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Sample records for abnormal endothelial function

  1. Catechin averts experimental diabetes mellitus-induced vascular endothelial structural and functional abnormalities.

    PubMed

    Bhardwaj, Pooja; Khanna, Deepa; Balakumar, Pitchai

    2014-03-01

    Diabetes mellitus is associated with an induction of vascular endothelial dysfunction (VED), an initial event that could lead to the pathogenesis of atherosclerosis and hypertension. Previous studies showed that catechin, a key component of green tea, possesses vascular beneficial effects. We investigated the effect of catechin hydrate in diabetes mellitus-induced experimental vascular endothelial abnormalities (VEA). Streptozotocin (50 mg/kg, i.p., once) administration to rats produced diabetes mellitus, which subsequently induced VEA in 8 weeks by markedly attenuating acetylcholine-induced endothelium-dependent relaxation in the isolated aortic ring preparation, decreasing aortic and serum nitrite/nitrate concentrations and impairing aortic endothelial integrity. These abnormalities in diabetic rats were accompanied with elevated aortic superoxide anion generation and serum lipid peroxidation in addition to hyperglycemia. Catechin hydrate treatment (50 mg/kg/day p.o., 3 weeks) markedly prevented diabetes mellitus-induced VEA and vascular oxidative stress. Intriguingly, in vitro incubation of L-NAME (100 μM), an inhibitor of nitric oxide synthase, or Wortmannin (100 nM), a selective inhibitor of phosphatidylinositol 3-kinase (PI3K), markedly prevented catechin hydrate-induced improvement in acetylcholine-provoked endothelium-dependent relaxation in the diabetic rat aorta. Moreover, catechin hydrate treatment considerably reduced the elevated level of serum glucose in diabetic rats. In conclusion, catechin hydrate treatment prevents diabetes mellitus-induced VED through the activation of endothelial PI3K signal and subsequent activation of eNOS and generation of nitric oxide. In addition, reduction in high glucose, vascular oxidative stress, and lipid peroxidation might additionally contribute to catechin hydrate-associated prevention of diabetic VEA. PMID:24048981

  2. [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.

  3. Endothelial Barrier and Its Abnormalities in Cardiovascular Disease

    PubMed Central

    Chistiakov, Dimitry A.; Orekhov, Alexander N.; Bobryshev, Yuri V.

    2015-01-01

    Endothelial cells (ECs) form a unique barrier between the vascular lumen and the vascular wall. In addition, the endothelium is highly metabolically active. In cardiovascular disease such as atherosclerosis and hypertension, normal endothelial function could be severely disturbed leading to endothelial dysfunction that then could progress to complete and irreversible loss of EC functionality and contribute to entire vascular dysfunction. Proatherogenic stimuli such as diabetes, dyslipidemia, and oxidative stress could initiate endothelial dysfunction and in turn vascular dysfunction and lead to the development of atherosclerotic arterial disease, a background for multiple cardiovascular disorders including coronary artery disease, acute coronary syndrome, stroke, and thrombosis. Intercellular junctions between ECs mediate the barrier function. Proinflammatory stimuli destabilize the junctions causing the disruption of the endothelial barrier and increased junctional permeability. This facilitates transendothelial migration of immune cells to the arterial intima and induction of vascular inflammation. Proatherogenic stimuli attack endothelial microtubule function that is regulated by acetylation of tubulin, an essential microtubular constituent. Chemical modification of tubulin caused by cardiometabolic risk factors and oxidative stress leads to reorganization of endothelial microtubules. These changes destabilize vascular integrity and increase permeability, which finally results in increasing cardiovascular risk. PMID:26696899

  4. Endothelial Barrier and Its Abnormalities in Cardiovascular Disease.

    PubMed

    Chistiakov, Dimitry A; Orekhov, Alexander N; Bobryshev, Yuri V

    2015-01-01

    Endothelial cells (ECs) form a unique barrier between the vascular lumen and the vascular wall. In addition, the endothelium is highly metabolically active. In cardiovascular disease such as atherosclerosis and hypertension, normal endothelial function could be severely disturbed leading to endothelial dysfunction that then could progress to complete and irreversible loss of EC functionality and contribute to entire vascular dysfunction. Proatherogenic stimuli such as diabetes, dyslipidemia, and oxidative stress could initiate endothelial dysfunction and in turn vascular dysfunction and lead to the development of atherosclerotic arterial disease, a background for multiple cardiovascular disorders including coronary artery disease, acute coronary syndrome, stroke, and thrombosis. Intercellular junctions between ECs mediate the barrier function. Proinflammatory stimuli destabilize the junctions causing the disruption of the endothelial barrier and increased junctional permeability. This facilitates transendothelial migration of immune cells to the arterial intima and induction of vascular inflammation. Proatherogenic stimuli attack endothelial microtubule function that is regulated by acetylation of tubulin, an essential microtubular constituent. Chemical modification of tubulin caused by cardiometabolic risk factors and oxidative stress leads to reorganization of endothelial microtubules. These changes destabilize vascular integrity and increase permeability, which finally results in increasing cardiovascular risk.

  5. Endothelial function in obstructive sleep apnea.

    PubMed

    Atkeson, Amy; Yeh, Susie Yim; Malhotra, Atul; Jelic, Sanja

    2009-01-01

    Untreated obstructive sleep apnea (OSA) is an independent risk factor for hypertension, myocardial infarction, and stroke. The repetitive hypoxia/reoxygenation and sleep fragmentation associated with OSA impair endothelial function. Endothelial dysfunction, in turn, may mediate increased risk for cardiovascular diseases. Specifically, in OSA, endothelial nitric oxide availability and repair capacity are reduced, whereas oxidative stress and inflammation are enhanced. Treatment of OSA improves endothelial vasomotor tone and reduces inflammation. We review the evidence and possible mechanisms of endothelial dysfunction as well as the effect of treatment on endothelial function in OSA.

  6. Do incretins improve endothelial function?

    PubMed Central

    2014-01-01

    An impaired endothelial function has been recognized in the early stage of atherosclerosis, and is a major factor affecting the future development of cardiovascular events. Type 2 diabetes mellitus (T2DM) is widely prevalent, and is one of the most important risk factors for cardiovascular disease. T2DM is associated with increases in both morbidity and mortality, particularly from cardiovascular disease. New therapies based on the incretin hormone and its actions are now becoming widely used, and appear to offer advantages over conventional therapies by keeping the body weight steady and limiting hypoglycemia, while also achieving attractive glycemic control. However, there is little data available about the effects of incretins on the cardiovascular system. This review will focus on the effects of incretin therapies, including glucagon-like peptide-1 (GLP-1) analogs and dipeptidyl peptidase (DPP)-4 inhibitors, on the endothelial function, and will discuss the potential mechanisms underlying these effects. PMID:24428883

  7. Endothelial RIG-I activation impairs endothelial function

    SciTech Connect

    Asdonk, Tobias; Nickenig, Georg; Zimmer, Sebastian

    2012-03-30

    Highlights: Black-Right-Pointing-Pointer RIG-I activation impairs endothelial function in vivo. Black-Right-Pointing-Pointer RIG-I activation alters HCAEC biology in vitro. Black-Right-Pointing-Pointer EPC function is affected by RIG-I stimulation in vitro. -- Abstract: Background: Endothelial dysfunction is a crucial part of the chronic inflammatory atherosclerotic process and is mediated by innate and acquired immune mechanisms. Recent studies suggest that pattern recognition receptors (PRR) specialized in immunorecognition of nucleic acids may play an important role in endothelial biology in a proatherogenic manner. Here, we analyzed the impact of endothelial retinoic acid inducible gene I (RIG-I) activation upon vascular endothelial biology. Methods and results: Wild type mice were injected intravenously with 32.5 {mu}g of the RIG-ligand 3pRNA (RNA with triphosphate at the 5 Prime end) or polyA control every other day for 7 days. In 3pRNA-treated mice, endothelium-depended vasodilation was significantly impaired, vascular oxidative stress significantly increased and circulating endothelial microparticle (EMP) numbers significantly elevated compared to controls. To gain further insight in RIG-I dependent endothelial biology, cultured human coronary endothelial cells (HCAEC) and endothelial progenitor cells (EPC) were stimulated in vitro with 3pRNA. Both cells types express RIG-I and react with receptor upregulation upon stimulation. Reactive oxygen species (ROS) formation is enhanced in both cell types, whereas apoptosis and proliferation is not significantly affected in HCAEC. Importantly, HCAEC release significant amounts of proinflammatory cytokines in response to RIG-I stimulation. Conclusion: This study shows that activation of the cytoplasmatic nucleic acid receptor RIG-I leads to endothelial dysfunction. RIG-I induced endothelial damage could therefore be an important pathway in atherogenesis.

  8. Analysis of Endothelial Barrier Function In Vitro

    PubMed Central

    Wang, Yuping; Alexander, J. Steven

    2016-01-01

    Increased microvascular solute permeability underlies many forms of pathophysiological conditions, including inflammation. Endothelial monolayer cultures provide an excellent model system which allows systemic and mechanistic study of endothelial barrier function and paracellular permeability in vitro. The endothelial-specific complexus adherens junction protein VE-cadherin and their intracellular complex form pericellular structures along the cell borders which are critical to regulate endothelial barrier function by controlling pericellular permeability of vasculature. Here, we describe methods for both visualizing and quantifying junctional permeability and barrier changes in endothelial monolayers in vitro. PMID:21874457

  9. Analysis of endothelial barrier function in vitro.

    PubMed

    Wang, Yuping; Alexander, J Steven

    2011-01-01

    Increased microvascular solute permeability underlies many forms of pathophysiological conditions, including inflammation. Endothelial monolayer cultures provide an excellent model system which allows systemic and mechanistic study of endothelial barrier function and paracellular permeability in vitro. The endothelial-specific complexus adherens junction protein VE-cadherin and their intracellular complex form pericellular structures along the cell borders which are critical to regulate endothelial barrier function by controlling pericellular permeability of vasculature. Here, we describe methods for both visualizing and quantifying junctional permeability and barrier changes in endothelial monolayers in vitro. PMID:21874457

  10. Evolving functions of endothelial cells in inflammation.

    PubMed

    Pober, Jordan S; Sessa, William C

    2007-10-01

    Inflammation is usually analysed from the perspective of tissue-infiltrating leukocytes. Microvascular endothelial cells at a site of inflammation are both active participants in and regulators of inflammatory processes. The properties of endothelial cells change during the transition from acute to chronic inflammation and during the transition from innate to adaptive immunity. Mediators that act on endothelial cells also act on leukocytes and vice versa. Consequently, many anti-inflammatory therapies influence the behaviour of endothelial cells and vascular therapeutics influence inflammation. This Review describes the functions performed by endothelial cells at each stage of the inflammatory process, emphasizing the principal mediators and signalling pathways involved and the therapeutic implications. PMID:17893694

  11. Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro.

    PubMed

    Ghosh, Kaustabh; Thodeti, Charles K; Dudley, Andrew C; Mammoto, Akiko; Klagsbrun, Michael; Ingber, Donald E

    2008-08-12

    Tumor blood vessels exhibit abnormal structure and function that cause disturbed blood flow and high interstitial pressure, which impair delivery of anti-cancer agents. Past efforts to normalize the tumor vasculature have focused on inhibition of soluble angiogenic factors, such as VEGF; however, capillary endothelial (CE) cell growth and differentiation during angiogenesis are also influenced by mechanical forces conveyed by the extracellular matrix (ECM). Here, we explored the possibility that tumor CE cells form abnormal vessels because they lose their ability to sense and respond to these physical cues. These studies reveal that, in contrast to normal CE cells, tumor-derived CE cells fail to reorient their actin cytoskeleton when exposed to uniaxial cyclic strain, exhibit distinct shape sensitivity to variations in ECM elasticity, exert greater traction force, and display an enhanced ability to retract flexible ECM substrates and reorganize into tubular networks in vitro. These behaviors correlate with a constitutively high level of baseline activity of the small GTPase Rho and its downstream effector, Rho-associated kinase (ROCK). Moreover, decreasing Rho-mediated tension by using the ROCK inhibitor, Y27632, can reprogram the tumor CE cells so that they normalize their reorientation response to uniaxial cyclic strain and their ability to form tubular networks on ECM gels. Abnormal Rho-mediated sensing of mechanical cues in the tumor microenvironment may therefore contribute to the aberrant behaviors of tumor CE cells that result in the development of structural abnormalities in the cancer microvasculature.

  12. Novel regulators of endothelial barrier function

    PubMed Central

    Ravindran, Krishnan; Kuebler, Wolfgang M.

    2014-01-01

    Endothelial barrier function is an essential and tightly regulated process that ensures proper compartmentalization of the vascular and interstitial space, while allowing for the diffusive exchange of small molecules and the controlled trafficking of macromolecules and immune cells. Failure to control endothelial barrier integrity results in excessive leakage of fluid and proteins from the vasculature that can rapidly become fatal in scenarios such as sepsis or the acute respiratory distress syndrome. Here, we highlight recent advances in our understanding on the regulation of endothelial permeability, with a specific focus on the endothelial glycocalyx and endothelial scaffolds, regulatory intracellular signaling cascades, as well as triggers and mediators that either disrupt or enhance endothelial barrier integrity, and provide our perspective as to areas of seeming controversy and knowledge gaps, respectively. PMID:25381026

  13. [Endothelial function: role, assessment and limits].

    PubMed

    Puissant, C; Abraham, P; Durand, S; Humeau-Heurtier, A; Faure, S; Rousseau, P; Mahé, G

    2014-02-01

    For several years, detecting and preventing cardiovascular diseases have become a major issue. Different methods have been developed to evaluate endothelial function. Endothelial dysfunction is one of the first steps leading to atherosclerosis. This review presents an insight into endothelial function, the interests of its assessment and methods for studying endothelial function. To date, the vascular endothelium must be considered as a specific organ with its own functions that contribute to the homeostasis of the cardiovascular system. Endothelial dysfunction typically corresponds to a decrease of nitric oxide NO bioavailability. Biological or physico-chemical methods may be used to assess dysfunction. Biological methods allow measuring NO metabolites and pro-inflammatory and vasoconstrictor mediators released by the endothelium. The physico-chemical methods include intra-coronary injections, plethysmography, flow-mediated dilation (FMD), digital plethysmography and optical techniques using laser (laser Doppler single-point, laser Doppler imager, laser speckle contrast imaging) that can be coupled with provocation tests (iontophoresis, microdialysis, post-ischemic hyperemia, local heating). The principle of each technique and its use in clinical practice are discussed. Studying endothelial dysfunction is a particularly promising field because of new drugs being developed. Nevertheless, assessment methodology still needs further development to enable reliable, non-invasive, reproducible, and inexpensive ways to analyze endothelial dysfunction.

  14. Mitochondria, endothelial cell function, and vascular diseases

    PubMed Central

    Tang, Xiaoqiang; Luo, Yu-Xuan; Chen, Hou-Zao; Liu, De-Pei

    2014-01-01

    Mitochondria are perhaps the most sophisticated and dynamic responsive sensing systems in eukaryotic cells. The role of mitochondria goes beyond their capacity to create molecular fuel and includes the generation of reactive oxygen species, the regulation of calcium, and the activation of cell death. In endothelial cells, mitochondria have a profound impact on cellular function under both healthy and diseased conditions. In this review, we summarize the basic functions of mitochondria in endothelial cells and discuss the roles of mitochondria in endothelial dysfunction and vascular diseases, including atherosclerosis, diabetic vascular dysfunction, pulmonary artery hypertension, and hypertension. Finally, the potential therapeutic strategies to improve mitochondrial function in endothelial cells and vascular diseases are also discussed, with a focus on mitochondrial-targeted antioxidants and calorie restriction. PMID:24834056

  15. JAK2V617F-positive endothelial cells contribute to clotting abnormalities in myeloproliferative neoplasms

    PubMed Central

    Etheridge, S. Leah; Roh, Michelle E.; Cosgrove, Megan E.; Sangkhae, Veena; Fox, Norma E.; Chen, Junmei; López, José A.; Kaushansky, Kenneth; Hitchcock, Ian S.

    2014-01-01

    The Janus kinase 2 (JAK2) V617F mutation is the primary pathogenic mutation in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Although thrombohemorrhagic incidents are the most common causes of morbidity and mortality in patients with MPNs, the events causing these clotting abnormalities remain unclear. To identify the cells responsible for the dysfunctional hemostasis, we used transgenic mice expressing JAK2V617F in specific lineages involved in thrombosis and hemostasis. When JAK2V617F was expressed in both hematopoietic and endothelial cells (ECs), the mice developed a significant MPN, characterized by thrombocytosis, neutrophilia, and splenomegaly. However, despite having significantly higher platelet counts than controls, these mice showed severely attenuated thrombosis following injury. Interestingly, platelet activation and aggregation in response to agonists was unaltered by JAK2V617F expression. Subsequent bone marrow transplants revealed the contribution of both endothelial and hematopoietic compartments to the attenuated thrombosis. Furthermore, we identified a potential mechanism for this phenotype through JAK2V617F-regulated inhibition of von Willebrand factor (VWF) function and/or secretion. JAK2V617F+ mice display a condition similar to acquired von Willebrand syndrome, exhibiting significantly less high molecular weight VWF and reduced agglutination to ristocetin. These findings greatly advance our understanding of thrombohemorrhagic events in MPNs and highlight the critical role of ECs in the pathology of hematopoietic malignancies. PMID:24469804

  16. Association of hypertension with coexistence of abnormal metabolism and inflammation and endothelial dysfunction.

    PubMed

    Zhang, Mingzhi; Wang, Guiyan; Wang, Aili; Tong, Weijun; Zhang, Yonghong

    2013-06-01

    To explore association of hypertension with coexistence of inflammation and endothelial dysfunction and abnormal metabolism, a community-based study was conducted among Mongolian people in China. Demographic characteristics and lifestyle risk factors were investigated, blood pressure, body weight and waist circumference were measured, fasting blood samples were obtained to measure blood lipids, fasting plasma glucose and the biomarkers of inflammation and endothelial dysfunction, C-reactive protein (CRP), soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble E-selectin (sE-selectin) and angiotensin II. Rates of abnormal metabolism, elevated CRP, elevated sICAM-1, elevated sE-selectin and elevated angiotensin II as well as coexistence of abnormal metabolism with the elevated biomarkers were all higher in hypertensives than these in normotensives (all p < 0.01). Compared with subjects with normal metabolism and without any elevated biomarker, multivariate adjusted odds ratio (95% confidence interval) of hypertension associated with abnormal metabolism, elevated CRP, elevated sICAM-1, elevated sE-selectin, elevated angiotensin II, coexistences of abnormal metabolism with elevated CRP, elevated sICAM-1,elevated sE-selectin and elevated angiotensin II were 2.209 (1.594-3.062), 2.820 (1.992-3.992), 2.370 (1.665-3.374), 1.893 (1.331-2.691), 2.545 (1.793-3.612), 2.990 (2.102-4.252), 2.551 (1.775-3.667), 2.223 (1.544-3.220), 3.135 (2.185-4.519), respectively. In conclusion, this study indicated that inflammation and endothelial dysfunction was associated with hypertension and abnormal metabolism, and individuals with co-existence of abnormal metabolism with inflammation and endothelial dysfunction had higher risk of prevalent hypertension among Mongolian population. This study suggests that further study on treatment for hypertension patients with coexistence of abnormal metabolism with inflammation and endothelial dysfunction should be conducted in the near

  17. Endothelial function in normotensive and high-normal hypertensive subjects.

    PubMed

    Plavnik, F L; Ajzen, S A; Christofalo, D M J; Barbosa, C S P; Kohlmann, O

    2007-06-01

    To evaluate the impact of a mild increment in blood pressure level on endothelial function, we evaluated 61 healthy volunteers (24 women, 37 men, and aged 35-50 years). All subjects underwent a blood chemistry panel to exclude any metabolic abnormalities and were submitted to a Doppler ultrasound of the brachial artery to assess endothelial function. We assessed the endothelial response to reactive hyperaemia and exogenous nitric oxide administration considering an increase in systolic blood pressure (SBP) at each 10-mm Hg interval. Our study population was divided as follows: SBP <115 mm Hg (SG1, n=13), SBP > or =115 mm Hg and <125 mm Hg (SG2, n=20), SBP > or = 125 mm Hg and <135 mm Hg (SG3, n=13) and SBP > or = 135 mm Hg and < 140 mm Hg (SG4, n=15). We found a significant difference in flow-mediated dilation among SG2, SG3 and SG4, 16.2+/-5.6, 13.4+/-5.2 and 11.5+/-3.6%, P<0.05, respectively). After nitrate administration, we observed a nonsignificant decrease in brachial artery dilation among groups, P=0.217. Our data showed in a healthy normotensive population, without any risk factor for atherosclerotic disease that small increases in SBP but not in diastolic blood pressure may impair endothelial function even in subjects considered as high-normal, meaning that this population deserves more attention than usually ascribed to intervene and prevent complications, as endothelial dysfunction may represent an early change in those who develop hypertension later in life. PMID:17287837

  18. Normal and abnormal human vestibular ocular function

    NASA Technical Reports Server (NTRS)

    Peterka, R. J.; Black, F. O.

    1986-01-01

    The major motivation of this research is to understand the role the vestibular system plays in sensorimotor interactions which result in spatial disorientation and motion sickness. A second goal was to explore the range of abnormality as it is reflected in quantitative measures of vestibular reflex responses. The results of a study of vestibular reflex measurements in normal subjects and preliminary results in abnormal subjects are presented in this report. Statistical methods were used to define the range of normal responses, and determine age related changes in function.

  19. Arterial endothelial function measurement method and apparatus

    DOEpatents

    Maltz, Jonathan S; Budinger, Thomas F

    2014-03-04

    A "relaxoscope" (100) detects the degree of arterial endothelial function. Impairment of arterial endothelial function is an early event in atherosclerosis and correlates with the major risk factors for cardiovascular disease. An artery (115), such as the brachial artery (BA) is measured for diameter before and after several minutes of either vasoconstriction or vasorelaxation. The change in arterial diameter is a measure of flow-mediated vasomodification (FMVM). The relaxoscope induces an artificial pulse (128) at a superficial radial artery (115) via a linear actuator (120). An ultrasonic Doppler stethoscope (130) detects this pulse 10-20 cm proximal to the point of pulse induction (125). The delay between pulse application and detection provides the pulse transit time (PTT). By measuring PTT before (160) and after arterial diameter change (170), FMVM may be measured based on the changes in PTT caused by changes in vessel caliber, smooth muscle tone and wall thickness.

  20. Vascular Endothelial Function & Self-Reported Sleep

    PubMed Central

    Behl, Muskaan; Bliwise, Donald; Veledar, Emir; Cunningham, Lynn; Vazquez, Jennifer; Brigham, Kenneth; Quyyumi, Arshed

    2013-01-01

    Background We investigated the relationship between self-reported sleep characteristics and brachial artery flow-mediated dilation (FMD) in a community-based population. Prior studies document that sleep apnea may be related to endothelial dysfunction but disagree whether subjective reports of sleep may also reflect such associations. Methods In 684 subjects (32% male) between 37 and 60 years enrolled in the Emory-Georgia Tech Predictive Health Institute study, we measured reported sleep characteristics using the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI) along with cardiovascular risk factors. Endothelial function was assessed using brachial artery FMD. Multivariate analysis of covariance was used to adjust for various cardiovascular risk factors including age, race, gender, smoking, hypertension, diabetes, and body mass index. Results Lower brachial artery FMD values were correlated with higher ESS scores (p = 0.0275), even after adjustment for risk factors (p = 0.03). Total PSQI score was unrelated to brachial artery FMD. However, lower sleep quality (PSQI component 1) was associated with lower brachial artery FMD (multivariate p = 0.038), and participants who coughed or snored during sleep also had lower brachial artery FMD (6.24±3.42%) compared to those who did not (6.92±4.30%) (p = 0.056). This difference remained significant after adjustment for risk factors (p = 0.03). Conclusion In a community-based population, our analysis indicates a significant association between sleepiness and snoring assessed by questionnaires and endothelial function. Simple subjective reports about individuals’ sleep may be highly revealing indicators of endothelial function impairment and thus important indicators of cardiovascular disease risk. PMID:23842206

  1. Mineralocorticoid receptor antagonists and endothelial function

    PubMed Central

    Maron, Bradley A.; Leopold, Jane A.

    2010-01-01

    Hyperaldosteronism has been associated with endothelial dysfunction and impaired vascular reactivity in patients with hypertension or congestive heart failure. The mineralocorticoid receptor (MR) antagonists spironolactone and eplerenone have been shown to reduce morbidity and mortality, in part, by ameliorating the adverse effects of aldosterone on vascular function. Although spironolactone and eplerenone are increasingly utilized in patients with cardiovascular disease, widespread clinical use is limited by the development of gynecomastia with spironolactone and hyperkalemia with both agents. This suggests that the development of newer agents with favorable side effect profiles is warranted. PMID:18729003

  2. The relationship between oxidised LDL, endothelial progenitor cells and coronary endothelial function in patients with CHD

    PubMed Central

    Watt, Jonathan; Kennedy, Simon; Ahmed, Nadeem; Hayhurst, James; McClure, John D; Berry, Colin; Wadsworth, Roger M; Oldroyd, Keith G

    2016-01-01

    Objective The balance between coronary endothelial dysfunction and repair is influenced by many protective and deleterious factors circulating in the blood. We studied the relationship between oxidised low-density lipoprotein (oxLDL), circulating endothelial progenitor cells (EPCs) and coronary endothelial function in patients with stable coronary heart disease (CHD). Methods 33 patients with stable CHD were studied. Plasma oxLDL was measured using ELISA, coronary endothelial function was assessed using intracoronary acetylcholine infusion and EPCs were quantified using flow cytometry for CD34+/KDR+ cells. Results Plasma oxLDL correlated positively with the number of EPCs in the blood (r=0.46, p=0.02). There was a positive correlation between the number of circulating EPCs and coronary endothelial function (r=0.42, p=0.04). There was no significant correlation between oxLDL and coronary endothelial function. Conclusions Plasma levels of oxLDL are associated with increased circulating EPCs in the blood of patients with CHD, which may reflect a host-repair response to endothelial injury. Patients with stable CHD had a high prevalence of coronary endothelial dysfunction, which was associated with lower numbers of circulating EPCs, suggesting a mechanistic link between endothelial dysfunction and the pathogenesis of atherosclerosis. PMID:26848395

  3. Possible involvement of PPARγ-associated eNOS signaling activation in rosuvastatin-mediated prevention of nicotine-induced experimental vascular endothelial abnormalities.

    PubMed

    Kathuria, Sonam; Mahadevan, Nanjaian; Balakumar, Pitchai

    2013-02-01

    Nicotine exposure via cigarette smoking and tobacco chewing is associated with vascular complications. The present study investigated the effect of rosuvastatin in nicotine (2 mg/kg/day, i.p., 4 weeks)-induced vascular endothelial dysfunction (VED) in rats. The development of VED was assessed by employing isolated aortic ring preparation and estimating aortic and serum nitrite/nitrate concentration. Further, scanning electron microscopy and hematoxylin-eosin staining of thoracic aorta were performed to assess the vascular endothelial integrity. Moreover, oxidative stress was assessed by estimating aortic superoxide anion generation and serum thiobarbituric acid-reactive substances. The nicotine administration produced VED by markedly reducing acetylcholine-induced endothelium-dependent relaxation, impairing the integrity of vascular endothelium, decreasing aortic and serum nitrite/nitrate concentration, increasing oxidative stress, and inducing lipid alteration. However, treatment with rosuvastatin (10 mg/kg/day, i.p., 4 weeks) markedly attenuated nicotine-induced vascular endothelial abnormalities, oxidative stress, and lipid alteration. Interestingly, the co-administration of peroxisome proliferator-activated receptor γ (PPARγ) antagonist, GW9662 (1 mg/kg/day, i.p., 2 weeks) submaximally, significantly prevented rosuvastatin-induced improvement in vascular endothelial integrity, endothelium-dependent relaxation, and nitrite/nitrate concentration in rats administered nicotine. However, GW9662 co-administration did not affect rosuvastatin-associated vascular anti-oxidant and lipid-lowering effects. The incubation of aortic ring, isolated from rosuvastatin-treated nicotine-administered rats, with L-NAME (100 μM), an inhibitor of nitric oxide synthase (NOS), significantly attenuated rosuvastatin-induced improvement in acetylcholine-induced endothelium-dependent relaxation. Rosuvastatin prevents nicotine-induced vascular endothelial abnormalities by activating

  4. Effect of fat and carbohydrate consumption on endothelial function.

    PubMed

    Ong, P J; Dean, T S; Hayward, C S; Della Monica, P L; Sanders, T A; Collins, P

    Consumption of a meal high in monounsaturated fat was associated with acute impairment of endothelial function when compared with a carbohydrate-rich meal. Such a divergent response in endothelial function may be important in the modulation of vascular function in health and disease.

  5. Immunological functions of liver sinusoidal endothelial cells

    PubMed Central

    Knolle, Percy A; Wohlleber, Dirk

    2016-01-01

    Liver sinusoidal endothelial cells (LSECs) line the liver sinusoids and separate passenger leukocytes in the sinusoidal lumen from hepatocytes. LSECs further act as a platform for adhesion of various liver-resident immune cell populations such as Kupffer cells, innate lymphoid cells or liver dendritic cells. In addition to having an extraordinary scavenger function, LSECs possess potent immune functions, serving as sentinel cells to detect microbial infection through pattern recognition receptor activation and as antigen (cross)-presenting cells. LSECs cross-prime naive CD8 T cells, causing their rapid differentiation into memory T cells that relocate to secondary lymphoid tissues and provide protection when they re-encounter the antigen during microbial infection. Cross-presentation of viral antigens by LSECs derived from infected hepatocytes triggers local activation of effector CD8 T cells and thereby assures hepatic immune surveillance. The immune function of LSECs complements conventional immune-activating mechanisms to accommodate optimal immune surveillance against infectious microorganisms while preserving the integrity of the liver as a metabolic organ. PMID:27041636

  6. Expression of abnormal von Willebrand factor by endothelial cells from a patient with type IIA von Willebrand disease.

    PubMed Central

    Levene, R B; Booyse, F M; Chediak, J; Zimmerman, T S; Livingston, D M; Lynch, D C

    1987-01-01

    Studies were conducted to characterize the biosynthesis of von Willebrand factor (vWf) by cultured endothelial cells (EC) derived from the umbilical vein of a patient with type IIA von Willebrand disease. The patient's EC, compared with those from normal individuals, produced vWf that had decreased amounts of large multimers and an increase in rapidly migrating satellite species, features characteristic of plasma vWf from patients with type IIA von Willebrand disease. The type IIA EC did produce a full spectrum of vWf multimers in both cell lysates and postculture medium, although the relative amounts of the largest species were decreased. The large multimers were degraded in conjunction with the appearance of rapidly migrating satellites that contained approximately equal to 170-kDa proteolytic fragments, suggesting that this patient's functional defect is due to abnormal proteolysis and not to a primary failure of vWf subunit oligomerization. Moreover, the observed degradation appears to result from an abnormal vWf molecule and not elevated protease levels. These results suggest that this patient's von Willebrand disease phenotype is caused by increased proteolytic sensitivity of his vWf protein. Images PMID:3306682

  7. [Endothelial function and the microcirculation in diabetes mellitus].

    PubMed

    Arosio, E; Minuz, P; Prior, M

    1999-01-01

    The role of endothelial dysfunction in the pathogenesis of diabetic microangiopathy is reviewed. Reversible alterations in microcirculation, consisting of increased capillary pressure, blood flow and endothelial permeability, can be detected at an early stage in diabetes mellitus. Irreversible structural modifications of the vascular wall, such as thickening of the basal membrane due to the extracellular accumulation of proteins, take place at later stages. Atherosclerosis further affects microcirculation in diabetes mellitus by decreasing autoregulatory capacity and blood flow reserve. Endothelial dysfunction has been observed to precede the onset of microvascular lesions, as demonstrated by reduction in the vasodilatory response to vasoactive agents and by alterations in the antithrombotic properties of the endothelium. Experimental data available so far suggest that endothelial dysfunction may be directly related to hyperglycemia. Abnormalities in lipoprotein metabolism, generation of glycation end products, and increased oxidative stress may also be responsible for the endothelial dysfunction in diabetes mellitus. Insulin resistance appears to be related to endothelial dysfunction in non-insulin-dependent diabetes mellitus through a reduction in the biological activity of endothelial-derived nitric oxide.

  8. The endothelial function in cardiac surgery.

    PubMed

    Ranucci, M

    2006-06-01

    Cardiac operations with cardiopulmonary bypass exerts many different actions which modify the natural function of endothelial cells. The main determinant is the activation of the coagulation system both through the intrinsic and extrinsic pathways, leading to an overwhelming thrombin formation. To counteract the coagulant effects of thrombin, heparin is used in large doses. As a result, the endothelium is asked to promote all its anticoagulant properties, basically through the AT release from the surface, the tissue factor pathway inhibitor release, and the activation of the protein C protein S system. At the end of cardiac operations, all these systems are depleted, and low levels of antithrombin, tissue factor pathway inhibitor, protein C are available for further anticoagulant effects. There is the evidence that levels of antithrombin activity below 50% at the end of cardiac operations with cardiopulmonary bypass are associated to bad outcomes in terms of surgical revision rate, thromboembolic events, and neurological events. Exogenous antithrombin administration has a well defined action in limiting thrombin formation during cardiac operations; however, we are still lacking an evidence-based information about the clinical impact of this and others possible preventive strategies based on exogenous administration of antithrombin before or during cardiac operations. PMID:16682923

  9. Skin microvascular endothelial function as a biomarker in cardiovascular diseases?

    PubMed

    Hellmann, Marcin; Roustit, Matthieu; Cracowski, Jean-Luc

    2015-08-01

    Skin microvascular endothelial function is impaired in many cardiovascular diseases, and could be therefore considered as a representative vascular bed. However, today, available evidence allows considering skin microvascular endothelial function neither as a diagnostic biomarker nor as a prognostic biomarker in cardiovascular diseases. Large follow-up studies using standardized methods should now be conducted to assess the potential predictive value of skin microvascular function in cardiovascular diseases.

  10. Metformin restores endothelial function in aorta of diabetic rats

    PubMed Central

    Sena, Cristina M; Matafome, Paulo; Louro, Teresa; Nunes, Elsa; Fernandes, Rosa; Seiça, Raquel M

    2011-01-01

    BACKGROUND AND PURPOSE The effects of metformin, an antidiabetic agent that improves insulin sensitivity, on endothelial function have not been fully elucidated. This study was designed to assess the effect of metformin on impaired endothelial function, oxidative stress, inflammation and advanced glycation end products formation in type 2 diabetes mellitus. EXPERIMENTAL APPROACH Goto-Kakizaki (GK) rats, an animal model of nonobese type 2 diabetes, fed with normal and high-fat diet during 4 months were treated with metformin for 4 weeks before evaluation. Systemic oxidative stress, endothelial function, insulin resistance, nitric oxide (NO) bioavailability, glycation and vascular oxidative stress were determined in the aortic rings of the different groups. A pro-inflammatory biomarker the chemokine CCL2 (monocyte chemoattractant protein-1) was also evaluated. KEY RESULTS High-fat fed GK rats with hyperlipidaemia showed increased vascular and systemic oxidative stress and impaired endothelial-dependent vasodilatation. Metformin treatment significantly improved glycation, oxidative stress, CCL2 levels, NO bioavailability and insulin resistance and normalized endothelial function in aorta. CONCLUSION AND IMPLICATIONS Metformin restores endothelial function and significantly improves NO bioavailability, glycation and oxidative stress in normal and high-fat fed GK rats. This supports the concept of the central role of metformin as a first-line therapeutic to treat diabetic patients in order to protect against endothelial dysfunction associated with type 2 diabetes mellitus. PMID:21250975

  11. Angiotensin-converting enzyme 2 activation improves endothelial function.

    PubMed

    Fraga-Silva, Rodrigo A; Costa-Fraga, Fabiana P; Murça, Tatiane M; Moraes, Patrícia L; Martins Lima, Augusto; Lautner, Roberto Q; Castro, Carlos H; Soares, Célia Maria A; Borges, Clayton L; Nadu, Ana Paula; Oliveira, Marilene L; Shenoy, Vinayak; Katovich, Michael J; Santos, Robson A S; Raizada, Mohan K; Ferreira, Anderson J

    2013-06-01

    Diminished release and function of endothelium-derived nitric oxide coupled with increases in reactive oxygen species production is critical in endothelial dysfunction. Recent evidences have shown that activation of the protective axis of the renin-angiotensin system composed by angiotensin-converting enzyme 2, angiotensin-(1-7), and Mas receptor promotes many beneficial vascular effects. This has led us to postulate that activation of intrinsic angiotensin-converting enzyme 2 would improve endothelial function by decreasing the reactive oxygen species production. In the present study, we tested 1-[[2-(dimetilamino)etil]amino]-4-(hidroximetil)-7-[[(4-metilfenil)sulfonil]oxi]-9H-xantona-9 (XNT), a small molecule angiotensin-converting enzyme 2 activator, on endothelial function to validate this hypothesis. In vivo treatment with XNT (1 mg/kg per day for 4 weeks) improved the endothelial function of spontaneously hypertensive rats and of streptozotocin-induced diabetic rats when evaluated through the vasorelaxant responses to acetylcholine/sodium nitroprusside. Acute in vitro incubation with XNT caused endothelial-dependent vasorelaxation in aortic rings of rats. This vasorelaxation effect was attenuated by the Mas antagonist D-pro7-Ang-(1-7), and it was reduced in Mas knockout mice. These effects were associated with reduction in reactive oxygen species production. In addition, Ang II-induced reactive oxygen species production in human aortic endothelial cells was attenuated by preincubation with XNT. These results showed that chronic XNT administration improves the endothelial function of hypertensive and diabetic rat vessels by attenuation of the oxidative stress. Moreover, XNT elicits an endothelial-dependent vasorelaxation response, which was mediated by Mas. Thus, this study indicated that angiotensin-converting enzyme 2 activation promotes beneficial effects on the endothelial function and it is a potential target for treating cardiovascular disease.

  12. Normalized endothelial function but sustained cardiovascular risk profile 11 years following a pregnancy complicated by preeclampsia.

    PubMed

    Östlund, Eva; Al-Nashi, Maha; Hamad, Rangeen Rafik; Larsson, Anders; Eriksson, Maria; Bremme, Katarina; Kahan, Thomas

    2013-12-01

    Women with a history of preeclampsia are at increased risk of future cardiovascular disease. Preeclampsia is associated with elevated blood pressure, inflammation and endothelial dysfunction, and these findings remain 1 year after delivery. Whether these abnormalities persist long after delivery, and whether they may contribute to future cardiovascular disease, is not well studied. We studied 15 women with a history of preeclampsia and 16 matched controls with an uncomplicated pregnancy 11 years following the index pregnancy; all had also been previously examined at 1 year. We assessed arterial stiffness (pulse wave analysis), 24 h ambulatory blood pressure and endothelial function (forearm flow-mediated dilatation and pulse wave analysis following β receptor agonist provocation), and determined markers of glucose and lipid metabolism, inflammation and vascular function. The preeclampsia group had higher blood pressures and reduced night/day blood pressure ratios, increased body mass index and reduced glucose tolerance, and increased levels of tissue necrosis factor receptor 1 and intracellular adhesion molecule-1, suggesting inflammatory and vascular activation. However, the endothelial impairment observed in the preeclampsia group at 1 year was normalized at 11 years, whereas the control group remained unchanged during follow-up. Our findings of higher blood pressures, impaired glucose tolerance and normalization of endothelial function 11 years after preeclampsia suggest cardiovascular risk factors present already before pregnancy to be more important than permanent endothelial damage for the increased risk of future cardiovascular complications in women with a history of preeclampsia.

