptional emergency cases also by non-carotid surgeons, if basic vascular-surgical techniques are controlled.

  17. Mechanics of Vascular Smooth Muscle.

    PubMed

    Ratz, Paul H

    2015-12-15

    Vascular smooth muscle (VSM; see Table 1 for a list of abbreviations) is a heterogeneous biomaterial comprised of cells and extracellular matrix. By surrounding tubes of endothelial cells, VSM forms a regulated network, the vasculature, through which oxygenated blood supplies specialized organs, permitting the development of large multicellular organisms. VSM cells, the engine of the vasculature, house a set of regulated nanomotors that permit rapid stress-development, sustained stress-maintenance and vessel constriction. Viscoelastic materials within, surrounding and attached to VSM cells, comprised largely of polymeric proteins with complex mechanical characteristics, assist the engine with countering loads imposed by the heart pump, and with control of relengthening after constriction. The complexity of this smart material can be reduced by classical mechanical studies combined with circuit modeling using spring and dashpot elements. Evaluation of the mechanical characteristics of VSM requires a more complete understanding of the mechanics and regulation of its biochemical parts, and ultimately, an understanding of how these parts work together to form the machinery of the vascular tree. Current molecular studies provide detailed mechanical data about single polymeric molecules, revealing viscoelasticity and plasticity at the protein domain level, the unique biological slip-catch bond, and a regulated two-step actomyosin power stroke. At the tissue level, new insight into acutely dynamic stress-strain behavior reveals smooth muscle to exhibit adaptive plasticity. At its core, physiology aims to describe the complex interactions of molecular systems, clarifying structure-function relationships and regulation of biological machines. The intent of this review is to provide a comprehensive presentation of one biomachine, VSM.

  18. Digital fluoroscopy as a valuable adjunct to open vascular operations.

    PubMed

    Lipsitz, Evan C; Veith, Frank J; Wain, Reese A

    2003-12-01

    The increasing availability of and vascular surgeons' familiarity with digital cine-fluoroscopy in the operating room has been facilitated by the advent and growing popularity of endovascular aortoiliac aneurysm repair and other endovascular techniques that are being incorporated into vascular surgical practice. Digital cine-fluoroscopy can also be used as a valuable adjunct to standard open vascular procedures in several ways including: performance of completion angiography, fluoroscopically-assisted thromboembolectomy, intraoperative planning angiography, fluoroscopically-guided pressure gradient measurements, achieving vascular control of proximal arteries, intraoperative thrombolysis of compromised outflow tracts, and angioplasty and stenting of lesions detected intraoperatively. These techniques can improve the outcome of standard vascular procedures by permitting the identification of inflow, outflow, conduit, and anastomotic defects intraoperatively and guiding their repair. Additionally, in many cases they can reduce the amount of exposure required, reduce intraoperative blood loss, and minimize trauma to vessels during thrombectomy. Fluoroscopic guidance can facilitate and improve these and other aspects of standard open vascular procedures. Conversely, the ability to perform open interventions can facilitate the performance of many endovascular interventions. It is becoming increasingly important to be facile with both open and E fluoroscopically guided techniques in order to fully treat the spectrum of vascular disease in an optimum fashion.

  19. Association of miRNA-145 expression in vascular smooth muscle cells with vascular damages in patients with lupus nephritis.

    PubMed

    Ding, Yan; Liao, Wang; Yi, Zhuwen; Xiang, Wei; He, Xiaojie

    2015-01-01

    miRNAs have been found to contribute to the regulation of multiple cellular processes, including cell apoptosis, differentiation and proliferation. The patients with lupus nephritis (LN) exhibit thickened renal vascular membrane and highly proliferative vascular smooth muscle cells (VSMCs). Of various miRNAs discovered, miR-145 is essential to mediate the proliferation of VSMCs and the formation of atherosclerotic plaques. In this study, we studied the pathological and vascular damage of renal LN, and the correlation between miR-145 expression in VSMCs and the vascular damages. Serum, urine, and renal biopsies were obtained from 41 patients with active LN. The serum and urinary VEGF levels were examined to confirm the renal damage of each patient. Biopsies were stained to observe the glomerular segmental lesions, sclerosis, and to evaluate the vascular damages. The expression of miR-145 was also examined to determine the correlation between its expression and the vascular damages. The expression of miR-145 was mainly detected in the renal VSMCs and the epithelial cells of glomerular proximal convoluted tubule. Nevertheless, the expression of miR-145 reduced as the tunicae media vasorum ratios increased, indicating the development of LN inhibits the expression of miR-145. Furthermore, our studies revealed no significant correlation among renal interstitial vascular damage, glomerular damage and severity classification of LN. Therefore, we suggest the damage of renal interstitial vascular should be considered as one of the factors to evaluate the severity of the LN.

  20. Cytoglobin regulates blood pressure and vascular tone through nitric oxide metabolism in the vascular wall

    NASA Astrophysics Data System (ADS)

    Liu, Xiaoping; El-Mahdy, Mohamed A.; Boslett, James; Varadharaj, Saradhadevi; Hemann, Craig; Abdelghany, Tamer M.; Ismail, Raed S.; Little, Sean C.; Zhou, Danlei; Thuy, Le Thi Thanh; Kawada, Norifumi; Zweier, Jay L.