  13. Effect of metformin on insulin-resistant endothelial cell function

    PubMed Central

    CHEN, HAIYAN; LI, JIE; YANG, OU; KONG, JIAN; LIN, GUANGZHU

    2015-01-01

    The aim of the present study was to investigate the effect of metformin on the function of insulin-resistant (IR) endothelial cells. A model of IR endothelial cells was established by incubating cells with 30 mM glucose, 1 μM dexamethasone and various concentrations of insulin. The nitric oxide (NO) content of the endothelial cells was determined by measuring the rate of nitroreductase production; the endothelin (ET) concentration was examined by enzyme-linked immunosorbent assay; and the expression levels of endothelial nitric oxide synthase (eNOS) were detected using western blotting. The optimal conditions for inducing insulin resistance in endothelial cells were a combination treatment of 10−4 mmol/l insulin, 30 mM glucose and 1 μM dexamethasone for 48 h. Notably, metformin administration significantly increased the NO content and reduced the ET-1 concentration in the IR cells compared with the non-treated control cells (P<0.05); furthermore, metformin significantly increased the intracellular eNOS protein expression in IR endothelial cells compared with the non-treated control cells (P<0.05), with an optimal metformin concentration of 10−3 mmol/l. Thus, the present study identified that metformin improves the function of IR endothelial cells, possibly through promoting eNOS protein expression and increasing the NO content. PMID:25663871

  14. Involvement of local lamellipodia in endothelial barrier function.

    PubMed

    Breslin, Jerome W; Zhang, Xun E; Worthylake, Rebecca A; Souza-Smith, Flavia M

    2015-01-01

    Recently we observed that endothelial cells cultured in tightly confluent monolayers display frequent local lamellipodia, and that thrombin, an agent that increases endothelial permeability, reduces lamellipodia protrusions. This led us to test the hypothesis that local lamellipodia contribute to endothelial barrier function. Movements of subcellular structures containing GFP-actin or VE-cadherin-GFP expressed in endothelial cells were recorded using time-lapse microscopy. Transendothelial electrical resistance (TER) served as an index of endothelial barrier function. Changes in both lamellipodia dynamics and TER were assessed during baseline and after cells were treated with either the barrier-disrupting agent thrombin, or the barrier-stabilizing agent sphingosine-1-phosphate (S1P). The myosin II inhibitor blebbistatin was used to selectively block lamellipodia formation, and was used to test their role in the barrier function of endothelial cell monolayers and isolated, perfused rat mesenteric venules. Myosin light chain (MLC) phosphorylation was assessed by immunofluorescence microscopy. Rac1 and RhoA activation were evaluated using G-LISA assays. The role of Rac1 was tested with the specific inhibitor NSC23766 or by expressing wild-type or dominant negative GFP-Rac1. The results show that thrombin rapidly decreased both TER and the lamellipodia protrusion frequency. S1P rapidly increased TER in association with increased protrusion frequency. Blebbistatin nearly abolished local lamellipodia protrusions while cortical actin fibers and stress fibers remained intact. Blebbistatin also significantly decreased TER of cultured endothelial cells and increased permeability of isolated rat mesenteric venules. Both thrombin and S1P increased MLC phosphorylation and activation of RhoA. However, thrombin and S1P had differential impacts on Rac1, correlating with the changes in TER and lamellipodia protrusion frequency. Overexpression of Rac1 elevated, while NSC23766 and

  15. Mechanotransduction at the basis of endothelial barrier function.

    PubMed

    Gulino-Debrac, Danielle

    2013-04-01

    Destabilization of cell-cell contacts involved in the maintenance of endothelial barrier function can lead to increased endothelial permeability. This increase in endothelial permeability results in an anarchical movement of fluid, solutes and cells outside the vasculature and into the surrounding tissues, thereby contributing to various diseases such as stroke or pulmonary edema. Thus, a better understanding of the molecular mechanisms regulating endothelial cell junction integrity is required for developing new therapies for these diseases. In this review, we describe the mechanotransduction mechanism at the basis of adherens junction strengthening at endothelial cell-cell contacts. More particularly, we report on the emerging role of α-catenin and EPLIN that act as a mechanotransmitter of myosin-IIgenerated traction forces. The interplay between α-catenin, EPLIN and the myosin-II machinery initiates the junctional recruitment of vinculin and α-actinin leading to a drastic remodeling of the actin cytoskeleton and to cortical actin ring reshaping. The pathways initiated by tyrosine phosphorylation of VE-cadherin at the basis of endothelial cell-cell junction remodeling is also reported, as it may be interrelated to α-catenin/ EPLIN-mediated mechanotransduction mechanisms. We also describe the junctional mechanosensory complex composed of PECAM-1, VE-cadherin and VEGFR2 that is able to transmit signaling pathway under the onset of shear stress. This mechanosensing mechanism, involved in the earliest events promoting atherogenesis, is required for endothelial cell alignment along flow direction. PMID:24665386

  16. Myelodysplastic syndromes: pathogenesis, functional abnormalities, and clinical implications.

    PubMed Central

    Jacobs, A

    1985-01-01

    The myelodysplastic syndromes represent a preleukaemic state in which a clonal abnormality of haemopoietic stem cell is characterised by a variety of phenotypic manifestations with varying degrees of ineffective haemopoiesis. This state probably develops as a sequence of events in which the earliest stages may be difficult to detect by conventional pathological techniques. The process is characterised by genetic changes leading to abnormal control of cell proliferation and differentiation. Expansion of an abnormal clone may be related to independence from normal growth factors, insensitivity to normal inhibitory factors, suppression of normal clonal growth, or changes in the immunological or nutritional condition of the host. The haematological picture is of peripheral blood cytopenias: a cellular bone marrow, and functional abnormalities of erythroid, myeloid, and megakaryocytic cells. In most cases marrow cells have an abnormal DNA content, often with disturbances of the cell cycle: an abnormal karyotype is common in premalignant clones. Growth abnormalities of erythroid or granulocyte-macrophage progenitors are common in marrow cultures, and lineage specific surface membrane markers indicate aberrations of differentiation. Progression of the disorder may occur through clonal expansion or through clonal evolution with a greater degree of malignancy. Current attempts to influence abnormal growth and differentiation have had only limited success. Clinical recognition of the syndrome depends on an acute awareness of the signs combined with the identification of clonal and functional abnormalities. PMID:2999194

  17. Diverse Functions of Endothelial NO Synthases System: NO and EDH

    PubMed Central

    Godo, Shigeo

    2016-01-01

    Abstract: Endothelium-dependent relaxations are predominantly regulated by nitric oxide (NO) in large conduit arteries and by endothelium-dependent hyperpolarization (EDH) in small resistance vessels. Although the nature of EDH factors varies depending on species and vascular beds, we have previously demonstrated that endothelial NO synthases (eNOS)-derived hydrogen peroxide (H2O2) is an EDH factor in animals and humans. This vessel size-dependent contribution of NO and EDH is, at least in part, attributable to the diverse roles of endothelial NOSs system; in large conduit arteries, eNOS mainly serves as a NO-generating system to elicit soluble guanylate cyclase–cyclic guanosine monophosphate-mediated relaxations, whereas in small resistance vessels, it serves as a superoxide-generating system to cause EDH/H2O2-mediated relaxations. Endothelial caveolin-1 may play an important role for the diverse roles of NOSs. Although reactive oxygen species are generally regarded harmful, the physiological roles of H2O2 have attracted much attention as accumulating evidence has shown that endothelium-derived H2O2 contributes to cardiovascular homeostasis. The diverse functions of endothelial NOSs system with NO and EDH/H2O2 could account for a compensatory mechanism in the setting of endothelial dysfunction. In this review, we will briefly summarize the current knowledge on the diverse functions of endothelial NOSs system: NO and EDH/H2O2. PMID:26647119

  18. Mesenchymal Stem Cells Ameliorate Atherosclerotic Lesions via Restoring Endothelial Function

    PubMed Central

    Lin, Yu-Ling; Yet, Shaw-Fang; Hsu, Yuan-Tong

    2015-01-01

    Transplantation of mesenchymal stem cells (MSCs) is beneficial in myocardial infarction and hind limb ischemia, but its ability to ameliorate atherosclerosis remains unknown. Here, the effects of MSCs on inhibiting endothelial dysfunction and atherosclerosis were investigated in human/mouse endothelial cells treated with oxidized low-density lipoprotein (oxLDL) and in apolipoprotein E-deficient (apoE−/−) mice fed a high-fat diet. Treatment with oxLDL inactivated the Akt/endothelial nitric-oxide synthase (eNOS) pathway, induced eNOS degradation, and inhibited nitric oxide (NO) production in endothelial cells. Coculture with human MSCs reversed the effects of oxLDL on endothelial cells and restored Akt/eNOS activity, eNOS level, and NO production. Reduction of endothelium-dependent relaxation and subsequent plaque formation were developed in apoE−/− mice fed a high-fat diet. Systemic infusion with mouse MSCs ameliorated endothelial dysfunction and plaque formation in high-fat diet-fed apoE−/− mice. Interestingly, treatment with interleukin-8 (IL8)/macrophage inflammatory protein-2 (MIP-2) alone induced the similar effects of human/mouse MSCs on oxLDL-treated human/mouse endothelial cells. Neutralization antibodies (Abs) against IL8/MIP-2 also blocked the effects of human/mouse MSCs on oxLDL-treated human/mouse endothelial cells. Consistently, MIP-2 injection alone induced the similar effect of MSCs on the endothelial function in high-fat diet-fed apoE−/− mice. The improvement in endothelial dysfunction by mouse MSCs was also blocked when pretreating MSCs with anti-MIP-2 Abs. In conclusion, MSC transplantation improved endothelial function and plaque formation in high-fat diet-fed apoE−/− mice. Activation of the Akt/eNOS pathway in endothelium by IL8/MIP-2 is involved in the protective effect of MSCs. The study helps support the use and clarify the mechanism of MSCs for ameliorating atherosclerosis. PMID:25504897

  19. Abnormal development of glomerular endothelial and mesangial cells in mice with targeted disruption of the lama3 gene.

    PubMed

    Abrass, C K; Berfield, A K; Ryan, M C; Carter, W G; Hansen, K M

    2006-09-01

    Mice with targeted disruption of the lama3 gene, which encodes the alpha3 chain of laminin-5 (alpha3beta3gamma2, 332), develop a blistering skin disease similar to junctional epidermolysis bullosa in humans. These animals also develop abnormalities in glomerulogenesis. In both wild-type and mutant animals (lama3(-/-)), podocytes secrete glomerular basement membrane and develop foot processes. Endothelial cells migrate into this scaffolding and secrete a layer of basement membrane that fuses with the one formed by the podocyte. In lama3(-/-) animals, glomerular maturation arrests at this stage. Endothelial cells do not attenuate, develop fenestrae, or form typical lumens, and mesangial cells (MCs) were not identified. LN alpha3 subunit (LAMA3) protein was identified in the basement membrane adjacent to glomerular endothelial cells (GEnCs) in normal rats and mice. In developing rat glomeruli, the LAMA3 subunit was first detectable in the early capillary loop stage, which corresponds to the stage at which maturation arrest was observed in the mutant mice. Lama3 mRNA and protein were identified in isolated rat and mouse glomeruli and cultured rat GEnCs, but not MC. These data document expression of LAMA3 in glomeruli and support a critical role for it in GEnC differentiation. Furthermore, LAMA3 chain expression and/or another product of endothelial cells are required for MC migration into the developing glomerulus. PMID:16850021

  20. Obstructive Sleep Apnoea Syndrome, Endothelial Function and Markers of Endothelialization. Changes after CPAP

    PubMed Central

    Sanchez Armengol, Angeles; Moreno-Luna, Rafael; Caballero-Eraso, Candela; Macher, Hada C.; Villar, Jose; Merino, Ana M; Castell, Javier; Capote, Francisco; Stiefel, Pablo

    2015-01-01

    Study objectives This study tries to assess the endothelial function in vivo using flow-mediated dilatation (FMD) and several biomarkers of endothelium formation/restoration and damage in patients with obstructive sleep apnoea (OSA) syndrome at baseline and after three months with CPAP therapy. Design Observational study, before and after CPAP therapy. Setting and Patients We studied 30 patients with apnoea/hypopnoea index (AHI) >15/h that were compared with themselves after three months of CPAP therapy. FMD was assessed non-invasively in vivo using the Laser-Doppler flowmetry. Circulating cell-free DNA (cf-DNA) and microparticles (MPs) were measured as markers of endothelial damage and the vascular endothelial growth factor (VEGF) was determined as a marker of endothelial restoration process. Measurements and results After three month with CPAP, FMD significantly increased (1072.26 ± 483.21 vs. 1604.38 ± 915.69 PU, p< 0.005) cf-DNA and MPs significantly decreased (187.93 ± 115.81 vs. 121.28 ± 78.98 pg/ml, p<0.01, and 69.60 ± 62.60 vs. 39.82 ± 22.14 U/μL, p<0.05, respectively) and VEGF levels increased (585.02 ± 246.06 vs. 641.11 ± 212.69 pg/ml, p<0.05). These changes were higher in patients with more severe disease. There was a relationship between markers of damage (r = -0.53, p<0.005) but not between markers of damage and restoration, thus suggesting that both types of markers should be measured together. Conclusions CPAP therapy improves FMD. This improvement may be related to an increase of endothelial restoration process and a decrease of endothelial damage. PMID:25815511

  1. Mineralocorticoid Receptors Modulate Vascular Endothelial Function in Human Obesity

    PubMed Central

    Hwang, Moon-Hyon; Yoo, Jeung-Ki; Luttrell, Meredith; Kim, Han-Kyul; Meade, Thomas H.; English, Mark; Segal, Mark S.; Christou, Demetra D.

    2015-01-01

    Obesity increases linearly with age and is associated with impaired vascular endothelial function and increased risk for cardiovascular disease. Mineralocorticoid receptors (MR) contribute to impaired vascular endothelial function in cardiovascular disease; however, their role in uncomplicated human obesity is unknown. Because plasma aldosterone levels are elevated in obesity and adipocytes may be a source of aldosterone, we hypothesized that MR modulate vascular endothelial function in older adults in an adiposity-dependent manner. To test this hypothesis, we administered MR blockade (Eplerenone; 100 mg/day) for 1 month in a balanced, randomized, double-blind, placebo-controlled, crossover study to 22 older adults (10 men, 55–79 years) varying widely in adiposity (body mass index: 20–45 kg/m2) but who were free from overt cardiovascular disease. We evaluated vascular endothelial function (brachial artery flow-mediated dilation [FMD] via ultrasonography) and oxidative stress (plasma F2-isoprostanes and vascular endothelial cell protein expression of nitrotyrosine and NADPH oxidase p47phox) during placebo and MR blockade. In the whole group, oxidative stress (P>0.05) and FMD did not change with MR blockade (6.39±0.67 vs. 6.23±0.73 %, P=0.7, placebo vs. Eplerenone). However, individual improvements in FMD in response to Eplerenone were associated with higher total body fat (body mass index: r=0.45, P=0.02 and DXA-derived % body fat: r=0.50, P=0.009) and abdominal fat (total: r=0.61, P=0.005, visceral: r=0.67, P=0.002 and subcutaneous: r=0.48, P=0.03). In addition, greater improvements in FMD with Eplerenone were related with higher baseline fasting glucose (r=0.53, P=0.01). MR influence vascular endothelial function in an adiposity-dependent manner in healthy older adults. PMID:23786536

  2. Assessing vascular endothelial function using frequency and rank order statistics

    NASA Astrophysics Data System (ADS)

    Wu, Hsien-Tsai; Hsu, Po-Chun; Sun, Cheuk-Kwan; Liu, An-Bang; Lin, Zong-Lin; Tang, Chieh-Ju; Lo, Men-Tzung

    2013-08-01

    Using frequency and rank order statistics (FROS), this study analyzed the fluctuations in arterial waveform amplitudes recorded from an air pressure sensing system before and after reactive hyperemia (RH) induction by temporary blood flow occlusion to evaluate the vascular endothelial function of aged and diabetic subjects. The modified probability-weighted distance (PWD) calculated from the FROS was compared with the dilatation index (DI) to evaluate its validity and sensitivity in the assessment of vascular endothelial function. The results showed that the PWD can provide a quantitative determination of the structural changes in the arterial pressure signals associated with regulation of vascular tone and blood pressure by intact vascular endothelium after the application of occlusion stress. Our study suggests that the use of FROS is a reliable noninvasive approach to the assessment of vascular endothelial degeneration in aging and diabetes.

  3. Diverticular Disease of the Colon: Neuromuscular Function Abnormalities.

    PubMed

    Bassotti, Gabrio; Villanacci, Vincenzo; Bernardini, Nunzia; Dore, Maria P

    2016-10-01

    Colonic diverticular disease is a frequent finding in daily clinical practice. However, its pathophysiological mechanisms are largely unknown. This condition is likely the result of several concomitant factors occurring together to cause anatomic and functional abnormalities, leading as a result to the outpouching of the colonic mucosa. A pivotal role seems to be played by an abnormal colonic neuromuscular function, as shown repeatedly in these patients, and by an altered visceral perception. There is recent evidence that these abnormalities might be related to the derangement of the enteric innervation, to an abnormal distribution of mucosal neuropeptides, and to low-grade mucosal inflammation. The latter might be responsible for the development of visceral hypersensitivity, often causing abdominal pain in a subset of these patients. PMID:27622368

  4. Metformin improves endothelial function in aortic tissue and microvascular endothelial cells subjected to diabetic hyperglycaemic conditions.

    PubMed

    Ghosh, Suparna; Lakshmanan, Arun P; Hwang, Mu Ji; Kubba, Haidar; Mushannen, Ahmed; Triggle, Chris R; Ding, Hong

    2015-12-01

    The cellular mechanisms whereby metformin, the first line drug for type 2 diabetes (T2DM), mediates its antidiabetic effects remain elusive, particularly as to whether metformin has a direct protective action on the vasculature. This study was designed to determine if a brief 3-h exposure to metformin protects endothelial function against the effects of hyperglycaemia. We investigated the protective effects of metformin on endothelial-dependent vasodilatation (EDV) in thoracic aortae from T2DM db/db mice and on high glucose (HG, 40 mM) induced changes in endothelial nitric oxide synthase (eNOS) signaling in mouse microvascular endothelial cells (MMECs) in culture. Exposure of aortae from db+/? non-diabetic control mice to high glucose (HG, 40 mM) containing Krebs for 3-h significantly (P<0.05) reduced acetylcholine (ACh)-induced EDV compared to ACh-induced EDV in aortae maintained in normal glucose (NG, 11 mM) Krebs. The reduction of EDV was partially reversed following a 3-h exposure to 50 μM metformin; metformin also improved ACh-induced EDV in aortae from diabetic db/db mice. Immunoblot analysis of MMECs cultured in HG versus NG revealed a significant reduction of the ratio of phosphorylated (p-eNOS)/eNOS and p-Akt/Akt, but not the expression of total eNOS or Akt. The 3-h exposure of MMECs to metformin significantly (P<0.05) reversed the HG-induced reduction in phosphorylation of both eNOS and Akt; however, no changes were detected for phosphorylation of AMPK or the expression of SIRT1. Our data indicate that a 3-h exposure to metformin can reverse/reduce the impact of HG on endothelial function, via mechanisms linked to increased phosphorylation of eNOS and Akt.

  5. RASA1 functions in EPHB4 signaling pathway to suppress endothelial mTORC1 activity

    PubMed Central

    Kawasaki, Jun; Aegerter, Sandrine; Fevurly, R. Dawn; Mammoto, Akiko; Mammoto, Tadanori; Sahin, Mustafa; Mably, John D.; Fishman, Steven J.; Chan, Joanne

    2014-01-01

    Vascular malformations are linked to mutations in RAS p21 protein activator 1 (RASA1, also known as p120RasGAP); however, due to the global expression of this gene, it is unclear how these mutations specifically affect the vasculature. Here, we tested the hypothesis that RASA1 performs a critical effector function downstream of the endothelial receptor EPHB4. In zebrafish models, we found that either RASA1 or EPHB4 deficiency induced strikingly similar abnormalities in blood vessel formation and function. Expression of WT EPHB4 receptor or engineered receptors with altered RASA1 binding revealed that the ability of EPHB4 to recruit RASA1 is required to restore blood flow in EPHB4-deficient animals. Analysis of EPHB4-deficient zebrafish tissue lysates revealed that mTORC1 is robustly overactivated, and pharmacological inhibition of mTORC1 in these animals rescued both vessel structure and function. Furthermore, overexpression of mTORC1 in endothelial cells exacerbated vascular phenotypes in animals with reduced EPHB4 or RASA1, suggesting a functional EPHB4/RASA1/mTORC1 signaling axis in endothelial cells. Tissue samples from patients with arteriovenous malformations displayed strong endothelial phospho-S6 staining, indicating increased mTORC1 activity. These results indicate that deregulation of EPHB4/RASA1/mTORC1 signaling in endothelial cells promotes vascular malformation and suggest that mTORC1 inhibitors, many of which are approved for the treatment of certain cancers, should be further explored as a potential strategy to treat patients with vascular malformations. PMID:24837431

  6. Reconciling abnormalities of brain network structure and function in schizophrenia.

    PubMed

    Fornito, Alex; Bullmore, Edward T

    2015-02-01

    Schizophrenia is widely regarded as a disorder of abnormal brain connectivity. Magnetic resonance imaging (MRI) suggests that patients show robust reductions of structural connectivity. However, corresponding changes in functional connectivity do not always follow, with increased functional connectivity being reported in many cases. Here, we consider different methodological and mechanistic accounts that might reconcile these apparently contradictory findings and argue that increased functional connectivity in schizophrenia likely represents a pathophysiological dysregulation of brain activity arising from abnormal neurodevelopmental wiring of structural connections linking putative hub regions of association cortex to other brain areas. Elucidating the pathophysiological significance of connectivity abnormalities in schizophrenia will be contingent on better understanding how network structure shapes and constrains function.

  7. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia.

    PubMed Central

    Stroes, E; Kastelein, J; Cosentino, F; Erkelens, W; Wever, R; Koomans, H; Lüscher, T; Rabelink, T

    1997-01-01

    In hypercholesterolemia, impaired nitric oxide activity has been associated with increased nitric oxide degradation by oxygen radicals. Deficiency of tetrahydrobiopterin, an essential cofactor of nitric oxide synthase, causes both impaired nitric oxide activity and increased oxygen radical formation. In this study we tested whether tetrahydrobiopterin deficiency contributes to the decreased nitric oxide activity observed in hypercholesterolemic patients. Therefore, L-mono-methyl-arginine to inhibit basal nitric oxide activity, serotonin to stimulate nitric oxide activity, and nitroprusside as endothelium-independent vasodilator were infused in the brachial artery of 13 patients with familial hypercholesterolemia and 13 matched controls. The infusions were repeated during coinfusion of L-arginine (200 microg/kg/min), tetrahydrobiopterin (500 microg/min), or the combination of both compounds. Forearm vasomotion was assessed using forearm venous occlusion plethysmography and expressed as ratio of blood flow between measurement and control arm (M/C ratio). Tetrahydrobiopterin infusion alone did not alter M/C ratio. Both the attenuated L-mono-methyl-arginine-induced vasoconstriction as well as the impaired serotonin-induced vasodilation were restored in patients during tetrahydrobiopterin infusion. Tetrahydrobiopterin had no effect in controls. In conclusion, this study demonstrates restoration of endothelial dysfunction by tetrahydrobiopterin suppletion in hypercholesterolemic patients. PMID:9011574

  8. Involvement of Local Lamellipodia in Endothelial Barrier Function

    PubMed Central

    Breslin, Jerome W.; Zhang, Xun E.; Worthylake, Rebecca A.; Souza-Smith, Flavia M.

    2015-01-01

    Recently we observed that endothelial cells cultured in tightly confluent monolayers display frequent local lamellipodia, and that thrombin, an agent that increases endothelial permeability, reduces lamellipodia protrusions. This led us to test the hypothesis that local lamellipodia contribute to endothelial barrier function. Movements of subcellular structures containing GFP-actin or VE-cadherin-GFP expressed in endothelial cells were recorded using time-lapse microscopy. Transendothelial electrical resistance (TER) served as an index of endothelial barrier function. Changes in both lamellipodia dynamics and TER were assessed during baseline and after cells were treated with either the barrier-disrupting agent thrombin, or the barrier-stabilizing agent sphingosine-1-phosphate (S1P). The myosin II inhibitor blebbistatin was used to selectively block lamellipodia formation, and was used to test their role in the barrier function of endothelial cell monolayers and isolated, perfused rat mesenteric venules. Myosin light chain (MLC) phosphorylation was assessed by immunofluorescence microscopy. Rac1 and RhoA activation were evaluated using G-LISA assays. The role of Rac1 was tested with the specific inhibitor NSC23766 or by expressing wild-type or dominant negative GFP-Rac1. The results show that thrombin rapidly decreased both TER and the lamellipodia protrusion frequency. S1P rapidly increased TER in association with increased protrusion frequency. Blebbistatin nearly abolished local lamellipodia protrusions while cortical actin fibers and stress fibers remained intact. Blebbistatin also significantly decreased TER of cultured endothelial cells and increased permeability of isolated rat mesenteric venules. Both thrombin and S1P increased MLC phosphorylation and activation of RhoA. However, thrombin and S1P had differential impacts on Rac1, correlating with the changes in TER and lamellipodia protrusion frequency. Overexpression of Rac1 elevated, while NSC23766 and

  9. Involvement of local lamellipodia in endothelial barrier function.

    PubMed

    Breslin, Jerome W; Zhang, Xun E; Worthylake, Rebecca A; Souza-Smith, Flavia M

    2015-01-01

    Recently we observed that endothelial cells cultured in tightly confluent monolayers display frequent local lamellipodia, and that thrombin, an agent that increases endothelial permeability, reduces lamellipodia protrusions. This led us to test the hypothesis that local lamellipodia contribute to endothelial barrier function. Movements of subcellular structures containing GFP-actin or VE-cadherin-GFP expressed in endothelial cells were recorded using time-lapse microscopy. Transendothelial electrical resistance (TER) served as an index of endothelial barrier function. Changes in both lamellipodia dynamics and TER were assessed during baseline and after cells were treated with either the barrier-disrupting agent thrombin, or the barrier-stabilizing agent sphingosine-1-phosphate (S1P). The myosin II inhibitor blebbistatin was used to selectively block lamellipodia formation, and was used to test their role in the barrier function of endothelial cell monolayers and isolated, perfused rat mesenteric venules. Myosin light chain (MLC) phosphorylation was assessed by immunofluorescence microscopy. Rac1 and RhoA activation were evaluated using G-LISA assays. The role of Rac1 was tested with the specific inhibitor NSC23766 or by expressing wild-type or dominant negative GFP-Rac1. The results show that thrombin rapidly decreased both TER and the lamellipodia protrusion frequency. S1P rapidly increased TER in association with increased protrusion frequency. Blebbistatin nearly abolished local lamellipodia protrusions while cortical actin fibers and stress fibers remained intact. Blebbistatin also significantly decreased TER of cultured endothelial cells and increased permeability of isolated rat mesenteric venules. Both thrombin and S1P increased MLC phosphorylation and activation of RhoA. However, thrombin and S1P had differential impacts on Rac1, correlating with the changes in TER and lamellipodia protrusion frequency. Overexpression of Rac1 elevated, while NSC23766 and

  10. Abnormal Functional Connectivity in Autism Spectrum Disorders during Face Processing

    ERIC Educational Resources Information Center

    Kleinhans, Natalia M.; Richards, Todd; Sterling, Lindsey; Stegbauer, Keith C.; Mahurin, Roderick; Johnson, L. Clark; Greenson, Jessica; Dawson, Geraldine; Aylward, Elizabeth

    2008-01-01

    Abnormalities in the interactions between functionally linked brain regions have been suggested to be associated with the clinical impairments observed in autism spectrum disorders (ASD). We investigated functional connectivity within the limbic system during face identification; a primary component of social cognition, in 19 high-functioning…

  11. Brief Report: Brain Mechanisms in Autism: Functional and Structural Abnormalities.

    ERIC Educational Resources Information Center

    Minshew, Nancy J.

    1996-01-01

    This paper summarizes results of research on functional and structural abnormalities of the brain in autism. The current concept of causation is seen to involve multiple biologic levels. A consistent profile of brain function and dysfunction across methods has been found and specific neuropathologic findings have been found; but some research…

  12. Electrical method for detection of endothelial cell shape change in real time: assessment of endothelial barrier function.

    PubMed Central

    Tiruppathi, C; Malik, A B; Del Vecchio, P J; Keese, C R; Giaever, I

    1992-01-01

    We have developed an electrical method to study endothelial cell shape changes in real time in order to examine the mechanisms of alterations in the endothelial barrier function. Endothelial shape changes were quantified by using a monolayer of endothelial cells grown on a small (10(-3) cm2) evaporated gold electrode and measuring the changes in electrical impedance. Bovine pulmonary microvessel endothelial cells and bovine pulmonary artery endothelial cells were used to study the effects of alpha-thrombin on cell-shape dynamics by the impedance measurement. alpha-Thrombin produced a dose-dependent decrease in impedance that occurred within 0.5 min in both cell types, indicative of retraction of endothelial cells and widening of interendothelial junctions because of "rounding up" of the cells. The alpha-thrombin-induced decrease in impedance persisted for approximately 2 hr, after which the value recovered to basal levels. Pretreatment of endothelial cells with the protein kinase C inhibitor, calphostin C, or with 8-bromoadenosine 3',5'-cyclic monophosphate prevented the decreased impedance, suggesting that the endothelial cell change is modulated by activation of second-messenger pathways. The alpha-thrombin-induced decrease in impedance was in agreement with the previously observed increases in transendothelial albumin permeability and evidence of formation of intercellular gaps after alpha-thrombin challenge. The impedance measurement may be a valuable in vitro method for the assessment of mechanisms of decreased endothelial barrier function occurring with inflammatory mediators. Since the rapidly occurring changes in endothelial cell shape in response to mediators such as thrombin are mediated activation of second-messenger pathways, the ability to monitor endothelial cell dynamics in real time may provide insights into the signal-transduction events mediating the increased endothelial permeability. PMID:1518814

  13. Endothelial function, folate pharmacogenomics, and neurocognition in psychotic disorders.

    PubMed

    Grove, Tyler; Taylor, Stephan; Dalack, Gregory; Ellingrod, Vicki

    2015-05-01

    Cardiovascular disease (CVD) is a well-described complication of schizophrenia, however, mechanisms connecting CVD with other facets of psychotic disorders, such as neurocognition, are not understood. The current study examined folate metabolism as a potential mechanism of CVD and neurocognitive deficits by: 1) using endothelial dysfunction as a biomarker of CVD, and 2) comparing enzymes associated with neurocognition, CVD, and critical to folate metabolism, methylenetetrahydrofolate reductase (MTHFR) and catechol-o-methyl transferase (COMT). Endothelial function was assessed in 147 participants with schizophrenia, schizoaffective disorder, and psychotic disorder not otherwise specified grouped by MTHFR and COMT allele status. Regression models were used to compare neurocognitive performance based on the Brief Assessment of Cognition in Schizophrenia (BACS). Overall, endothelial function predicted BACS composite z-scores after controlling for age, race, level of education, serum folate levels, and MTHFR/COMT risk allele status. Participants with at least one or more MTHFR and/or COMT risk alleles had lower BACS Composite and BACS Symbol Coding adjusted mean z-scores than those with both MTHFR CC and COMT Met/Met genotypes. Thus, endothelial dysfunction may contribute to the neurocognitive deficits seen in psychotic disorders. CVD interventions may not only reduce CVD-related morbidity, but also lessen progressive neurocognitive deficits reported in psychotic disorders.

  14. [The general practitioner and abnormal liver function tests].

    PubMed

    Hallez, R

    1997-09-01

    In case of abnormal liver function tests, it's necessary to distinguish different situations, starting from this first data. We will successively consider: the high and moderate acute increases of aminotransferase, the chronic increases of aminotransferase, the isolated cholestase picture and the isolated increases of gamma GT or of bilirubine. We will finish with a partial survey about drug-induced liver diseases.

  15. XIAP reverses various functional activities of FRNK in endothelial cells

    SciTech Connect

    Ahn, Sunyoung; Kim, Hyun Jeong; Chi, Sung-Gil; Park, Heonyong

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer FRNK domain is recruited into focal adhesion (FA), controlling endothelial cell adhesion. Black-Right-Pointing-Pointer XIAP binds the FRNK domain of FAK. Black-Right-Pointing-Pointer XIAP inhibits recruitment of FRNK into Fas and FRNK-promoted cell adhesion. Black-Right-Pointing-Pointer XIAP plays a key role in vascular functions of FRNK or FRNK domain-mediated vascular functions of FAK. -- Abstract: In endothelial cells, focal adhesion kinase (FAK) regulates cell proliferation, migration, adhesion, and shear-stimulated activation of MAPK. We recently found that FAK is recruited into focal adhesion (FA) sites through interactions with XIAP (X-chromosome linked inhibitor of apoptosis protein) and activated by Src kinase in response to shear stress. In this study, we examined which domain(s) of FAK is(are) important for various vascular functions such as FA recruiting, XIAP-binding and shear stress-stimulated ERK activation. Through a series of experiments, we determined that the FRNK domain is recruited into FA sites and promotes endothelial cell adhesion. Interestingly, XIAP knockdown was shown to reduce FA recruitment of FRNK and the cell adhesive effect of FRNK. In addition, we found that XIAP interacts with FRNK, suggesting cross-talk between XIAP and FRNK. We also demonstrated that FRNK inhibits endothelial cell migration and shear-stimulated ERK activation. These inhibitory effects of FRNK were reversed by XIAP knockdown. Taken together, we can conclude that XIAP plays a key role in vascular functions of FRNK or FRNK domain-mediated vascular functions of FAK.

  16. The Association between Circulating MicroRNA Levels and Coronary Endothelial Function

    PubMed Central

    Widmer, R. Jay; Chung, Woo-Young; Herrmann, Joerg; Jordan, Kyra L.; Lerman, Lilach O.; Lerman, Amir

    2014-01-01

    Human microRNAs (miRs) have been implicated in human diseases presumably through the downregulation and silencing of targeted genes via post-translational modifications. However, their role in the early stage of coronary atherosclerosis is not known. The aim of this study was to test the hypothesis that patients with early atherosclerosis and coronary endothelial dysfunction (CED) have alterations in transcoronary miR gradients. Patients underwent coronary angiography and endothelial function testing in the cardiac catheterization laboratory. Patients were divided into abnormal (n = 26) and normal (n = 22) microvascular coronary endothelial function based on intracoronary response to infused acetylcholine measured as a percent change in coronary blood flow (CBF) and arterial diameter. Blood samples were obtained simultaneously from the aorta and coronary sinus at the time of catheterization for RNA isolation, and miR subsequently assessed. Baseline characteristics were similar in both groups. Patients with microvascular CED displayed transcoronary gradients significantly elevated in miR-92a and miR-133 normalized to C-elegans-39 miR. Percent change in CBF and the transcoronary gradient of miR-133 displayed a significant inverse correlation (r2 = 0.11, p = 0.03). Thus, we present novel data whereupon selected miRs demonstrate elevated transcoronary gradients in patients with microvascular CED. The current findings support further studies on the mechanistic role of miRs in coronary atherosclerosis and in humans. PMID:25310838

  17. Differences in endothelial function between Korean-Asians and Caucasians

    PubMed Central

    Yim, Jongeun; Petrofsky, Jerrold; Berk, Lee; Daher, Noha; Lohman, Everett

    2012-01-01

    Summary Background The vascular endothelium plays an integral role in maintaining vascular homeostasis, including the regulation of blood flow, vascular tone, and platelet aggregation. The aim of this study was to see if there were any differences in endothelial function between Koreans and Caucasians. Material/Methods This was accomplished by 2 measures of endothelial function – the response to local heat and the response to vascular occlusion. Ten Caucasian and 10 Korean male and female subjects participated (<35 years old). Endothelial function was assessed by the skin blood flow response to local heat using a thermode for 6 minutes at 3 temperatures (38°C, 40°C and 42°C) and by vascular occlusion for 4 minutes followed by release and measurement of skin blood flow for 2 minutes. Results When applying 6 minutes of local heat at 3 different temperatures (38°C, 40°C, and 42°C), the skin blood flows were significantly higher for all temperatures in Caucasians as compared with Koreans, with peak blood flow of 223±48.1, 413.7±132.1, and 517.4±135.8 flux in Caucasians and 126.4±41.3, 251±77.9, and 398±97.2 flux in Koreans, respectively (p=0.001). Results of this study support the idea that the skin blood flow response to occlusion was significantly higher in Caucasians (peak 411.9±88.9 flux) than Koreans (peak 332.4±75.8 flux) (p=0.016). Conclusions These findings suggest that Koreans may have lower endothelial function than Caucasians, which may be explained, in part, by genetic variations between the 2 ethnic groups. PMID:22648248

  18. Comparison of peripheral endothelial function in shift versus nonshift workers.

    PubMed

    Suessenbacher, Alois; Potocnik, Miriam; Dörler, Jakob; Fluckinger, Gabriele; Wanitschek, Maria; Pachinger, Otmar; Frick, Matthias; Alber, Hannes F

    2011-03-15

    Shift working is related to increased cardiovascular morbidity. Peripheral endothelial dysfunction, an inherent feature of early atherosclerosis, has been suggested as a surrogate marker of cardiovascular risk. Whether shift working is associated with peripheral endothelial dysfunction has not been investigated to date. A total of 48 male shift workers (SWs) and 47 male nonshift workers (NSWs) (mean age 43 ± 5 years) were recruited from a glass manufactory. The SWs and NSWs were matched according to age, body mass index, smoking habits, family history of premature coronary artery disease, prevalence of hypercholesterolemia and hypertension, and work place. Their sport habits were also documented. Peripheral endothelial function was assessed using the EndoPAT technique to determine the peripheral arterial tone (PAT) index. According to the study design, no difference was found in the risk factor profiles between the SWs and NSWs. Despite a greater percentage of regular physical activity among the SWs (16.7 vs 4.3%, p = 0.05), shift working was associated with a reduced PAT index compared to working only on the day shift (PAT index 1.73 ± 0.4 vs 1.94 ± 0.5, p = 0.03). In the NSW group, the participants with regular physical training (n = 16) had a greater PAT index than those without regular physical activity (n = 12; PAT index 2.28 ± 0.45 vs 1.86 ± 0.51, p = 0.03). No such difference was found in the SWs. In conclusion, SWs had a reduced PAT index compared with NSWs, suggesting endothelial dysfunction. Therefore, the known increased cardiovascular risk in those shift working might be related to endothelial dysfunction.