    2017-04-01

    The identity of the specific nitric oxide dioxygenase (NOD) that serves as the main in vivo regulator of O2-dependent NO degradation in smooth muscle remains elusive. Cytoglobin (Cygb) is a recently discovered globin expressed in fibroblasts and smooth muscle cells with unknown function. Cygb, coupled with a cellular reducing system, efficiently regulates the rate of NO consumption by metabolizing NO in an O2-dependent manner with decreased NO consumption in physiological hypoxia. Here we show that Cygb is a major regulator of NO degradation and cardiovascular tone. Knockout of Cygb greatly prolongs NO decay, increases vascular relaxation, and lowers blood pressure and systemic vascular resistance. We further demonstrate that downregulation of Cygb prevents angiotensin-mediated hypertension. Thus, Cygb has a critical role in the regulation of vascular tone and disease. We suggest that modulation of the expression and NOD activity of Cygb represents a strategy for the treatment of cardiovascular disease.

  1. Cytoglobin regulates blood pressure and vascular tone through nitric oxide metabolism in the vascular wall

    PubMed Central

    Liu, Xiaoping; El-Mahdy, Mohamed A.; Boslett, James; Varadharaj, Saradhadevi; Hemann, Craig; Abdelghany, Tamer M.; Ismail, Raed S.; Little, Sean C.; Zhou, Danlei; Thuy, Le Thi Thanh; Kawada, Norifumi; Zweier, Jay L.

    2017-01-01

    The identity of the specific nitric oxide dioxygenase (NOD) that serves as the main in vivo regulator of O2-dependent NO degradation in smooth muscle remains elusive. Cytoglobin (Cygb) is a recently discovered globin expressed in fibroblasts and smooth muscle cells with unknown function. Cygb, coupled with a cellular reducing system, efficiently regulates the rate of NO consumption by metabolizing NO in an O2-dependent manner with decreased NO consumption in physiological hypoxia. Here we show that Cygb is a major regulator of NO degradation and cardiovascular tone. Knockout of Cygb greatly prolongs NO decay, increases vascular relaxation, and lowers blood pressure and systemic vascular resistance. We further demonstrate that downregulation of Cygb prevents angiotensin-mediated hypertension. Thus, Cygb has a critical role in the regulation of vascular tone and disease. We suggest that modulation of the expression and NOD activity of Cygb represents a strategy for the treatment of cardiovascular disease. PMID:28393874

  2. The pathobiology of vascular dementia

    PubMed Central

    Iadecola, Costantino

    2013-01-01

    Vascular cognitive impairment defines alterations in cognition, ranging from subtle deficits to full-blown dementia, attributable to cerebrovascular causes. Often coexisting with Alzheimer’s disease, mixed vascular and neurodegenerative dementia has emerged as the leading cause of age-related cognitive impairment. Central to the disease mechanism is the crucial role that cerebral blood vessels play in brain health, not only for the delivery of oxygen and nutrients, but also for the trophic signaling that links inextricably the well being of neurons and glia to that of cerebrovascular cells. This review will examine how vascular damage disrupts these vital homeostatic interactions, focusing on the hemispheric white matter, a region at heightened risk for vascular damage, and on the interplay between vascular factors and Alzheimer’s disease. Finally, preventative and therapeutic prospects will be examined, highlighting the importance of midlife vascular risk factor control in the prevention of late-life dementia. PMID:24267647

  3. Determination of the optical properties of vascular tissues: potential applications in vascular-targeting photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Tian, Yongbin; Chen, Ping; Lin, Lie; Huang, Zheng; Tang, Guoqing; Xu, Heping

    2007-11-01

    It has been proven that photodynamic therapy (PDT) is effective in treating various malignant and non-malignant diseases. In the treatment of certain non-malignant vascular diseases, such as wet age-related macular degeneration (AMD) and port wine stains (PWS), unlike in the treatment of malignant solid tumors, light irradiation usually starts immediately after the intravenous (IV) injection of photosensitizers while the photosensitizers is mainly circulating inside blood vessels. Under such vascular-targeting action mode, photoreactions between photosensitizers and light can selectively destruct the vascular tissues. Light distribution is complex so that it is important to understand the optical properties of targeted vessels and surrounding tissues. To better determine the optical properties of vascular tissues, we developed a tissue-simulating phantom and adopted frequency-domain measurement of phase difference. Absorption and reduced scattering coefficients in blood vessels were estimated and light distribution was simulated by the Monte Carlo method. These determinations are essential for the implication of better light dosimetry models in clinical photodynamic therapy and vascular-targeting PDT, in particular.

  4. Vascular Distribution of Nanomaterials

    PubMed Central

    Stapleton, Phoebe A.; Nurkiewicz, Timothy R.

    2014-01-01

    Once considered primarily occupational, novel nanotechnology innovation and application has led to widespread domestic use and intentional biomedical exposures. With these exciting advances, the breadth and depth of toxicological considerations must also be expanded. The vascular system interacts with every tissue in the body, striving to homeostasis. Engineered nanomaterials (ENM) have been reported to distribute in many different organs and tissues. However, these observations have tended to use approaches requiring tissue homogenization and/or gross organ analyses. These techniques, while effective in establishing presence, preclude an exact determination of where ENM are deposited within a tissue. It is necessary to identify this exact distribution and deposition of ENM throughout the cardiovascular system, with respect to vascular hemodynamics and in vivo/ in vitro ENM modifications taken into account if nanotechnology is to achieve its full potential. Distinct levels of the vasculature will first be described as individual compartments. Then the vasculature will be considered as a whole. These unique compartments and biophysical conditions will be discussed in terms of their propensity to favor ENM deposition. Understanding levels of the vasculature will also be discussed. Ultimately, future studies must verify the mechanisms speculated on and presented herein. PMID:24777845

  5. History of vascular access.

    PubMed

    Dudrick, Stanley J

    2006-01-01

    Milestones in the history of the development of vascular access and the subsequent advances in practical clinical applications of the knowledge, techniques, technology, and experience to the beneficial management of a variety of patients are described. The original achievements are presented and briefly discussed primarily, but not exclusively, in relationship to the successful development of parenteral nutrition (PN). Beginning with the discovery of the circulation of blood, landmark events, resulting from astute observations, experimentation, and ingenious technological advances, are summarized or outlined chronologically over the past 4 centuries, with emphasis on the many recent accomplishments of basic and clinical scientists during the past 6 decades. Brief descriptions of several seminal contributions to safe and effective IV access, management, and therapy acknowledge and recognize the historical highlights that have allowed a complex and potentially hazardous therapeutic modality to evolve into a commonly applied useful adjunct to our current inpatient and outpatient armamentarium. A comprehensive list of references documents the highlights of the development of vascular access for the student of history.

  6. Tumoral and Choroidal Vascularization

    PubMed Central

    Jost, Maud; Maillard, Catherine; Lecomte, Julie; Lambert, Vincent; Tjwa, Marc; Blaise, Pierre; Alvarez Gonzalez, Maria-Luz; Bajou, Khalid; Blacher, Silvia; Motte, Patrick; Humblet, Chantal; Defresne, Marie Paule; Thiry, Marc; Frankenne, Francis; Gothot, André; Carmeliet, Peter; Rakic, Jean-Marie; Foidart, Jean-Michel; Noël, Agnès

    2007-01-01

    An adequate balance between serine proteases and their plasminogen activator inhibitor-1 (PAI-1) is critical for pathological angiogenesis. PAI-1 deficiency in mice is associated with impaired choroidal neovascularization (CNV) and tumoral angiogenesis. In the present work, we demonstrate unexpected differences in the contribution of bone marrow (BM)-derived cells in these two processes regulated by PAI-1. PAI-1−/− mice grafted with BM-derived from wild-type mice were able to support laser-induced CNV formation but not skin carcinoma vascularization. Engraftment of irradiated wild-type mice with PAI-1−/− BM prevented CNV formation, demonstrating the crucial role of PAI-1 delivered by BM-derived cells. In contrast, the transient infiltration of tumor transplants by local PAI-1-producing host cells rather than by BM cells was sufficient to rescue tumor growth and angiogenesis in PAI-1-deficient mice. These data identify PAI-1 as a molecular determinant of a local permissive soil for tumor angiogenesis. Altogether, the present study demonstrates that different cellular mechanisms contribute to PAI-1-regulated tumoral and CNV. PAI-1 contributes to BM-dependent choroidal vascularization and to BM-independent tumor growth and angiogenesis. PMID:17717143

  7. Anaesthesia for vascular emergencies.

    PubMed

    Ellard, L; Djaiani, G

    2013-01-01

    Patients presenting with vascular emergencies including acute aortic syndrome, ruptured thoracic or abdominal aortic aneurysms, thoracic aortic trauma and acute lower limb ischaemia have a high risk of peri-operative morbidity and mortality. Although anatomical suitability is not universal, endovascular surgery may improve mortality and the results of ongoing randomised controlled trials are awaited. Permissive hypotension pre-operatively should be the standard of care with the systolic blood pressure kept to 50-100 mmHg as long as consciousness is maintained. The benefit of local anaesthesia over general anaesthesia is not definitive and this decision should be tailored for a given patient and circumstance. Cerebrospinal fluid drainage for prevention of paraplegia is often impractical in the emergency setting and is not backed by strong evidence; however, it should be considered postoperatively if symptoms develop. We discuss the pertinent anaesthetic issues when a patient presents with a vascular emergency and the impact that endovascular repair has on anaesthetic management. Anaesthesia © 2012 The Association of Anaesthetists of Great Britain and Ireland.

  8. Vascular-derived kinins and local control of vascular tone.

    PubMed

    Nolly, H; Damiani, M T; Miatello, R

    1994-08-01

    The vascular wall itself, through a complex interplay of endocrine, neurocrine and autoparacrine mechanisms, plays an active role in vascular homeostasis. The endothelial cell senses humoral and hemodynamic changes and responds by secreting a variety of metabolically active substances that act locally causing either vasodilatation or vasoconstriction. Kallikrein (KK) and the mRNA for KK are present in arteries and veins. Vascular KK releases kinins from kininogen which circulate in plasma and is also present in vascular tissue. Vascular-derived kinins induce vasodilatation through the release of endothelial compounds (prostacyclin, EDRFs and cytochrome P-450). Disturbance in the delicate balance between vasodilators and vasoconstrictors may play a role in the development of hypertension. Vascular kallikrein (VKK) was significantly (P < 0.05) elevated after 2 weeks of development of renovascular and mineralocorticoid hypertension, and blood pressure was only slightly elevated. However, VKK decreased in both experimental models when blood pressure was increased. It is possible that the increase in VKK in the early stages resulted in increased local vasodilatory activity, thus counteracting the rise in blood pressure. As hypertension developed, KK was significantly decreased in arteries. The decrease in arterial KK during established hypertension is most likely secondary to high blood pressure. When the endothelium is damaged by high blood pressure, diabetes, excessive LDL cholesterol or cigarette smoking, a net imbalance favoring vasoconstriction, proliferation and migration of cells and increased lipid deposition predisposes to specific vascular diseases. Converting enzyme inhibitors (CEI) blunt the proliferative response of vascular smooth muscle cells after endothelial injury. The cardiovascular protective effects of CEI are mediated in part by the antihypertrophic, antihyperplastic and antithrombotic effects of kinins. The vascular kallikrein-kinin system has a