  19. Connectivity and functional profiling of abnormal brain structures in pedophilia

    PubMed Central

    Poeppl, Timm B.; Eickhoff, Simon B.; Fox, Peter T.; Laird, Angela R.; Rupprecht, Rainer; Langguth, Berthold; Bzdok, Danilo

    2015-01-01

    Despite its 0.5–1% lifetime prevalence in men and its general societal relevance, neuroimaging investigations in pedophilia are scarce. Preliminary findings indicate abnormal brain structure and function. However, no study has yet linked structural alterations in pedophiles to both connectional and functional properties of the aberrant hotspots. The relationship between morphological alterations and brain function in pedophilia as well as their contribution to its psychopathology thus remain unclear. First, we assessed bimodal connectivity of structurally altered candidate regions using meta-analytic connectivity modeling (MACM) and resting-state correlations employing openly accessible data. We compared the ensuing connectivity maps to the activation likelihood estimation (ALE) maps of a recent quantitative meta-analysis of brain activity during processing of sexual stimuli. Second, we functionally characterized the structurally altered regions employing meta-data of a large-scale neuroimaging database. Candidate regions were functionally connected to key areas for processing of sexual stimuli. Moreover, we found that the functional role of structurally altered brain regions in pedophilia relates to nonsexual emotional as well as neurocognitive and executive functions, previously reported to be impaired in pedophiles. Our results suggest that structural brain alterations affect neural networks for sexual processing by way of disrupted functional connectivity, which may entail abnormal sexual arousal patterns. The findings moreover indicate that structural alterations account for common affective and neurocognitive impairments in pedophilia. The present multi-modal integration of brain structure and function analyses links sexual and nonsexual psychopathology in pedophilia. PMID:25733379

  20. Abnormal thalamocortical structural and functional connectivity in juvenile myoclonic epilepsy

    PubMed Central

    O’Muircheartaigh, Jonathan; Vollmar, Christian; Barker, Gareth J.; Kumari, Veena; Symms, Mark R.; Thompson, Pam; Duncan, John S.; Koepp, Matthias J.

    2012-01-01

    Juvenile myoclonic epilepsy is the most common idiopathic generalized epilepsy, characterized by frequent myoclonic jerks, generalized tonic-clonic seizures and, less commonly, absences. Neuropsychological and, less consistently, anatomical studies have indicated frontal lobe dysfunction in the disease. Given its presumed thalamo–cortical basis, we investigated thalamo–cortical structural connectivity, as measured by diffusion tensor imaging, in a cohort of 28 participants with juvenile myoclonic epilepsy and detected changes in an anterior thalamo–cortical bundle compared with healthy control subjects. We then investigated task-modulated functional connectivity from the anterior thalamic region identified using functional magnetic resonance imaging in a task consistently shown to be impaired in this group, phonemic verbal fluency. We demonstrate an alteration in task-modulated connectivity in a region of frontal cortex directly connected to the thalamus via the same anatomical bundle, and overlapping with the supplementary motor area. Further, we show that the degree of abnormal connectivity is related to disease severity in those with active seizures. By integrating methods examining structural and effective interregional connectivity, these results provide convincing evidence for abnormalities in a specific thalamo–cortical circuit, with reduced structural and task-induced functional connectivity, which may underlie the functional abnormalities in this idiopathic epilepsy. PMID:23250883

  1. Impaired endothelial function and blood flow in repetitive strain injury.

    PubMed

    Brunnekreef, J; Brunnekreef, J J; Benda, N; Benda, N M M; Schreuder, T; Schreuder, T H A; Hopman, M; Hopman, M T E; Thijssen, D; Thijssen, D H J

    2012-10-01

    Repetitive Strain Injury (RSI) is a disabling upper extremity overuse injury that may be associated with pathophysiological changes in the vasculature. In this study we investigated whether RSI is associated with endothelial dysfunction and impaired exercise-induced blood flow in the affected forearm. 10 patients with RSI (age, 40.2 ± 10.3; BMI, 23.8 ± 3.3) and 10 gender- and age-matched control subjects (age, 38.0 ± 12.4; BMI, 22.7 ± 3.4) participated in this study. Brachial artery blood flow was measured at rest and during 3-min periods of isometric handgrip exercise at 15%, 30% and 45% of the individual maximal voluntary contraction. Brachial artery endothelial function was assessed as the flow mediated dilation (FMD), by measuring brachial artery diameter and velocity before and after 5-min ischemic occlusion. We found a lower exercise-induced brachial artery blood flow in patients with RSI than in controls (p=0.04). Brachial artery FMD was significantly lower in patients with RSI than in controls (p<0.01), whilst a lower FMD was also found in patient with unilateral RSI when comparing the affected arm with the non-affected arm (p=0.04). Our results suggest that patients with RSI have an attenuated exercise-induced blood flow and an impaired endothelial function in the affected arm. These findings importantly improve our understanding of the pathophysiological mechanism of RSI.

  2. The role of BMPs in endothelial cell function and dysfunction.

    PubMed

    Dyer, Laura A; Pi, Xinchun; Patterson, Cam

    2014-09-01

    The bone morphogenetic protein (BMP) family of proteins has a multitude of roles throughout the body. In embryonic development, BMPs promote endothelial specification and subsequent venous differentiation. The BMP pathway also plays important roles in the adult vascular endothelium, promoting angiogenesis and mediating shear and oxidative stress. The canonical BMP pathway functions through the Smad transcription factors; however, other intracellular signaling cascades can be activated, and receptor complexes beyond the traditional type I and type II receptors add additional layers of regulation. Dysregulated BMP signaling has been linked to vascular diseases including pulmonary hypertension and atherosclerosis. This review addresses recent advances in the roles of BMP signaling in the endothelium and how BMPs affect endothelial dysfunction and human disease. PMID:24908616

  3. Epoxyeicosatrienoic Acids and 20-Hydroxyeicosatetraenoic Acid on Endothelial and Vascular Function.

    PubMed

    Imig, J D

    2016-01-01

    Endothelial and vascular smooth cells generate cytochrome P450 (CYP) arachidonic acid metabolites that can impact endothelial cell function and vascular homeostasis. The objective of this review is to focus on the physiology and pharmacology of endothelial CYP metabolites. The CYP pathway produces two types of eicosanoid products: epoxyeicosatrienoic acids (EETs), formed by CYP epoxygenases, and hydroxyeicosatetraenoic acids (HETEs), formed by CYP hydroxylases. Advances in CYP enzymes, EETs, and 20-HETE by pharmacological and genetic means have led to a more complete understanding of how these eicosanoids impact on endothelial cell function. Endothelial-derived EETs were initially described as endothelial-derived hyperpolarizing factors. It is now well recognized that EETs importantly contribute to numerous endothelial cell functions. On the other hand, 20-HETE is the predominant CYP hydroxylase synthesized by vascular smooth muscle cells. Like EETs, 20-HETE acts on endothelial cells and impacts importantly on endothelial and vascular function. An important aspect for EETs and 20-HETE endothelial actions is their interactions with hormonal and paracrine factors. These include interactions with the renin-angiotensin system, adrenergic system, puringeric system, and endothelin. Alterations in CYP enzymes, 20-HETE, or EETs contribute to endothelial dysfunction and cardiovascular diseases such as ischemic injury, hypertension, and atherosclerosis. Recent advances have led to the development of potential therapeutics that target CYP enzymes, 20-HETE, or EETs. Thus, future investigation is required to obtain a more complete understanding of how CYP enzymes, 20-HETE, and EETs regulate endothelial cell function.

  4. Interrogating TGF-β Function and Regulation in Endothelial Cells.

    PubMed

    Maring, J A; van Meeteren, L A; Goumans, M J; Ten Dijke, Peter

    2016-01-01

    Transforming growth factor-β (TGF-β) is a multifunctional cytokine with important roles in embryogenesis and maintaining tissue homeostasis during adult life. There are three isoforms of TGF-β, i.e., TGF-β1, -β2, and -β3, which signal by binding to a complex of transmembrane type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. In most cell types TGF-β signals via TGF-β type II receptor (TβRII) and TβRI, also termed activin receptor-like kinase 5 (ALK5). In endothelial cells, TGF-β signals via ALK5 and ALK1. These two type I receptors mediate opposite cellular response for TGF-β. The co-receptor endoglin, highly expressed on proliferating endothelial cells, facilitates TGF-β/ALK1 and inhibits TGF-β/ALK5 signaling. Knockout of TGF-β receptors in mice all result in embryonic lethality during midgestation from defects in angiogenesis, illustrating the pivotal role of TGF-β in this process. This chapter introduces methods for examining the function and regulation of TGF-β in angiogenesis in in vitro assays using cultured endothelial cells and ex vivo metatarsal explants.

  5. Abnormal fronto-striatal functional connectivity in Parkinson's disease.

    PubMed

    Xu, Jinping; Zhang, Jiuquan; Wang, Jiaojian; Li, Guanglin; Hu, Qingmao; Zhang, Yuanchao

    2016-02-01

    Parkinson's disease (PD) is characterized by the relatively selective depletion of dopamine in the striatum, which consequently leads to dysfunctions in cortico-striatal-thalamic-cortical circuitries. It has been shown that the most common cognitive deficits in PD patients are related to the fronto-striatal circuits. In PD, most previous functional connectivity studies have been performed using seed-based methods to identify the brain regions that are abnormally connected to one or more seeds, but these cannot be used to quantify the interactions between one region and all other regions in a particular network. Functional connectivity degree, which is a measurement that can be used to quantify the functional or structural connectivity of a complex brain network, was adopted in this study to assess the interactions of the fronto-striatal network. Compared to healthy controls, PD patients had significantly decreased total functional connectivity degree for the left putamen and the right globus pallidum in fronto-striatal networks. Additionally, negative correlations between the fronto-pallial functional connectivity degree (i.e., the right globus pallidum with the left middle frontal gyrus, and with the right triangular part of inferior frontal gyrus) and disease duration were observed in PD patients. The results of this study demonstrate that fronto-striatal functional connectivity is abnormal in patients with PD and indicate that these deficits might be the result of motor and cognitive dysfunctions in PD patients. PMID:26724369

  6. Loss of cystic fibrosis transmembrane conductance regulator impairs lung endothelial cell barrier function and increases susceptibility to microvascular damage from cigarette smoke

    PubMed Central

    2014-01-01

    Abstract Abnormal lung microvascular endothelial vascular barrier function may contribute to pulmonary inflammation, such as that occurring during inhalation of cigarette smoke (CS). Cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel expressed in both epithelial and endothelial cells, regulates the organization of tight junctions between epithelial cells and has also been implicated in the transport of sphingosine-1 phosphate (S1P), a vascular barrier–enhancing sphingolipid. Because CS has been shown to affect CFTR function, we hypothesized that CFTR function contributes to lung endothelial cell barrier and that CFTR dysfunction worsens CS-induced injury. CFTR inhibitors GlyH-101 or CFTRinh172 caused a dose-dependent increase in pulmonary or bronchial endothelial monolayer permeability, which peaked after 4 hours. CFTR inhibition was associated with both intercellular gaps and actin stress fiber formation compared with vehicle-treated cells. Increasing endothelial S1P, either by exogenous treatment or by inhibition of its degradation, significantly improved the barrier function in CFTR-inhibited monolayers. Both cultured lung endothelia and the lung microcirculation visualized in vivo with intravital two-photon imaging of transgenic mice deficient in CFTR showed that CFTR dysfunction increased susceptibility to CS-induced permeability. These results suggested that CFTR function might be required for lung endothelial barrier, including adherence junction stability. Loss of CFTR function, especially concomitant to CS exposure, might promote lung inflammation by increasing endothelial cell permeability, which could be ameliorated by S1P. PMID:25006445

  7. Effect of ramipril therapy on abnormal left atrial appendage function.

    PubMed

    Asker, M; Timucin, O B; Asker, S; Karadag, M F

    2011-01-01

    This study investigated whether ramipril treatment has a beneficial effect on left atrial appendage (LAA) function in patients with systemic hypertension in sinus rhythm. Patients with untreated systemic hypertension and normal left ventricular systolic function in sinus rhythm (n = 20; six males/14 females; age 35 - 69 years, mean ± SD 52.8 ± 8.9 years) were evaluated using transthoracic and transoesophageal echocardiography at baseline and after 6 months of treatment with 5 mg/day ramipril. Mean systolic and diastolic blood pressures decreased significantly after ramipril therapy. Baseline LAA emptying velocity was below the age-related reference value for this parameter, indicating abnormal LAA function. There were significant increases in the LAA filling and emptying velocities after ramipril treatment. It is concluded that the decrease in blood pressure and haemodynamic improvements brought about by ramipril therapy resulted in improved LAA function in hypertensive patients with normal left ventricular systolic function in sinus rhythm.

  8. Angiocrine functions of organ-specific endothelial cells

    PubMed Central

    Rafii, Shahin; Butler, Jason M; Ding, Bi-Sen

    2016-01-01

    Preface Endothelial cells lining blood vessel capillaries are not just passive conduits for delivering blood. Tissue-specific endothelium establish specialized vascular niches that deploy specific sets of growth factors, known as angiocrine factors, which actively participate in inducing, specifying, patterning, and guiding organ regeneration and maintaining homeostasis and metabolism. Angiocrine factors upregulated in response to injury orchestrates self-renewal and differentiation of tissue-specific repopulating resident stem and progenitor cells into functional organs. Uncovering the precise mechanisms whereby physiological-levels of angiocrine factors are spatially and temporally produced, and distributed by organotypic endothelium to repopulating cells, will lay the foundation for driving organ repair without scarring. PMID:26791722

  9. Abnormalities of vascular structure and function in pediatric hypertension.

    PubMed

    Urbina, Elaine M

    2016-07-01

    Hypertension is associated with adverse cardiovascular (CV) events in adults. Measures of vascular structure and function, including increased carotid intima-media thickness (cIMT) and elevated arterial stiffness predict hard CV events in adulthood. Newer data suggest that abnormalities in target organ damage are occurring in adolescents and young adults with high blood pressure. In this review, we discuss the techniques for measuring vascular dysfunction in young people and the evidence linking blood pressure levels to this type of target organ damage.

  10. Assessment of endothelial and neurovascular function in human skin microcirculation.

    PubMed

    Roustit, Matthieu; Cracowski, Jean-Luc

    2013-07-01

    Peripheral microvascular dysfunction has been described in many physiological and pathological conditions. Owing to its accessibility, the cutaneous microcirculation provides a unique index of microvascular function. Skin microvascular function has therefore been proposed as a prognostic marker or for evaluating the effect of drugs on the microcirculation. Various reactivity tests, coupled with techniques measuring skin blood flux, are used to non-invasively explore both endothelial and neurovascular microvascular functioning in humans. We review the advantages and limitations of the main reactivity tests, including post-occlusive reactive hyperemia, local thermal hyperemia, pressure-induced vasodilation, and iontophoresis of vasodilators, combined with measurement techniques such as laser Doppler and laser speckle contrast imaging. Recent advances in our comprehension of the physiological pathways underlying these reactivity tests, as well as technological developments in microcirculation imaging, have provided reliable and reproducible tools for studying the microcirculation.

  11. Exercise training improves endothelial function in young prehypertensives

    PubMed Central

    Beck, Darren T; Casey, Darren P; Martin, Jeffrey S; Emerson, Blaze D; Braith, Randy W

    2015-01-01

    Prehypertensives exhibit marked endothelial dysfunction, a risk factor for future cardiovascular morbidity and mortality. However, the ability of exercise to ameliorate endothelial dysfunction in prehypertensives is grossly underinvestigated. This prospective randomized and controlled study examined the separate effects of resistance and endurance training on conduit artery endothelial function in young prehypertensives. Forty-three unmedicated prehypertensive (systolic blood pressure [SBP]=120–139 mmHg; diastolic blood pressure [DBP]=80–89 mmHg) but otherwise healthy men and women and 15 normotensive matched time-controls (NMTC); n = 15) between 18 and 35 y of age met screening requirements and participated in the study. Prehypertensive subjects were randomly assigned to either a resistance exercise training (PHRT; n = 15), endurance exercise training (PHET; n = 13) or time-control group (PHTC; n = 15). The treatment groups performed exercise training three days per week for eight weeks. The control groups did not initiate exercise programs throughout the study. Flow mediated dilation (FMD) of the brachial artery, biomarkers of enodothelial function and peripheral blood pressure were evaluated before and after exercise intervention or time-matched control. PHRT and PHET reduced resting SBP (9.6 ± 3.6 and 11.9 ± 3.4 mmHg, respectively; P < 0.05) and DBP (8.0 ± 5.1 and 7.2 ± 3.4 mmHg, respectively; P < 0.05). Exercise training improved brachial artery FMD absolute diameter, percent dilation and normalized percent dilation by 30%, 34% and 19% for PHRT, P < 0.05; and by 54%, 63% and 75% for PHET, P < 0.05; respectively. PHRT and PHET increased plasma concentrations of 6-keto prostaglandin F1α (19% and 22%, respectively; P < 0.05), NOx (19% and 23%, respectively; P < 0.05), and reduced endothelin-1 by (16% and 24%, respectively; P < 0.01). This study provides novel evidence that resistance and endurance exercise separately have beneficial effects on resting

  12. Does L-carnitine improve endothelial function in hemodialysis patients?

    PubMed Central

    Sabri, Mohammad Reza; Fahimi, Farnaz; Hajialiasgar, Soheila; Etminan, Abbas; Nazemi, Sarir; Salehi, Farzaneh

    2012-01-01

    Background: Atherosclerosis is the leading cause of death in hemodialysis patients. These patients are also very prone to L-carnitine deficiency due to kidney disease. In this clinical trial, we investigated the effect of oral L-carnitine on endothelial function of these patients. Materials ans Methods: We studied 31 adult chronic hemodialysis patients in our center and divided them into two groups. The first group (n = 20) received 1500 mg/dialysis interval (every other day) oral L-carnitine. The control group (n = 11) received placebo for one month. Ultrasonographic measurements of flow mediated dilation and carotid intima-media thickness were performed before and after one month of L-carnitine and placebo therapy. Results: This study showed that after one month of L-carnitine or placebo therapy there was no significant improvement in flow mediated dilation (p = 0.80 and p = 0.59, respectively) or decrease in carotid intima-media thickness (p = 0.12 and p = 0.50, respectively). Conclusions: Our study revealed that one month of oral L-carnitine therapy did not improve endothelial function in hemodialysis patients. Long-term studies with large sample size using intravenous form and higher doses of the drug are required to clarify the questionable role of L-carnitine in hemodialysis patients. PMID:23626603

  13. Brief Exposure to Secondhand Smoke Reversibly Impairs Endothelial Vasodilatory Function

    PubMed Central

    2014-01-01

    Introduction: We sought to determine the effects of brief exposures to low concentrations of tobacco secondhand smoke (SHS) on arterial flow-mediated dilation (FMD, a nitric oxide-dependent measure of vascular endothelial function), in a controlled animal model never before exposed to smoke. In humans, SHS exposure for 30min impairs FMD. It is important to gain a better understanding of the acute effects of exposure to SHS at low concentrations and for brief periods of time. Methods: We measured changes in FMD in rats exposed to a range of real-world levels of SHS for durations of 30min, 10min, 1min, and 4 breaths (roughly 15 s). Results: We observed a dose-response relationship between SHS particle concentration over 30min and post-exposure impairment of FMD, which was linear through the range typically encountered in smoky restaurants and then saturated at higher concentrations. One min of exposure to SHS at moderate concentrations was sufficient to impair FMD. Conclusions: Brief SHS exposure at real-world levels reversibly impairs FMD. Even 1min of SHS exposure can cause reduction of endothelial function. PMID:24302638

  14. Vascular endothelium: functioning in norm, changes in atherosclerosis and current dietary approaches to improve endothelial function.

    PubMed

    Chistiakov, Dimitry A; Revin, Victor V; Sobenin, Igor A; Orekhov, Alexander N; Bobryshev, Yuri V

    2015-01-01

    The endothelium represents not only a simple cellular monolayer that lines the vascular tree in humans and other vertebrates. Depending on the location, the endothelium shows significant morphological and functional heterogeneity through differentiated expression of pro- and anticoagulant factors, presence and frequency of intercellular contacts, variable contractility, cell shape, and volume. Altogether, these properties are crucial for adjustment of the endothelial function and further maintenance of the adequate homeostasis in response in local microenvironmental changes. Endothelial cells (ECs) play a critical role in coordinated regulation of blood flow. This is achieved due to the capacity of ECs to create the active anti-thrombotic surface that supports blood fluidity and transfer of blood cells and biomolecules. However, in certain vascular regions that can occur in inflamed sites or in sites with high hydrodynamic shear stress, ECs could lost their anti-thrombotic properties and switch their normal quiescent phenotype towards the prothrombotic, proadhesion, and proinflammatory state. In such an athero-prone site, the proper endothelial function is impaired that increases risk for formation of the atherosclerotic plaque. The endothelial dysfunction not only precedes atherosclerosis but greatly contributes to atherogenesis in all disease stages. Healthy lifestyle and regular intake of correct antioxidant-rich diet such as fresh fruits, vegetables, olive oil, red wine, and tea have beneficial effects on endothelial function and could therefore reduce the cardiovascular risk. PMID:25723463

  15. Abnormal Default System Functioning in Depression: Implications for Emotion Regulation.

    PubMed

    Messina, Irene; Bianco, Francesca; Cusinato, Maria; Calvo, Vincenzo; Sambin, Marco

    2016-01-01

    Depression is widely seen as the result of difficulties in regulating emotions. Based on neuroimaging studies on voluntary emotion regulation, neurobiological models have focused on the concept of cognitive control, considering emotion regulation as a shift toward involving controlled processes associated with activation of the prefrontal and parietal executive areas, instead of responding automatically to emotional stimuli. According to such models, the weaker executive area activation observed in depressed patients is attributable to a lack of cognitive control over negative emotions. Going beyond the concept of cognitive control, psychodynamic models describe the development of individuals' capacity to regulate their emotional states in mother-infant interactions during childhood, through the construction of the representation of the self, others, and relationships. In this mini-review, we link these psychodynamic models with recent findings regarding the abnormal functioning of the default system in depression. Consistently with psychodynamic models, psychological functions associated with the default system include self-related processing, semantic processes, and implicit forms of emotion regulation. The abnormal activation of the default system observed in depression may explain the dysfunctional aspects of emotion regulation typical of the condition, such as an exaggerated negative self-focus and rumination on self-esteem issues. We also discuss the clinical implications of these findings with reference to the therapeutic relationship as a key tool for revisiting impaired or distorted representations of the self and relational objects.

  16. Abnormal Default System Functioning in Depression: Implications for Emotion Regulation

    PubMed Central

    Messina, Irene; Bianco, Francesca; Cusinato, Maria; Calvo, Vincenzo; Sambin, Marco

    2016-01-01

    Depression is widely seen as the result of difficulties in regulating emotions. Based on neuroimaging studies on voluntary emotion regulation, neurobiological models have focused on the concept of cognitive control, considering emotion regulation as a shift toward involving controlled processes associated with activation of the prefrontal and parietal executive areas, instead of responding automatically to emotional stimuli. According to such models, the weaker executive area activation observed in depressed patients is attributable to a lack of cognitive control over negative emotions. Going beyond the concept of cognitive control, psychodynamic models describe the development of individuals’ capacity to regulate their emotional states in mother-infant interactions during childhood, through the construction of the representation of the self, others, and relationships. In this mini-review, we link these psychodynamic models with recent findings regarding the abnormal functioning of the default system in depression. Consistently with psychodynamic models, psychological functions associated with the default system include self-related processing, semantic processes, and implicit forms of emotion regulation. The abnormal activation of the default system observed in depression may explain the dysfunctional aspects of emotion regulation typical of the condition, such as an exaggerated negative self-focus and rumination on self-esteem issues. We also discuss the clinical implications of these findings with reference to the therapeutic relationship as a key tool for revisiting impaired or distorted representations of the self and relational objects. PMID:27375536

  17. Abnormal Default System Functioning in Depression: Implications for Emotion Regulation.

    PubMed

    Messina, Irene; Bianco, Francesca; Cusinato, Maria; Calvo, Vincenzo; Sambin, Marco

    2016-01-01

    Depression is widely seen as the result of difficulties in regulating emotions. Based on neuroimaging studies on voluntary emotion regulation, neurobiological models have focused on the concept of cognitive control, considering emotion regulation as a shift toward involving controlled processes associated with activation of the prefrontal and parietal executive areas, instead of responding automatically to emotional stimuli. According to such models, the weaker executive area activation observed in depressed patients is attributable to a lack of cognitive control over negative emotions. Going beyond the concept of cognitive control, psychodynamic models describe the development of individuals' capacity to regulate their emotional states in mother-infant interactions during childhood, through the construction of the representation of the self, others, and relationships. In this mini-review, we link these psychodynamic models with recent findings regarding the abnormal functioning of the default system in depression. Consistently with psychodynamic models, psychological functions associated with the default system include self-related processing, semantic processes, and implicit forms of emotion regulation. The abnormal activation of the default system observed in depression may explain the dysfunctional aspects of emotion regulation typical of the condition, such as an exaggerated negative self-focus and rumination on self-esteem issues. We also discuss the clinical implications of these findings with reference to the therapeutic relationship as a key tool for revisiting impaired or distorted representations of the self and relational objects. PMID:27375536

  18. Functional abnormalities of experimental autogenous vein graft neoendothelium.

    PubMed Central

    Cross, K S; el-Sanadiki, M N; Murray, J J; Mikat, E M; McCann, R L; Hagen, P O

    1988-01-01

    When a vein is grafted into the arterial circulation, the endothelium of the graft is damaged. Regeneration of an intact neoendothelium occurs, but the functional properties of this surface have not been clarified. In this study, the functional integrity of the neoendothelium of veins grafted into the carotid artery of the rabbit was assessed through the use of acetylcholine and histamine to stimulate the production of the important endothelium-derived relaxing factor (EDRF). Control veins, precontracted with norepinephrine [10(-5) M], relaxed after exposure to acetylcholine [( 10(-7) M], 42.4% +/- 6.4%, p = 0.008) and histamine [( 10(-6) M], 30.6% +/- 4.3%, p = 0.03). This relaxation response was abolished after mechanical removal of the endothelium. By contrast, neither acetylcholine nor histamine caused an endothelium-dependent relaxation in the vein grafts, even though scanning electron microscopy demonstrated the presence of a morphologically intact endothelium. However, addition of stabilized EDRF purified from cultured endothelial cells induced relaxation of the vein grafts (35.8% +/- 3.6%, p = 0.002). These data indicate that vein graft endothelium is unable to produce EDRF in response to exposure to acetylcholine or histamine. The inability to produce this potent smooth muscle cell relaxing factor and anti-aggregatory substance may be a predisposition to vein graft failure. Images Figs. 4A-C. Fig. 4. (Continued) Fig. 4. (Continued) Figs. 5A-C. Fig. 5. (Continued) Fig. 5. (Continued) Fig. 6. PMID:3263843

  19. Abnormal Pulmonary Function in Adults with Sickle Cell Anemia

    PubMed Central

    Klings, Elizabeth S.; Wyszynski, Diego F.; Nolan, Vikki G.; Steinberg, Martin H.

    2006-01-01

    Rationale: Pulmonary complications of sickle cell anemia (Hb-SS) commonly cause morbidity, yet few large studies of pulmonary function tests (PFTs) in this population have been reported. Objectives: PFTs (spirometry, lung volumes, and diffusion capacity for carbon monoxide [DLCO]) from 310 adults with Hb-SS were analyzed to determine the pattern of pulmonary dysfunction and their association with other systemic complications of sickle cell disease. Methods: Raw PFT data were compared with predicted values. Each subject was subclassified into one of five groups: obstructive physiology, restrictive physiology, mixed obstructive/restrictive physiology, isolated low DLCO, or normal. The association between laboratory data of patients with decreased DLCO or restrictive physiology and those of normal subjects was assessed by multivariate linear regression. Measurements and Main Results: Normal PFTs were present in only 31 of 310 (10%) patients. Overall, adults with Hb-SS were characterized by decreased total lung capacities (70.2 ± 14.7% predicted) and DlCO (64.5 ± 19.9%). The most common PFT patterns were restrictive physiology (74%) and isolated low DlCO (13%). Decreased DLCO was associated with thrombocytosis (p = 0.05), with hepatic dysfunction (elevated alanine aminotransferase; p = 0.07), and a trend toward renal dysfunction (elevated blood urea nitrogen and creatinine; p = 0.05 and 0.07, respectively). Conclusions: Pulmonary function is abnormal in 90% of adult patients with Hb-SS. Common abnormalities include restrictive physiology and decreased DLCO. Decreased DLCO may indicate more severe sickle vasculopathy characterized by impaired hepatic and renal function. PMID:16556694

  20. microRNAs as Pharmacological Targets in Endothelial Cell Function and Dysfunction

    PubMed Central

    Chamorro-Jorganes, Aránzazu; Araldi, Elisa; Suárez, Yajaira

    2013-01-01

    Endothelial cell dysfunction is a term which implies the dysregulation of normal endothelial cell functions, including impairment of the barrier functions, control of vascular tone, disturbance of proliferative, migratory and morphogenic capacities of endothelial cells, as well as control of leukocyte trafficking. MicroRNAs (miRNAs) are short non-coding RNAs that have emerged as critical regulators of gene expression acting predominantly at the post-transcriptional level. This review summarizes the latest insights in the identification of endothelial-specific miRNAs and their targets, as well as their roles in controlling endothelial cell functions in both autocrine and paracrine manner. In addition, we discuss the therapeutic potential for the treatment of endothelial cell dysfunction and associated vascular pathophysiological conditions. PMID:23603154

  1. Endothelial function is associated with myocardial diastolic function in women with systemic lupus erythematosus.

    PubMed

    Chin, Calvin W L; Chin, Chee-Yang; Ng, Marie X R; Le, Thu-Thao; Huang, Fei-Qiong; Fong, Kok-Yong; Thumboo, Julian; Tan, Ru-San

    2014-09-01

    Endothelial dysfunction is associated with traditional and systemic lupus erythematosus (SLE)-specific risk factors, and early data suggest reversibility of endothelial dysfunction with therapy. The clinical relevance of endothelial function assessment has been limited by the lack of studies, demonstrating its prognostic significance and impact on early myocardial function. Therefore, we aimed to determine the association between endothelial and myocardial diastolic function in SLE women. Women with SLE and no coronary artery disease were prospectively recruited and underwent radionuclide myocardial perfusion imaging (MPI) (Jetstream, Philips, the Netherlands) to exclude subclinical myocardial ischemia. Cardiac and vascular functions were assessed in all patients (Alpha 10, Aloka, Tokyo). Diastolic function was assessed using pulse wave early (E) and late mitral blood inflow and myocardial tissue Doppler (mean of medial and lateral annulus e') velocities. Endothelial function was measured using brachial artery flow-mediated vasodilatation (FMD%). Univariate and multivariate linear regressions were used to assess the association between FMD% and myocardial diastolic function, adjusting for potential confounders. Thirty-eight patients without detectable myocardial ischemia on MPI were studied (mean age 44 ± 10 years; mean disease duration 14 ± 6 years). About 61 % of patients had normal diastolic function (E/e' ≤ 8), and 5 % of patients had definite diastolic dysfunction with E/e' > 13 (mean 7.1 ± 2.9). FMD% was associated with E/e' (regression coefficient β = -0.35; 95 % CI -0.62 to -0.08; p = 0.01) independent of systolic blood pressure, age, and SLICC/ACR Damage Index. PMID:24549405

  2. Progenitor endothelial cell involvement in Alzheimer's disease

    SciTech Connect

    Budinger, Thomas F.

    2003-05-01

    There is compelling evidence that endothelial cells of the brain and periphery are dysfunctional in Alzheimer's Disease. There is evidence for a fundamental defect in, or abnormal aging of, endothelial progenitor cells in atherosclerosis. The possibility that endothelial cell defects are a primary cause for Alzheimer's Disease or other dementias can be researched by molecular and cell biology studies as well as cell trafficking studies using recently demonstrated molecular imaging methods. The evidence for abnormal endothelial function and the methods to explore this hypothesis are presented.

  3. Impacts of nanoparticles on cardiovascular diseases: modulating metabolism and function of endothelial cells.

    PubMed

    Meng, Jie; Yang, Xian-da; Jia, Lee; Liang, Xing-Jie; Wang, Chen

    2012-10-01

    Endothelial cells have very important functions, one of which is their contribution to regulating molecule and nutrient exchanges between the blood and peripheral tissues. Dysfunction of endothelial cells plays an essential role in the progression of cardiovascular diseases (CVD) such as atherosclerosis and coronary heart disease. With the recent progress of nanotechnology, increasing numbers of studies have focused on the effects of nanoparticles on CVD. In this article, we review the biological characters of endothelial cells, evaluate the impacts of nanoparticles on the behavior and functions of endothelial cells, analyze advantages and disadvantages of various nanoparticles, and discuss potential applications of nanoparticles to CVD treatment.

  4. A Role for the Long Noncoding RNA SENCR in Commitment and Function of Endothelial Cells.

    PubMed

    Boulberdaa, Mounia; Scott, Elizabeth; Ballantyne, Margaret; Garcia, Raquel; Descamps, Betty; Angelini, Gianni D; Brittan, Mairi; Hunter, Amanda; McBride, Martin; McClure, John; Miano, Joseph M; Emanueli, Costanza; Mills, Nicholas L; Mountford, Joanne C; Baker, Andrew H

    2016-05-01

    Despite the increasing importance of long noncoding RNA in physiology and disease, their role in endothelial biology remains poorly understood. Growing evidence has highlighted them to be essential regulators of human embryonic stem cell differentiation. SENCR, a vascular-enriched long noncoding RNA, overlaps the Friend Leukemia Integration virus 1 (FLI1) gene, a regulator of endothelial development. Therefore, we wanted to test the hypothesis that SENCR may contribute to mesodermal and endothelial commitment as well as in endothelial function. We thus developed new differentiation protocols allowing generation of endothelial cells from human embryonic stem cells using both directed and hemogenic routes. The expression of SENCR was markedly regulated during endothelial commitment using both protocols. SENCR did not control the pluripotency of pluripotent cells; however its overexpression significantly potentiated early mesodermal and endothelial commitment. In human umbilical endothelial cell (HUVEC), SENCR induced proliferation, migration, and angiogenesis. SENCR expression was altered in vascular tissue and cells derived from patients with critical limb ischemia and premature coronary artery disease compared to controls. Here, we showed that SENCR contributes to the regulation of endothelial differentiation from pluripotent cells and controls the angiogenic capacity of HUVEC. These data give novel insight into the regulatory processes involved in endothelial development and function.

  5. A Role for the Long Noncoding RNA SENCR in Commitment and Function of Endothelial Cells

    PubMed Central

    Boulberdaa, Mounia; Scott, Elizabeth; Ballantyne, Margaret; Garcia, Raquel; Descamps, Betty; Angelini, Gianni D; Brittan, Mairi; Hunter, Amanda; McBride, Martin; McClure, John; Miano, Joseph M; Emanueli, Costanza; Mills, Nicholas L; Mountford, Joanne C; Baker, Andrew H

    2016-01-01

    Despite the increasing importance of long noncoding RNA in physiology and disease, their role in endothelial biology remains poorly understood. Growing evidence has highlighted them to be essential regulators of human embryonic stem cell differentiation. SENCR, a vascular-enriched long noncoding RNA, overlaps the Friend Leukemia Integration virus 1 (FLI1) gene, a regulator of endothelial development. Therefore, we wanted to test the hypothesis that SENCR may contribute to mesodermal and endothelial commitment as well as in endothelial function. We thus developed new differentiation protocols allowing generation of endothelial cells from human embryonic stem cells using both directed and hemogenic routes. The expression of SENCR was markedly regulated during endothelial commitment using both protocols. SENCR did not control the pluripotency of pluripotent cells; however its overexpression significantly potentiated early mesodermal and endothelial commitment. In human umbilical endothelial cell (HUVEC), SENCR induced proliferation, migration, and angiogenesis. SENCR expression was altered in vascular tissue and cells derived from patients with critical limb ischemia and premature coronary artery disease compared to controls. Here, we showed that SENCR contributes to the regulation of endothelial differentiation from pluripotent cells and controls the angiogenic capacity of HUVEC. These data give novel insight into the regulatory processes involved in endothelial development and function. PMID:26898221

  6. SFAs do not impair endothelial function and arterial stiffness123

    PubMed Central

    Sanders, Thomas AB; Lewis, Fiona J; Goff, Louise M; Chowienczyk, Philip J

    2013-01-01

    Background: It is uncertain whether saturated fatty acids (SFAs) impair endothelial function and contribute to arterial stiffening. Objective: We tested the effects of replacing SFAs with monounsaturated fatty acids (MUFAs) or carbohydrates on endothelial function and arterial stiffness. Design: With the use of a parallel-designed randomized controlled trial in 121 insulin-resistant men and women, we measured vascular function after 1 mo of consumption of a high-SFA (HS) diet and after 24 wk after random assignment to the HS diet or diets that contained <10% SFAs and were high in either MUFAs or carbohydrates. The primary outcome was a change in flow-mediated dilation (FMD), and secondary outcomes were changes in carotid to femoral pulse wave velocity (PWV) and plasma 8-isoprostane F2α-III concentrations. Results: For 112 participants with data available for analysis on the specified outcomes, no significant differences were shown. FMD with the HS reference diet was 6.7 ± 2.2%, and changes (95% CIs) after 6 mo of intervention were +0.3 (−0.4, 1.1), −0.2 (−0.8, 0.5), and −0.1 (−0.6, 0.7) with HS, high-MUFA (HM), and high-carbohydrate (HC) diets, respectively. After consumption of the HS reference diet, the geometric mean (±SD) PWV was 7.67 ± 1.62 m/s, and mean percentages of changes (95% CIs) were −1.0 (−6.2, 4.3) with the HS diet, 2.7 (−1.4, 6.9) with the HM diet, and −1.0 (−5.5, 3.4) with the HC diet. With the HS reference diet, the geometric mean (±SD) plasma 8-isoprostane F2α-III concentration was 176 ± 85 pmol/L, and mean percentage of changes (95% CIs) were 1 (−12, 14) with the HS diet, 6 (−5, 16) with the HM diet, and 4 (−7, 16) with the HC diet. Conclusion: The replacement of SFAs with MUFAs or carbohydrates in healthy subjects does not affect vascular function. This trial was registered at Current Controlled Trials (http://www.controlled-trials.com/ISRCTN) as ISRCTN 29111298. PMID:23964054

  7. Cardiac microvascular endothelial cells express a functional Ca+ -sensing receptor.

    PubMed

    Berra Romani, Roberto; Raqeeb, Abdul; Laforenza, Umberto; Scaffino, Manuela Federica; Moccia, Francesco; Avelino-Cruz, Josè Everardo; Oldani, Amanda; Coltrini, Daniela; Milesi, Veronica; Taglietti, Vanni; Tanzi, Franco

    2009-01-01

    The mechanism whereby extracellular Ca(2+) exerts the endothelium-dependent control of vascular tone is still unclear. In this study, we assessed whether cardiac microvascular endothelial cells (CMEC) express a functional extracellular Ca(2+)-sensing receptor (CaSR) using a variety of techniques. CaSR mRNA was detected using RT-PCR, and CaSR protein was identified by immunocytochemical analysis. In order to assess the functionality of the receptor, CMEC were loaded with the Ca(2+)-sensitive fluorochrome, Fura-2/AM. A number of CaSR agonists, such as spermine, Gd(3+), La(3+) and neomycin, elicited a heterogeneous intracellular Ca(2+) signal, which was abolished by disruption of inositol 1,4,5-trisphosphate (InsP(3)) signaling and by depletion of intracellular stores with cyclopiazonic acid. The inhibition of the Na(+)/Ca(2+) exchanger upon substitution of extracellular Na(+) unmasked the Ca(2+) signal triggered by an increase in extracellular Ca(2+) levels. Finally, aromatic amino acids, which function as allosteric activators of CaSR, potentiated the Ca(2+) response to the CaSR agonist La(3+). These data provide evidence that CMEC express CaSR, which is able to respond to physiological agonists by mobilizing Ca(2+) from intracellular InsP(3)-sensitive stores.