  9. Vascular restenosis - striving for therapy.

    PubMed

    Schiele, Thomas M; Krötz, Florian; Klauss, Volker

    2004-11-01

    Restenosis is the limiting entity following coronary angioplasty. It is associated with significant morbidity, mortality and cost, and thus represents a major clinical and economical problem. Despite technical improvements, restenosis after conventional balloon angioplasty occurs in 30 - 60% of cases. Coronary stenting was able to reduce the incidence by approximately 30%; nevertheless, some 250,000 patients experience in-stent restenotic lesions/year worldwide. In-stent restenosis has been recognised as very difficult to manage, with a repeat restenosis rate of 50%, regardless of the angioplasty device used. So far, only vascular brachytherapy has convincingly reduced the incidence of repeat in-stent restenosis (by 50%) and thus, has emerged as the gold standard of therapy. The introduction of drug-eluting stents has shown a great deal of promise for the treatment of both de novo and restenotic lesions, with reported restenosis rates of < 10%, and benefit for virtually all patient subsets at a higher risk of restenosis. This review outlines the pathophysiology, epidemiology and predictors of the restenosis process, and places emphasis on the various treatment options for its prevention and therapy.

  10. Vascular pattern formation in plants.

    PubMed

    Scarpella, Enrico; Helariutta, Ykä

    2010-01-01

    Reticulate tissue systems exist in most multicellular organisms, and the principles underlying the formation of cellular networks have fascinated philosophers, mathematicians, and biologists for centuries. In particular, the beautiful and varied arrangements of vascular tissues in plants have intrigued mankind since antiquity, yet the organizing signals have remained elusive. Plant vascular tissues form systems of interconnected cell files throughout the plant body. Vascular cells are aligned with one another along continuous lines, and vascular tissues differentiate at reproducible positions within organ environments. However, neither the precise path of vascular differentiation nor the exact geometry of vascular networks is fixed or immutable. Several recent advances converge to reconcile the seemingly conflicting predictability and plasticity of vascular tissue patterns. A control mechanism in which an apical-basal flow of signal establishes a basic coordinate system for body axis formation and vascular strand differentiation, and in which a superimposed level of radial organizing cues elaborates cell patterns, would generate a reproducible tissue configuration in the context of an underlying robust, self-organizing structure, and account for the simultaneous regularity and flexibility of vascular tissue patterns.

  11. Vascular cognitive impairment and dementia

    PubMed Central

    Gorelick, Philip B.; Counts, Scott E.; Nyenhuis, David

    2016-01-01

    Vascular contributions to cognitive impairment are receiving heightened attention as potentially modifiable factors for dementias of later life. These factors have now been linked not only to vascular cognitive disorders but also Alzheimer’s disease. In this chapter we review 3 related topics that address vascular contributions to cognitive impairment: 1. vascular pathogenesis and mechanisms; 2. neuropsychological and neuroimaging phenotypic manifestations of cerebrovascular disease; and 3. prospects for prevention of cognitive impairment of later life based on cardiovascular and stroke risk modification.1 PMID:26704177

  12. Placental Vascular Tree as Biomarker of Autism/ASD Risk

    DTIC Science & Technology

    2012-09-01

    Risk Longitudinal Investigation (EARLI, high-autism risk) placentas compared 76 unselected National Children’s Study (NCS) placentas . Using methods...unique to our team to quantify vascular network structure, we have demonstrated, in summary, that EARLI placentas as a group show significant placental...vascular points and reduced mean vessel caliber as compared to NCS placentas . In addition, in EARLI placentas as a group, chorionic surface arteries, but

  13. Development of a clinical prediction rule to improve peripheral intravenous cannulae first attempt success in the emergency department and reduce post insertion failure rates: the Vascular Access Decisions in the Emergency Room (VADER) study protocol

    PubMed Central

    Carr, Peter J; Rippey, James C R; Cooke, Marie L; Bharat, Chrianna; Murray, Kevin; Higgins, Niall S; Foale, Aileen; Rickard, Claire M

    2016-01-01

    Introduction Peripheral intravenous cannula (PIVC) insertion is one of the most common clinical interventions performed in emergency care worldwide. However, factors associated with successful PIVC placement and maintenance are not well understood. This study seeks to determine the predictors of first time PIVC insertion success in emergency department (ED) and identify the rationale for removal of the ED inserted PIVC in patients admitted to the hospital ward. Reducing failed insertion attempts and improving peripheral intravenous cannulation practice could lead to better staff and patient experiences, as well as improving hospital efficiency. Methods and analysis We propose an observational cohort study of PIVC insertions in a patient population presenting to ED, with follow-up observation of the PIVC in subsequent admissions to the hospital ward. We will collect specific PIVC observational data such as; clinician factors, patient factors, device information and clinical practice variables. Trained researchers will gather ED PIVC insertion data to identify predictors of insertion success. In those admitted from the ED, we will determine the dwell time of the ED-inserted PIVC. Multivariate regression analyses will be used to identify factors associated with insertions success and PIVC failure and standard statistical validation techniques will be used to create and assess the effectiveness of a clinical predication rule. Ethics and dissemination The findings of our study will provide new evidence to improve insertion success rates in the ED setting and identify strategies to reduce premature device failure for patients admitted to hospital wards. Results will unravel a complexity of factors that contribute to unsuccessful PIVC attempts such as patient and clinician factors along with the products, technologies and infusates used. Trial registration number ACTRN12615000588594; Pre-results. PMID:26868942

  14. Chemerin Regulates Crosstalk Between Adipocytes and Vascular Cells Through Nox.

    PubMed

    Neves, Karla Bianca; Nguyen Dinh Cat, Aurelie; Lopes, Rheure Alves Moreira; Rios, Francisco Jose; Anagnostopoulou, Aikaterini; Lobato, Nubia Souza; de Oliveira, Ana Maria; Tostes, Rita C; Montezano, Augusto C; Touyz, Rhian M

    2015-09-01

    Adipocytes produce adipokines, including chemerin, a chemoattractant that mediates effects through its ChemR23 receptor. Chemerin has been linked to endothelial dysfunction and vascular injury in pathological conditions, such as obesity, diabetes mellitus, and hypertension. Molecular mechanisms underlying this are elusive. Here we assessed whether chemerin through redox-sensitive signaling influences molecular processes associated with vascular growth, apoptosis, and inflammation. Human microvascular endothelial cells and vascular smooth muscle cells were stimulated with chemerin (50 ng/mL). Chemerin increased generation of reactive oxygen species and phosphorylation of mitogen-activated protein kinases, effects that were inhibited by ML171, GKT137831 (Nox inhibitors), and N-acetylcysteine (reactive oxygen species scavenger). Chemerin increased mRNA expression of proinflammatory mediators in vascular cells and increased monocyte-to-endothelial cell attachment. In human vascular smooth muscle cells, chemerin induced phosphorylation of mitogen-activated protein kinases and stimulated proliferation (increased proliferating cell nuclear antigen expression [proliferation marker] and BrdU incorporation [proliferation assay]). Chemerin decreased phosphatidylinositol 3-kinase/protein kinase B activation and increased TUNEL-positive human vascular smooth muscle cells. In human microvascular endothelial cells, chemerin reduced endothelial nitric oxide synthase activity and nitric oxide production. Adipocyte-conditioned medium from obese/diabetic mice (db/db), which have elevated chemerin levels, increased reactive oxygen species generation in vascular smooth muscle cells, whereas adipocyte-conditioned medium from control mice had no effect. Chemerin actions were blocked by CCX 832, a ChemR23 inhibitor. Our data demonstrate that chemerin, through Nox activation and redox-sensitive mitogen-activated protein kinases signaling, exerts proapoptotic, proinflammatory, and

  15. Additive Manufacturing of Vascular Grafts and Vascularized Tissue Constructs.

    PubMed

    Elomaa, Laura; Yang, Yunzhi Peter

    2017-01-10

    There is a great need for engineered vascular grafts among patients with cardiovascular diseases who are in need of bypass therapy and lack autologous healthy blood vessels. In addition, because of the severe worldwide shortage of organ donors, there is an increasing need for engineered vascularized tissue constructs as an alternative to organ transplants. Additive manufacturing (AM) offers great advantages and flexibility of fabrication of cell-laden, multimaterial, and anatomically shaped vascular grafts and vascularized tissue constructs. Various inkjet-, extrusion-, and photocrosslinking-based AM techniques have been applied to the fabrication of both self-standing vascular grafts and porous, vascularized tissue constructs. This review discusses the state-of-the-art research on the use of AM for vascular applications and the key criteria for biomaterials in the AM of both acellular and cellular constructs. We envision that new smart printing materials that can adapt to their environment and encourage rapid endothelialization and remodeling will be the key factor in the future for the successful AM of personalized and dynamic vascular tissue applications.

  16. Vascular dysfunctions following spinal cord injury

    PubMed Central

    Popa, F; Grigorean, VT; Onose, G; Sandu, AM; Popescu, M; Burnei, G; Strambu, V; Sinescu, C

    2010-01-01

    The aim of this article is to analyze the vascular dysfunctions occurring after spinal cord injury (SCI). Vascular dysfunctions are common complications of SCI. Cardiovascular disturbances are the leading causes of morbidity and mortality in both acute and chronic stages of SCI. Neuroanatomy and physiology of autonomic nervous system, sympathetic and parasympathetic, is reviewed. SCI implies disruption of descendent pathways from central centers to spinal sympathetic neurons, originating in intermediolateral nuclei of T1–L2 cord segments. Loss of supraspinal control over sympathetic nervous system results in reduced overall sympathetic activity below the level of injury and unopposed parasympathetic outflow through intact vagal nerve. SCI associates significant vascular dysfunction. Spinal shock occurs during the acute phase following SCI and it is a transitory suspension of function and reflexes below the level of the injury. Neurogenic shock, part of spinal shock, consists of severe arterial hypotension and bradycardia. Autonomic dysreflexia appears during the chronic phase, after spinal shock resolution, and it is a life–threatening syndrome of massive imbalanced reflex sympathetic discharge occurring in patients with SCI above the splanchnic sympathetic outflow (T5–T6). Arterial hypotension with orthostatic hypotension occurs in both acute and chronic phases. The etiology is multifactorial. We described a few factors influencing the orthostatic hypotension occurrence in SCI: sympathetic nervous system dysfunction, low plasma catecholamine levels, rennin–angiotensin–aldosterone activity, peripheral alpha–adrenoceptor hyperresponsiveness, impaired function of baroreceptors, hyponatremia and low plasmatic volume, cardiovascular deconditioning, morphologic changes in sympathetic neurons, plasticity within spinal circuits, and motor deficit leading to loss of skeletal muscle pumping activity. Additional associated cardiovascular concerns in SCI, such as