  8. Functional interactions as a survival strategy against abnormal aggregation

    PubMed Central

    Laura, Masino; Giuseppe, Nicastro; Lesley, Calder; Michele, Vendruscolo; Annalisa, Pastore

    2011-01-01

    Protein aggregation is under intense scrutiny because of its role in human disease. Although increasing evidence indicates that protein native states are highly protected against aggregation, the specific protection mechanisms are poorly understood. Insight into such mechanisms can be gained through study of the relatively few proteins that aggregate under native conditions. Ataxin-3, the protein responsible for Spinocerebellar ataxia type 3, a polyglutamine expansion disease, represents one of such examples. Polyglutamine expansion is central for determining solubility and aggregation rates of ataxin-3, but these properties are profoundly modulated by its N-terminal Josephin domain. This work aims at identifying the regions that promote Josephin fibrillogenesis and rationalizing the mechanisms that protect Josephin and nonexpanded ataxin-3 from aberrant aggregation. Using different biophysical techniques, aggregation propensity predictions and rational design of amino acid substitutions, we show that Josephin has an intrinsic tendency to fibrillize under native conditions and that fibrillization is promoted by two solvent-exposed patches, which are also involved in recognition of natural substrates, such as ubiquitin. Indeed, designed mutations at these patches or substrate binding significantly reduce Josephin aggregation kinetics. Our results provide evidence that protein nonpathologic function can play an active role in preventing aberrant fibrillization and suggest the molecular mechanism whereby this occurs in ataxin-3.—Masino, L., Nicastro, G., Calder, L., Vendruscolo, M., Pastore, A. Functional interactions as a survival strategy against abnormal aggregation. PMID:20810784

  9. Effects of irrigation solutions on corneal endothelial function.

    PubMed

    Yagoubi, M I; Armitage, W J; Diamond, J; Easty, D L

    1994-04-01

    Rabbit corneas were perfused in vitro with an irrigation solution for 90 minutes. This was followed by 6 hours of perfusion with tissue culture medium TC199 during which endothelial function was assessed by monitoring rates of swelling during a period of perfusion in the absence of bicarbonate ions, and subsequent rates of thinning when bicarbonate ions were restored to the perfusate. Corneal thickness (measured with an ultrasonic pachymeter) immediately following excision was 401 microns (SD 19, n = 23). During the 90 minute perfusion at 35 degrees C, corneas exposed to balanced salt solution (BSS), Hartmann's solution or 0.9% NaCl (all initially at room temperature) swelled, respectively, at 14 (SD 2.3, n = 4), 11 (SD 2.6, n = 4), and 70 (SD 4.3, n = 4) microns/h. Cold Hartmann's solution (initially at 4 degrees C) caused corneas to swell at 9 (SD 2.3, n = 4) microns/h. On the other hand, corneas perfused with BSS Plus thinned at 9 (SD 3.4, n = 4) microns/h and TC199 with Earle's salts had little effect on thickness. Rates of swelling and thinning during the following assessment perfusion showed no apparent effects of prior exposure to any of the irrigation solutions on the barrier properties or pump function of the endothelium. Despite this, the increased thickness of corneas exposed initially to BSS, cold Hartmann's solution, or 0.9% NaCl was not fully reversed, even by the end of the 6 hour assessment perfusion. In contrast, the swelling observed in corneas exposed to Hartmann's solution at room temperature was reversed and these corneas had returned to their normal thickness by the end of the assessment period. All corneas, even those exposed to 0.9% NaCl, had an intact endothelial mosaic with no evidence of damage or cell loss, although morphological differences in cell shape and the appearance of cell borders were evident compared with freshly isolated cornea. PMID:8199119

  10. Biochemical and functional abnormalities in hypercholesterolemic rabbit platelets

    SciTech Connect

    Dalal, K.B.; Ebbe, S.; Mazoyer, E.; Carpenter, D.; Yee, T. )

    1990-02-01

    This study was designed to elucidate changes in rabbit platelet lipids induced by a cholesterol rich diet and to explore the possible correlation of these lipid changes with platelet abnormalities. Pronounced biochemical alterations were observed when serum cholesterol levels of 700-1000 mg% were reached. Hypercholesterolemic (HC) platelets contained 37% more neutral lipids and 16% less phospholipids than the controls. Lysolecithin, cholesterol esters and phosphatidylinositol (PI) levels were increased in HC platelets, and the levels of phosphatidylcholine (PC) were decreased. The cholesterol/phospholipid molar ratio of lipidemic platelets increased from 0.55 +/- 0.011 to 0.89 +/- 0.016 (P less than 0.01) in eight weeks. HC platelets had 90% more arachidonic acid (AA) in the PI than normal platelets. No significant changes in AA of PC were observed. Platelet function was monitored by the uptake and release of (14C)serotonin in platelet rich plasma (PRP), using varying concentrations of collagen as an aggregating agent. The uptake of (14C)serotonin in HC and normal platelets ranged from 78-94%. The percent of (14C)serotonin released from normal and HC platelets was proportional to the concentration of collagen. However, lipidemic platelets were hyperreactive to low concentrations of collagen. Incorporation of 50 microM acetylsalicylic acid into the aggregating medium suppressed the release of (14C)serotonin in normal PRP by more than 90%, but had only a partial effect on lipidemic PRP.

  11. Glycogen synthase kinase 3β inhibition enhanced proliferation, migration and functional re-endothelialization of endothelial progenitor cells in hypercholesterolemia microenvironment

    PubMed Central

    Cui, Bin; Jin, Jun; Ding, Xiaohan; Deng, Mengyang; Yu, Shiyong; Song, MingBao; Yu, Yang; Zhao, Xiaohui; Chen, Jianfei

    2015-01-01

    Hypercholesterolemia impairs the quantity and function of endothelial progenitor cell. We hypothesized that glycogen synthase kinase 3β activity is involved in regulating biological function of endothelial progenitor cells in hypercholesterolemia microenvironment. For study, endothelial progenitor cells derived from apolipoprotein E-deficient mice fed with high-fat diet were used. Glycogen synthase kinase 3β activity was interfered with glycogen synthase kinase 3β inhibitor lithium chloride or transduced with replication defective adenovirus vector expressing catalytically inactive glycogen synthase kinase 3β (GSK3β-KM). Functions of endothelial progenitor cells, proliferation, migration, secretion and network formation of endothelial progenitor cells were assessed in vitro. The expression of phospho-glycogen synthase kinase 3β, β-catenin and cyclinD1 in endothelial progenitor cells was detected by Western blot. The in vivo function re-endothelialization and vasodilation were also analyzed by artery injury model transplanted with glycogen synthase kinase 3β-inhibited endothelial progenitor cells. We demonstrated that while the proliferation, migration, network formation as well as VEGF and NO secretion were impaired in apolipoprotein E-deficient endothelial progenitor cells, glycogen synthase kinase 3β inhibition significantly improved all these functions. Apolipoprotein E-deficient endothelial progenitor cells showed decreased phospho-glycogen synthase kinase 3β, β-catenin and cyclinD1 expression, whereas these signals were enhanced by glycogen synthase kinase 3β inhibition and accompanied with β-catenin nuclear translocation. Our in vivo model showed that glycogen synthase kinase 3β inhibition remarkably increased re-endothelial and vasodilation. Taken together, our data suggest that inhibition of glycogen synthase kinase 3β is associated with endothelial progenitor cell biological functions both in vitro and in vivo. It might be an important

  12. Acute exposure to diesel exhaust impairs nitric oxide-mediated endothelial vasomotor function by increasing endothelial oxidative stress.

    PubMed

    Wauters, Aurélien; Dreyfuss, Céline; Pochet, Stéphanie; Hendrick, Patrick; Berkenboom, Guy; van de Borne, Philippe; Argacha, Jean-François

    2013-08-01

    Exposure to diesel exhaust was recently identified as an important cardiovascular risk factor, but whether it impairs nitric oxide (NO)-mediated endothelial function and increases production of reactive oxygen species (ROS) in endothelial cells is not known. We tested these hypotheses in a randomized, controlled, crossover study in healthy male volunteers exposed to ambient and polluted air (n=12). The effects of skin microvascular hyperemic provocative tests, including local heating and iontophoresis of acetylcholine and sodium nitroprusside, were assessed using a laser Doppler imager. Before local heating, skin was pretreated by iontophoresis of either a specific NO-synthase inhibitor (L-N-arginine-methyl-ester) or a saline solution (Control). ROS production was measured by chemiluminescence using the lucigenin technique in human umbilical vein endothelial cells preincubated with serum from 5 of the subjects. Exposure to diesel exhaust reduced acetylcholine-induced vasodilation (P<0.01) but did not affect vasodilation with sodium nitroprusside. Moreover, the acetylcholine/sodium nitroprusside vasodilation ratio decreased from 1.51 ± 0.1 to 1.06 ± 0.07 (P<0.01) and was correlated to inhaled particulate matter 2.5 (r=-0.55; P<0.01). NO-mediated skin thermal vasodilatation decreased from 466 ± 264% to 29 ± 123% (P<0.05). ROS production was increased after polluted air exposure (P<0.01) and was correlated with the total amount of inhaled particulate matter <2.5 μm (PM2.5). In healthy subjects, acute experimental exposure to diesel exhaust impaired NO-mediated endothelial vasomotor function and promoted ROS generation in endothelial cells. Increased PM2.5 inhalation enhances microvascular dysfunction and ROS production. PMID:23798345

  13. Acute exposure to diesel exhaust impairs nitric oxide-mediated endothelial vasomotor function by increasing endothelial oxidative stress.

    PubMed

    Wauters, Aurélien; Dreyfuss, Céline; Pochet, Stéphanie; Hendrick, Patrick; Berkenboom, Guy; van de Borne, Philippe; Argacha, Jean-François

    2013-08-01

    Exposure to diesel exhaust was recently identified as an important cardiovascular risk factor, but whether it impairs nitric oxide (NO)-mediated endothelial function and increases production of reactive oxygen species (ROS) in endothelial cells is not known. We tested these hypotheses in a randomized, controlled, crossover study in healthy male volunteers exposed to ambient and polluted air (n=12). The effects of skin microvascular hyperemic provocative tests, including local heating and iontophoresis of acetylcholine and sodium nitroprusside, were assessed using a laser Doppler imager. Before local heating, skin was pretreated by iontophoresis of either a specific NO-synthase inhibitor (L-N-arginine-methyl-ester) or a saline solution (Control). ROS production was measured by chemiluminescence using the lucigenin technique in human umbilical vein endothelial cells preincubated with serum from 5 of the subjects. Exposure to diesel exhaust reduced acetylcholine-induced vasodilation (P<0.01) but did not affect vasodilation with sodium nitroprusside. Moreover, the acetylcholine/sodium nitroprusside vasodilation ratio decreased from 1.51 ± 0.1 to 1.06 ± 0.07 (P<0.01) and was correlated to inhaled particulate matter 2.5 (r=-0.55; P<0.01). NO-mediated skin thermal vasodilatation decreased from 466 ± 264% to 29 ± 123% (P<0.05). ROS production was increased after polluted air exposure (P<0.01) and was correlated with the total amount of inhaled particulate matter <2.5 μm (PM2.5). In healthy subjects, acute experimental exposure to diesel exhaust impaired NO-mediated endothelial vasomotor function and promoted ROS generation in endothelial cells. Increased PM2.5 inhalation enhances microvascular dysfunction and ROS production.

  14. Associations of endothelial function and air temperature in diabetic subjects

    EPA Science Inventory

    Background and Objective: Epidemiological studies consistently show that air temperature is associated with changes in cardiovascular morbidity and mortality. However, the biological mechanisms underlying the association remain largely unknown. As one index of endothelial functio...

  15. The Assessment of Endothelial Function – From Research into Clinical Practice

    PubMed Central

    Flammer, Andreas J.; Anderson, Todd; Celermajer, David S.; Creager, Mark A.; Deanfield, John; Ganz, Peter; Hamburg, Naomi; Lüscher, Thomas F.; Shechter, Michael; Taddei, Stefano; Vita, Joseph A; Lerman, Amir

    2012-01-01

    The discovery of the endothelium as a crucial organ for the regulation of the vasculature to physiological needs and the recognition of endothelial dysfunction as a key pathological condition - which is associated with most if not all cardiovascular risk factors - led to a tremendous boost of endothelial research in the past 3 decades. Despite the possibility to measure endothelial function in the individual and its widespread use in research, its use as a clinical tool in daily medicine is not established yet. We review the most common methods to assess vascular function in humans and discuss their advantages and disadvantages. Furthermore we give an overview about clinical settings were endothelial function measurements may be valuable in individual patients. Specifically, we provide information why endothelial function is not only a risk marker for cardiovascular risk but may also provides prognostic information beyond commonly used risk scores in primary prevention, and in patients with already established coronary disease. We conclude, that non-invasive endothelial function measurements provide valuable additional information, however, to ascertain its use for daily clinical practice, future research should determine whether endothelial function can be used to guide treatment in the individual and if this translates into better outcomes. PMID:22869857

  16. An Epoxyisoprostane is a Major Regulator of Endothelial Cell Function

    PubMed Central

    Zhong, Wei; Springstead, James R.; Al-Mubarak, Ramea; Lee, Sangderk; Li, Rongsong; Emert, Benjamin; Berliner, Judith A.; Jung, Michael E.

    2014-01-01

    The goal of these studies was to determine the effect of 5,6-epoxyisoprostane, EI, on human aortic endothelial cells (HAEC). EI can form as a phospholipase product of 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphocholine, PEIPC, a pro-inflammatory molecule that accumulates in sites of inflammation where phospholipases are also increased. To determine the effect of EI on HAEC, we synthesized several stereoisomers of EI using a convergent approach from the individual optically pure building blocks, the epoxyaldehydes 5 and 6 and the bromoenones 14 and 16. The desired stereoisomer of EI can be prepared from these materials in only six operations and thus large amounts of the product can be obtained. The trans/trans isomers had the most potent activity, suggesting specificity in the interaction of EI with the cell surface. EI has potent anti-inflammatory effects in HAEC. EI strongly inhibits the production of MCP-1, a major monocyte chemotactic factor, and either decreases or minimally increases the levels of ten pro-inflammatory molecules increased by PEIPC. EI also strongly downregulates the inflammatory effects of IL-1β, a major inflammatory cytokine. Thus EI, a hydrolytic product of PEIPC, has potent anti-inflammatory function. PMID:24117045

  17. Coffee and endothelial function: a battle between caffeine and antioxidants?

    PubMed

    Buscemi, S; Batsis, J A; Arcoleo, G; Verga, S

    2010-10-01

    Although coffee is largely consumed by adults in Western countries, controversy exists about its impact on the cardiovascular system. We recently demonstrated that caffeinated and decaffeinated espresso coffee have different acute effects on endothelial function in healthy subjects, measured using flow-mediated dilation (FMD) of the brachial artery. In this study, we measured the anti-oxidant capacity of two coffee substances in terms of free stable radical 2,2-diphenyl-1-picryl-hydrazyl 50% inhibition (I(50) DPPH). The caffeinated coffee had a slightly higher anti-oxidant capacity than decaffeinated espresso coffee (I(50) DPPH: 1.13±0.02 vs 1.30±0.03 μl; P<0.001). We suggest that the unfavourable effects observed after caffeinated coffee ingestion are due to caffeine and that the antioxidant activity is responsible for the increased FMD observed after decaffeinated coffee ingestion. Further clinical and epidemiological studies are needed to understand the chronic effects of coffee consumption on health.

  18. Impairment of Endothelial Function by Little Cigar Secondhand Smoke

    PubMed Central

    Liu, Jiangtao; Wang, Xiaoyin; Narayan, Shilpa; Glantz, Stanton A.; Schick, Suzaynn F.; Springer, Matthew L.

    2015-01-01

    Objectives Little cigars and cigarillos are gaining in popularity as cigarette use wanes, mainly due to relaxed regulatory standards that make them cheaper, easier to buy individually, and available in a variety of flavors not allowed in cigarettes. To address whether they should be regulated as strictly as cigarettes, we investigated whether little cigar secondhand smoke (SHS) decreases vascular endothelial function like that of cigarettes. Methods We exposed rats to SHS from little cigars, cigarettes, or chamber air, for 10 minutes and measured the resulting acute impairment of arterial flow-mediated dilation (FMD). Results SHS from both little cigars and cigarettes impaired FMD. Impairment was greater after exposure to little cigar SHS than by cigarette SHS relative to pre-exposure values, although the post-exposure FMD values were not significantly different from each other. Conclusions Exposure to little cigar SHS leads to impairment of FMD that is at least equal to that resulting from similar levels of cigarette SHS. Our findings support the need to prevent even brief exposure to little cigar SHS, and support tobacco control policies that regulate little cigars as strictly as cigarettes. PMID:26753171

  19. The association between functional and morphological assessments of endothelial function in patients with rheumatoid arthritis: a cross-sectional study

    PubMed Central

    2013-01-01

    Introduction Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD). One of the earliest manifestations of CVD is endothelial dysfunction (ED), which can lead to functional and morphological vascular abnormalities. Several non-invasive assessments of vascular function and morphology can be utilised to assess vascular health, but little is known about the association between each of these assessments in patients with RA, and they tend to be used interchangeably in the literature. The objective of the present study was to examine associations between measures of vascular function and morphology in patients with RA. Methods A total of 201 RA patients (155 females, median (25th to 75th percentile) age: 67 (59 to 73)) underwent assessments of microvascular endothelium-dependent and endothelium-independent function (laser Doppler imaging with iontophoresis of acetylcholine and sodium-nitroprusside respectively), macrovascular endothelium-dependent and endothelium-independent function (flow-mediated dilatation and glyceryl-trinitrate-mediated dilation respectively), and vascular morphology (pulse wave analysis, carotid intima-media thickness (cIMT), and carotid plaque). Results Spearman's correlations revealed that from the functional parameters, only macrovascular endothelium-independent function was inversely associated with cIMT (-0.294 (P < 0.001)) after applying the Bonferroni correction for multiple comparisons. For carotid plaque, t tests showed that macrovascular endothelium-independent function was lower in patients with plaque than without (15.5 ± 8.3 vs. 23.1 ± 9.1%, P = 0.002, respectively). Conclusions With the exception of macrovascular endothelium-independent function, all other measures of vascular function were not associated with vascular morphology. This suggests that different assessments of vascular function and morphology in patients with RA reflect quite distinct mechanisms and phases of the

  20. Isolation, Characterization, and Functional Analysis of Ferret Lymphatic Endothelial Cells

    PubMed Central

    Berendam, Stella J.; Fallert-Junecko, Beth A.; Murphy-Corb, Michael A.; Fuller, Deborah H.; Reinhart, Todd A.

    2014-01-01

    The lymphatic endothelium (LE) serves as a conduit for transport of immune cells and soluble antigens from peripheral tissues to draining lymph nodes (LNs), contributing to development of host immune responses and possibly dissemination of microbes. Lymphatic endothelial cells (LECs) are major constituents of the lymphatic endothelium. These specialized cells could play important roles in initiation of host innate immune responses through sensing of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), including toll-like receptors (TLRs). LECs secrete pro-inflammatory cytokines and chemokines to create local inflammatory conditions for recruitment of naïve antigen presenting cells (APCs) such as dendritic cells (DCs) to sites of infection and/or vaccine administration. In this study, we examined the innate immune potential of primary LEC populations derived from multiple tissues of an animal model for human infectious diseases -- the ferret. We generated a total of six primary LEC populations from lung, tracheal, and mesenteric LN tissues from three different ferrets. Standard RT-PCR characterization of these primary LECs showed that they varied in their expression of LEC markers. The ferret LECs were examined for their ability to respond to poly I:C (TLR3 and RIG-1 ligand) and other known TLR ligands as measured by production of proinflammatory cytokine (IFNα, IL6, IL10, Mx1, and TNFα) and chemokine (CCL5, CCL20, and CXCL10) mRNAs using real time RT-PCR. Poly I:C exposure induced robust proinflammatory responses by all of the primary ferret LECs. Chemotaxis was performed to determine the functional activity of CCL20 produced by the primary lung LECs and showed that the LEC-derived CCL20 was abundant and functional. Taken together, our results continue to reveal the innate immune potential of primary LECs during pathogen-host interactions and expand our understanding of the roles of LECs might play in health and disease in

  1. Endothelial Microparticle-Derived Reactive Oxygen Species: Role in Endothelial Signaling and Vascular Function

    PubMed Central

    Burger, Dylan; Turner, Maddison; Munkonda, Mercedes N.; Touyz, Rhian M.

    2016-01-01

    Endothelial microparticles are effectors of endothelial damage; however mechanisms involved are unclear. We examined the effects of eMPs on cultured endothelial cells (ECs) and isolated vessels and investigated the role of eMP-derived reactive oxygen species (ROS) and redox signaling in these processes. eMPs were isolated from EC media and their ability to directly produce ROS was assessed by lucigenin and liquid chromatography. Nicotinamide adenine dinucleotide phosphate oxidase (Nox) subunits were probed by Western blot. ECs were treated with eMPs and effects on kinase signaling, superoxide anion (O2∙−) generation, and nitric oxide (NO) production were examined. Acetylcholine-mediated vasorelaxation was assessed by myography in eMP-treated mesenteric arteries. eMPs contained Nox1, Nox2, Nox4, p47phox, p67phox, and p22phox and they produced ROS which was inhibited by the Nox inhibitor, apocynin. eMPs increased phosphorylation of ERK1/2 and Src, increased O2∙− production, and decreased A23187-induced NO production in ECs. Pretreatment of eMPs with apocynin diminished eMP-mediated effects on ROS and NO production but had no effect on eMP-mediated kinase activation or impairment in vasorelaxation. Our findings identify a novel mechanism whereby eMP-derived ROS contributes to MP bioactivity. These interactions may be important in conditions associated with vascular injury and increased eMP formation. PMID:27313830

  2. Endothelial Microparticle-Derived Reactive Oxygen Species: Role in Endothelial Signaling and Vascular Function.

    PubMed

    Burger, Dylan; Turner, Maddison; Munkonda, Mercedes N; Touyz, Rhian M

    2016-01-01

    Endothelial microparticles are effectors of endothelial damage; however mechanisms involved are unclear. We examined the effects of eMPs on cultured endothelial cells (ECs) and isolated vessels and investigated the role of eMP-derived reactive oxygen species (ROS) and redox signaling in these processes. eMPs were isolated from EC media and their ability to directly produce ROS was assessed by lucigenin and liquid chromatography. Nicotinamide adenine dinucleotide phosphate oxidase (Nox) subunits were probed by Western blot. ECs were treated with eMPs and effects on kinase signaling, superoxide anion (O2 (∙-)) generation, and nitric oxide (NO) production were examined. Acetylcholine-mediated vasorelaxation was assessed by myography in eMP-treated mesenteric arteries. eMPs contained Nox1, Nox2, Nox4, p47(phox), p67(phox), and p22(phox) and they produced ROS which was inhibited by the Nox inhibitor, apocynin. eMPs increased phosphorylation of ERK1/2 and Src, increased O2 (∙-) production, and decreased A23187-induced NO production in ECs. Pretreatment of eMPs with apocynin diminished eMP-mediated effects on ROS and NO production but had no effect on eMP-mediated kinase activation or impairment in vasorelaxation. Our findings identify a novel mechanism whereby eMP-derived ROS contributes to MP bioactivity. These interactions may be important in conditions associated with vascular injury and increased eMP formation. PMID:27313830

  3. Prohibitin-1 maintains the angiogenic capacity of endothelial cells by regulating mitochondrial function and senescence

    PubMed Central

    Schleicher, Michael; Shepherd, Benjamin R.; Suarez, Yajaira; Fernandez-Hernando, Carlos; Yu, Jun; Pan, Yong; Acevedo, Lisette M.; Shadel, Gerald S.; Sessa, William C.

    2008-01-01

    Prohibitin 1 (PHB1) is a highly conserved protein that is mainly localized to the inner mitochondrial membrane and has been implicated in regulating mitochondrial function in yeast. Because mitochondria are emerging as an important regulator of vascular homeostasis, we examined PHB1 function in endothelial cells. PHB1 is highly expressed in the vascular system and knockdown of PHB1 in endothelial cells increases mitochondrial production of reactive oxygen species via inhibition of complex I, which results in cellular senescence. As a direct consequence, both Akt and Rac1 are hyperactivated, leading to cytoskeletal rearrangements and decreased endothelial cell motility, e.g., migration and tube formation. This is also reflected in an in vivo angiogenesis assay, where silencing of PHB1 blocks the formation of functional blood vessels. Collectively, our results provide evidence that PHB1 is important for mitochondrial function and prevents reactive oxygen species–induced senescence and thereby maintains the angiogenic capacity of endothelial cells. PMID:18195103

  4. Evaluation of the Effects of Different Energy Drinks and Coffee on Endothelial Function.

    PubMed

    Molnar, Janos; Somberg, John C

    2015-11-01

    Endothelial function plays an important role in circulatory physiology. There has been differing reports on the effect of energy drink on endothelial function. We set out to evaluate the effect of 3 energy drinks and coffee on endothelial function. Endothelial function was evaluated in healthy volunteers using a device that uses digital peripheral arterial tonometry measuring endothelial function as the reactive hyperemia index (RHI). Six volunteers (25 ± 7 years) received energy drink in a random order at least 2 days apart. Drinks studied were 250 ml "Red Bull" containing 80 mg caffeine, 57 ml "5-hour Energy" containing 230 mg caffeine, and a can of 355 ml "NOS" energy drink containing 120 mg caffeine. Sixteen volunteers (25 ± 5 years) received a cup of 473 ml coffee containing 240 mg caffeine. Studies were performed before drink (baseline) at 1.5 and 4 hours after drink. Two of the energy drinks (Red Bull and 5-hour Energy) significantly improved endothelial function at 4 hours after drink, whereas 1 energy drink (NOS) and coffee did not change endothelial function significantly. RHI increased by 82 ± 129% (p = 0.028) and 63 ± 37% (p = 0.027) after 5-hour Energy and Red Bull, respectively. The RHI changed after NOS by 2 ± 30% (p = 1.000) and by 7 ± 30% (p = 1.000) after coffee. In conclusion, some energy drinks appear to significantly improve endothelial function. Caffeine does not appear to be the component responsible for these differences.

  5. Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure

    PubMed Central

    Kothiya, Milankumar; Galvani, Sylvain; Obinata, Hideru; Bucci, Mariarosaria; Giordano, Frank J; Jiang, Xian-Cheng; Hla, Timothy; Di Lorenzo, Annarita

    2015-01-01

    Endothelial dysfunction is a critical factor in many cardiovascular diseases, including hypertension. Although lipid signaling has been implicated in endothelial dysfunction and cardiovascular disease, specific molecular mechanisms are poorly understood. Here we report that Nogo-B, a membrane protein of the endoplasmic reticulum, regulates endothelial sphingolipid biosynthesis with direct effects on vascular function and blood pressure. Nogo-B inhibits serine palmitoyltransferase, the rate-limiting enzyme of the de novo sphingolipid biosynthetic pathway, thereby controlling production of endothelial sphingosine 1-phosphate and autocrine, G protein–coupled receptor–dependent signaling by this metabolite. Mice lacking Nogo-B either systemically or specifically in endothelial cells are hypotensive, resistant to angiotensin II–induced hypertension and have preserved endothelial function and nitric oxide release. In mice that lack Nogo-B, pharmacological inhibition of serine palmitoyltransferase with myriocin reinstates endothelial dysfunction and angiotensin II–induced hypertension. Our study identifies Nogo-B as a key inhibitor of local sphingolipid synthesis and shows that autocrine sphingolipid signaling within the endothelium is critical for vascular function and blood pressure homeostasis. PMID:26301690

  6. Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure.

    PubMed

    Cantalupo, Anna; Zhang, Yi; Kothiya, Milankumar; Galvani, Sylvain; Obinata, Hideru; Bucci, Mariarosaria; Giordano, Frank J; Jiang, Xian-Cheng; Hla, Timothy; Di Lorenzo, Annarita

    2015-09-01

    Endothelial dysfunction is a critical factor in many cardiovascular diseases, including hypertension. Although lipid signaling has been implicated in endothelial dysfunction and cardiovascular disease, specific molecular mechanisms are poorly understood. Here we report that Nogo-B, a membrane protein of the endoplasmic reticulum, regulates endothelial sphingolipid biosynthesis with direct effects on vascular function and blood pressure. Nogo-B inhibits serine palmitoyltransferase, the rate-limiting enzyme of the de novo sphingolipid biosynthetic pathway, thereby controlling production of endothelial sphingosine 1-phosphate and autocrine, G protein-coupled receptor-dependent signaling by this metabolite. Mice lacking Nogo-B either systemically or specifically in endothelial cells are hypotensive, resistant to angiotensin II-induced hypertension and have preserved endothelial function and nitric oxide release. In mice that lack Nogo-B, pharmacological inhibition of serine palmitoyltransferase with myriocin reinstates endothelial dysfunction and angiotensin II-induced hypertension. Our study identifies Nogo-B as a key inhibitor of local sphingolipid synthesis and shows that autocrine sphingolipid signaling within the endothelium is critical for vascular function and blood pressure homeostasis. PMID:26301690

  7. The Therapeutic Function of the Instructor in Abnormal Psychology.

    ERIC Educational Resources Information Center

    Halgin, Richard P.

    1982-01-01

    Describes three main types of therapeutic problems which college instructors of abnormal psychology courses may encounter with their students. Students may seek the instructor's assistance in helping a relative or acquaintance or for self-help. Often a student may not seek help but may display pathological behavior. (AM)

  8. Paricalcitol and endothelial function in chronic kidney disease trial.

    PubMed

    Zoccali, Carmine; Curatola, Giuseppe; Panuccio, Vincenzo; Tripepi, Rocco; Pizzini, Patrizia; Versace, Marica; Bolignano, Davide; Cutrupi, Sebastiano; Politi, Raffaele; Tripepi, Giovanni; Ghiadoni, Lorenzo; Thadhani, Ravi; Mallamaci, Francesca

    2014-11-01

    Altered vitamin D metabolism and low levels of the active form of this vitamin, 1,25-dihydroxy-vitamin D, is a hallmark of chronic kidney disease (CKD), but there is still no randomized controlled trial testing the effect of active forms of vitamin D on vascular function in patients with CKD. Paricalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY) is a double-blinded randomized controlled trial (ClinicalTrials.gov, NCT01680198) testing the effect of an active form of vitamin D, paricalcitol (2 μg/d×12 weeks) on endothelium-dependent and endothelium-independent vasodilatation in 88 patients with stage 3 to 4 CKD and parathormone >65 pg/mL (paricalcitol, n=44; placebo, n=44). Paricalcitol treatment reduced parathormone (-75 pg/mL; 95% confidence interval, -90 to -60), whereas parathormone showed a small rise during placebo (21 pg/mL; 95% confidence interval, 5-36). Blood pressure did not change in both study arms. Baseline flow-mediated dilation was identical in patients on paricalcitol (3.6±2.9%) and placebo (3.6±2.9%) groups. After 12 weeks of treatment, flow-mediated dilation rose in the paricalcitol but not in the placebo group, and the between-group difference in flow-mediated dilation changes (the primary end point, 1.8%; 95% confidence interval, 0.3-3.1%) was significant (P=0.016), and the mean proportional change in flow-mediated dilation was 61% higher in paricalcitol-treated patients than in placebo-treated patients. Such an effect was abolished 2 weeks after stopping the treatment. No effect of paricalcitol on endothelium-independent vasodilatation was registered. Paricalcitol improves endothelium-dependent vasodilatation in patients with stage 3 to 4 CKD. Findings in this study support the hypothesis that vitamin D may exert favorable effects on the cardiovascular system in patients with CKD.

  9. Effect of CPAP on Endothelial Function in Subjects With Obstructive Sleep Apnea: A Meta-Analysis.

    PubMed

    Xu, Huajun; Wang, Yuyu; Guan, Jian; Yi, Hongliang; Yin, Shankai

    2015-05-01

    Obstructive sleep apnea (OSA) is related to endothelial dysfunction. CPAP is the first-line treatment for OSA. We conducted a meta-analysis to evaluate the effect of CPAP on endothelial function in subjects with OSA. The PubMed, Embase, and Cochrane Library databases were searched. The overall effects were measured by the weighted mean difference with a 95% CI. Subgroup and meta-regression analyses were used to explore the sources of between-study heterogeneity. Eleven studies were eligible for the meta-analysis. A random-effects model revealed that CPAP significantly improved endothelial function as assessed by flow-mediated dilation (weighted mean difference of 2.92, 95% CI 2.21-3.63, P < .001), whereas there was no significant improvement in endothelial function in response to nitroglycerin-mediated dilation (weighted mean difference of 0.90, 95% CI -1.63 to 3.43, P = .48). Age, sex, CPAP compliance and duration, and sleep-related variables had no effect on reduction in arterial stiffness after CPAP. Sensitivity analyses indicated that the protective effect of CPAP on endothelial function was robust. CPAP significantly improved flow-mediated dilation in subjects with OSA. Long-term randomized controlled trials with larger sample sizes are needed to confirm the positive effect of CPAP on endothelial function in subjects with OSA.

  10. Regulation of brain endothelial barrier function by microRNAs in health and neuroinflammation.

    PubMed

    Lopez-Ramirez, Miguel Alejandro; Reijerkerk, Arie; de Vries, Helga E; Romero, Ignacio Andres

    2016-08-01

    Brain endothelial cells constitute the major cellular element of the highly specialized blood-brain barrier (BBB) and thereby contribute to CNS homeostasis by restricting entry of circulating leukocytes and blood-borne molecules into the CNS. Therefore, compromised function of brain endothelial cells has serious consequences for BBB integrity. This has been associated with early events in the pathogenesis of several disorders that affect the CNS, such as multiple sclerosis, HIV-associated neurologic disorder, and stroke. Recent studies demonstrate that brain endothelial microRNAs play critical roles in the regulation of BBB function under normal and neuroinflammatory conditions. This review will focus on emerging evidence that indicates that brain endothelial microRNAs regulate barrier function and orchestrate various phases of the neuroinflammatory response, including endothelial activation in response to cytokines as well as restoration of inflamed endothelium into a quiescent state. In particular, we discuss novel microRNA regulatory mechanisms and their contribution to cellular interactions at the neurovascular unit that influence the overall function of the BBB in health and during neuroinflammation.-Lopez-Ramirez, M. A., Reijerkerk, A., de Vries, H. E., Romero, I. A. Regulation of brain endothelial barrier function by microRNAs in health and neuroinflammation.

  11. Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function.

    PubMed

    Gruber, Robert; Elias, Peter M; Crumrine, Debra; Lin, Tzu-Kai; Brandner, Johanna M; Hachem, Jean-Pierre; Presland, Richard B; Fleckman, Philip; Janecke, Andreas R; Sandilands, Aileen; McLean, W H Irwin; Fritsch, Peter O; Mildner, Michael; Tschachler, Erwin; Schmuth, Matthias

    2011-05-01

    Although it is widely accepted that filaggrin (FLG) deficiency contributes to an abnormal barrier function in ichthyosis vulgaris and atopic dermatitis, the pathomechanism of how FLG deficiency provokes a barrier abnormality in humans is unknown. We report here that the presence of FLG mutations in Caucasians predicts dose-dependent alterations in epidermal permeability barrier function. Although FLG is an intracellular protein, the barrier abnormality occurred solely via a paracellular route in affected stratum corneum. Abnormal barrier function correlated with alterations in keratin filament organization (perinuclear retraction), impaired loading of lamellar body contents, followed by nonuniform extracellular distribution of secreted organelle contents, and abnormalities in lamellar bilayer architecture. In addition, we observed reductions in corneodesmosome density and tight junction protein expression. Thus, FLG deficiency provokes alterations in keratinocyte architecture that influence epidermal functions localizing to the extracellular matrix. These results clarify how FLG mutations impair epidermal permeability barrier function.

  12. Fo Shou San, an Ancient Chinese Herbal Decoction, Protects Endothelial Function through Increasing Endothelial Nitric Oxide Synthase Activity

    PubMed Central

    Bi, Cathy W. C.; Xu, Li; Tian, Xiao Yu; Liu, Jian; Zheng, Ken Y. Z.; Lau, Chi Wai; Lau, David T. W.; Choi, Roy C. Y.; Dong, Tina T. X.; Huang, Yu; Tsim, Karl W. K.

    2012-01-01

    Fo Shou San (FSS) is an ancient herbal decoction comprised of Chuanxiong Rhizoma (CR; Chuanxiong) and Angelicae Sinensis Radix (ASR; Danggui) in a ratio of 2∶3. Previous studies indicate that FSS promotes blood circulation and dissipates blood stasis, thus which is being used widely to treat vascular diseases. Here, we aim to determine the cellular mechanism for the vascular benefit of FSS. The treatment of FSS reversed homocysteine-induced impairment of acetylcholine (ACh)-evoked endothelium-dependent relaxation in aortic rings, isolated from rats. Like radical oxygen species (ROS) scavenger tempol, FSS attenuated homocysteine-stimulated ROS generation in cultured human umbilical vein endothelial cells (HUVECs), and it also stimulated the production of nitric oxide (NO) as measured by fluorescence dye and biochemical assay. In addition, the phosphorylation levels of both Akt kinase and endothelial NO synthases (eNOS) were markedly increased by FSS treatment, which was abolished by an Akt inhibitor triciribine. Likewise, triciribine reversed FSS-induced NO production in HUVECs. Finally, FSS elevated intracellular Ca2+ levels in HUVECs, and the Ca2+ chelator BAPTA-AM inhibited the FSS-stimulated eNOS phosphorylation. The present results show that this ancient herbal decoction benefits endothelial function through increased activity of Akt kinase and eNOS; this effect is causally via a rise of intracellular Ca2+ and a reduction of ROS. PMID:23284736

  13. Abnormal ventilation scans in middle-aged smokers. Comparison with tests of overall lung function

    SciTech Connect

    Barter, S.J.; Cunningham, D.A.; Lavender, J.P.; Gibellino, F.; Connellan, S.J.; Pride, N.B.