  17. Vascular dysfunctions following spinal cord injury.

    PubMed

    Popa, Constantin; Popa, Florian; Grigorean, Valentin Titus; Onose, Gelu; Sandu, Aurelia Mihaela; Popescu, Mihai; Burnei, Gheorghe; Strambu, Victor; Sinescu, Crina

    2010-01-01

    The aim of this article is to analyze the vascular dysfunctions occurring after spinal cord injury (SCI). Vascular dysfunctions are common complications of SCI. Cardiovascular disturbances are the leading causes of morbidity and mortality in both acute and chronic stages of SCI. Neuroanatomy and physiology of autonomic nervous system, sympathetic and parasympathetic, is reviewed. SCI implies disruption of descendent pathways from central centers to spinal sympathetic neurons, originating in intermediolateral nuclei of T1-L2 cord segments. Loss of supraspinal control over sympathetic nervous system results in reduced overall sympathetic activity below the level of injury and unopposed parasympathetic outflow through intact vagal nerve. SCI associates significant vascular dysfunction. Spinal shock occurs during the acute phase following SCI and it is a transitory suspension of function and reflexes below the level of the injury. Neurogenic shock, part of spinal shock, consists of severe arterial hypotension and bradycardia. Autonomic dysreflexia appears during the chronic phase, after spinal shock resolution, and it is a life-threatening syndrome of massive imbalanced reflex sympathetic discharge occurring in patients with SCI above the splanchnic sympathetic outflow (T5-T6). Arterial hypotension with orthostatic hypotension occurs in both acute and chronic phases. The etiology is multifactorial. We described a few factors influencing the orthostatic hypotension occurrence in SCI: sympathetic nervous system dysfunction, low plasma catecholamine levels, rennin-angiotensin-aldosterone activity, peripheral alpha-adrenoceptor hyperresponsiveness, impaired function of baroreceptors, hyponatremia and low plasmatic volume, cardiovascular deconditioning, morphologic changes in sympathetic neurons, plasticity within spinal circuits, and motor deficit leading to loss of skeletal muscle pumping activity. Additional associated cardiovascular concerns in SCI, such as deep vein

  18. Mediterranean Diet, Alzheimer Disease, and Vascular Mediation

    PubMed Central

    Scarmeas, Nikolaos; Stern, Yaakov; Mayeux, Richard; Luchsinger, Jose A.

    2011-01-01

    Objectives To examine the association between the Mediterranean diet (MeDi) and Alzheimer disease (AD) in a different AD population and to investigate possible mediation by vascular pathways. Design, Setting, Patients, and Main Outcome Measures A case-control study nested within a community-based cohort in New York, NY. Adherence to the MeDi (0- to 9-point scale with higher scores indicating higher adherence) was the main predictor of AD status (194 patients with AD vs 1790 nondemented subjects) in logistic regression models that were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, smoking, medical comorbidity index, and body mass index (calculated as weight in kilograms divided by height in meters squared). We investigated whether there was attenuation of the association between MeDi and AD when vascular variables (stroke, diabetes mellitus, hypertension, heart disease, lipid levels) were simultaneously introduced in the models (which would constitute evidence of mediation). Results Higher adherence to the MeDi was associated with lower risk for AD (odds ratio, 0.76; 95% confidence interval, 0.67–0.87; P<.001). Compared with subjects in the lowest MeDi tertile, subjects in the middle MeDi tertile had an odds ratio of 0.47 (95% confidence interval, 0.29–0.76) and those at the highest tertile an odds ratio of 0.32 (95% confidence interval, 0.17–0.59) for AD (P for trend <.001). Introduction of the vascular variables in the model did not change the magnitude of the association. Conclusions We note once more that higher adherence to the MeDi is associated with a reduced risk for AD. The association does not seem to be mediated by vascular comorbidity. This could be the result of either other biological mechanisms (oxidative or inflammatory) being implicated or measurement error of the vascular variables. PMID:17030648

  19. Mediterranean diet, Alzheimer disease, and vascular mediation.

    PubMed

    Scarmeas, Nikolaos; Stern, Yaakov; Mayeux, Richard; Luchsinger, Jose A

    2006-12-01

    To examine the association between the Mediterranean diet (MeDi) and Alzheimer disease (AD) in a different AD population and to investigate possible mediation by vascular pathways. Design, Setting, Patients, and A case-control study nested within a community-based cohort in New York, NY. Adherence to the MeDi (0- to 9-point scale with higher scores indicating higher adherence) was the main predictor of AD status (194 patients with AD vs 1790 nondemented subjects) in logistic regression models that were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, smoking, medical comorbidity index, and body mass index (calculated as weight in kilograms divided by height in meters squared). We investigated whether there was attenuation of the association between MeDi and AD when vascular variables (stroke, diabetes mellitus, hypertension, heart disease, lipid levels) were simultaneously introduced in the models (which would constitute evidence of mediation). Higher adherence to the MeDi was associated with lower risk for AD (odds ratio, 0.76; 95% confidence interval, 0.67-0.87; P<.001). Compared with subjects in the lowest MeDi tertile, subjects in the middle MeDi tertile had an odds ratio of 0.47 (95% confidence interval, 0.29-0.76) and those at the highest tertile an odds ratio of 0.32 (95% confidence interval, 0.17-0.59) for AD (P for trend <.001). Introduction of the vascular variables in the model did not change the magnitude of the association. We note once more that higher adherence to the MeDi is associated with a reduced risk for AD. The association does not seem to be mediated by vascular comorbidity. This could be the result of either other biological mechanisms (oxidative or inflammatory) being implicated or measurement error of the vascular variables.

  20. (-)-DEPRENYL INHIBITS VASCULAR HYPERPERMEABILITY FOLLOWING HEMORRHAGIC SHOCK

    PubMed Central

    J., Binu Tharakan; Whaley, Greg; Hunter, Felicia A.; Smythe, W. Roy; Childs, Ed W.

    2010-01-01

    Recent studies from our laboratory demonstrated the involvement of endothelial cell reactive oxygen species (ROS) formation and activation of apoptotic signaling in vascular hyperpermeability following hemorrhagic shock (HS). The objective of this study was to determine if (-)-deprenyl, an antioxidant with anti-apoptotic properties would attenuate HS-induced vascular hyperpermeability. In rats, HS was induced by withdrawing blood to reduce the MAP to 40 mmHg for 60 minutes followed by resuscitation for 60 minutes. To study hyperpermeability, the rats were injected with FITC-albumin (50 mg/kg) and the changes in integrated optical intensity of the mesenteric post-capillary venules were obtained intra and extra vascularly utilizing intravital microscopy. Mitochondrial ROS formation and mitochondrial transmembrane potential (ΔΨm) were studied using dihydrorhodamine 123 and JC-1 respectively. Mitochondrial release of cytochrome c was determined using ELISA and caspase-3 activity by a fluorometric assay. Parallel studies were performed in rat lung microvascular endothelial cells (RLMEC) utilizing pro-apoptotic BAK as inducer of hyperpermeability. Hemorrhagic shock induced vascular hyperpermeability, mitochondrial ROS formation, decrease in ΔΨm, release of cytochrome c and caspase-3 activation (p < 0.05). (-)-Deprenyl (0.15 mg/Kg) attenuated all these effects (p < 0.05). Similarly in RLMEC, (-)-deprenyl attenuated BAK peptide induced monolayer hyperpermeability (p < 0.05), ROS formation, decrease in ΔΨm, cytochrome c release (p < 0.05) and activation of caspase-3 (p < 0.05). The protective effects of (-)-deprenyl on vascular barrier functions may be due to its protective effects on ΔΨm thereby preventing mitochondrial release of cytochrome c and caspase-3 mediated disruption of endothelial adherens junctions. PMID:19373132

  1. Functional and molecular mapping of uncoupling between vascular permeability and loss of vascular maturation in ovarian carcinoma xenografts: the role of stroma cells in tumor angiogenesis.

    PubMed

    Gilad, Assaf A; Israely, Tomer; Dafni, Hagit; Meir, Gila; Cohen, Batya; Neeman, Michal

    2005-11-01

    Maintaining homogeneous perfusion in tissues undergoing remodeling and vascular expansion requires tight orchestration of the signals leading to endothelial sprouting and subsequent recruitment of perivascular contractile cells and vascular maturation. This regulation, however, is frequently disrupted in tumors. We previously demonstrated the role of tumor-associated myofibroblasts in vascularization and exit from dormancy of human ovarian carcinoma xenografts in nude mice. The aim of this work was to determine the contribution of stroma- and tumor cell-derived angiogenic growth factors to the heterogeneity of vascular permeability and maturation in MLS human ovarian carcinoma tumors. We show by RT-PCR and by in situ hybridization that VEGF was expressed by the tumor cells, while angiopoietin-1 and -2 were expressed only by the infiltrating host stroma cells. Vascular maturation was detected in vivo by vasoreactivity to hypercapnia, measured by BOLD contrast MRI and validated by immunostaining of histologic sections to alpha-smooth muscle actin. Vascular permeability was measured in vivo by dynamic contrast-enhanced MRI using albumin-based contrast material and validated in histologic sections by fluorescent staining of the biotinylated contrast material. MRI as well as histologic correlation maps between vascular maturation and vascular permeability revealed a wide range of vascular phenotypes, in which the distribution of vascular maturation and vasoreactivity did not overlap spatially with reduced permeability. The large heterogeneity in the degree of vascular maturation and permeability is consistent with the differential expression pattern of VEGF and angiopoietins during tumor angiogenesis.