    1985-07-01

    The uniformity of regional ventilation during tidal breathing has been assessed using continuous inhalation of krypton-81m in 43 male, lifelong nonsmokers and 46 male, current cigarette smokers (mean daily consumption 24.1 cigarettes/day) between 44 and 61 yr of age and with mild or no respiratory symptoms. All subjects had normal chest radiographs. The results of the ventilation scans were compared with tests of overall lung function (spirometry, maximal expiratory flow-volume curves, and single-breath N2 test). Diffuse abnormalities of the ventilation scan were found in 19 (41%) of the 46 smokers but in none of the nonsmokers. Focal abnormalities were found in 7 smokers and 3 nonsmokers. Smokers showed the expected abnormalities in overall lung function (reduced FEV1 and VC, increased single-breath N2 slope, and closing volume), but in individual smokers there was only a weak relation between the severity of abnormality of overall lung function and an abnormal ventilation scan. Abnormal scans could be found when overall lung function was normal and were not invariably found when significant abnormalities in FEV1/VC or N2 slope were present. There was no relation between the presence of chronic expectoration and an abnormal scan. The prognostic significance of an abnormal ventilation scan in such smokers remains to be established.

  14. You're Only as Old as Your Arteries: Translational Strategies for Preserving Vascular Endothelial Function with Aging

    PubMed Central

    Kaplon, Rachelle E.; Gioscia-Ryan, Rachel A.; LaRocca, Thomas J.

    2014-01-01

    Endothelial dysfunction develops with age and increases the risk of age-associated vascular disorders. Nitric oxide insufficiency, oxidative stress, and chronic low-grade inflammation, induced by upregulation of adverse cellular signaling processes and imbalances in stress resistance pathways, mediate endothelial dysfunction with aging. Healthy lifestyle behaviors preserve endothelial function with aging by inhibiting these mechanisms, and novel nutraceutical compounds that favorably modulate these pathways hold promise as a complementary approach for preserving endothelial health. PMID:24985329

  15. MicroRNA-147b Regulates Vascular Endothelial Barrier Function by Targeting ADAM15 Expression

    PubMed Central

    Chatterjee, Victor; Beard, Richard S.; Reynolds, Jason J.; Haines, Ricci; Guo, Mingzhang; Rubin, Matthew; Guido, Jenny; Wu, Mack H.; Yuan, Sarah Y.

    2014-01-01

    A disintegrin and metalloproteinase15 (ADAM15) has been shown to be upregulated and mediate endothelial hyperpermeability during inflammation and sepsis. This molecule contains multiple functional domains with the ability to modulate diverse cellular processes including cell adhesion, extracellular matrix degradation, and ectodomain shedding of transmembrane proteins. These characteristics make ADAM15 an attractive therapeutic target in various diseases. The lack of pharmacological inhibitors specific to ADAM15 prompted our efforts to identify biological or molecular tools to alter its expression for further studying its function and therapeutic implications. The goal of this study was to determine if ADAM15-targeting microRNAs altered ADAM15-induced endothelial barrier dysfunction during septic challenge by bacterial lipopolysaccharide (LPS). An in silico analysis followed by luciferase reporter assay in human vascular endothelial cells identified miR-147b with the ability to target the 3′ UTR of ADAM15. Transfection with a miR-147b mimic led to decreased total, as well as cell surface expression of ADAM15 in endothelial cells, while miR-147b antagomir produced an opposite effect. Functionally, LPS-induced endothelial barrier dysfunction, evidenced by a reduction in transendothelial electric resistance and increase in albumin flux across endothelial monolayers, was attenuated in cells treated with miR-147b mimics. In contrast, miR-147b antagomir exerted a permeability-increasing effect in vascular endothelial cells similar to that caused by LPS. Taken together, these data suggest the potential role of miR147b in regulating endothelial barrier function by targeting ADAM15 expression. PMID:25333931

  16. Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions

    PubMed Central

    Pedrosa, Ana-Rita; Trindade, Alexandre; Carvalho, Catarina; Graça, José; Carvalho, Sandra; Peleteiro, Maria C.; Adams, Ralf H.; Duarte, António

    2015-01-01

    Angiogenesis is an essential process required for tumor growth and progression. The Notch signaling pathway has been identified as a key regulator of the neo-angiogenic process. Jagged-1 (Jag1) is a Notch ligand required for embryonic and retinal vascular development, which direct contribution to the regulation of tumor angiogenesis remains to be fully characterized. The current study addresses the role of endothelial Jagged1-mediated Notch signaling in the context of tumoral angiogenesis in two different mouse tumor models: subcutaneous Lewis Lung Carcinoma (LLC) tumor transplants and the autochthonous Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP). The role of endothelial Jagged1 in tumor growth and neo-angiogenesis was investigated with endothelial-specific Jag1 gain- and loss-of-function mouse mutants (eJag1OE and eJag1cKO). By modulating levels of endothelial Jag1, we observed that this ligand regulates tumor vessel density, branching, and perivascular maturation, thus affecting tumor vascular perfusion. The pro-angiogenic function is exerted by its ability to positively regulate levels of Vegfr-2 while negatively regulating Vegfr-1. Additionally, endothelial Jagged1 appears to exert an angiocrine function possibly by activating Notch3/Hey1 in tumor cells, promoting proliferation, survival and epithelial-to-mesenchymal transition (EMT), potentiating tumor development. These findings provide valuable mechanistic insights into the role of endothelial Jagged1 in promoting solid tumor development and support the notion that it may constitute a promising target for cancer therapy. PMID:26213336

  17. The association between microvascular and macrovascular endothelial function in patients with rheumatoid arthritis: a cross-sectional study

    PubMed Central

    2011-01-01

    Introduction Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD). One of the earliest manifestations of CVD is endothelial dysfunction (ED). ED can occur in both the microcirculation and the macrocirculation, and these manifestations might be relatively independent of each other. Little is known about the association between endothelial function in the microcirculation and the macrocirculation in RA. The objectives of the present study were to examine the relationship between microvascular and macrovascular endothelial function in patients with RA. Methods Ninety-nine RA patients (72 females, mean age (± SD) 56 ± 12 years), underwent assessments of endothelial-dependent (acetylcholine) and endothelial-independent (sodium nitroprusside) microvascular vasodilatory function (laser Doppler imaging with iontophoresis), as well as endothelial-dependent (flow-mediated dilation) and endothelial-independent (glyceryl trinitrate-mediated dilation) macrovascular vasodilatory function. Vasodilatory function was calculated as the percentage increase after each stimulus was applied relative to baseline values. Results Pearson correlations showed that microvascular endothelial-dependent function was not associated with macrovascular endothelial-dependent function (r (90 patients) = 0.10, P = 0.34). Similarly, microvascular endothelial-independent function was not related to macrovascular endothelial-independent function (r (89 patients) = 0.00, P = 0.99). Conclusions Microvascular and macrovascular endothelial function were independent of each other in patients with RA, suggesting differential regulation of endothelial function in these two vascular beds. Assessments of both vascular beds may provide more meaningful clinical information on vascular risk in RA, but this hypothesis needs to be confirmed in long-term prospective studies. PMID:21693023

  18. Endothelial function in pre-pubertal children at risk of developing cardiomyopathy: a new frontier

    PubMed Central

    Tavares, Aline Cristina; Bocchi, Edimar Alcides; Guimarães, Guilherme Veiga

    2012-01-01

    Although it is known that obesity, diabetes, and Kawasaki's disease play important roles in systemic inflammation and in the development of both endothelial dysfunction and cardiomyopathy, there is a lack of data regarding the endothelial function of pre-pubertal children suffering from cardiomyopathy. In this study, we performed a systematic review of the literature on pre-pubertal children at risk of developing cardiomyopathy to assess the endothelial function of pre-pubertal children at risk of developing cardiomyopathy. We searched the published literature indexed in PubMed, Bireme and SciELO using the keywords ‘endothelial', ‘children', ‘pediatric' and ‘infant' and then compiled a systematic review. The end points were age, the pubertal stage, sex differences, the method used for the endothelial evaluation and the endothelial values themselves. No studies on children with cardiomyopathy were found. Only 11 papers were selected for our complete analysis, where these included reports on the flow-mediated percentage dilatation, the values of which were 9.80±1.80, 5.90±1.29, 4.50±0.70, and 7.10±1.27 for healthy, obese, diabetic and pre-pubertal children with Kawasaki's disease, respectively. There was no significant difference in the dilatation, independent of the endothelium, either among the groups or between the genders for both of the measurements in children; similar results have been found in adolescents and adults. The endothelial function in cardiomyopathic children remains unclear because of the lack of data; nevertheless, the known dysfunctions in children with obesity, type 1 diabetes and Kawasaki's disease may influence the severity of the cardiovascular symptoms, the prognosis, and the mortality rate. The results of this study encourage future research into the consequences of endothelial dysfunction in pre-pubertal children. PMID:22473410

  19. Preserved Microvascular Endothelial Function in Young, Obese Adults with Functional Loss of Nitric Oxide Signaling

    PubMed Central

    Harrell, John W.; Johansson, Rebecca E.; Evans, Trent D.; Sebranek, Joshua J.; Walker, Benjamin J.; Eldridge, Marlowe W.; Serlin, Ronald C.; Schrage, William G.

    2015-01-01

    Data indicate endothelium-dependent dilation (EDD) may be preserved in the skeletal muscle microcirculation of young, obese adults. Preserved EDD might be mediated by compensatory mechanisms, impeding insight into preclinical vascular dysfunction. We aimed to determine the functional roles of nitric oxide synthase (NOS) and cyclooxygenase (COX) toward EDD in younger obese adults. We first hypothesized EDD would be preserved in young, obese adults. Further, we hypothesized a reduced contribution of NOS in young, obese adults would be replaced by increased COX signaling. Microvascular EDD was assessed with Doppler ultrasound and brachial artery infusion of acetylcholine (ACh) in younger (27 ± 1 year) obese (n = 29) and lean (n = 46) humans. Individual and combined contributions of NOS and COX were examined with intra-arterial infusions of l-NMMA and ketorolac, respectively. Vasodilation was quantified as an increase in forearm vascular conductance (ΔFVC). Arterial endothelial cell biopsies were analyzed for protein expression of endothelial nitric oxide synthase (eNOS). ΔFVC to ACh was similar between groups. After l-NMMA, ΔFVC to ACh was greater in obese adults (p < 0.05). There were no group differences in ΔFVC to ACh with ketorolac. With combined NOS-COX inhibition, ΔFVC was greater in obese adults at the intermediate dose of ACh. Surprisingly, arterial endothelial cell eNOS and phosphorylated eNOS were similar between groups. Younger obese adults exhibit preserved EDD and eNOS expression despite functional dissociation of NOS-mediated vasodilation and similar COX signaling. Compensatory NOS- and COX-independent vasodilatory mechanisms conceal reduced NOS contributions in otherwise healthy obese adults early in life, which may contribute to vascular dysfunction. PMID:26733880

  20. Preserved Microvascular Endothelial Function in Young, Obese Adults with Functional Loss of Nitric Oxide Signaling.

    PubMed

    Harrell, John W; Johansson, Rebecca E; Evans, Trent D; Sebranek, Joshua J; Walker, Benjamin J; Eldridge, Marlowe W; Serlin, Ronald C; Schrage, William G

    2015-01-01

    Data indicate endothelium-dependent dilation (EDD) may be preserved in the skeletal muscle microcirculation of young, obese adults. Preserved EDD might be mediated by compensatory mechanisms, impeding insight into preclinical vascular dysfunction. We aimed to determine the functional roles of nitric oxide synthase (NOS) and cyclooxygenase (COX) toward EDD in younger obese adults. We first hypothesized EDD would be preserved in young, obese adults. Further, we hypothesized a reduced contribution of NOS in young, obese adults would be replaced by increased COX signaling. Microvascular EDD was assessed with Doppler ultrasound and brachial artery infusion of acetylcholine (ACh) in younger (27 ± 1 year) obese (n = 29) and lean (n = 46) humans. Individual and combined contributions of NOS and COX were examined with intra-arterial infusions of l-NMMA and ketorolac, respectively. Vasodilation was quantified as an increase in forearm vascular conductance (ΔFVC). Arterial endothelial cell biopsies were analyzed for protein expression of endothelial nitric oxide synthase (eNOS). ΔFVC to ACh was similar between groups. After l-NMMA, ΔFVC to ACh was greater in obese adults (p < 0.05). There were no group differences in ΔFVC to ACh with ketorolac. With combined NOS-COX inhibition, ΔFVC was greater in obese adults at the intermediate dose of ACh. Surprisingly, arterial endothelial cell eNOS and phosphorylated eNOS were similar between groups. Younger obese adults exhibit preserved EDD and eNOS expression despite functional dissociation of NOS-mediated vasodilation and similar COX signaling. Compensatory NOS- and COX-independent vasodilatory mechanisms conceal reduced NOS contributions in otherwise healthy obese adults early in life, which may contribute to vascular dysfunction. PMID:26733880

  1. Association of Kidney Function with Changes in the Endothelial Surface Layer

    PubMed Central

    Dane, Martijn J.C.; Khairoun, Meriem; Lee, Dae Hyun; van den Berg, Bernard M.; Eskens, Bart J.M.; Boels, Margien G.S.; van Teeffelen, Jurgen W.G.E.; Rops, Angelique L.W.M.M.; van der Vlag, Johan; van Zonneveld, Anton Jan; Reinders, Marlies E.J.; Vink, Hans; Rabelink, Ton J.

    2014-01-01

    Background and objectives ESRD is accompanied by endothelial dysfunction. Because the endothelial glycocalyx (endothelial surface layer) governs interactions between flowing blood and the vessel wall, perturbation could influence disease progression. This study used a novel noninvasive sidestream–darkfield imaging method, which measures the accessibility of red blood cells to the endothelial surface layer in the microcirculation (perfused boundary region), to investigate whether renal function is associated with endothelial surface layer dimensions. Design, setting, participants, & measurements Perfused boundary region was measured in control participants (n=10), patients with ESRD (n=23), participants with normal kidney function after successful living donor kidney transplantation (n=12), and patients who developed interstitial fibrosis/tubular atrophy after kidney transplantation (n=10). In addition, the endothelial activation marker angiopoietin-2 and shed endothelial surface layer components syndecan-1 and soluble thrombomodulin were measured using ELISA. Results Compared with healthy controls (1.82±0.16 µm), ESRD patients had a larger perfused boundary region (+0.23; 95% confidence interval, 0.46 to <0.01; P<0.05), which signifies loss of endothelial surface layer dimensions. This large perfused boundary region was accompanied by higher circulating levels of syndecan-1 (+57.71; 95% confidence interval, 17.38 to 98.04; P<0.01) and soluble thrombomodulin (+12.88; 95% confidence interval, 0.29 to 25.46; P<0.001). After successful transplantation, the perfused boundary region was indistinguishable from healthy controls (without elevated levels of soluble thrombomodulin or syndecan-1). In contrast, however, patients who developed interstitial fibrosis and tubular atrophy showed a large perfused boundary region (+0.36; 95% confidence interval, 0.09 to 0.63; P<0.01) and higher levels of endothelial activation markers. In addition, a significant correlation

  2. Endothelium-Derived 5-Methoxytryptophan Protects Endothelial Barrier Function by Blocking p38 MAPK Activation

    PubMed Central

    Chu, Ling-Yun; Wang, Yi-Fu; Cheng, Huei-Hsuan; Kuo, Cheng-Chin; Wu, Kenneth K.

    2016-01-01

    The endothelial junction is tightly controlled to restrict the passage of blood cells and solutes. Disruption of endothelial barrier function by bacterial endotoxins, cytokines or growth factors results in inflammation and vascular damage leading to vascular diseases. We have identified 5-methoxytryptophan (5-MTP) as an anti-inflammatory factor by metabolomic analysis of conditioned medium of human fibroblasts. Here we postulated that endothelial cells release 5-MTP to protect the barrier function. Conditioned medium of human umbilical vein endothelial cells (HUVECs) prevented endothelial hyperpermeability and VE-cadherin downregulation induced by VEGF, LPS and cytokines. We analyzed the metabolomic profile of HUVEC conditioned medium and detected 5-MTP but not melatonin, serotonin or their catabolites, which was confirmed by enzyme-linked immunosorbent assay. Addition of synthetic pure 5-MTP preserved VE-cadherin and maintained barrier function despite challenge with pro-inflammatory mediators. Tryptophan hydroxylase-1, an enzyme required for 5-MTP biosynthesis, was downregulated in HUVECs by pro-inflammatory mediators and it was accompanied by reduction of 5-MTP. 5-MTP protected VE-cadherin and prevented endothelial hyperpermeability by blocking p38 MAPK activation. A chemical inhibitor of p38 MAPK, SB202190, exhibited a similar protective effect as 5-MTP. To determine whether 5-MTP prevents vascular hyperpermeability in vivo, we evaluated the effect of 5-MTP administration on LPS-induced murine microvascular permeability with Evans blue. 5-MTP significantly prevented Evans blue dye leakage. Our findings indicate that 5-MTP is a new class of endothelium-derived molecules which protects endothelial barrier function by blocking p38 MAPK. PMID:27002329

  3. Endothelium-Derived 5-Methoxytryptophan Protects Endothelial Barrier Function by Blocking p38 MAPK Activation.

    PubMed

    Chu, Ling-Yun; Wang, Yi-Fu; Cheng, Huei-Hsuan; Kuo, Cheng-Chin; Wu, Kenneth K

    2016-01-01

    The endothelial junction is tightly controlled to restrict the passage of blood cells and solutes. Disruption of endothelial barrier function by bacterial endotoxins, cytokines or growth factors results in inflammation and vascular damage leading to vascular diseases. We have identified 5-methoxytryptophan (5-MTP) as an anti-inflammatory factor by metabolomic analysis of conditioned medium of human fibroblasts. Here we postulated that endothelial cells release 5-MTP to protect the barrier function. Conditioned medium of human umbilical vein endothelial cells (HUVECs) prevented endothelial hyperpermeability and VE-cadherin downregulation induced by VEGF, LPS and cytokines. We analyzed the metabolomic profile of HUVEC conditioned medium and detected 5-MTP but not melatonin, serotonin or their catabolites, which was confirmed by enzyme-linked immunosorbent assay. Addition of synthetic pure 5-MTP preserved VE-cadherin and maintained barrier function despite challenge with pro-inflammatory mediators. Tryptophan hydroxylase-1, an enzyme required for 5-MTP biosynthesis, was downregulated in HUVECs by pro-inflammatory mediators and it was accompanied by reduction of 5-MTP. 5-MTP protected VE-cadherin and prevented endothelial hyperpermeability by blocking p38 MAPK activation. A chemical inhibitor of p38 MAPK, SB202190, exhibited a similar protective effect as 5-MTP. To determine whether 5-MTP prevents vascular hyperpermeability in vivo, we evaluated the effect of 5-MTP administration on LPS-induced murine microvascular permeability with Evans blue. 5-MTP significantly prevented Evans blue dye leakage. Our findings indicate that 5-MTP is a new class of endothelium-derived molecules which protects endothelial barrier function by blocking p38 MAPK.

  4. Inhibitor-κB kinase attenuates Hsp90-dependent endothelial nitric oxide synthase function in vascular endothelial cells

    PubMed Central

    Konopinski, Ryszard; Krishnan, Manickam; Roman, Linda; Bera, Alakesh; Hongying, Zheng; Habib, Samy L.; Mohan, Sumathy

    2015-01-01

    Endothelial nitric oxide (NO) synthase (eNOS) is the predominant isoform that generates NO in the blood vessels. Many different regulators, including heat shock protein 90 (Hsp90), govern eNOS function. Hsp90-dependent phosphorylation of eNOS is a critical event that determines eNOS activity. In our earlier study we demonstrated an inhibitor-κB kinase-β (IKKβ)-Hsp90 interaction in a high-glucose environment. In the present study we further define the putative binding domain of IKKβ on Hsp90. Interestingly, IKKβ binds to the middle domain of Hsp90, which has been shown to interact with eNOS to stimulate its activity. This new finding suggests a tighter regulation of eNOS activity than was previously assumed. Furthermore, addition of purified recombinant IKKβ to the eNOS-Hsp90 complex reduces the eNOS-Hsp90 interaction and eNOS activity, indicating a competition for Hsp90 between eNOS and IKKβ. The pathophysiological relevance of the IKKβ-Hsp90 interaction has also been demonstrated using in vitro vascular endothelial growth factor-mediated signaling and an Ins2Akita in vivo model. Our study further defines the preferential involvement of α- vs. β-isoforms of Hsp90 in the IKKβ-eNOS-Hsp90 interaction, even though both Hsp90α and Hsp90β stimulate NO production. These studies not only reinforce the significance of maintaining a homeostatic balance of eNOS and IKKβ within the cell system that regulates NO production, but they also confirm that the IKKβ-Hsp90 interaction is favored in a high-glucose environment, leading to impairment of the eNOS-Hsp90 interaction, which contributes to endothelial dysfunction and vascular complications in diabetes. PMID:25652452

  5. Examining Endothelial Function and Platelet Reactivity in Patients with Depression before and after SSRI Therapy.

    PubMed

    Dawood, Tye; Barton, David A; Lambert, Elisabeth A; Eikelis, Nina; Lambert, Gavin W

    2016-01-01

    Although it is recognized that patients with major depressive disorder (MDD) are at increased risk of developing cardiovascular disease (CVD) the mechanisms responsible remain unknown. Endothelial dysfunction is one of the first signs of CVD. Using two techniques, flow-mediated dilatation in response to reactive hyperemia and laser Doppler velocimetry with iontophoresis, we examined endothelial function in the forearm before and after serotonin-specific reuptake inhibitor (SSRI) treatment in 31 patients with MDD. Measurement of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, soluble P-selectin, and noradrenaline in plasma was also performed. Prior to treatment, markers of endothelial and vascular function and platelet reactivity were within the normal range. Following SSRI therapy (95 ± 5 days) symptoms of depression were reduced (paired difference between pre- and post-treatment Hamilton rating -18 ± 1, P < 0.001) with 19 patients recovered and 4 remitted. There occurred no significant change in markers of endothelial or vascular function following SSRI therapy. The improvement in Hamilton depression rating in response to therapy could be independently predicted by the baseline arterial plasma noradrenaline concentration (r (2) = 0.36, P = 0.003). In this cohort of patients with MDD, SSRI therapy did not influence endothelial function or markers of vascular or platelet reactivity. Patient response to SSRI therapy could be predicted by the initial circulating level of noradrenaline, with noradrenaline levels being lower in responders. PMID:26924994

  6. Examining Endothelial Function and Platelet Reactivity in Patients with Depression before and after SSRI Therapy

    PubMed Central

    Dawood, Tye; Barton, David A.; Lambert, Elisabeth A.; Eikelis, Nina; Lambert, Gavin W.

    2016-01-01

    Although it is recognized that patients with major depressive disorder (MDD) are at increased risk of developing cardiovascular disease (CVD) the mechanisms responsible remain unknown. Endothelial dysfunction is one of the first signs of CVD. Using two techniques, flow-mediated dilatation in response to reactive hyperemia and laser Doppler velocimetry with iontophoresis, we examined endothelial function in the forearm before and after serotonin-specific reuptake inhibitor (SSRI) treatment in 31 patients with MDD. Measurement of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, soluble P-selectin, and noradrenaline in plasma was also performed. Prior to treatment, markers of endothelial and vascular function and platelet reactivity were within the normal range. Following SSRI therapy (95 ± 5 days) symptoms of depression were reduced (paired difference between pre- and post-treatment Hamilton rating −18 ± 1, P < 0.001) with 19 patients recovered and 4 remitted. There occurred no significant change in markers of endothelial or vascular function following SSRI therapy. The improvement in Hamilton depression rating in response to therapy could be independently predicted by the baseline arterial plasma noradrenaline concentration (r2 = 0.36, P = 0.003). In this cohort of patients with MDD, SSRI therapy did not influence endothelial function or markers of vascular or platelet reactivity. Patient response to SSRI therapy could be predicted by the initial circulating level of noradrenaline, with noradrenaline levels being lower in responders. PMID:26924994

  7. Dietary polyphenols regulate endothelial function and prevent cardiovascular disease.

    PubMed

    Yamagata, Kazuo; Tagami, Motoki; Yamori, Yukio

    2015-01-01

    Vascular endothelial cell (EC) dysfunction strongly induces development of cardiovascular and cerebrovascular diseases. Epidemiologic studies demonstrated a preventative effect of dietary polyphenols toward cardiovascular disease. In studies using cultured vascular ECs, polyphenols were recognized to regulate nitric oxide and endothelin-1 (ET-1) production. Furthermore, epigallocatechin-3-gallate inhibited the expression of adhesion molecules by a signaling pathway that is similar to that of high-density lipoprotein and involves induction of Ca(2+)/calmodulin-dependent kinase II, liver kinase B, and phosphatidylinositol 3-kinase expression. The effects of polyphenols on ECs include antioxidant activity and enhancement of the expression of several protective proteins, including endothelial nitric oxide synthase and paraoxonase 1. However, the observed effects of dietary polyphenols in vitro do not always translate to an in vivo setting. As such, there are many questions concerning their physiological mode of action. In this review, we discuss research on the effect of dietary polyphenols on cardiovascular disease and their protective effect on EC dysfunction.

  8. Endothelial and platelet function alterations in HIV-infected patients.

    PubMed

    Gresele, P; Falcinelli, E; Sebastiano, M; Baldelli, F

    2012-03-01

    The HIV epidemic has huge dimensions: in 2009, 33.3million people worldwide, including 2.5million children, were affected by human immunodeficiency virus (HIV) infection. The introduction of Highly Active Anti-Retroviral Therapy (HAART) has significantly modified the course of HIV disease, with longer survival and improved quality of life, but it has simultaneously lead to the appearance of previously unrecognized complications, such as ischemic cardiovascular events. Many studies have shown a higher rate of premature atherosclerosis in patients with HIV infection, leading to coronary, cerebrovascular, or peripheral arterial disease. However, it is still debated whether cardiovascular complications are a consequence of HIV infection itself or of the long-term use of HAART. In particular, myocardial infarction has been suggested to be associated with the use of abacavir. Endothelial dysfunction and platelet activation are markers of atherosclerosis and of increased cardiovascular risk. Here we review the evidence that endothelial dysfunction and platelet alterations are associated with chronic HIV infection, the possible role of different HAARTs, and the possible pathophysiologic mechanisms. Potential therapeutic implications are also discussed.

  9. Polymeric stent materials dysregulate macrophage and endothelial cell functions: implications for coronary artery stent

    PubMed Central

    Wang, Xintong; Zachman, Angela L.; Chun, Young Wook; Shen, Fang-Wen; Hwang, Yu-Shik; Sung, Hak-Joon

    2014-01-01

    Background Biodegradable polymers have been applied as bulk or coating materials for coronary artery stents. The degradation of polymers, however, could induce endothelial dysfunction and aggravate neointimal formation. Here we use polymeric microparticles to simulate and demonstrate the effects of degraded stent materials on phagocytic activity, cell death and dysfunction of macrophages and endothelial cells. Methods Microparticles made of low molecular weight polyesters were incubated with human macrophages and coronary artery endothelial cells (ECs). Microparticle-induced phagocytosis, cytotoxicity, apoptosis, cytokine release and surface marker expression were determined by immunostaining or ELISA. Elastase expression was analyzed by ELISA and the elastase-mediated polymer degradation was assessed by mass spectrometry. Results We demonstrated poly(D,L-lactic acid) (PLLA) and polycaprolactone (PCL) microparticles induced cytotoxicity in macrophages and ECs, partially through cell apoptosis. The particle treatment alleviated EC phagocytosis, as opposed to macrophages, but enhanced the expression of vascular cell adhesion molecule-1 (VCAM) along with decreased nitric oxide production, indicating ECs were activated and lost their capacity to maintain homeostasis. The activation of both cell types induced release of elastase or elastase-like protease, which further accelerated polymer degradation. Conclusions This study revealed that low molecule weight PLLA and PCL microparticles increased cytotoxicity and dysregulated endothelial cell function, which in turn enhanced elastase release and polymer degradation. These indicate polymer or polymer-coated stents impose a risk of endothelial dysfunction after deployment which can potentially lead to delayed endothelialization, neointimal hyperplasia and late thrombosis. PMID:24820736

  10. The natural antioxidants, pomegranate extract and soy isoflavones, favourably modulate canine endothelial cell function.

    PubMed

    Baumgartner-Parzer, Sabina M; Waldenberger, Ferdinand Rudolf; Freudenthaler, Angelika; Ginouvès-Guerdoux, Amandine; McGahie, David; Gatto, Hugues

    2012-01-01

    Cardiovascular disease, preceded by vascular endothelial dysfunction, is a prominent cause of death in dogs. L-carnitine and taurine, well known for their antioxidative capacity, beneficially affect cardiovascular disease as well as certain dog cardiomyopathies. It is well established that vascular endothelial dysfunction precedes cardiovascular disease and that "vasoprotective factors" (NO and antioxidants) prevent apoptosis, whereas "risk factors" such as oxidized LDL, hyperglycemia, and free fatty acids trigger it in cultured human vascular endothelial cells. Whereas human vascular cell in vitro models are widely established and used for the characterisation of potential vasoprotective substances, such models are not available for canine endothelial cells. In the present study we therefore developed an in vitro model, which allows the testing of the effects of different substances on proliferation and apoptosis in canine aortic endothelial cells. This model was used to test L-carnitine, taurine, pomegranate extract, and Soy Isoflavones in comparison to reference substances (glutathione and pioglitazone) previously shown to modulate human endothelial cell function. L-carnitine and taurine neither exhibited antiproliferative nor antiapoptotic activities in the context of this study. However extracts from pomegranate and soy isoflavones dramatically reduced proliferation and apoptosis in a dose dependent fashion, being in line with a vasoprotective activity in dogs.

  11. Abnormal Liver Function Tests in an Anorexia Nervosa Patient and an Atypical Manifestation of Refeeding Syndrome

    PubMed Central

    Vootla, Vamshidhar R.; Daniel, Myrta

    2015-01-01

    Refeeding syndrome is defined as electrolyte and fluid abnormalities that occur in significantly malnourished patients when they are refed orally, enterally, or parenterally. The principal manifestations include hypophosphatemia, hypokalemia, vitamin deficiencies, volume overload and edema. This can affect multiple organ systems, such as the cardiovascular, pulmonary, or neurological systems, secondary to the above-mentioned abnormalities. Rarely, patients may develop gastrointestinal symptoms and show abnormal liver function test results. We report the case of a 52-year-old woman with anorexia nervosa who developed refeeding syndrome and simultaneous elevations of liver function test results, which normalized upon the resolution of the refeeding syndrome. PMID:26351414

  12. Abnormal Liver Function Tests in an Anorexia Nervosa Patient and an Atypical Manifestation of Refeeding Syndrome.

    PubMed

    Vootla, Vamshidhar R; Daniel, Myrta

    2015-01-01

    Refeeding syndrome is defined as electrolyte and fluid abnormalities that occur in significantly malnourished patients when they are refed orally, enterally, or parenterally. The principal manifestations include hypophosphatemia, hypokalemia, vitamin deficiencies, volume overload and edema. This can affect multiple organ systems, such as the cardiovascular, pulmonary, or neurological systems, secondary to the above-mentioned abnormalities. Rarely, patients may develop gastrointestinal symptoms and show abnormal liver function test results. We report the case of a 52-year-old woman with anorexia nervosa who developed refeeding syndrome and simultaneous elevations of liver function test results, which normalized upon the resolution of the refeeding syndrome.

  13. Implicit function theorem as a realization of the Lagrange principle. Abnormal points

    SciTech Connect

    Arutyunov, A V

    2000-02-28

    A smooth non-linear map is studied in a neighbourhood of an abnormal (degenerate) point. Inverse function and implicit function theorems are proved. The proof is based on the examination of a family of constrained extremal problems; second-order necessary conditions, which make sense also in the abnormal case, are used in the process. If the point under consideration is normal, then these conditions turn into the classical ones.

  14. Estradiol pretreatment attenuated nicotine-induced endothelial cell apoptosis via estradiol functional membrane receptor.

    PubMed

    Wang, Li-li; Zhao, Jian-li; Lau, Wayne-Bond; Zhang, Yan-qing; Qiao, Zhong-dong; Wang, Ya-jing

    2011-06-01

    Cigarette smoking is highly associated with increased cardiovascular disease complications. The female population, however, manifests reduced cardiovascular morbidity. We define nicotine's effect upon human umbilical vein endothelial cells (HUVECs), determine whether estradiol might ameliorate endothelial dysfunction via its membrane estrogen receptor (mER), and attempt to elucidate the underlying mechanisms. Endothelial cells were pretreated with estradiol-BSA and measured resultant ion flux across the cells via the patch clamp technique to assess mER is functionality. Estradiol-BSA administration was associated with 30% decreased nicotine-induced apoptosis and also attenuated nicotine-activated phosphorylation of p38 and ERK. Pretreatment of estradiol-BSA triggered a low calcium influx, suggesting ahead low influx calcium played a critical role in the underlying protective mechanisms of estradiol. Furthermore, this estradiol-BSA protection against apoptosis remained effective in the presence of tamoxifen, an intracellular estrogen receptor (iER) inhibitor. Additionally, tamoxifen did not abolish estradiol-BSA's inhibitory effect upon p38 and ERK's activation, giving evidence to the obligatory role of p38 and ERK signaling in the estradiol-BSA's anti-apoptotic action via mER. Our study provides evidence that nicotine enhances endothelial cell apoptosis, but estrogen exerts anti-apoptotic effect through its functional membrane estrogen receptor. Clinically, the nicotine in cigarettes might contribute to endothelial dysfunction, whereas ambient estradiol may provide cellular protection against nicotine-induced injury through its functional membrane receptor via MAPK pathway downregulation.

  15. Establishment of outgrowth endothelial cells from peripheral blood.

    PubMed

    Martin-Ramirez, Javier; Hofman, Menno; van den Biggelaar, Maartje; Hebbel, Robert P; Voorberg, Jan

    2012-09-01

    Blood outgrowth endothelial cells (BOECs) are important tools when investigating diagnostic and therapeutic approaches for vascular disease. In this protocol, mononuclear cells are isolated from peripheral blood and plated on type I collagen at ∼135,000 cells per cm(2) in endothelial cell differentiation medium. On average, 0.34 colonies of endothelial cells per milliliter of blood can be obtained. Colonies of endothelial cells become visible after 14-28 d. Upon confluence, these rapidly expanding colonies can be passaged and have been shown to propagate up to 10(18)-fold. Isolated BOECs are phenotypically similar to vascular endothelial cells, as revealed by their cobblestone morphology, the presence of endothelial cell-specific Weibel-Palade bodies and the expression of endothelial cell markers such as VE-cadherin. The protocol presented here also provides a particularly useful tool for the ex vivo assessment of endothelial cell function from patients with different vascular abnormalities. PMID:22918388

  16. Association between anthropometry, cardiometabolic risk factors, & early life factors & adult measures of endothelial function: Results from the New Delhi Birth Cohort

    PubMed Central

    Huffman, Mark D.; Khalil, Anita; Osmond, Clive; Fall, Caroline H. D.; Tandon, Nikhil; Lakshmy, Ramakrishnan; Ramji, Siddharth; Gera, Tarun; Prabhakaran, Poornima; Dey Biswas, S. K.; Reddy, K. Srinath; Bhargava, Santosh K.; Sachdev, Harshpal S.; Prabhakaran, Dorairaj

    2015-01-01

    Background & objectives: Abnormal endothelial function represents a preclinical marker of atherosclerosis. This study was conducted to evaluate associations between anthropometry, cardiometabolic risk factors, and early life factors and adult measures of endothelial function in a young urban Indian cohort free of clinical cardiovascular disease. Methods: Absolute changes in brachial artery diameter following cuff inflation and sublingual nitroglycerin (400 µg) were recorded to evaluate endothelium-dependent and -independent measures of endothelial function in 600 participants (362 men; 238 women) from the New Delhi Birth Cohort (2006-2009). Data on anthropometry, cardiometabolic risk factors, medical history, socio-economic position, and lifestyle habits were collected. Height and weight were recorded at birth, two and 11 yr of age. Age- and sex-adjusted linear regression models were developed to evaluate these associations. Results: The mean age of participants was 36±1 yr. Twenty two per cent men and 29 per cent women were obese (BMI > 30 kg/m2). Mean systolic blood pressure (SBP) was 131±14 and 119±13 mmHg, and diabetes prevalence was 12 and 8 per cent for men and women, respectively. Brachial artery diameter was higher for men compared with women both before (3.48±0.37 and 2.95±0.35 cm) and after hyperaemia (3.87±0.37 vs. 3.37±0.35 cm). A similar difference was seen before and after nitroglycerin. Markers of increased adiposity, smoking, SBP, and metabolic syndrome, but not early life anthropometry, were inversely associated with endothelial function after adjustment for age and sex. Interpretation & conclusions: The analysis of the current prospective data from a young urban Indian cohort showed that cardiometabolic risk factors, but not early life anthropometry, were associated with worse endothelial function. PMID:26831418

  17. Liver sinusoidal endothelial cells (LSECs) function and NAFLD; NO-based therapy targeted to the liver.

    PubMed

    Maslak, Edyta; Gregorius, Aleksandra; Chlopicki, Stefan

    2015-08-01

    Liver sinusoidal endothelial cells (LSECs) present unique, highly specialised endothelial cells in the body. Unlike the structure and function of typical, vascular endothelial cells, LSECs are comprised of fenestrations, display high endocytic capacity and play a prominent role in maintaining overall liver homeostasis. LSEC dysfunction has been regarded as a key event in multiple liver disorders; however, its role and diagnostic, prognostic and therapeutic significance in nonalcoholic fatty liver disease (NAFLD) is still neglected. The purpose of this review is to provide an overview of the importance of LSECs in NAFLD. Attention is focused on the LSECs-mediated NO-dependent mechanisms in NAFLD development. We briefly describe the unique, highly specialised phenotype of LSECs and consequences of LSEC dysfunction on function of hepatic stellate cells (HSC) and hepatocytes. The potential efficacy of liver selective NO donors against liver steatosis and novel treatment approaches to modulate LSECs-driven liver pathology including NAFLD are also highlighted.

  18. Androgen Modulates Functions of Endothelial Progenitor Cells through Activated Egr1 Signaling.

    PubMed

    Ye, Yizhou; Li, Xizhe; Zhang, You; Shen, Zhenya; Yang, Junjie

    2016-01-01

    Researches show that androgens have important effects on migration of endothelial cells and endothelial protection in coronary heart disease. Endothelial progenitor cells (EPCs) as a progenitor cell type that can differentiate into endothelial cells, have a critical role in angiogenesis and endothelial protection. The relationship between androgen and the functions of EPCs has animated much interest and controversy. In this study, we investigated the angiogenic and migratory functions of EPCs after treatment by dihydrotestosterone (DHT) and the molecular mechanisms as well. We found that DHT treatment enhanced the incorporation of EPCs into tubular structures formed by HUVECs and the migratory activity of EPCs in the transwell assay dose dependently. Moreover, microarray analysis was performed to explore how DHT changes the gene expression profiles of EPCs. We found 346 differentially expressed genes in androgen-treated EPCs. Angiogenesis-related genes like Egr-1, Vcan, Efnb2, and Cdk2ap1 were identified to be regulated upon DHT treatment. Furthermore, the enhanced angiogenic and migratory abilities of EPCs after DHT treatment were inhibited by Egr1-siRNA transfection. In conclusion, our findings suggest that DHT markedly enhances the vessel forming ability and migration capacity of EPCs. Egr1 signaling may be a possible pathway in this process. PMID:26697079

  19. Loss of functional endothelial connexin40 results in exercise-induced hypertension in mice.

    PubMed

    Morton, Susan K; Chaston, Daniel J; Howitt, Lauren; Heisler, Jillian; Nicholson, Bruce J; Fairweather, Stephen; Bröer, Stefan; Ashton, Anthony W; Matthaei, Klaus I; Hill, Caryl E

    2015-03-01

    During activity, coordinated vasodilation of microcirculatory networks with upstream supply vessels increases blood flow to skeletal and cardiac muscles and reduces peripheral resistance. Endothelial dysfunction in humans attenuates activity-dependent vasodilation, resulting in exercise-induced hypertension in otherwise normotensive individuals. Underpinning activity-dependent hyperemia is an ascending vasodilation in which the endothelial gap junction protein, connexin (Cx)40, plays an essential role. Because exercise-induced hypertension is proposed as a forerunner to clinical hypertension, we hypothesized that endothelial disruption of Cx40 function in mice may create an animal model of this condition. To this end, we created mice in which a mutant Cx40T152A was expressed alongside wildtype Cx40 selectively in the endothelium. Expression of the Cx40T152A transgene in Xenopus oocytes and mouse coronary endothelial cells in vitro impaired both electric and chemical conductance and acted as a dominant-negative against wildtype Cx40, Cx43, and Cx45, but not Cx37. Endothelial expression of Cx40T152A in Cx40T152ATg mice attenuated ascending vasodilation, without effect on radial coupling through myoendothelial gap junctions. Using radiotelemetry, Cx40T152ATg mice showed an activity-dependent increase in blood pressure, which was significantly greater than in wildtype mice, but significantly less than in chronically hypertensive, Cx40knockout mice. The increase in heart rate with activity was also greater than in wildtype or Cx40knockout mice. We conclude that the endothelial Cx40T152A mutation attenuates activity-dependent vasodilation, producing a model of exercise-induced hypertension. These data highlight the importance of endothelial coupling through Cx40 in regulating blood pressure during activity.

  20. Abnormal Red Cell Structure and Function in Neuroacanthocytosis

    PubMed Central

    Cluitmans, Judith C. A.; Tomelleri, Carlo; Yapici, Zuhal; Dinkla, Sip; Bovee-Geurts, Petra; Chokkalingam, Venkatachalam; De Franceschi, Lucia; Brock, Roland; Bosman, Giel J. G. C. M.

    2015-01-01

    Background Panthothenate kinase-associated neurodegeneration (PKAN) belongs to a group of hereditary neurodegenerative disorders known as neuroacanthocytosis (NA). This genetically heterogeneous group of diseases is characterized by degeneration of neurons in the basal ganglia and by the presence of deformed red blood cells with thorny protrusions, acanthocytes, in the circulation. Objective The goal of our study is to elucidate the molecular mechanisms underlying this aberrant red cell morphology and the corresponding functional consequences. This could shed light on the etiology of the neurodegeneration. Methods We performed a qualitative and semi-quantitative morphological, immunofluorescent, biochemical and functional analysis of the red cells of several patients with PKAN and, for the first time, of the red cells of their family members. Results We show that the blood of patients with PKAN contains not only variable numbers of acanthocytes, but also a wide range of other misshapen red cells. Immunofluorescent and immunoblot analyses suggest an altered membrane organization, rather than quantitative changes in protein expression. Strikingly, these changes are not limited to the red blood cells of PKAN patients, but are also present in the red cells of heterozygous carriers without neurological problems. Furthermore, changes are not only present in acanthocytes, but also in other red cells, including discocytes. The patients’ cells, however, are more fragile, as observed in a spleen-mimicking device. Conclusion These morphological, molecular and functional characteristics of red cells in patients with PKAN and their family members offer new tools for diagnosis and present a window into the pathophysiology of neuroacanthocytosis. PMID:25933379

  1. High density lipoproteins and endothelial functions: mechanistic insights and alterations in cardiovascular disease.

    PubMed

    Riwanto, Meliana; Landmesser, Ulf

    2013-12-01

    Prospective population studies in the primary prevention setting have shown that reduced plasma levels of HDL cholesterol are associated with an increased risk of coronary disease and myocardial infarction. Experimental and translational studies have further revealed several potential anti-atherogenic effects of HDL, including protective effects on endothelial cell functions. HDL has been suggested to protect endothelial cell functions by prevention of oxidation of LDL and its adverse endothelial effects. Moreover, HDL from healthy subjects can directly stimulate endothelial cell production of nitric oxide and anti-inflammatory, anti-apoptotic, and anti-thrombotic effects as well as endothelial repair processes. However, several recent clinical trials using HDL cholesterol-raising agents, such as torcetrapib, dalcetrapib, and niacin, did not demonstrate a significant reduction of cardiovascular events in patients with coronary disease. Of note, growing evidence suggests that the vascular effects of HDL can be highly heterogeneous and vasoprotective properties of HDL are altered in patients with coronary disease. Characterization of underlying mechanisms and understanding of the clinical relevance of this "HDL dysfunction" is currently an active field of cardiovascular research. Notably, in some recent studies no clear association of higher HDL cholesterol levels with a reduced risk of cardiovascular events was observed in patients with already established coronary disease. A greater understanding of mechanisms of action of HDL and its altered vascular effects is therefore critical within the context of HDL-targeted therapies. In this review, we will address different effects of HDL on endothelial cell functions potentially relevant to atherosclerotic vascular disease and explore molecular mechanisms leading to "dysfunctional HDL".

  2. HFE gene: Structure, function, mutations, and associated iron abnormalities.

    PubMed

    Barton, James C; Edwards, Corwin Q; Acton, Ronald T

    2015-12-15

    The hemochromatosis gene HFE was discovered in 1996, more than a century after clinical and pathologic manifestations of hemochromatosis were reported. Linked to the major histocompatibility complex (MHC) on chromosome 6p, HFE encodes the MHC class I-like protein HFE that binds beta-2 microglobulin. HFE influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism. Common HFE mutations account for ~90% of hemochromatosis phenotypes in whites of western European descent. We review HFE mapping and cloning, structure, promoters and controllers, and coding region mutations, HFE protein structure, cell and tissue expression and function, mouse Hfe knockouts and knockins, and HFE mutations in other mammals with iron overload. We describe the pertinence of HFE and HFE to mechanisms of iron homeostasis, the origin and fixation of HFE polymorphisms in European and other populations, and the genetic and biochemical basis of HFE hemochromatosis and iron overload.

  3. Ultrasound-stimulated microbubble enhancement of radiation treatments: endothelial cell function and mechanism

    PubMed Central

    Al-Mahrouki, Azza A.; Wong, Emily; Czarnota, Gregory J.

    2015-01-01

    Endothelial cell death caused by novel microbubble-enhanced ultrasound cancer therapy leads to secondary tumour cell death. In order to characterize and optimize these treatments, the molecular mechanisms resulting from the interaction with endothelial cells were investigated here. Endothelial cells (HUVEC) were treated with ultrasound-stimulated microbubbles (US/MB), radiation (XRT), or a combination of US/MB+XRT. Effects on cells were evaluated at 0, 3, 6, and 24 hours after treatment. Experiments took place in the presence of modulators of sphingolipid-based signalling including ceramide, fumonisin B1, monensin, and sphingosine-1-phosphate. Experimental outcomes were evaluated using histology, TUNEL, clonogenic survival methods, immuno-fluorescence, electron microscopy, and endothelial cell blood-vessel-like tube forming assays. Fewer cells survived after treatment using US/MB+XRT compared to either the control or XRT. The functional ability to form tubes was only reduced in the US/ MB+XRT condition in the control, the ceramide, and the sphingosine-1-phosphate treated groups. The combined treatment had no effect on tube forming ability in either the fumonisin B1 or in the monensin exposed groups, since both interfere with ceramide production at different cellular sites. In summary, experimental results supported the role of ceramide signalling as a key element in cell death initiation with treatments using US/MB+XRT to target endothelial cells. PMID:26909363

  4. A simplified approach to assessing penile endothelial function in young individuals at risk of erectile dysfunction.

    PubMed

    Wu, Hsien-Tsai; Lee, Chun-Ho; Chen, Chin-Jung; Tsai, I-Ting; Sun, Cheuk-Kwan

    2012-01-01

    Erectile dysfunction (ED) reflects a risk for systemic cardiovascular diseases by virtue of a common etiology of vascular endothelial dysfunction, which is increasingly reported to affect young adults. On the basis of physiological phenomenon of reactive hyperemia (RH), systemic and penile endothelial functions in healthy young adults were compared with the use of digital data on arterial waveforms before and after RH induction. Between July 2009 and March 2011, 32 young adult volunteers with normal erectile functions were recruited. Questionnaires on medical histories and sexual functions and blood samples for testosterone and biochemical analyses were obtained. Dilatation index (DI) and penile arterial waveform amplitude (PAWA) ratios for assessing systemic and penile endothelial function were acquired with an air pressure sensing system on the arm and a penile arterial waveform analyzing system on the penis, respectively. A total cholesterol/high-density lipoprotein (TC/HDL) ratio greater than 4.1 was used to define high risk for ED. Remarkable positive correlation was noted between DI and PAWA ratio (r = .640, P < .001). DI showed significant positive associations with serum testosterone (P = .012) and serum HDL level, whereas it showed negative correlations with total triglyceride and glycosylated hemoglobulin levels, body weight, waist circumference, body mass index, and diastolic blood pressure. Similarly, the PAWA ratio showed significant positive correlations with serum testosterone (P < .001) and HDL levels, but negative associations with body weight, waist circumference, and body mass index. Both DI and PAWA ratio successfully identified participants at high risk for ED (eg, TC/HDL ratio > 4.1; P < .05). Our results demonstrated that penile endothelial function can be assessed by evaluating systemic endothelial function in young healthy adults for early identification of risk for ED.

  5. Effects of Fe particle irradiation on human endothelial barrier structure and function

    NASA Astrophysics Data System (ADS)

    Sharma, Preety; Guida, Peter; Grabham, Peter

    2014-07-01

    Space travel involves exposure to biologically effective heavy ion radiation and there is consequently a concern for possible degenerative disorders in humans. A significant target for radiation effects is the microvascular system, which is crucial to healthy functioning of the tissues. Its pathology is linked to disrupted endothelial barrier function and is not only a primary event in a range of degenerative diseases but also an important influencing factor in many others. Thus, an assessment of the effects of heavy ion radiation on endothelial barrier function would be useful for estimating the risks of space travel. This study was aimed at understanding the effects of high LET Fe particles (1 GeV/n) and is the first investigation of the effects of charged particles on the function of the human endothelial barrier. We used a set of established and novel endpoints to assess barrier function after exposure. These include, trans-endothelial electrical resistance (TEER), morphological effects, localization of adhesion and cell junction proteins (in 2D monolayers and in 3D tissue models), and permeability of molecules through the endothelial barrier. A dose of 0.50 Gy was sufficient to cause a progressive reduction in TEER measurements that were significant 48 hours after exposure. Concurrently, there were morphological changes and a 14% loss of cells from monolayers. Gaps also appeared in the normally continuous cell-border localization of the tight junction protein - ZO-1 but not the Platelet endothelial cell adhesion molecule (PECAM-1) in both monolayers and in 3D vessel models. Disruption of barrier function was confirmed by increased permeability to 3 kDa and 10 kDa dextran molecules. A dose of 0.25 Gy caused no detectible change in cell number, morphology, or TEER, but did cause barrier disruption since there were gaps in the cell border localization of ZO-1 and an increased permeability to 3 kDa dextran. These results indicate that Fe particles potently have

  6. Abnormal tracheal smooth muscle function in the CF mouse

    PubMed Central

    Wallace, Helen L; Southern, Kevin W; Connell, Marilyn G; Wray, Susan; Burdyga, Theodor

    2013-01-01

    Increased airway smooth muscle (ASM) contractility is thought to underlie symptoms of airway hyperresponsiveness (AHR). In the cystic fibrosis (CF) airway, ASM anomalies have been reported, but have not been fully characterized and the underlying mechanisms are largely unknown. We examined ASM in an adult CF mouse tracheal ring preparation, and determined whether changes in contractility were associated with altered ASM morphology. We looked for inherent changes in the cellular pathways involved in contractility, and characterized trachea morphology in the adult trachea and in an embryonic lung culture model during development. Results showed that that there was a reduction in tracheal caliber in CF mice as indicated by a reduction in the number of cartilage rings; proximal cross-sectional areas of cftr−/− tracheas and luminal areas were significantly smaller, but there was no difference in the area or distribution of smooth muscle. Morphological differences observed in adult trachea were not evident in the embryonic lung at 11.5 days gestation or after 72 h in culture. Functional data showed a significant reduction in the amplitude and duration of contraction in response to carbachol (CCh) in Ca-free conditions. The reduction in contraction was agonist specific, and occurred throughout the length of the trachea. These data show that there is a loss in the contractile capacity of the CF mouse trachea due to downregulation of the pathway specific to acetylcholine (ACh) activation. This reduction in contraction is not associated with changes in the area or distribution of ASM. PMID:24400140

  7. Endothelial Function in the Time of the Giants: Paul M. Vanhoutte Lecture

    PubMed Central

    Heistad, Donald D.

    2010-01-01

    Paul Vanhoutte is one of the fathers of vascular biology. Among his great contributions, he demonstrated that endothelium modulates vasomotor response to vasoactive products (including serotonin) that are released when platelets aggregate in an artery. He found in arteries ex vivo that when endothelium is dysfunctional, in atherosclerosis or hypertension, normal relaxation to aggregation of platelets is impaired, and vessels may contract. He proposed that this mechanism may predispose to vasospasm. Our experiments in vivo indicated that atherosclerosis greatly potentiates vasoconstrictor responses to serotonin in the limb, brain, and eye of monkeys. We proposed that transient ischemic attacks may be mediated by platelet-induced vasospasm. We observed endothelial dysfunction in atherosclerotic monkeys, with improvement of endothelial function when hypercholesterolemia was corrected. Recently, we have studied the aortic valve (which has unique endothelium) in hypercholesterolemic mice, to examine the pathophysiology of aortic valvular stenosis. Oxidative stress is increased in stenotic valves, and severe aortic stenosis develops in about one-third of old, hypercholesterolemic mice. In stenotic aortic valves from humans, there is increased oxidative stress near calcified regions of the valves. Oxidative stress may trigger expression of pro-calcific genes in the aortic valve. Finally, we have used gene transfer of extracellular superoxide dismutase (ecSOD) to study endothelial effects of oxidative stress. Gene transfer of normal ecSOD improves endothelial dysfunction in several disease states, but gene transfer of ecSODR213G, a gene variant of ecSOD that is common in humans, fails to improve endothelial function. Gene transfer approaches may be useful to study mechanisms by which gene variants predispose to endothelial dysfunction and vascular disease. PMID:19033817

  8. Effects of sodium and potassium supplementation on endothelial function: a fully controlled dietary intervention study.

    PubMed

    Gijsbers, Lieke; Dower, James I; Schalkwijk, Casper G; Kusters, Yvo H A M; Bakker, Stephan J L; Hollman, Peter C H; Geleijnse, Johanna M

    2015-11-14

    High Na and low K intakes have adverse effects on blood pressure, which increases the risk for CVD. The role of endothelial dysfunction and inflammation in this pathophysiological process is not yet clear. In a randomised placebo-controlled cross-over study in untreated (pre)hypertensives, we examined the effects of Na and K supplementation on endothelial function and inflammation. During the study period, subjects were provided with a diet that contained 2·4 g/d of Na and 2·3 g/d of K for a 10 460 kJ (2500 kcal) intake. After 1-week run-in, subjects received capsules with supplemental Na (3·0 g/d), supplemental K (2·8 g/d) or placebo, for 4 weeks each, in random order. After each intervention, circulating biomarkers of endothelial function and inflammation were measured. Brachial artery flow-mediated dilation (FMD) and skin microvascular vasomotion were assessed in sub-groups of twenty-two to twenty-four subjects. Of thirty-seven randomised subjects, thirty-six completed the study. Following Na supplementation, serum endothelin-1 was increased by 0·24 pg/ml (95 % CI 0·03, 0·45), but no change was seen in other endothelial or inflammatory biomarkers. FMD and microvascular vasomotion were unaffected by Na supplementation. K supplementation reduced IL-8 levels by 0·28 pg/ml (95 % CI 0·03, 0·53), without affecting other circulating biomarkers. FMD was 1·16 % (95% CI 0·37, 1·96) higher after K supplementation than after placebo. Microvascular vasomotion was unaffected. In conclusion, a 4-week increase in Na intake increased endothelin-1, but had no effect on other endothelial or inflammatory markers. Increased K intake had a beneficial effect on FMD and possibly IL-8, without affecting other circulating endothelial or inflammatory biomarkers.

  9. Functional characterization of late outgrowth endothelial progenitor cells in patients with end-stage renal failure

    PubMed Central

    Zhao, Jing; Bolton, Eleanor M; Randle, Lucy; Bradley, John Andrew; Lever, Andrew M L

    2014-01-01

    Renal transplantation is potentially curative in renal failure, but long-term efficacy is limited by untreatable chronic rejection. Endothelial damage contributes to chronic rejection and is potentially repairable by circulating endothelial progenitor cells (EPC). The frequency and function of EPC are variably influenced by end-stage renal failure (ESRF). Here, we isolated and functionally characterized the late outgrowth EPC (LO-EPC) from ESRF patients to investigate their potential for endothelial repair. Patients with ESRF generated more LO-EPC colonies than healthy controls and had higher plasma levels of IL-1rα, IL-16, IL-6, MIF, VEGF, Prolactin, and PLGF. Patients' LO-EPC displayed normal endothelial cell morphology, increased secretion of PLGF, MCP-1, and IL-1β, and normal network formation in vitro and in vivo. They demonstrated decreased adhesion to extracellular matrix. Integrin gene profiles and protein expression were comparable in patients and healthy volunteers. In some patients, mesenchymal stem cells (MSC) were co-isolated and could be differentiated into adipocytes and osteocytes in vitro. This is the first study to characterize LO-EPC from patients with ESRF. Their behavior in vitro reflects the presence of elevated trophic factors; their ability to proliferate in vitro and angiogenic function makes them candidates for prevention of chronic rejection. Their impaired adhesion and the presence of MSC are areas for potential therapeutic intervention. PMID:24471420

  10. Sex differences in endothelial function of aged hypertriglyceridemic rats – effect of atorvastatin treatment

    PubMed Central

    Bacova, Barbora; Vlkovicova, Jana; Navarova, Jana; Tribulova, Narcis

    2012-01-01

    The aim of the study was to test the hypothesis that the effect of atorvastatin on endothelium-dependent relaxation of the superior mesenteric artery (SMA) may differ in male vs. female aged hypertriglyceridemic rats (HTGs). Experiments were performed on 11-month-old male and female Prague hereditary HTGs. Atorvastatin (ATO) was administered p.o. in the dose of 0.30 mg/100g/day. Controls received vehiculum. After two months of ATO administration blood pressure, serum triglycerides (TG) and total cholesterol (CHOL) were determined. Endothelial function of SMA was studied in vitro using evaluation of relaxant responses of precontracted SMA to acetylcholine. The serum TG of control male HTGs were found to be statistically higher than those of female controls, while CHOL and blood pressure did not share gender differences. Responses of SMA of female control HTGs were statistically decreased compared to their male counterparts. ATO treatment induced decrease in blood pressure and TG of both males and females, yet CHOL values were reduced only in females. The protective effect of ATO on SMA endothelial function was much more pronounced in females compared to males. We conclude that vascular endothelial dysfunction of aged HTG rats is more severe and more attenuated by ATO in females compared to males. The protective effect of ATO on vascular endothelial function does not seem to depend solely on its lipid lowering action. PMID:23554556

  11. Preserved function of late outgrowth endothelial cells in medically-treated hypertensive patients under well-controlled conditions

    PubMed Central

    Chen, Zhi; Herrmann, Sandra M. S.; Zhu, Xiangyang; Jordan, Kyra L.; Gloviczki, Monika L.; Lerman, Amir; Textor, Stephen C.; Lerman, Lilach O.

    2014-01-01

    Endothelial-progenitor-cells participate in renal repair, but their number and function may be impaired by exposure to cardiovascular risk factors. The number of circulating endothelial-progenitor-cells is decreased in essential and renovascular hypertensive patients, but the effects of hypertension on endothelial-progenitor-cell function are incompletely understood. We hypothesized that endothelial-progenitor-cell function was preserved under well-controlled conditions in treated hypertensive patients. Patients with atherosclerotic-renal-artery-stenosis (n=22) or essential-hypertension (n=24) were studied during controlled sodium intake and anti-hypertensive regimen. Late-outgrowth-endothelial-progenitor-cells were isolated from the inferior vena cava and renal vein blood of atherosclerotic-renal-artery-stenosis and essential-hypertension patients, and a peripheral vein of matched normotensive controls (n=18). The angiogenic function of endothelial-progenitor-cells was assessed in vitro and multi-detector computer tomography used to measure single-kidney hemodynamics and function in atherosclerotic-renal-artery-stenosis and essential-hypertension patients. Inflammatory biomarkers and endothelial-progenitor-cell homing signals levels and renal release were calculated. Inferior vena cava and renal vein-obtained endothelial-progenitor-cell function were similar in atherosclerotic-renal-artery-stenosis and essential-hypertension patients, and comparable to that in normal controls (tube length 171.86±16.846, 191.09±14.222, 174.925±19.774μm, respectively). Function of renal vein-obtained endothelial-progenitor-cells directly correlated with stenotic-kidney glomerular filtration rate, endothelial-progenitor-cell homing factors and anti-inflammatory mediator levels in atherosclerotic-renal-artery-stenosis patients. Therefore, endothelial-progenitor-cell function was relatively preserved in atherosclerotic-renal-artery-stenosis patients, although it directly correlated

  12. Early-stage visual processing abnormalities in high-functioning autism spectrum disorder (ASD).

    PubMed

    Baruth, Joshua M; Casanova, Manuel F; Sears, Lonnie; Sokhadze, Estate

    2010-06-01

    It has been reported that individuals with autism spectrum disorder (ASD) have abnormal responses to the sensory environment. For these individuals sensory overload can impair functioning, raise physiological stress, and adversely affect social interaction. Early-stage (i.e. within 200ms of stimulus onset) auditory processing abnormalities have been widely examined in ASD using event-related potentials (ERP), while ERP studies investigating early-stage visual processing in ASD are less frequent. We wanted to test the hypothesis of early-stage visual processing abnormalities in ASD by investigating ERPs elicited in a visual oddball task using illusory figures. Our results indicate that individuals with ASD have abnormally large cortical responses to task irrelevant stimuli over both parieto-occipital and frontal regions-of-interest (ROI) during early stages of visual processing compared to the control group. Furthermore, ASD patients showed signs of an overall disruption in stimulus discrimination, and had a significantly higher rate of motor response errors.

  13. Assessments of endothelial function and arterial stiffness are reproducible in patients with COPD

    PubMed Central

    Rodriguez-Miguelez, Paula; Seigler, Nichole; Bass, Leon; Dillard, Thomas A; Harris, Ryan A

    2015-01-01

    Background Elevated cardiovascular disease risk is observed in patients with COPD. Non-invasive assessments of endothelial dysfunction and arterial stiffness have recently emerged to provide mechanistic insight into cardiovascular disease risk in COPD; however, the reproducibility of endothelial function and arterial stiffness has yet to be investigated in this patient population. Objectives This study sought to examine the within-day and between-day reproducibility of endothelial function and arterial stiffness in patients with COPD. Methods Baseline diameter, peak diameter, flow-mediated dilation, augmentation index, augmentation index at 75 beats per minute, and pulse wave velocity were assessed three times in 17 patients with COPD (six males, eleven females, age range 47–75 years old; forced expiratory volume in 1 second =51.5% predicted). Session A and B were separated by 3 hours (within-day), whereas session C was conducted at least 7 days following session B (between-day). Reproducibility was assessed by: 1) paired t-tests, 2) coefficients of variation, 3) coefficients of variation prime, 4) intra-class correlation coefficient, 5) Pearson’s correlations (r), and 6) Bland–Altman plots. Five acceptable assessments were required to confirm reproducibility. Results Six out of six within-day criteria were met for endothelial function and arterial stiffness outcomes. Six out of six between-day criteria were met for baseline and peak diameter, augmentation index and pulse wave velocity, whereas five out of six criteria were met for flow-mediated dilation. Conclusion The present study provides evidence for within-day and between-day reproducibility of endothelial function and arterial stiffness in patients with COPD. PMID:26396509

  14. Assessment of endothelial function in patients with fibromyalgia--cardiac ultrasound study.

    PubMed

    Cho, Kyoung Im; Lee, Ji Hyun; Kim, Seong Man; Lee, Hyeon Gook; Kim, Tae Ik

    2011-05-01

    In patients with fibromyalgia (FM) syndrome, stress and pain may chronically enhance sympathetic activity, altering cardiovascular response and inducing endothelial dysfunction. We investigated endothelial function in FM patients using echocardiography and analyzed whether endothelial function was affected by the clinical parameters of FM. Fifty-five postmenopausal women with FM and 35 healthy controls were included. Endothelial function was examined by brachial artery flow-mediated dilatation (FMD, endothelium dependent) and response to 40 μg of sublingual nitroglycerine (NTG-induced dilatation, endothelium independent). FM patients underwent manual tender point survey and completed visual analogue scale (VAS) of pain and fibromyalgia impact questionnaire (FIQ). The study participants were subdivided into two groups based on the sum of the FIQ score (group A, FIQ ≥ 50, group B, <50). The FMD value (5.7 ± 3.9% vs. 7.0 ± 1.4%, P = 0.008) and NTG-induced dilatation (12.5 ± 5.1% vs. 14.7 ± 2.5%, P = 0.006) were significantly lower in FM group than healthy control. There were no significant differences in FMD between groups A and B (5.4 ± 3.3% vs. 6.6 ± 3.5%, P = 0.19). However, significant decreases were noted in NTG-induced dilatation values of group A compared with those of group B (11.0 ± 4.4% vs. 14.3 ± 3.8%, P = 0.004). FMD and NTG-induced dilatation showed a significant inverse association with pain VAS and FIQ. Pain exerts a negative effect on endothelial function in FM patients, and that effect was significantly different according to the FIQ score.

  15. [Promotion of Function of Endothelial Progenitor Cells with Shexiang Baoxin Pill Treatment under Shear Stress].

    PubMed

    Li, Gang; Chen, Yang; Wu, Jiang

    2015-08-01

    The aim of this study was to investigate whether shear stress could promote function of endothelial progenitor cells (EPCs) with Shexiang Baoxin Pill (SBP) treatment in vitro, and to study whether shear stress contributed to vascular injury repair by EPCs. EPCs were isolated and characterized; EPCs' proliferation, migration, adhesion, tube formation and eNOS protein level in vitro were investigated by culturing confluent EPCs in 4 mg/mL SBP under physiological shear stress (15 dyne/cm2) for up to 24 hours. Afterwards, EPCs were transfused into rats after wire-induced carotid artery injury augmented re-endothelialization. The results showed that, compared to the SBP group, the shear stress+SBP group obviously enhanced EPCs proliferation, migration, adhesion, tube formation and eNOS protein expression in vitro (P<0.01). After one week, immunofluorescence staining showed that endothelial regeneration rate obviously enhanced in shear stress+SBP group (P<0.01). The present study demonstrates that shear stress can promote function of endothelial progenitor cells treated with SBP, which improves the vascular injury repair potentials of EPCs. PMID:26710458

  16. Can pain intensity in osteoarthritis joint be indicator of the impairment of endothelial function?

    PubMed

    Laskarin, Gordana; Persic, Viktor; Kukic, Sandra Rusac; Massari, Drazen; Legovic, Anita; Boban, Marko; Miskulin, Rajko; Rogoznica, Marija; Kehler, Tatjana

    2016-09-01

    We propose that pathological remodeling in joint tissues of osteoarthritis (OA) patients persistently stimulates local secretion of pro-inflammatory mediators, which overflow into the blood, activating leukocytes that impair endothelial function and accelerate the atherosclerotic process. During periods of pain, endothelial dysfunction progresses more aggressively due to elevated secretion of these pro-inflammatory mediators, which are involved in both atherosclerosis and the sensation of pain. Concentrations of pro-inflammatory cytokines and their antagonists, activating and decoy receptors of the broad interleukin (IL)-1 and IL-17 families, IL-15, and monocyte chemotactic protein-1 should be measured in peripheral blood samples of OA patients and compared with (I) OA clinical severity; (II) subclinical parameters of atherosclerosis; (III) ischemic heart disease risk factors; (IV) soluble factors indicating endothelial dysfunction; (V) degree of bone destruction; and (VI) results of a six-minute walk test. Arthroscopy and joint replacement surgery provide an opportunity to estimate mRNA and protein expression of inflammatory mediators in specimens of synovial fluid, synovial membrane, cartilage, and/or subarticular bone. A range of methods, including questionnaires, X-ray, computed tomography, ultrasound, enzyme-linked immunosorbent assay, immunohistology, immunofluorescence, and reverse transcription and in situ polymerase chain reaction are available. Understanding the inflammatory and immune mechanisms underlying OA may allow the early identification of patients at high risk of cardiovascular disease, independently of classical coronary risk factors. Pain may constitute an extrinsic indicator of currently worsening endothelial function. PMID:27515191

  17. Comparative evaluation of the impact on endothelial cells induced by different nanoparticle structures and functionalization

    PubMed Central

    Müller, Ines; Ernst, Peter; Schäfer, Miriam; Rosman, Christina; Schick, Isabel; Köhler, Oskar; Oehring, Hartmut; Breus, Vladimir V; Basché, Thomas; Sönnichsen, Carsten; Tremel, Wolfgang

    2015-01-01

    Summary In the research field of nanoparticles, many studies demonstrated a high impact of the shape, size and surface charge, which is determined by the functionalization, of nanoparticles on cell viability and internalization into cells. This work focused on the comparison of three different nanoparticle types to give a better insight into general rules determining the biocompatibility of gold, Janus and semiconductor (quantum dot) nanoparticles. Endothelial cells were subject of this study, since blood is the first barrier after intravenous nanoparticle application. In particular, stronger effects on the viability of endothelial cells were found for nanoparticles with an elongated shape in comparison to spherical ones. Furthermore, a positively charged nanoparticle surface (NH2, CyA) leads to the strongest reduction in cell viability, whereas neutral and negatively charged nanoparticles are highly biocompatible to endothelial cells. These findings are attributed to a rapid internalization of the NH2-functionalized nanoparticles in combination with the damage of intracellular membranes. Interestingly, the endocytotic pathway seems to be a size-dependent process whereas nanoparticles with a size of 20 nm are internalized by caveolae-mediated endocytosis and nanoparticles with a size of 40 nm are taken up by clathrin-mediated internalization and macropinocytosis. Our results can be summarized to formulate five general rules, which are further specified in the text and which determine the biocompatibility of nanoparticles on endothelial cells. Our findings will help to design new nanoparticles with optimized properties concerning biocompatibility and uptake behavior with respect to the respective intended application. PMID:25821668

  18. TNFα-Damaged-HUVECs Microparticles Modify Endothelial Progenitor Cell Functional Activity

    PubMed Central

    Luna, Carlos; Carmona, Andrés; Alique, Matilde; Carracedo, Julia; Ramirez, Rafael

    2015-01-01

    Endothelial progenitor cells (EPCs) have an important role in the maintenance of vascular integrity and homeostasis. While there are many studies that explain EPCs mechanisms action, there are few studies that demonstrate how they interact with other emerging physiological elements such as Endothelial Microparticles (EMPs). EMPs are membranous structures with a size between 100 and 1000 nm that act as molecular information transporter in biological systems and are known as an important elements in develop different pathologies; moreover a lot of works explains that are novel biomarkers. To elucidate these interactions, we proposed an in vitro model of endothelial damage mediated by TNFalpha, in which damaged EMPs and EPCs are in contact to assess EPCs functional effects. We have observed that damaged EMPs can modulate several EPCs classic factors as colony forming units (CFUs), contribution to repair a physically damaged endothelium (wound healing), binding to mature endothelium, and co-adjuvants to the formation of new vessels in vitro (angiogenesis). All of these in a dose-dependent manner. Damaged EMPs at a concentration of 103 MPs/ml have an activating effect of these capabilities, while at concentrations of 105 MPs/ml these effects are attenuated or reduced. This in vitro model helps explain that in diseases where there is an imbalance between these two elements (EPCs and damaged EMPs), the key cellular elements in the regeneration and maintenance of vascular homeostasis (EPCs) are not fully functional, and could explain, at least in part, endothelial dysfunction associated in various pathologies. PMID:26733886

  19. Coniferyl Aldehyde Attenuates Radiation Enteropathy by Inhibiting Cell Death and Promoting Endothelial Cell Function

    PubMed Central

    Son, Yeonghoon; Jang, Jun-Ho; Lee, Yoon-Jin; Kim, Sung-Ho; Ko, Young-Gyo; Lee, Yun-Sil; Lee, Hae-June

    2015-01-01

    Radiation enteropathy is a common complication in cancer patients. The aim of this study was to investigate whether radiation-induced intestinal injury could be alleviated by coniferyl aldehyde (CA), an HSF1-inducing agent that increases cellular HSP70 expression. We systemically administered CA to mice with radiation enteropathy following abdominal irradiation (IR) to demonstrate the protective effects of CA against radiation-induced gastrointestinal injury. CA clearly alleviated acute radiation-induced intestinal damage, as reflected by the histopathological data and it also attenuated sub-acute enteritis. CA prevented intestinal crypt cell death and protected the microvasculature in the lamina propria during the acute and sub-acute phases of damage. CA induced HSF1 and HSP70 expression in both intestinal epithelial cells and endothelial cells in vitro. Additionally, CA protected against not only the apoptotic cell death of both endothelial and epithelial cells but also the loss of endothelial cell function following IR, indicating that CA has beneficial effects on the intestine. Our results provide novel insight into the effects of CA and suggest its role as a therapeutic candidate for radiation-induced enteropathy due to its ability to promote rapid re-proliferation of the intestinal epithelium by the synergic effects of the inhibition of cell death and the promotion of endothelial cell function. PMID:26029925

  20. Post-Exercise Ankle-Brachial Pressure Index Demonstrates Altered Endothelial Function in the Elderly

    PubMed Central

    Sato, Shinji; Masami, Kozue; Otsuki, Shingo; Tanaka, Shiro; Nakayama, Noriko; Makita, Shigeru; Koshiyama, Hiroyuki; Nohara, Ryuji

    2011-01-01

    Background: The ankle-brachial pressure index (ABI), the ratio of the systolic blood pressure of the ankle to the systolic brachial pressure, is commonly measured at rest, but ABI values post-exercise enhance the sensitivity of the test and can be used to identify atherosclerotic vascular damage. However, it has not been established whether or not enhanced post-exercise ABI is also associated with endothelial dysfunction. We hypothesized that a decrease in post-exercise ABI is related to impaired endothelial function. Purpose: To investigate alterations in post-exercise ABI values and endothelial dysfunction in the elderly. Methods: The study population comprised 35 men and women aged 51–77 years (mean age: 66 years). Patients with peripheral arterial disease or a history of heart failure were excluded. The ABI was estimated at rest and immediately after exercise. The exercise protocol comprised 2.5 min of active pedal flexion exercises at a speed of 60 times/min. Endothelial function was assessed by measuring flow-mediated vasodilation (FMD) in the brachial artery using ultrasound imaging. Results: No correlation was found between FMD and the ABI at rest. However, a weak correlation was found between FMD and post-exercise ABI (r = 0.46, P = 0.06). A strong correlation was observed between FMD and a decrease in post-exercise ABI compared to baseline readings (r = −0.52, P = 0.01). Multiple linear regression analysis was used to generate a prediction equation for FMD using the percentage decrease in post-exercise ABI. Significant correlations were observed between the ultrasound imaging-measured FMD and the predicted FMD (R2 = 0.27, P = 0.001). Conclusions: Post-exercise ABI appears to be a simple surrogate marker for endothelial function in the elderly, although larger studies are required for validation. PMID:23885186

  1. Effects of Recombinant Human Erythropoietin on Resistance Artery Endothelial Function in Stage 4 Chronic Kidney Disease

    PubMed Central

    Briet, Marie; Barhoumi, Tlili; Mian, Muhammad Oneeb Rehman; Sierra, Cristina; Boutouyrie, Pierre; Davidman, Michael; Bercovitch, David; Nessim, Sharon J.; Frisch, Gershon; Paradis, Pierre; Lipman, Mark L.; Schiffrin, Ernesto L.

    2013-01-01

    Background Recent studies have raised concern about the safety of erythropoiesis‐stimulating agents because of evidence of increased risk of hypertension and cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. In the present study, we investigated the effects of recombinant human erythropoietin (EPO) on endothelial function of gluteal subcutaneous resistance arteries isolated from 17 stage 4 patients (estimated glomerular filtration rate 21.9±7.4 mL/min per 1.73 m2) aged 63±13 years. Methods and Results Arteries were mounted on a pressurized myograph. EPO impaired endothelium‐dependent relaxation in a concentration‐dependent manner. The maximal response to acetylcholine with EPO at 1, 10, and 20 IU/mL was reduced by 12%, 34%, and 43%, respectively, compared with the absence of EPO (P<0.001). EPO‐induced endothelial dysfunction was significantly associated with carotid stiffness and history of cardiovascular events. EPO had no effect on norepinephrine‐induced vasoconstriction or sodium nitroprusside–induced relaxation. ABT‐627, an endothelin type A receptor antagonist, and tempol, a superoxide dismutase mimetic, partially reversed the altered endothelial function in the presence of EPO (P<0.01). Increased expression of endothelin‐1 was found in the vessel wall after incubation with EPO. Conclusions EPO alters endothelial function of resistance arteries in CKD patients via a mechanism involving in part oxidative stress and signaling through an endothelin type A receptor. EPO‐induced endothelial dysfunction could contribute to deleterious effects of EPO described in large interventional trials. PMID:23584809

  2. [Endothelial glycocalyx of blood circulation. II. Biological functions, state at norm and pathology, bioengineering application].

    PubMed

    Maksimenko, A V; Turashev, A D

    2014-01-01

    In normal state, a complex multicomponent system called glycocalyx is present on the surface of endothelial vascular system. Due to complexity of its composition and location on the border between vessel wall and blood circulation, glycocalyx participates in a number of functions supporting the metabolism of the vascular wall. In pathological conditions undergo complete or partial loss of this structure, which leads to inconsistencies in the vascular wall and change its functions. The functions of endothelial glycocalyx are its involvement in the regulation of vascular permeability, transduction and transformation by the shear stress of blood flow on endothelium, the molecular regulation of glycocalyx microenvironment and its interaction with circulating blood cells. Also briefly be considered participation of glycocalyx in the implementation of cardiovascular diseases, their correction, bioengineering application of glycocalyx and its components.