  2. Role of vascular oxidative stress in obesity and metabolic syndrome.

    PubMed

    Youn, Ji-Youn; Siu, Kin Lung; Lob, Heinrich E; Itani, Hana; Harrison, David G; Cai, Hua

    2014-07-01

    Obesity is associated with vascular diseases that are often attributed to vascular oxidative stress. We tested the hypothesis that vascular oxidative stress could induce obesity. We previously developed mice that overexpress p22phox in vascular smooth muscle, tg(sm/p22phox), which have increased vascular ROS production. At baseline, tg(sm/p22phox) mice have a modest increase in body weight. With high-fat feeding, tg(sm/p22phox) mice developed exaggerated obesity and increased fat mass. Body weight increased from 32.16 ± 2.34 g to 43.03 ± 1.44 g in tg(sm/p22phox) mice (vs. 30.81 ± 0.71 g to 37.89 ± 1.16 g in the WT mice). This was associated with development of glucose intolerance, reduced HDL cholesterol, and increased levels of leptin and MCP-1. Tg(sm/p22phox) mice displayed impaired spontaneous activity and increased mitochondrial ROS production and mitochondrial dysfunction in skeletal muscle. In mice with vascular smooth muscle-targeted deletion of p22phox (p22phox(loxp/loxp)/tg(smmhc/cre) mice), high-fat feeding did not induce weight gain or leptin resistance. These mice also had reduced T-cell infiltration of perivascular fat. In conclusion, these data indicate that vascular oxidative stress induces obesity and metabolic syndrome, accompanied by and likely due to exercise intolerance, vascular inflammation, and augmented adipogenesis. These data indicate that vascular ROS may play a causal role in the development of obesity and metabolic syndrome. © 2014 by the American Diabetes Association.

  3. 219 vascular fellows' perception of the future of vascular surgery.

    PubMed

    Hingorani, Anil P; Ascher, Enrico; Marks, Natalie; Shiferson, Alexander; Puggioni, Alessandra; Tran, Victor; Patel, Nirav; Jacob, Theresa

    2009-01-01

    In an attempt to identify the fellows' concerns about the future of the field of vascular surgery, we conducted a survey consisting of 22 questions at an annual national meeting in March from 2004 to 2007. In order to obtain accurate data, all surveys were kept anonymous. The fellows were asked (1) what type of practice they anticipated they would be in, (2) what the new training paradigm for fellows should be, (3) to assess their expectation of the needed manpower with respect to the demand for vascular surgeons, (4) what were major threats to the future of vascular surgery, (5) whether they had heard of and were in favor of the American Board of Vascular Surgery (ABVS), (6) who should be able to obtain vascular privileges, and (7) about their interest in an association for vascular surgical trainees. Of 273 attendees, 219 (80%) completed the survey. Males made up 87% of those surveyed, and 60% were between the ages of 31 and 35 years. Second-year fellows made up 82% of those surveyed. Those expecting to join a private, academic, or mixed practice made up 35%, 28%, and 20% of the respondents, respectively, with 71% anticipating entering a 100% vascular practice. Forty percent felt that 5 years of general surgery with 2 years of vascular surgery should be the training paradigm, while 45% suggested 3 and 3 years, respectively. A majority, 79%, felt that future demand would exceed the available manpower, while 17% suggested that manpower would meet demand. The major challenges to the future of vascular surgery were felt to be competition from cardiology (82%) or radiology (30%) and lack of an independent board (29%). Seventeen percent were not aware of the ABVS, and only 2% were against it; 71% suggested that vascular privileges be restricted to board-certified vascular surgeons. Seventy-six percent were interested in forming an association for vascular trainees to address the issues of the future job market (67%), endovascular training during fellowship (56

  4. VASCULAR CLOSURE DEVICE FAILURE IN CONTEMPORARY PRACTICE

    PubMed Central

    Vidi, Venkatesan D.; Matheny, Michael E.; Govindarajulu, Usha S.; Normand, Sharon-Lise T.; Robbins, Susan L.; Agarwal, Vikram V.; Bangalore, Sripal; Resnic, Frederic S.

    2012-01-01

    Objectives To assess the frequency and predictors of vascular closure device (VCD) deployment failure, and its association with vascular complications of three commonly used VCDs. Background VCDs are commonly used following percutaneous coronary intervention (PCI) on the basis of studies demonstrating reduced time to ambulation, increased patient comfort, and possible reduction in vascular complications as compared to manual compression. However, limited data are available on the frequency and predictors of VCD failure, and the association of deployment failure with vascular complications. Methods From a de-identified dataset provided by Massachusetts Department of Health, 23,813 consecutive interventional coronary procedures that used either a collagen plug-based (n=18,533) or nitinol clip-based (n=2,284) or suture-based (n=2,996) VCD between 06/2005 and 12/2007 were identified. We defined VCD failure as unsuccessful deployment or failure to achieve immediate access site hemostasis. Results Among 23,813 procedures, VCD failed in 781 (3.3%) procedures (2.1% of collagen plug-based, 6.1% of suture-based, 9.5% of nitinol clip-based). Patients with VCD failure had excess risk of ‘any’ (7.7% versus 2.8%; P<0.001), major (3.3% versus 0.8%; P<0.001), or minor (5.8% versus 2.1%; P<0.001) vascular complications compared with successful VCD deployment. In a propensity-score adjusted analysis, when compared with collagen plug-based VCD (Reference OR =1.0), nitinol clip-based VCD had 2-fold increased risk (OR 2.0, 95% CI: 1.8–2.3, p<0.001) and suture-based VCD had 1.25-fold increased risk (OR 1.25, 95% CI: 1.2–1.3, p<0.001) for VCD failure. VCD failure was a significant predictor of subsequent vascular complications for both collagen plug-based VCD and nitinol clip-based VCD, but not for suture-based VCD. Conclusion VCD failure rates vary depending upon the types of VCD used and are associated with significantly higher vascular complications as compared to deployment

  5. Treatment with pyrophosphate inhibits uremic vascular calcification.

    PubMed

    O'Neill, W Charles; Lomashvili, Koba A; Malluche, Hartmut H; Faugere, Marie-Claude; Riser, Bruce L

    2011-03-01

    Pyrophosphate, which may be deficient in