  3. Liver Function Test Abnormalities in Patients with Inflammatory Bowel Diseases: A Hospital-based Survey

    PubMed Central

    Cappello, Maria; Randazzo, Claudia; Bravatà, Ivana; Licata, Anna; Peralta, Sergio; Craxì, Antonio; Almasio, Piero Luigi

    2014-01-01

    BACKGROUND AND AIMS Inflammatory bowel diseases (IBD) are frequently associated with altered liver function tests (LFTs). The causal relationship between abnormal LFTs and IBD is unclear. The aim of our study was to evaluate the prevalence and etiology of LFTs abnormalities and their association with clinical variables in a cohort of IBD patients followed up in a single center. MATERIALS AND METHODS A retrospective review was undertaken of all consecutive IBD in- and outpatients routinely followed up at a single referral center. Clinical and demographic parameters were recorded. Subjects were excluded if they had a previous diagnosis of chronic liver disease. LFT abnormality was defined as an increase in aspartate aminotransferase, (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), or total bilirubin. RESULTS A cohort of 335 patients (179 males, mean age 46.0 ± 15.6 years) was analyzed. Abnormal LFTs were detected in 70 patients (20.9%). In most cases, the alterations were mild and spontaneously returned to normal values in about 60% of patients. Patients with abnormal LFTs were less frequently on treatment with aminosalicylates (22.8 vs. 36.6%, P = 0.04). The most frequent cause for transient abnormal LFTs was drug-induced cholestasis (34.1%), whereas fatty liver was the most frequent cause of persistent liver damage (65.4%). A cholestatic pattern was found in 60.0% of patients and was mainly related to older age, longer duration of disease, and hypertension. CONCLUSIONS The prevalence of LFT abnormalities is relatively high in IBD patients, but the development of severe liver injury is exceptional. Moreover, most alterations of LFTs are mild and spontaneously return to normal values. Drug-induced hepatotoxicity and fatty liver are the most relevant causes of abnormal LFTs in patients with IBD. PMID:24966712

  4. Long-term, regular remote ischemic preconditioning improves endothelial function in patients with coronary heart disease.

    PubMed

    Liang, Y; Li, Y P; He, F; Liu, X Q; Zhang, J Y

    2015-06-01

    Remote ischemic preconditioning (RIPre) can prevent myocardial injury. The purpose of this study was to assess the beneficial effects of long-term regular RIPre on human arteries. Forty patients scheduled for coronary artery bypass graft (CABG) surgery were assigned randomly to a RIPre group (n=20) or coronary heart disease (CHD) group (n=20). Twenty patients scheduled for mastectomy were enrolled as a control group. RIPre was achieved by occluding arterial blood flow 5 min with a mercury sphygmomanometer followed by a 5-min reperfusion period, and this was repeated 4 times. The RIPre procedure was repeated 3 times a day for 20 days. In all patients, arterial fragments discarded during surgery were collected to evaluate endothelial function by flow-mediated dilation (FMD), CD34(+) monocyte count, and endothelial nitric oxide synthase (eNOS expression). Phosphorylation levels of STAT-3 and Akt were also assayed to explore the underlying mechanisms. Compared with the CHD group, long-term regular RIPre significantly improved FMD after 20 days (8.5±2.4 vs 4.9±4.2%, P<0.05) and significantly reduced troponin after CABG surgery (0.72±0.31 and 1.64±0.19, P<0.05). RIPre activated STAT-3 and increased CD34(+) endothelial progenitor cell counts found in arteries. Long-term, regular RIPre improved endothelial function in patients with CHD, possibly due to STAT-3 activation, and this may have led to an increase in endothelial progenitor cells.

  5. Bone Marrow Transplantation Improves Endothelial Function in Hypertensive Dahl Salt-Sensitive Rats

    PubMed Central

    Yu, Hong; Shao, Hongwei; Yan, Jing; Tsoukias, Nikolaos M.; Zhou, Ming-Sheng

    2012-01-01

    Bone marrow-derived endothelial progenitor cells (EPCs) constitute an important endogenous system in the maintenance of endothelial integrity and vascular homeostasis. Cardiovascular risk factors are associated with a reduced number and functional capacity of EPCs. Here we investigated the effect of transplantation of bone marrow-derived cells from Dahl salt-resistant rat into age-matched Dahl salt-sensitive (DS) rat on blood pressure, endothelial function, and circulating EPC number. The recipient DS rats were fed a normal (0.5% NaCl, NS) or high salt (4% NaCl, HS) diet for 6 weeks after BMT. DS rats on a NS or a HS diet without BMT were used as controls. Hypertensive DS (HS-DS) rat (systolic blood pressure: 213 ± 4 mmHg vs. 152 ± 4 mmHg in NS, p<0.05) manifested impaired endothelium-dependent relaxation to acetylcholine (EDR), increased gene expression of vascular oxidative stress and proinflamamtory cytokines, and decreased eNOS expression. BMT on HS-DS rat significantly improved EDR and eNOS expression, reduced oxidative stress without reduction in SBP (206 ± 6 mmHg). Flow cytometry analysis showed that there was no difference in the number of circulating EPCs, demonstrated by expression of EPC markers CD34, cKit, and vascular endothelial growth factor, between hypertensive and normotensive rats. Surprisingly, BMT resulted in a 5–10 fold increase in the above-mentioned EPC markers in hypertensive, but not normotensive rat. These results suggest that DS rat has an impaired ability to increase bone marrow-derived EPCs in response to HS diet challenge, which may contribute to endothelial dysfunction. PMID:22995801

  6. Geraniol improves endothelial function by inhibiting NOX-2 derived oxidative stress in high fat diet fed mice.

    PubMed

    Wang, Xiaoyu; Zhao, Shiqi; Su, Mengqi; Sun, Li; Zhang, Song; Wang, Dingyu; Liu, Zhaorui; Yuan, Yue; Liu, Yang; Li, Yue

    2016-05-20

    Endothelial dysfunction occurs in obese patients and high-fat diet (HFD) fed experimental animals. While geraniol has been reported to ameliorate inflammation and oxidative stress, inhibit tumor cell proliferation, and improve atherosclerosis, its direct effect on endothelial function remains uncharacterized. The present study therefore investigated the effect of geraniol on endothelial function in HFD mice and its underlying mechanisms. C57 BL/6 mice were fed an HFD (n = 40) or a normal diet (n = 20) for 8 weeks. HFD fed mice then were randomized to intraperitoneal treatment with geraniol (n = 20) or vehicle (n = 20) for another 6 weeks. Acetylcholine (Ach)-induced endothelial dependent vasorelaxation was measured on wire myography; reactive oxygen species (ROS) generation was assessed by fluorescence imaging, and NADPH oxidases (NOXs) and adhesive molecules VCAM-1 and ICAM-1 protein expression by western blotting. Geraniol improved endothelial function in HFD fed mice, as evidenced by its: 1. restoring endothelial dependent vasorelaxation induced by Ach, and reversing increased VCAM-1 and ICAM-1 expression; 2. attenuating HFD induced increased serum TBARS and aortic ROS generation; and 3. downregulating aortic NOX-2 expression in both HFD fed mice and in palmitic acid treated endothelial cells. Geraniol therefore protects against endothelial dysfunction induced by HFD through reducing NOX-2 associated ROS generation.

  7. Tumors skew endothelial cells to disrupt NK cell, T-cell and macrophage functions

    PubMed Central

    Mulligan, Jennifer K.; Lathers, Deanne M. R.

    2012-01-01

    Introduction Patients and mice with solid tumors, such as Lewis lung carcinoma (LLC), have defects in functions of immune effector cells. Endothelial cells, a component of the tumor vasculature, are potential regulators of immune cell functions. Therefore, these studies examined the impact of exposure to LLC tumor on the ability of endothelial cells to modulate immune cell functions. Materials and methods Endothelial cells were pre-treated with LLC tumor-conditioned medium (EndoT-sup) for 24 h. Control endothelial cells that were exposed to medium (EndoMedia) or epithelial cell-conditioned medium (EndoEpi-sup). After the initial 24 h incubation, endothelial cells were washed and fresh media was added. Cells were allowed to incubate for an additional 24 h. Supernatants from EndoMedia, EndoEpi-sup or EndoT-sup were collected and assayed for immune modulatory products and for immune modulatory activity. Results Supernatant from EndoT-sup contained increased levels of PGE2, IL-6 and VEGF as compared to EndoMedia and EndoEpi-sup controls. NK cell activity, as measured by TNF-α and IFN-γ secretion, was increased following exposure to media conditioned by EndoMedia and EndoEpi-sup. Exposure of NK cells to supernatants of EndoT-sup, also increases TNF-α and IFN-γ secretion, but to a lesser extent than by EndoMedia and EndoEpi-sup. Examination of macrophage functions demonstrated that supernatant from EndoT-sup decreased microbead phagocytosis and increased production of the immune suppressive mediators, IL-10 and PGE2. Lastly, T-cell responses to stimulation with anti-CD3 in the presence of supernatants from EndoT-sup were examined. IFN-γ production by CD8+ T-cells was reduced after exposure to EndoT-sup-conditioned medium, as compared to cells treatments with medium or control conditioned medium. Production of IFN-γ by CD4+ T-cells exposed to EndoT-sup was not altered. Conclusions Taken together, these studies demonstrate that tumors skew endothelial cells to

  8. Effect of CPAP therapy on endothelial function in obstructive sleep apnoea: A systematic review and meta-analysis.

    PubMed

    Schwarz, Esther I; Puhan, Milo A; Schlatzer, Christian; Stradling, John R; Kohler, Malcolm

    2015-08-01

    Obstructive sleep apnoea (OSA) is a prevalent sleep-related breathing disorder associated with adverse cardiovascular outcome. Endothelial dysfunction is one of the proposed mechanistic links between OSA and the increased cardiovascular risk. Treatment with continuous positive airway pressure (CPAP) may reverse this detrimental pathophysiological consequence of OSA. Most studies on the effect of CPAP on endothelial function in OSA are limited by their low sample size. The objective of this systematic review was to assess the effect CPAP therapy on endothelial function in patients with OSA. We conducted a systematic review and meta-analysis searching literature databases up to August 2013 for randomized controlled trials (RCTs) on the effect of CPAP on endothelial function in OSA, assessed by flow-mediated dilatation (FMD) and other validated techniques. The primary outcome for the meta-analysis (DerSimonian/Laird random-effects method) was the treatment effect on FMD. Eight RCTs comparing the effects of therapeutic CPAP versus subtherapeutic CPAP (or no intervention) on endothelial function involving 245 OSA patients were included in the systematic review. The studies are consistent in effect direction, showing an improvement of endothelial function by CPAP. Four RCTs involving 150 patients could be used for the meta-analysis. Compared to the control group, CPAP therapy (range 2-24 weeks) significantly increased absolute % FMD by 3.87% (95% confidence interval: 1.93-5.80, P < 0.001). In patients with OSA, CPAP therapy improves endothelial function significantly and to a clinically important extent.

  9. Hepatocyte growth factor enhances the barrier function in primary cultures of rat brain microvascular endothelial cells.

    PubMed

    Yamada, Narumi; Nakagawa, Shinsuke; Horai, Shoji; Tanaka, Kunihiko; Deli, Maria A; Yatsuhashi, Hiroshi; Niwa, Masami

    2014-03-01

    The effects of hepatocyte growth factor (HGF) on barrier functions were investigated by a blood-brain barrier (BBB) in vitro model comprising a primary culture of rat brain capillary endothelial cells (RBEC). In order to examine the response of the peripheral endothelial cells to HGF, human umbilical vascular endothelial cells (HUVEC) and human dermal microvascular endothelial cells (HMVEC) were also treated with HGF. HGF decreased the permeability of RBEC to sodium fluorescein and Evans blue albumin, and dose-dependently increased transendothelial electrical resistance (TEER) in RBEC. HGF altered the immunochemical staining pattern of F-actin bands and made ZO-1 staining more distinct on the linear cell borders in RBEC. In contrast, HGF increased sodium fluorescein and Evans blue albumin permeability in HMVEC and HUVEC, and decreased TEER in HMVEC. In HMVEC, HGF reduced cortical actin bands and increased stress fiber density, and increased the zipper-like appearance of ZO-1 staining. Western blot analysis showed that HGF significantly increased the amount of ZO-1 and VE-cadherin. HGF seems to act on the BBB to strengthen BBB integrity. These findings indicated that cytoskeletal rearrangement and cell-cell adhesion, such as through VE-cadherin and ZO-1, are candidate mechanisms for the influence of HGF on the BBB. The possibility that HGF has therapeutic significance in protecting the BBB from damage needs to be considered. PMID:24370951

  10. Effects of erythritol on endothelial function in patients with type 2 diabetes mellitus: a pilot study.

    PubMed

    Flint, Nir; Hamburg, Naomi M; Holbrook, Monika; Dorsey, Pamela G; LeLeiko, Rebecca M; Berger, Alvin; de Cock, Peter; Bosscher, Douwina; Vita, Joseph A

    2014-01-01

    Sugar substitutes are important in the dietary management of diabetes mellitus. Erythritol is a non-caloric dietary bulk sweetener that reverses endothelial dysfunction in diabetic rats. We completed a pilot study to examine the effects of erythritol on vascular function in patients with type 2 diabetes mellitus. Participants (n = 24) consumed erythritol 36 g/day as an orange-flavored beverage for 4 weeks and a single dose of 24 g during the baseline and final visits. We assessed vascular function before and after acute (2 h) and chronic (4 weeks) erythritol consumption. Acute erythritol improved endothelial function measured by fingertip peripheral arterial tonometry (0.52 ± 0.48 to 0.87 ± 0.29 au, P = 0.005). Chronic erythritol decreased central pulse pressure (47 ± 13 to 41 ± 9 mmHg, P = 0.02) and tended to decrease carotid-femoral pulse wave velocity (P = 0.06). Thus, erythritol consumption acutely improved small vessel endothelial function, and chronic treatment reduced central aortic stiffness. Erythritol may be a preferred sugar substitute for patients with diabetes mellitus.

  11. Functional Brain Network Abnormalities during Verbal Working Memory Performance in Adolescents and Young Adults with Dyslexia

    ERIC Educational Resources Information Center

    Wolf, Robert Christian; Sambataro, Fabio; Lohr, Christina; Steinbrink, Claudia; Martin, Claudia; Vasic, Nenad

    2010-01-01

    Behavioral and functional neuroimaging studies indicate deficits in verbal working memory (WM) and frontoparietal dysfunction in individuals with dyslexia. Additionally, structural brain abnormalities in dyslexics suggest a dysconnectivity of brain regions associated with phonological processing. However, little is known about the functional…

  12. Low yield of unselected testing in patients with acutely abnormal liver function tests

    PubMed Central

    Chadwick, Andrew

    2015-01-01

    Objectives To audit the diagnostic yield and cost implications of the use of a ‘liver screen’ for inpatients with abnormal liver function tests. Design We performed a retrospective audit of inpatients with abnormal liver function tests. We analysed all investigations ordered including biochemistry, immunology, virology and radiology. The final diagnosis was ascertained in each case, and the diagnostic yield and cost per positive diagnosis for each investigation were calculated. Setting St Thomas’ NHS Trust. Participants All inpatients investigated for abnormal liver function tests over a 12-month period. Main outcome measures We calculated the percentage of courses due to each diagnosis, the yield of each investigation and the cost per positive diagnosis for each investigation. Results A total of 308 patients were included, and a final diagnosis was made in 224 patients (73%) on the basis of both clinical data and investigations. There was considerable heterogeneity in the tests included in an acute liver screen. History and ultrasound yielded the most diagnoses (40% and 30%, respectively). The yield of autoimmune and metabolic screens was minimal. Conclusions Our results demonstrate the low yield of unselected testing in patients with abnormal liver function tests. A thorough history, ultrasound and testing for blood-borne viruses are the cornerstones of diagnosis. Specialist input should be sought before further testing. Prospective studies to evaluate the yield and cost-effectiveness of different testing strategies are needed. PMID:26770816

  13. Spironolactone and chlorthalidone in uncontrolled elderly hypertensive patients treated with calcium antagonists and angiotensin II receptor-blocker: effects on endothelial function, inflammation, and oxidative stress.

    PubMed

    Yamanari, Hiroshi; Nakamura, Kazufumi; Miura, Daiji; Yamanari, Shuichi; Ohe, Tohru

    2009-10-01

    The side effects of thiazide-type diuretics include metabolic abnormality and increased oxidative stress, which might cause endothelial dysfunction despite blood pressure reduction. In hypertensive patients with heart failure, treatment with an aldosterone antagonist resulted in improvements in endothelial function and significant blood pressure reduction. The purpose of the present study was to evaluate the differences between spironolactone and chlorthalidone in hypertensive elderly patients treated with calcium antagonists and angiotensin II receptor blockers. Fourteen uncontrolled hypertensive patients treated with amlodipine and candesartan were included in this study. The study was an open-label randomized crossover comparison of 16 weeks treatment with spironolactone against chlorthalidone added to amlodipine and candesartan. Blood pressure significantly decreased in patients treated with both spironolactone and chlorthalidone. Chlorthalidone reduced flow mediated dilation significantly compared to the baseline condition and spironolactone. Serum high sensitively C-reactive protein and uric acid increased significantly in chlorthalidone-treated patients compared to spironolactone treated patients. We conclude that spironolactone may be a more useful add-on therapy than chlorthalidone in hypertensive patients inadequately controlled on candesartan and amlodipine, because spironolactone preserves endothelial function and reduces inflammation compared to chlorthalidone.

  14. Renin-Angiotensin System Blockade Associated with Statin Improves Endothelial Function in Diabetics

    PubMed Central

    Gismondi, Ronaldo Altenburg; Bedirian, Ricardo; Pozzobon, Cesar Romaro; Ladeira, Márcia Cristina; Oigman, Wille; Neves, Mário Fritsch

    2015-01-01

    Background Studies suggest that statins have pleiotropic effects, such as reduction in blood pressure, and improvement in endothelial function and vascular stiffness. Objective To analyze if prior statin use influences the effect of renin-angiotensin-aldosterone system inhibitors on blood pressure, endothelial function, and vascular stiffness. Methods Patients with diabetes and hypertension with office systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 80 mmHg had their antihypertensive medications replaced by amlodipine during 6 weeks. They were then randomized to either benazepril or losartan for 12 additional weeks while continuing on amlodipine. Blood pressure (assessed with ambulatory blood pressure monitoring), endothelial function (brachial artery flow-mediated dilation), and vascular stiffness (pulse wave velocity) were evaluated before and after the combined treatment. In this study, a post hoc analysis was performed to compare patients who were or were not on statins (SU and NSU groups, respectively). Results The SU group presented a greater reduction in the 24-hour systolic blood pressure (from 134 to 122 mmHg, p = 0.007), and in the brachial artery flow-mediated dilation (from 6.5 to 10.9%, p = 0.003) when compared with the NSU group (from 137 to 128 mmHg, p = 0.362, and from 7.5 to 8.3%, p = 0.820). There was no statistically significant difference in pulse wave velocity (SU group: from 9.95 to 9.90 m/s, p = 0.650; NSU group: from 10.65 to 11.05 m/s, p = 0.586). Conclusion Combined use of statins, amlodipine, and renin-angiotensin-aldosterone system inhibitors improves the antihypertensive response and endothelial function in patients with hypertension and diabetes. PMID:26465872

  15. Endothelial and Microcirculatory Function and Dysfunction in Sepsis.

    PubMed

    Colbert, James F; Schmidt, Eric P

    2016-06-01

    The microcirculation is a series of arterioles, capillaries, and venules that performs essential functions of oxygen and nutrient delivery, customized to the unique physiologic needs of the supplied organ. The homeostatic microcirculatory response to infection can become harmful if overactive and/or dysregulated. Pathologic microcirculatory dysfunction can be directly visualized by intravital microscopy or indirectly measured via detection of circulating biomarkers. Although several treatments have been shown to protect the microcirculation during sepsis, they have not improved patient outcomes when applied indiscriminately. Future outcomes-oriented studies are needed to test sepsis therapeutics when personalized to a patient's microcirculatory dysfunction. PMID:27229643

  16. Citrus Polyphenol Hesperidin Stimulates Production of Nitric Oxide in Endothelial Cells while Improving Endothelial Function and Reducing Inflammatory Markers in Patients with Metabolic Syndrome

    PubMed Central

    Rizza, Stefano; Muniyappa, Ranganath; Iantorno, Micaela; Kim, Jeong-a; Chen, Hui; Pullikotil, Philomena; Senese, Nicoletta; Tesauro, Manfredi; Lauro, Davide; Cardillo, Carmine

    2011-01-01

    Context: Hesperidin, a citrus flavonoid, and its metabolite hesperetin may have vascular actions relevant to their health benefits. Molecular and physiological mechanisms of hesperetin actions are unknown. Objective: We tested whether hesperetin stimulates production of nitric oxide (NO) from vascular endothelium and evaluated endothelial function in subjects with metabolic syndrome on oral hesperidin therapy. Design, Setting, and Interventions: Cellular mechanisms of action of hesperetin were evaluated in bovine aortic endothelial cells (BAEC) in primary culture. A randomized, placebo-controlled, double-blind, crossover trial examined whether oral hesperidin administration (500 mg once daily for 3 wk) improves endothelial function in individuals with metabolic syndrome (n = 24). Main Outcome Measure: We measured the difference in brachial artery flow-mediated dilation between placebo and hesperidin treatment periods. Results: Treatment of BAEC with hesperetin acutely stimulated phosphorylation of Src, Akt, AMP kinase, and endothelial NO synthase to produce NO; this required generation of H2O2. Increased adhesion of monocytes to BAEC and expression of vascular cell adhesion molecule-1 in response to TNF-α treatment was reduced by pretreatment with hesperetin. In the clinical study, when compared with placebo, hesperidin treatment increased flow-mediated dilation (10.26 ± 1.19 vs. 7.78 ± 0.76%; P = 0.02) and reduced concentrations of circulating inflammatory biomarkers (high-sensitivity C-reactive protein, serum amyloid A protein, soluble E-selectin). Conclusions: Novel mechanisms for hesperetin action in endothelial cells inform effects of oral hesperidin treatment to improve endothelial dysfunction and reduce circulating markers of inflammation in our exploratory clinical trial. Hesperetin has vasculoprotective actions that may explain beneficial cardiovascular effects of citrus consumption. PMID:21346065

  17. Total Sleep Deprivation Alters Endothelial Function in Rats: A Nonsympathetic Mechanism

    PubMed Central

    Sauvet, Fabien; Florence, Geneviève; Van Beers, Pascal; Drogou, Catherine; Lagrume, Christophe; Chaumes, Cyrielle; Ciret, Sylvain; Leftheriotis, Georges; Chennaoui, Mounir

    2014-01-01

    cyclooxygenase pathway alterations. Citation: Sauvet F; Florence G; Van Beers P; Drogou C; Lagrume C; Chaumes C; Ciret S; Leftheriotis G; Chennaoui M. Total sleep deprivation alters endothelial function in rats: a nonsympathetic mechanism. SLEEP 2014;37(3):465-473. PMID:24587568

  18. Somatosensory cortex functional connectivity abnormalities in autism show opposite trends, depending on direction and spatial scale

    PubMed Central

    Khan, Sheraz; Michmizos, Konstantinos; Tommerdahl, Mark; Ganesan, Santosh; Kitzbichler, Manfred G.; Zetino, Manuel; Garel, Keri-Lee A.; Herbert, Martha R.; Hämäläinen, Matti S.

    2015-01-01

    Functional connectivity is abnormal in autism, but the nature of these abnormalities remains elusive. Different studies, mostly using functional magnetic resonance imaging, have found increased, decreased, or even mixed pattern functional connectivity abnormalities in autism, but no unifying framework has emerged to date. We measured functional connectivity in individuals with autism and in controls using magnetoencephalography, which allowed us to resolve both the directionality (feedforward versus feedback) and spatial scale (local or long-range) of functional connectivity. Specifically, we measured the cortical response and functional connectivity during a passive 25-Hz vibrotactile stimulation in the somatosensory cortex of 20 typically developing individuals and 15 individuals with autism, all males and right-handed, aged 8–18, and the mu-rhythm during resting state in a subset of these participants (12 per group, same age range). Two major significant group differences emerged in the response to the vibrotactile stimulus. First, the 50-Hz phase locking component of the cortical response, generated locally in the primary (S1) and secondary (S2) somatosensory cortex, was reduced in the autism group (P < 0.003, corrected). Second, feedforward functional connectivity between S1 and S2 was increased in the autism group (P < 0.004, corrected). During resting state, there was no group difference in the mu-α rhythm. In contrast, the mu-β rhythm, which has been associated with feedback connectivity, was significantly reduced in the autism group (P < 0.04, corrected). Furthermore, the strength of the mu-β was correlated to the relative strength of 50 Hz component of the response to the vibrotactile stimulus (r = 0.78, P < 0.00005), indicating a shared aetiology for these seemingly unrelated abnormalities. These magnetoencephalography-derived measures were correlated with two different behavioural sensory processing scores (P < 0.01 and P < 0.02 for the autism

  19. Influence of circadian blood pressure profile on endothelial function in patients with and without arterial hypertension.

    PubMed

    Rekhviashvili, A; Giorgobiani, T; Minashvili, A; Baganashvili, E

    2015-03-01

    Little is known about the relationship between the circadian BP rhythm and endothelial function in patients with essential hypertension. Consequently, we have hypothesized, that hypertensive patients with non-dipper circadian BP profile have more deteriorated endothelial function, than those with dipper BP profile. 57 untreated hypertensive patients and 17 normotensive controls were undergone to the anthropometrical measurements, physical examinations, review of their medical histories, 24-hour ABPM and vascular doppler-echography with high resolution ultrasound. Circadian BP profile was not independent from the BP level; namely, dipper profile was more frequent in normotensives. Independent from hypertension, dipper patients had significantly higher FMD%. In the whole study population, FMD showed strong negative correlation with 24-hour SBP, DBP and PP. Our study confirms the presence of disturbed endothelium-dependent vasodilatation in AH. Furthermore, our study showed that non-dipper circadian BP rhythm is associated with the significant impairment of endothelial function. Consequently, we can suggest that patients with non-dipper circadian BP profile could be assessed as a high risk group, which might need permanent supervising for avoiding of future cardiovascular and cerebrovascular complications. PMID:25879555

  20. Effects of Different Therapeutic Ultrasound Waveforms on Endothelial Function in Healthy Volunteers: A Randomized Clinical Trial.

    PubMed

    Cruz, Jeferson Mendes; Hauck, Melina; Cardoso Pereira, Ana Paula; Moraes, Maicon Borges; Martins, Cassio Noronha; da Silva Paulitsch, Felipe; Plentz, Rodrigo Della Méa; Peres, William; Vargas da Silva, Antônio Marcos; Signori, Luis Ulisses

    2016-02-01

    The purpose of this study was to determine the effects of different therapeutic 1-MHz ultrasound waveforms on endothelial function before and after cyclooxygenase (COX) inhibition. Forty-two healthy volunteers aged 27.2 ± 3.8 y underwent interventions and an evaluation for endothelial function (n = 15; with COX inhibition, n = 15; duration of the vasodilator effect, n = 12) by technique flow-mediated dilation. Continuous ultrasound therapy (0.4 W/cm(2 SATA)), pulsed ultrasound therapy (20% duty cycle, 0.08 W/cm(2 SATA)) or placebo (equipment power off) was randomly applied over the brachial artery for 5 min. COX inhibition (aspirin) was carried out 30 min before treatments. In relation to the placebo, flow-mediated dilation increased by 4.8% using continuous ultrasound and by 3.4% using pulsed ultrasound. After COX, flow-mediated dilation was enhanced by 2.1% by continuous ultrasound and 2.6% by pulsed ultrasound. This vasodilation persisted for 20 min. Continuous and pulsed therapeutic 1-MHz ultrasound waveforms improved endothelial function in humans, which provided them with anti-inflammatory vascular effects.

  1. [Effect of physical exercise on endothelial function, indicators of inflammation and oxidative stress].

    PubMed

    Skrypnik, Damian; Bogdański, Paweł; Madry, Edyta; Pupek-Musialik, Danuta; Walkowiak, Jarosław

    2014-02-01

    Endothelium plays an important role in regulation of the activity of inflammation and oxidative stress. Numerous studies have shown that physical training affects endothelial function. It is proven that regular physical activity reduces the seventy of inflammation and the risk of cardiovascular events. Changes observed in effect of physical activity include increase in production of nitric oxide (NO), a decrease of plaque volume, a decrease in vascular wall viscosity and an increase in diastolic coronary perfusion. It has been shown that exercise reduces cardiovascular risk in subjects with diabetes, metabolic syndrome, coronary heart disease and hypertension, as well as in healthy people. In above populations the benefits result from improved endothelial function. It has been proven that regular physical activity improves enzymatic antioxidant systems and the immune response. It is a result of the stimulating effect of muscle tissue micro-injuries and recruitment of various cell types of the inflammatory response and their migration deeper into the tissues. The biggest changes in the immune response are observed in prolonged aerobic exercise. Physical activity has a significant impact on endothelial function, intensity of inflammatory processes and exponents of oxidative stress. There is a need for further researches, in particular in order to determine the optimal model of training.

  2. Influence of circadian blood pressure profile on endothelial function in patients with and without arterial hypertension.

    PubMed

    Rekhviashvili, A; Giorgobiani, T; Minashvili, A; Baganashvili, E

    2015-03-01

    Little is known about the relationship between the circadian BP rhythm and endothelial function in patients with essential hypertension. Consequently, we have hypothesized, that hypertensive patients with non-dipper circadian BP profile have more deteriorated endothelial function, than those with dipper BP profile. 57 untreated hypertensive patients and 17 normotensive controls were undergone to the anthropometrical measurements, physical examinations, review of their medical histories, 24-hour ABPM and vascular doppler-echography with high resolution ultrasound. Circadian BP profile was not independent from the BP level; namely, dipper profile was more frequent in normotensives. Independent from hypertension, dipper patients had significantly higher FMD%. In the whole study population, FMD showed strong negative correlation with 24-hour SBP, DBP and PP. Our study confirms the presence of disturbed endothelium-dependent vasodilatation in AH. Furthermore, our study showed that non-dipper circadian BP rhythm is associated with the significant impairment of endothelial function. Consequently, we can suggest that patients with non-dipper circadian BP profile could be assessed as a high risk group, which might need permanent supervising for avoiding of future cardiovascular and cerebrovascular complications.

  3. Curcumin ingestion and exercise training improve vascular endothelial function in postmenopausal women.

    PubMed

    Akazawa, Nobuhiko; Choi, Youngju; Miyaki, Asako; Tanabe, Yoko; Sugawara, Jun; Ajisaka, Ryuichi; Maeda, Seiji

    2012-10-01

    Vascular endothelial function is declines with aging and is associated with an increased risk of cardiovascular disease. Lifestyle modification, particularly aerobic exercise and dietary adjustment, has a favorable effect on vascular aging. Curcumin is a major component of turmeric with known anti-inflammatory and anti-oxidative effects. We investigated the effects of curcumin ingestion and aerobic exercise training on flow-mediated dilation as an indicator endothelial function in postmenopausal women. A total of 32 postmenopausal women were assigned to 3 groups: control, exercise, and curcumin groups. The curcumin group ingested curcumin orally for 8 weeks. The exercise group underwent moderate aerobic exercise training for 8 weeks. Before and after each intervention, flow-mediated dilation was measured. No difference in baseline flow-mediated dilation or other key dependent variables were detected among the groups. Flow-mediated dilation increased significantly and equally in the curcumin and exercise groups, whereas no changes were observed in the control group. Our results indicated that curcumin ingestion and aerobic exercise training can increase flow-mediated dilation in postmenopausal women, suggesting that both can potentially improve the age-related decline in endothelial function.

  4. Control of MCT1 function in cerebrovascular endothelial cells by intracellular pH.

    PubMed

    Uhernik, Amy L; Tucker, Carrie; Smith, Jeffrey P

    2011-02-28

    Monocarboxylic Acid Transporter 1 (MCT1) is expressed on the plasma membrane of cerebrovascular endothelial cells where it is the only known facilitator of lactic acid transport across the blood brain barrier. During stroke, brain injury, and certain other brain pathologies, anaerobic glycolysis produces severe lactic acidosis of brain tissue leading to brain cell damage. Therefore, a better understanding of factors that control MCT1 function may be the key to better understanding the origins and treatment of pathological lactic acidosis. In this study, we characterized the effects of intracellular pH in controlling MCT1 function and showed that microtubule disruption targeted this mechanism in rat cerebrovascular endothelial cells. Acidic intracellular pH values were shown to strongly inhibit lactic acid transport into the cytoplasmic space, while alkalinization of the cytoplasm significantly enhanced this transport function. These results support a better understanding of how cerebrovascular endothelial MCT1 may contribute to the development of lactic acidosis in brain pathologies, and suggest targeting it as a novel therapy.

  5. The impact of decreases in air temperature and increases in ozone on markers of endothelial function in individuals having type-2 diabetes

    EPA Science Inventory

    Several studies have reported an association between air pollution and endothelial dysfunction, especially in individuals having diabetes. However, very few studies have examined the impact of air temperature on endothelial function. The objective of this analysis was to investig...

  6. Abnormal hippocampal structure and function in clinical anxiety and comorbid depression.

    PubMed

    Cha, Jiook; Greenberg, Tsafrir; Song, Inkyung; Blair Simpson, Helen; Posner, Jonathan; Mujica-Parodi, Lilianne R

    2016-05-01

    Given the high prevalence rates of comorbidity of anxiety and depressive disorders, identifying a common neural pathway to both disorders is important not only for better diagnosis and treatment, but also for a more complete conceptualization of each disease. Hippocampal abnormalities have been implicated in anxiety and depression, separately; however, it remains unknown whether these abnormalities are also implicated in their comorbidity. Here we address this question by testing 32 adults with generalized anxiety disorder (15 GAD only and 17 comorbid MDD) and 25 healthy controls (HC) using multimodal MRI (structure, diffusion and functional) and automated hippocampal segmentation. We demonstrate that (i) abnormal microstructure of the CA1 and CA2-3 is associated with GAD/MDD comorbidity and (ii) decreased anterior hippocampal reactivity in response to repetition of the threat cue is associated with GAD (with or without MDD comorbidity). In addition, mediation-structural equation modeling (SEM) reveals that our hippocampal and dimensional symptom data are best explained by a model describing a significant influence of abnormal hippocampal microstructure on both anxiety and depression-mediated through its impact on abnormal hippocampal threat processing. Collectively, our findings show a strong association between changes in hippocampal microstructure and threat processing, which together may present a common neural pathway to comorbidity of anxiety and depression.

  7. Effect of Meditation on Endothelial Function in Black Americans with Metabolic Syndrome: A Randomized Trial

    PubMed Central

    Vaccarino, Viola; Kondwani, Kofi A.; Kelley, Mary E.; Murrah, Nancy V.; Boyd, Linda; Ahmed, Yusuf; Meng, Yuan X.; Gibbons, Gary H.; Hooper, W. Craig; De Staercke, Christine; Quyyumi, Arshed A.

    2013-01-01

    Objectives Psychological stress may play a role in metabolic syndrome. A consequence of metabolic syndrome is endothelial dysfunction, which is also influenced by psychological stress. We sought to compare the effect of consciously resting meditation (CRM), a sound (mantra)-based meditation, with a control intervention of health education (HE) on endothelial function in the setting of metabolic syndrome. Methods Sixty-eight black Americans with metabolic system risk factors (age 30 to 65 years) were randomized to either CRM (N=33), or to HE (N=35); interventions were matched for frequency and duration of sessions and lasted 12 months. Endothelial function was assessed by brachial artery flow-mediated dilation (FMD%) at baseline, 6 and 12 months. Arterial elasticity, metabolic risk factors, psychosocial and behavioral variables were secondary endpoints. Results Although FMD % improved in the CRM group over 12 months, this increase was not significantly higher than in the HE group (p=0.51 for the interaction between group and time). Non-endothelium dependent dilation and arterial elasticity did not change in either group. Most metabolic syndrome risk factors showed beneficial trends in the CRM group only. A risk factor score counting the number of metabolic syndrome components decreased in the CRM group but not in the control HE group (p=0.049 for the interaction between treatment group and time). Conclusions Among black Americans with metabolic syndrome risk factors, CRM, a sound-based meditation, did not improve endothelial function significantly more than a control intervention of health education. CRM resulted in favorable trends in metabolic syndrome risk factors which were examined as secondary outcomes. PMID:23788695

  8. CD34+ Cells Represent Highly Functional Endothelial Progenitor Cells in Murine Bone Marrow

    PubMed Central

    Yang, Junjie; Ii, Masaaki; Kamei, Naosuke; Alev, Cantas; Kwon, Sang-Mo; Kawamoto, Atsuhiko; Akimaru, Hiroshi; Masuda, Haruchika; Sawa, Yoshiki; Asahara, Takayuki

    2011-01-01

    Background Endothelial progenitor cells (EPCs) were shown to have angiogenic potential contributing to neovascularization. However, a clear definition of mouse EPCs by cell surface markers still remains elusive. We hypothesized that CD34 could be used for identification and isolation of functional EPCs from mouse bone marrow. Methodology/Principal Findings CD34+ cells, c-Kit+/Sca-1+/Lin− (KSL) cells, c-Kit+/Lin− (KL) cells and Sca-1+/Lin− (SL) cells were isolated from mouse bone marrow mononuclear cells (BMMNCs) using fluorescent activated cell sorting. EPC colony forming capacity and differentiation capacity into endothelial lineage were examined in the cells. Although CD34+ cells showed the lowest EPC colony forming activity, CD34+ cells exhibited under endothelial culture conditions a more adherent phenotype compared with the others, demonstrating the highest mRNA expression levels of endothelial markers vWF, VE-cadherin, and Flk-1. Furthermore, a dramatic increase in immediate recruitment of cells to the myocardium following myocardial infarction and systemic cell injection was observed for CD34+ cells comparing with others, which could be explained by the highest mRNA expression levels of key homing-related molecules Integrin β2 and CXCR4 in CD34+ cells. Cell retention and incorporation into the vasculature of the ischemic myocardium was also markedly increased in the CD34+ cell-injected group, giving a possible explanation for significant reduction in fibrosis area, significant increase in neovascularization and the best cardiac functional recovery in this group in comparison with the others. Conclusion These findings suggest that mouse CD34+ cells may represent a functional EPC population in bone marrow, which could benefit the investigation of therapeutic EPC biology. PMID:21655289

  9. Endothelial Function and Serum Concentration of Toxic Metals in Frequent Consumers of Fish

    PubMed Central

    Buscemi, Silvio; Vasto, Sonya; Di Gaudio, Francesca; Grosso, Giuseppe; Bergante, Sonia; Galvano, Fabio; Massenti, Fatima Maria; Amodio, Emanuele; Rosafio, Giuseppe; Verga, Salvatore

    2014-01-01

    Background Endothelial dysfunction is involved in the pathogenesis of atherosclerosis. Consumption of fish is associated with reduced cardiovascular risk, but there is paucity of data concerning its effect on endothelial function. Furthermore, investigation of the effects of fish consumption on health must take into account the ingestion of contaminants, including transition metals and some metalloids, which may have unfavorable effects on health, including those on the cardiovascular system. We investigated the association between fish consumption, endothelial function (flow mediated dilation of the brachial artery), and serum concentration of some toxic metals in apparently healthy people. Methods Twenty-nine high fish consumers (at least 3 portions a week) were compared with 25 low fish consumers (less than 1 portion a week). All participants were free of diabetes, cardiovascular or other systemic diseases. Serum metal (antimonium, arsenic, mercury, lead, cobalt, copper, zinc, selenium, strontium) concentrations were measured in subgroups of 24 high fish consumers and 19 low fish consumers. Results Both groups exhibited similar habitual dietary patterns, age and anthropometric characteristics. The high fish consumers had higher flow mediated dilation (9.7±1.8 vs. 7.3±1.9%; P<0.001), but also higher serum concentrations of mercury (5.87±2.69 vs. 1.65±1.10 mcg/L; P<0.001) and arsenic (6.04±3.25 vs. 2.30±1.58 mcg/L; P<0.001). The fasting plasma glucose concentrations were significantly correlated with both mercury (r = 0.39; P = 0.01) and arsenic concentrations (r = 0.55; P<0.001). Conclusions Habitual consumption of high amounts of fish is associated with better endothelial function despite higher serum concentrations of mercury and arsenic. PMID:25401695

  10. Intermedin Stabilized Endothelial Barrier Function and Attenuated Ventilator-induced Lung Injury in Mice

    PubMed Central

    Müller-Redetzky, Holger Christian; Kummer, Wolfgang; Pfeil, Uwe; Hellwig, Katharina; Will, Daniel; Paddenberg, Renate; Tabeling, Christoph; Hippenstiel, Stefan; Suttorp, Norbert; Witzenrath, Martin

    2012-01-01

    Background Even protective ventilation may aggravate or induce lung failure, particularly in preinjured lungs. Thus, new adjuvant pharmacologic strategies are needed to minimize ventilator-induced lung injury (VILI). Intermedin/Adrenomedullin-2 (IMD) stabilized pulmonary endothelial barrier function in vitro. We hypothesized that IMD may attenuate VILI-associated lung permeability in vivo. Methodology/Principal Findings Human pulmonary microvascular endothelial cell (HPMVEC) monolayers were incubated with IMD, and transcellular electrical resistance was measured to quantify endothelial barrier function. Expression and localization of endogenous pulmonary IMD, and its receptor complexes composed of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs) 1–3 were analyzed by qRT-PCR and immunofluorescence in non ventilated mouse lungs and in lungs ventilated for 6 h. In untreated and IMD treated mice, lung permeability, pulmonary leukocyte recruitment and cytokine levels were assessed after mechanical ventilation. Further, the impact of IMD on pulmonary vasoconstriction was investigated in precision cut lung slices (PCLS) and in isolated perfused and ventilated mouse lungs. IMD stabilized endothelial barrier function in HPMVECs. Mechanical ventilation reduced the expression of RAMP3, but not of IMD, CRLR, and RAMP1 and 2. Mechanical ventilation induced lung hyperpermeability, which was ameliorated by IMD treatment. Oxygenation was not improved by IMD, which may be attributed to impaired hypoxic vasoconstriction due to IMD treatment. IMD had minor impact on pulmonary leukocyte recruitment and did not reduce cytokine levels in VILI. Conclusions/Significance IMD may possibly provide a new approach to attenuate VILI. PMID:22563471

  11. Anthocyanin Bioavailability from Acute Cranberry Juice Consumption and Evidence of Effects on Endothelial Function in Patients with Coronary Artery Disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Epidemiologic studies suggest an inverse correlation between intake of flavonoidcontaining foods and cardiovascular risk. Multiple health beneficial effect of flavonoids have been proposed to account for this observation, including effects on endothelial function. Cranberries contain relatively high...

  12. Abnormal Vascular Function and Hypertension in Mice Deficient in Estrogen Receptor β

    NASA Astrophysics Data System (ADS)

    Zhu, Yan; Bian, Zhao; Lu, Ping; Karas, Richard H.; Bao, Lin; Cox, Daniel; Hodgin, Jeffrey; Shaul, Philip W.; Thorén, Peter; Smithies, Oliver; Gustafsson, Jan-Åke; Mendelsohn, Michael E.

    2002-01-01

    Blood vessels express estrogen receptors, but their role in cardiovascular physiology is not well understood. We show that vascular smooth muscle cells and blood vessels from estrogen receptor β (ERβ)-deficient mice exhibit multiple functional abnormalities. In wild-type mouse blood vessels, estrogen attenuates vasoconstriction by an ERβ-mediated increase in inducible nitric oxide synthase expression. In contrast, estrogen augments vasoconstriction in blood vessels from ERβ-deficient mice. Vascular smooth muscle cells isolated from ERβ-deficient mice show multiple abnormalities of ion channel function. Furthermore, ERβ-deficient mice develop sustained systolic and diastolic hypertension as they age. These data support an essential role for ERβ in the regulation of vascular function and blood pressure.

  13. Structural and functional characterization of endothelial microparticles released by cigarette smoke.

    PubMed

    Serban, Karina A; Rezania, Samin; Petrusca, Daniela N; Poirier, Christophe; Cao, Danting; Justice, Matthew J; Patel, Milan; Tsvetkova, Irina; Kamocki, Krzysztof; Mikosz, Andrew; Schweitzer, Kelly S; Jacobson, Sean; Cardoso, Angelo; Carlesso, Nadia; Hubbard, Walter C; Kechris, Katerina; Dragnea, Bogdan; Berdyshev, Evgeny V; McClintock, Jeanette; Petrache, Irina

    2016-01-01

    Circulating endothelial microparticles (EMPs) are emerging as biomarkers of chronic obstructive pulmonary disease (COPD) in individuals exposed to cigarette smoke (CS), but their mechanism of release and function remain unknown. We assessed biochemical and functional characteristics of EMPs and circulating microparticles (cMPs) released by CS. CS exposure was sufficient to increase microparticle levels in plasma of humans and mice, and in supernatants of primary human lung microvascular endothelial cells. CS-released EMPs contained predominantly exosomes that were significantly enriched in let-7d, miR-191; miR-126; and miR125a, microRNAs that reciprocally decreased intracellular in CS-exposed endothelium. CS-released EMPs and cMPs were ceramide-rich and required the ceramide-synthesis enzyme acid sphingomyelinase (aSMase) for their release, an enzyme which was found to exhibit significantly higher activity in plasma of COPD patients or of CS-exposed mice. The ex vivo or in vivo engulfment of EMPs or cMPs by peripheral blood monocytes-derived macrophages was associated with significant inhibition of efferocytosis. Our results indicate that CS, via aSMase, releases circulating EMPs with distinct microRNA cargo and that EMPs affect the clearance of apoptotic cells by specialized macrophages. These targetable effects may be important in the pathogenesis of diseases linked to endothelial injury and inflammation in smokers. PMID:27530098

  14. Instrumental noise estimates stabilize and quantify endothelial cell micro-impedance barrier function parameter estimates

    SciTech Connect

    English, Anthony E; Moy, Alan B; Kruse, Kara L; Ward, Richard C; Kirkpatrick, Stacy S; GoldmanM.D., Mitchell H

    2009-04-01

    A novel transcellular micro-impedance biosensor, referred to as the electric cell-substrate impedance sensor or ECIS, has become increasingly applied to the study and quantification of endothelial cell physiology. In principle, frequency dependent impedance measurements obtained from this sensor can be used to estimate the cell cell and cell matrix impedance components of endothelial cell barrier function based on simple geometric models. Few studies, however, have examined the numerical optimization of these barrier function parameters and established their error bounds. This study, therefore, illustrates the implementation of a multi-response Levenberg Marquardt algorithm that includes instrumental noise estimates and applies it to frequency dependent porcine pulmonary artery endothelial cell impedance measurements. The stability of cell cell, cell matrix and membrane impedance parameter estimates based on this approach is carefully examined, and several forms of parameter instability and refinement illustrated. Including frequency dependent noise variance estimates in the numerical optimization reduced the parameter value dependence on the frequency range of measured impedances. The increased stability provided by a multi-response non-linear fit over one-dimensional algorithms indicated that both real and imaginary data should be used in the parameter optimization. Error estimates based on single fits and Monte Carlo simulations showed that the model barrier parameters were often highly correlated with each other. Independently resolving the different parameters can, therefore, present a challenge to the experimentalist and demand the use of non-linear multivariate statistical methods when comparing different sets of parameters.

  15. Adaptation of β-Cell and Endothelial Function to Carbohydrate Loading: Influence of Insulin Resistance

    PubMed Central

    Hurwitz, Barry E.; Schneiderman, Neil; Marks, Jennifer B.; Mendez, Armando J.; Gonzalez, Alex; Llabre, Maria M.; Smith, Steven R.; Bizzotto, Roberto; Santini, Eleonora; Manca, Maria Laura; Skyler, Jay S.; Mari, Andrea

    2015-01-01

    High-carbohydrate diets have been associated with β-cell strain, dyslipidemia, and endothelial dysfunction. We examined how β-cell and endothelial function adapt to carbohydrate overloading and the influence of insulin resistance. On sequential days in randomized order, nondiabetic subjects (classified as insulin-sensitive [IS] [n = 64] or insulin-resistant [IR] [n = 79] by euglycemic clamp) received four mixed meals over 14 h with either standard (300 kcal) or double carbohydrate content. β-Cell function was reconstructed by mathematical modeling; brachial artery flow-mediated dilation (FMD) was measured before and after each meal. Compared with IS, IR subjects showed higher glycemia and insulin hypersecretion due to greater β-cell glucose and rate sensitivity; potentiation of insulin secretion, however, was impaired. Circulating free fatty acids (FFAs) were less suppressed in IR than IS subjects. Baseline FMD was reduced in IR, and postprandial FMD attenuation occurred after each meal, particularly with high carbohydrate, similarly in IR and IS. Throughout the two study days, higher FFA levels were significantly associated with lower (incretin-induced) potentiation and impaired FMD. In nondiabetic individuals, enhanced glucose sensitivity and potentiation upregulate the insulin secretory response to carbohydrate overloading. With insulin resistance, this adaptation is impaired. Defective suppression of endogenous FFA is one common link between impaired potentiation and vascular endothelial dysfunction. PMID:25754957

  16. Soy provides modest benefits on endothelial function without affecting inflammatory biomarkers in adults at cardiometabolic risk

    PubMed Central

    Reverri, Elizabeth J.; LaSalle, Colette D.; Franke, Adrian A.; Steinberg, Francene M.

    2015-01-01

    Scope Systemic inflammation, endothelial dysfunction, and oxidative stress are involved in the pathogenesis of the metabolic syndrome (MetS). Epidemiological evidence supports an association between whole soy food consumption and reduced risk of cardiovascular disease (CVD). The objective of this randomized, controlled, crossover study was to evaluate the effects of soy nut consumption on inflammatory biomarkers and endothelial function and to assess whether isoflavone metabolism to secondary products, equol and/or O-desmethylangolensin (ODMA), modifies these responses. Methods and Results n=17 adults at cardiometabolic risk were randomly assigned to the order of two snack interventions, soy nuts and macronutrient-matched control snack, for four weeks each, separated by a two week washout period. Outcome measures included biomarkers of inflammation, oxidative stress, and glycemic control (ELISA and clinical analyzers), endothelial function and arterial stiffness (peripheral arterial tonometry (PAT)), and isoflavone metabolites (LC-MS/MS). Results revealed that consuming soy nuts improved arterial stiffness as assessed by the augmentation index using PAT (P=0.03), despite lack of improvement in inflammatory biomarkers. Addition of equol and/ODMA production status as covariates did not significantly change these results. Conclusions Soy nuts when added to a usual diet for one month provide some benefit on arterial stiffness in adults at cardiometabolic risk. PMID:25351805

  17. Structural and functional characterization of endothelial microparticles released by cigarette smoke

    PubMed Central

    Serban, Karina A.; Rezania, Samin; Petrusca, Daniela N.; Poirier, Christophe; Cao, Danting; Justice, Matthew J.; Patel, Milan; Tsvetkova, Irina; Kamocki, Krzysztof; Mikosz, Andrew; Schweitzer, Kelly S.; Jacobson, Sean; Cardoso, Angelo; Carlesso, Nadia; Hubbard, Walter C.; Kechris, Katerina; Dragnea, Bogdan; Berdyshev, Evgeny V.; McClintock, Jeanette; Petrache, Irina

    2016-01-01

    Circulating endothelial microparticles (EMPs) are emerging as biomarkers of chronic obstructive pulmonary disease (COPD) in individuals exposed to cigarette smoke (CS), but their mechanism of release and function remain unknown. We assessed biochemical and functional characteristics of EMPs and circulating microparticles (cMPs) released by CS. CS exposure was sufficient to increase microparticle levels in plasma of humans and mice, and in supernatants of primary human lung microvascular endothelial cells. CS-released EMPs contained predominantly exosomes that were significantly enriched in let-7d, miR-191; miR-126; and miR125a, microRNAs that reciprocally decreased intracellular in CS-exposed endothelium. CS-released EMPs and cMPs were ceramide-rich and required the ceramide-synthesis enzyme acid sphingomyelinase (aSMase) for their release, an enzyme which was found to exhibit significantly higher activity in plasma of COPD patients or of CS-exposed mice. The ex vivo or in vivo engulfment of EMPs or cMPs by peripheral blood monocytes-derived macrophages was associated with significant inhibition of efferocytosis. Our results indicate that CS, via aSMase, releases circulating EMPs with distinct microRNA cargo and that EMPs affect the clearance of apoptotic cells by specialized macrophages. These targetable effects may be important in the pathogenesis of diseases linked to endothelial injury and inflammation in smokers. PMID:27530098

  18. Endothelial PECAM-1 and its function in vascular physiology and atherogenic pathology.

    PubMed

    Chistiakov, Dimitry A; Orekhov, Alexander N; Bobryshev, Yuri V

    2016-06-01

    Platelet endothelial cell adhesion molecule (PECAM-1) is highly expressed in vascular cells such as endothelial cells (ECs) and blood-borne cells like platelets and leukocytes. In ECs, this molecule controls junctional and adhesive properties. In physiological conditions, PECAM-1 supports the endothelial barrier function. In inflammation that is observed in vessels affected by atherosclerosis, the function of PECAM-1 is impaired, an event that leads to increased adhesion of neutrophils and other leukocytes to ECs, decreased vascular integrity, and higher leukocyte transmigration to the intima media. PECAM-1 has six extracellular immunoglobulin (Ig)-like domains that support attraction and adhesion of leukocytes to ECs. The cytoplasmic tail of PECAM-1 contains two tyrosine residues (Tyr-663 and Tyr-686) that could be phosphorylated by Src family protein kinases is involved in the intracellular signaling. Actually, those tyrosines are the part of the immunoreceptor tyrosine-based inhibition motifs (ITIMs) that inhibit inflammation. However, in atherosclerosis, the PECAM-1-dependent immune suppression is disturbed. This in turn facilitates recruitment of leukocytes and supports proatherogenic inflammation. PMID:27079772

  19. Endothelial function in a cardiovascular risk population with borderline ankle–brachial index

    PubMed Central

    Syvänen, Kari; Korhonen, Päivi; Partanen, Auli; Aarnio, Pertti

    2011-01-01

    Introduction: The diagnosis of peripheral arterial disease (PAD) can be made by measuring the ankle–brachial index (ABI). Traditionally ABI values > 1.00–1.40 have been considered normal and ABI ≤ 0.90 defines PAD. Recent studies, however, have shown that individuals with ABI values between 0.90–1.00 are also at risk of cardiovascular events. We studied this cardiovascular risk population subgroup in order to determine their endothelial function using peripheral arterial tonometry (PAT). Methods: We selected 66 individuals with cardiovascular risk and borderline ABI. They all had hypertension, newly diagnosed glucose disorder, metabolic syndrome, obesity, or a ten year risk of cardiovascular disease death of 5% or more according to the Systematic Coronary Risk Evaluation System (SCORE). Subjects with previously diagnosed diabetes or cardiovascular disease were excluded. Endothelial function was assessed by measuring the reactive hyperemia index (RHI) from fingertips using an Endo-PAT device. Results: The mean ABI was 0.95 and mean RHI 2.11. Endothelial dysfunction, defined as RHI < 1.67, was detected in 15/66 (23%) of the subjects. There were no statistically significant differences in RHI values between subjects with different cardiovascular risk factors. The only exception was that subjects with impaired fasting glucose (IFG) had slightly lower RHI values (mean RHI 1.91) than subjects without IFG (mean RHI 2.24) (P = 0.02). Conclusions: In a cardiovascular risk population with borderline ABI nearly every fourth subject had endothelial dysfunction, indicating an elevated risk of cardiovascular events. This might point out a subgroup of individuals in need of more aggressive treatment for their risk factors. PMID:21415923

  20. Abnormal interhemispheric resting state functional connectivity of the insula in heroin users under methadone maintenance treatment.

    PubMed

    Wang, Peng-Wei; Lin, Huang-Chi; Liu, Gin-Chung; Yang, Yi-Hsin Connie; Ko, Chih-Hung; Yen, Cheng-Fang

    2016-09-30

    Abnormal interhemispheric functional connectivity is attracting more and more attention in the field of substance use. This study aimed to examine 1) the differences in interhemispheric functional connections of the insula with the contralateral insula and other brain regions between heroin users under methadone maintenance treatment (MMT) and healthy controls, and 2) the association between heroin users' interhemispheric insular functional connectivity using resting functional magnetic resonance imaging (fMRI) and the results of urine heroin analysis. Sixty male right-handed persons, including 30 with heroin dependence under MMT and 30 healthy controls, were recruited to this study. Resting fMRI experiments and urine heroin analysis were performed. Compared with the controls, the heroin users had a significantly lower interhemispheric insular functional connectivity. They also exhibited lower functional connectivity between insula and contralateral inferior orbital frontal lobe. After controlling for age, educational level and methadone dosage, less deviation of the interhemispheric insula functional connectivity was significantly associated with a lower risk of a positive urine heroin analysis result. Our findings demonstrated that the heroin users under MMT had abnormal long-range and interhemispheric resting functional connections. Those with a less dysfunctional interhemispheric insula functional connectivity had a lower risk of a positive urine heroin test. PMID:27497215

  1. Functional interplay between endothelial nitric oxide synthase and membrane type 1–matrix metalloproteinase in migrating endothelial cells

    PubMed Central

    Genís, Laura; Gonzalo, Pilar; Tutor, Antonio S.; Gálvez, Beatriz G.; Martínez-Ruiz, Antonio; Zaragoza, Carlos; Lamas, Santiago; Tryggvason, Karl; Apte, Suneel S.

    2007-01-01

    Nitric oxide (NO) is essential for vascular homeostasis and is also a critical modulator of angiogenesis; however, the molecular mechanisms of NO action during angiogenesis remain elusive. We have investigated the potential relationship between NO and membrane type 1–matrix metalloproteinase (MT1-MMP) during endothelial migration and capillary tube formation. Endothelial NO synthase (eNOS) colocalizes with MT1-MMP at motility-associated structures in migratory human endothelial cells (ECs); moreover, NO is produced at these structures and is released into the medium during EC migration. We have therefore addressed 2 questions: (1) the putative regulation of MT1-MMP by NO in migratory ECs; and (2) the requirement for MT1-MMP in NO-induced EC migration and tube formation. NO upregulates MT1-MMP membrane clustering on migratory human ECs, and this is accompanied by increased degradation of type I collagen substrate. MT1-MMP membrane expression and localization are impaired in lung ECs from eNOS-deficient mice, and these cells also show impaired migration and tube formation in vitro. Inhibition of MT1-MMP with a neutralizing antibody impairs NOinduced tube formation by human ECs, and NO-induced endothelial migration and tube formation are impaired in lung ECs from mice deficient in MT1-MMP. MT1-MMP thus appears to be a key molecular effector of NO during the EC migration and angiogenic processes, and is a potential therapeutic target for NO-associated vascular disorders. PMID:17606763

  2. High-density lipoproteins as modulators of endothelial cell functions: alterations in patients with coronary artery disease.

    PubMed

    Kratzer, Adelheid; Giral, Hector; Landmesser, Ulf

    2014-08-01

    Alteration of endothelial cell functions, including reduced endothelial nitric oxide (NO) availability, increased endothelial cell apoptosis, adhesion molecule/chemokine expression and pro-thrombotic activation are thought to contribute to the pathophysiology of atherosclerosis and coronary-artery-disease (CAD) with its clinical complications, such as acute coronary syndromes. High-density lipoproteins (HDL) from healthy subjects or reconstituted HDL have been observed to exert potential direct anti-atherogenic effects by modulating these endothelial cell functions. Importantly, endothelial effects of HDL have now been reported to be highly heterogeneous, and are modulated as part of immune responses. More recently, this has also been observed for HDL of patients with CAD, where HDL becomes potentially pro-inflammatory and endothelial-protective properties are markedly altered. Several mechanisms may lead to these altered endothelial effects of HDL in patients with CAD, including oxidative modification of HDL-associated lipids and proteins, such as apoA-I and paraoxonase-1, and alterations of HDL-proteome. These findings have to be considered with respect to interpretation of recent clinical studies failing to demonstrate reduced cardiovascular events by HDL-cholesterol raising strategies in patients with CAD. Both clinical and genetic studies suggest that HDL-cholesterol levels alone are not a sufficient therapeutic target in patients with CAD. The focus of this review is to summarize the role of HDL onto endothelial homeostasis and to describe recently characterized molecular pathways involved. We highlight how structural and functional modifications of HDL particles in patients with CAD may perturb the physiological homeostasis and lead to a loss of endothelial-protective properties of HDL in patients with CAD.

  3. Exercise training improves vascular endothelial function in patients with type 1 diabetes.

    PubMed

    Fuchsjäger-Mayrl, Gabriele; Pleiner, Johannes; Wiesinger, Günther F; Sieder, Anna E; Quittan, Michael; Nuhr, Martin J; Francesconi, Claudia; Seit, Hans-Peter; Francesconi, Mario; Schmetterer, Leopold; Wolzt, Michael

    2002-10-01

    OBJECTIVE-Impaired endothelial function of resistance and conduit arteries can be detected in patients with type 1 diabetes. We studied whether a persistent improvement of endothelial function can be achieved by regular physical training. RESEARCH DESIGN AND METHODS-The study included 26 patients with type 1 diabetes of 20 +/- 10 years' duration and no overt angiopathy; 18 patients (42 +/- 10 years old) participated in a bicycle exercise training program, and 8 patients with type 1 diabetes (33 +/- 11 years old) served as control subjects. Vascular function of conduit arteries was assessed by flow-mediated and endothelium-independent dilation of the brachial artery and of resistance vessels by the response of ocular fundus pulsation amplitudes to intravenous N(G)-monomethyl-L-arginine (L-NMMA) at baseline, after 2 and 4 months of training, and 8 months after cessation of regular exercise. RESULTS-Training increased peak oxygen uptake (VO(2max)) by 13% after 2 months and by 27% after 4 months (P = 0.04). Flow-mediated dilation (FMD) of the brachial artery increased from 6.5 +/- 1.1 to 9.8 +/- 1.1% (P = 0.04) by training. L-NMMA administration decreased fundus pulsation amplitude (FPA) by 9.1 +/- 0.9% before training and by 13.4 +/- 1.5% after 4 months of training (P = 0.02). VO(2max), FMD, and FPA were unchanged in the control group. Vascular effects from training were abrogated 8 months after cessation of exercise. CONCLUSIONS-Our study demonstrates that aerobic exercise training can improve endothelial function in different vascular beds in patients with long-standing type 1 diabetes, who are at considerable risk for diabetic angiopathy. However, the beneficial effect on vascular function is not maintained in the absence of exercise.

  4. Modulation of cerebral endothelial cell function by TGF-β in glioblastoma: VEGF-dependent angiogenesis versus endothelial mesenchymal transition.

    PubMed

    Krishnan, Shanmugarajan; Szabo, Emese; Burghardt, Isabel; Frei, Karl; Tabatabai, Ghazaleh; Weller, Michael

    2015-09-01

    Glioblastoma are among the most angiogenic tumors. The molecular mechanisms that control blood vessel formation by endothelial cells (EC) in glioblastoma remain incompletely understood. Transforming growth factor-β (TGF-β) is a key regulatory cytokine that has proinvasive and stemness-maintaining autocrine properties in glioblastoma and confers immunosuppression to the tumor microenvironment. Here we characterize potential pro- and anti-angiogenic activities of TGF-β in the context of glioblastoma in vitro, using human brain-derived microvascular endothelial cells (hCMEC/D3) and glioblastoma-derived endothelial cells (GMEC) as model systems. We find that TGF-β induces vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) mRNA expression and protein release in a TGF-β receptor (TβR) II / activin-like kinase (ALK)-5-dependent manner under normoxia and hypoxia, defining potential indirect proangiogenic activity of TGF-β in glioblastoma. In parallel, exogenous TGF-β has also inhibitory effects on EC properties and induces endothelial-mesenchymal transition (EndMT) in hCMEC and GMEC. Accordingly, direct inhibition of endogenous TGF-β/ALK-5 signalling increases EC properties such as tube formation, von-Willebrand factor (vWF) and claudin (CLDN) 5 expression. Yet, the supernatant of TGF-β-stimulated hCMEC and GMEC strongly promotes EC-related gene expression and tube formation in a cediranib-sensitive manner. These observations shed light on the complex pro- and anti-angiogenic pathways involving the cross-talk between TGF-β and VEGF/PLGF signalling in glioblastoma which may involve parallel stimulation of angiogenesis and EndMT in distinct target cell populations.

  5. Nuclear Countermeasure Activity of TP508 Linked to Restoration of Endothelial Function and Acceleration of DNA Repair

    PubMed Central

    Olszewska-Pazdrak, Barbara; McVicar, Scott D.; Rayavara, Kempaiah; Moya, Stephanie M.; Kantara, Carla; Gammarano, Chris; Olszewska, Paulina; Fuller, Gerald M.; Sower, Laurie E.; Carney, Darrell H.

    2016-01-01

    There is increasing evidence that radiation-induced damage to endothelial cells and loss of endothelial function may contribute to both acute radiation syndromes and long-term effects of whole-body nuclear irradiation. Therefore, several drugs are being developed to mitigate the effects of nuclear radiation, most of these drugs will target and protect or regenerate leukocytes and platelets. Our laboratory has demonstrated that TP508, a 23-amino acid thrombin peptide, activates endothelial cells and stem cells to revascularize and regenerate tissues. We now show that TP508 can mitigate radiation-induced damage to endothelial cells in vitro and in vivo. Our in vitro results demonstrate that human endothelial cells irradiation attenuates nitric oxide (NO) signaling, disrupts tube formation and induces DNA double-strand breaks (DSB). TP508 treatment reverses radiation effects on NO signaling, restores tube formation and accelerates the repair of radiation-induced DSB. The radiation-mitigating effects of TP508 on endothelial cells were also seen in CD-1 mice where systemic injection of TP508 stimulated endothelial cell sprouting from aortic explants after 8 Gy irradiation. Systemic doses of TP508 that mitigated radiation-induced endothelial cell damage, also significantly increased survival of CD-1 mice when injected 24 h after 8.5 Gy exposure. These data suggest that increased survival observed with TP508 treatment may be due to its effects on vascular and microvascular endothelial cells. Our study supports the usage of a regenerative drug such as TP508 to activate endothelial cells as a countermeasure for mitigating the effects of nuclear radiation. PMID:27388041

  6. Association of Microvascular Function and Endothelial Biomarkers With Clinical Outcome in Dengue: An Observational Study

    PubMed Central

    Yacoub, Sophie; Lam, Phung Khanh; Vu, Le Hoang Mai; Le, Thi Lien; Ha, Ngo Thanh; Toan, Tran Thi; Van, Nguyen Thu; Quyen, Nguyen Than Ha; Le Duyen, Huynh Thi; Van Kinh, Nguyen; Fox, Annette; Mongkolspaya, Juthathip; Wolbers, Marcel; Simmons, Cameron Paul; Screaton, Gavin Robert; Wertheim, Heiman; Wills, Bridget

    2016-01-01

    Background. The hallmark of severe dengue is increased microvascular permeability, but alterations in the microcirculation and their evolution over the course of dengue are unknown. Methods. We conducted a prospective observational study to evaluate the sublingual microcirculation using side-stream dark-field imaging in patients presenting early (<72 hours after fever onset) and patients hospitalized with warning signs or severe dengue in Vietnam. Clinical findings, microvascular function, global hemodynamics assessed with echocardiography, and serological markers of endothelial activation were determined at 4 time points. Results. A total of 165 patients were enrolled. No difference was found between the microcirculatory parameters comparing dengue with other febrile illnesses. The proportion of perfused vessels (PPV) and the mean flow index (MFI) were lower in patients with dengue with plasma than those without leakage (PPV, 88.1% vs 90.6% [P = .01]; MFI, 2.1 vs 2.4 [P = .007]), most markedly during the critical phase. PPV and MFI were correlated with the endothelial activation markers vascular cell adhesion molecule 1 (P < .001 for both) and angiopoietin 2 (P < .001 for both), negatively correlated. Conclusions. Modest microcirculatory alterations occur in dengue, are associated with plasma leakage, and are correlate with molecules of endothelial activation, angiopoietin 2 and vascular cell adhesion molecule 1. PMID:27230099

  7. Shell matters: Magnetic targeting of SPIONs and in vitro effects on endothelial and monocytic cell function.

    PubMed

    Matuszak, Jasmin; Dörfler, Philipp; Zaloga, Jan; Unterweger, Harald; Lyer, Stefan; Dietel, Barbara; Alexiou, Christoph; Cicha, Iwona

    2015-01-01

    Superparamagnetic iron oxide nanoparticles (SPIONs) are versatile and easily functionalized agents with high potential for diagnostic and therapeutic intravascular applications. In this study, we analyzed the responses of endothelial (ECs) and monocytic cells to three different types of SPIONs, in order to assess the influence of physico-chemical properties on the biological reactions to SPIONs. The following formulations were used: (1) Lauric acid-coated and BSA-stabilized SPION-1,(2) Lauric acid/BSA-coated SPION-2 and (3) dextran-coated SPION-3. SPION-1 were strongly internalized by ECs and reduced their viability in static conditions. Additionally, they had a dose-dependent inhibitory effect on monocytic cell chemotaxis to MCP-1, but did not affect monocytic cell recruitment by ECs. SPION-2 uptake was less pronounced, both in ECs and monocytic cells, and these particles were better tolerated by the vascular cells. Not being internalized by endothelial or monocytic cells, SPION-3 did not induce relevant effects on cell viability, motility or endothelial-monocytic cell interactions.Taken together, localized accumulation of circulating SPION under physiologic-like flow conditions and their cellular uptake depends on the physicochemical characteristics. Our findings suggest that SPION-2 are suitable for magnetic targeting of atherosclerotic plaques. Due to their excellent biocompatibility and low internalization, SPION-3 may represent a suitable imaging agent for intravascular applications. PMID:26410877

  8. Prevalence and Determinants of True Thyroid Dysfunction Among Pediatric Referrals for Abnormal Thyroid Function Tests

    PubMed Central

    Lahoti, Amit; Klein, Jason; Schumaker, Tiffany; Vuguin, Patricia; Frank, Graeme

    2016-01-01

    Background/Aims. Abnormalities in thyroid function tests (TFTs) are a common referral reason for pediatric endocrine evaluation. However, a sizable proportion of these laboratory abnormalities do not warrant therapy or endocrine follow-up. The objectives of this study were (a) to evaluate the prevalence of true thyroid dysfunction among pediatric endocrinology referrals for abnormal TFTs; (b) to identify the historical, clinical, and laboratory characteristics that predict decision to treat. Methods. This was a retrospective chart review of patients evaluated in pediatric endocrinology office during a weekly clinic designated for new referrals for abnormal TFTs in 2010. Results. A total of 230 patients were included in the study. Median age at referral was 12 years (range = 2-18); 56% were females. Routine screening was cited as the reason for performing TFTs by 33% patients. Majority was evaluated for hypothyroidism (n = 206). Elevated thyroid-stimulating hormone was the most common referral reason (n = 140). A total of 41 out of 206 patients were treated for hypothyroidism. Conclusions. Prevalence of hypothyroidism was 20%. Thyroid follow-up was not recommended for nearly one third of the patients. Among all the factors analyzed, an elevated thyroid-stimulating hormone level and antithyroglobulin antibodies strongly correlated with the decision to treat (P < .005). PMID:27336020

  9. Early-stage visual processing abnormalities in high-functioning autism spectrum disorder (ASD)

    PubMed Central

    Baruth, Joshua M.; Casanova, Manuel F.; Sears, Lonnie; Sokhadze, Estate

    2012-01-01

    It has been reported that individuals with autism spectrum disorder (ASD) have abnormal responses to the sensory environment. For these individuals sensory overload can impair functioning, raise physiological stress, and adversely affect social interaction. Early-stage (i.e. within 200ms of stimulus onset) auditory processing abnormalities have been widely examined in ASD using event-related potentials (ERP), while ERP studies investigating early-stage visual processing in ASD are less frequent. We wanted to test the hypothesis of early-stage visual processing abnormalities in ASD by investigating ERPs elicited in a visual oddball task using illusory figures. Our results indicate that individuals with ASD have abnormally large cortical responses to task irrelevant stimuli over both parieto-occipital and frontal regions-of-interest (ROI) during early stages of visual processing compared to the control group. Furthermore, ASD patients showed signs of an overall disruption in stimulus discrimination, and had a significantly higher rate of motor response errors. PMID:22563527

  10. Abnormal functional brain asymmetry in depression: evidence of biologic commonality between major depression and dysthymia.

    PubMed

    Bruder, Gerard E; Stewart, Jonathan W; Hellerstein, David; Alvarenga, Jorge E; Alschuler, Daniel; McGrath, Patrick J

    2012-04-30

    Prior studies have found abnormalities of functional brain asymmetry in patients having a major depressive disorder (MDD). This study aimed to replicate findings of reduced right hemisphere advantage for perceiving dichotic complex tones in depressed patients, and to determine whether patients having "pure" dysthymia show the same abnormality of perceptual asymmetry as MDD. It also examined gender differences in lateralization, and the extent to which abnormalities of perceptual asymmetry in depressed patients are dependent on gender. Unmedicated patients having either a MDD (n=96) or "pure" dysthymic disorder (n=42) and healthy controls (n=114) were tested on dichotic fused-words and complex-tone tests. Patient and control groups differed in right hemisphere advantage for complex tones, but not left hemisphere advantage for words. Reduced right hemisphere advantage for tones was equally present in MDD and dysthymia, but was more evident among depressed men than depressed women. Also, healthy men had greater hemispheric asymmetry than healthy women for both words and tones, whereas this gender difference was not seen for depressed patients. Dysthymia and MDD share a common abnormality of hemispheric asymmetry for dichotic listening.

  11. Prevalence and Determinants of True Thyroid Dysfunction Among Pediatric Referrals for Abnormal Thyroid Function Tests.

    PubMed

    Lahoti, Amit; Klein, Jason; Schumaker, Tiffany; Vuguin, Patricia; Frank, Graeme

    2016-01-01

    Background/Aims. Abnormalities in thyroid function tests (TFTs) are a common referral reason for pediatric endocrine evaluation. However, a sizable proportion of these laboratory abnormalities do not warrant therapy or endocrine follow-up. The objectives of this study were (a) to evaluate the prevalence of true thyroid dysfunction among pediatric endocrinology referrals for abnormal TFTs; (b) to identify the historical, clinical, and laboratory characteristics that predict decision to treat. Methods. This was a retrospective chart review of patients evaluated in pediatric endocrinology office during a weekly clinic designated for new referrals for abnormal TFTs in 2010. Results. A total of 230 patients were included in the study. Median age at referral was 12 years (range = 2-18); 56% were females. Routine screening was cited as the reason for performing TFTs by 33% patients. Majority was evaluated for hypothyroidism (n = 206). Elevated thyroid-stimulating hormone was the most common referral reason (n = 140). A total of 41 out of 206 patients were treated for hypothyroidism. Conclusions. Prevalence of hypothyroidism was 20%. Thyroid follow-up was not recommended for nearly one third of the patients. Among all the factors analyzed, an elevated thyroid-stimulating hormone level and antithyroglobulin antibodies strongly correlated with the decision to treat (P < .005).

  12. Boldine protects endothelial function in hyperglycemia-induced oxidative stress through an antioxidant mechanism.

    PubMed

    Lau, Yeh Siang; Tian, Xiao Yu; Huang, Yu; Murugan, Dharmani; Achike, Francis I; Mustafa, Mohd Rais

    2013-02-01

    Increased oxidative stress is involved in the pathogenesis and progression of diabetes. Antioxidants are therapeutically beneficial for oxidative stress-associated diseases. Boldine ([s]-2,9-dihydroxy-1,10-dimethoxyaporphine) is a major alkaloid present in the leaves and bark of the boldo tree (Peumus boldus Molina), with known an antioxidant activity. This study examined the protective effects of boldine against high glucose-induced oxidative stress in rat aortic endothelial cells (RAEC) and its mechanisms of vasoprotection related to diabetic endothelial dysfunction. In RAEC exposed to high glucose (30 mM) for 48 h, pre-treatment with boldine reduced the elevated ROS and nitrotyrosine formation, and preserved nitric oxide (NO) production. Pre-incubation with β-NAPDH reduced the acetylcholine-induced endothelium-dependent relaxation; this attenuation was reversed by boldine. Compared with control, endothelium-dependent relaxation in the aortas of streptozotocin (STZ)-treated diabetic rats was significantly improved by both acute (1 μM, 30 min) and chronic (20mg/kg/daily, i.p., 7 days) treatment with boldine. Intracellular superoxide and peroxynitrite formation measured by DHE fluorescence or chemiluminescence assay were higher in sections of aortic rings from diabetic rats compared with control. Chronic boldine treatment normalized ROS over-production in the diabetic group and this correlated with reduction of NAD(P)H oxidase subunits, NOX2 and p47(phox). The present study shows that boldine reversed the increased ROS formation in high glucose-treated endothelial cells and restored endothelial function in STZ-induced diabetes by inhibiting oxidative stress and thus increasing NO bioavailability. PMID:23178655

  13. Irisin Increased the Number and Improved the Function of Endothelial Progenitor Cells in Diabetes Mellitus Mice

    PubMed Central

    Wang, Jinxiang; Song, Mingbao; Zhou, Fang; Fu, Dagan; Ruan, Guangping; Zhu, Xiangqing; Bai, Yinyin; Huang, Lan; Pang, Rongqing; Kang, Huali

    2016-01-01

    Abstract: The dysfunction of endothelial progenitor cells (EPCs) was found to be associated with vascular complications in diabetes mellitus (DM) patients. Previous studies found that regular exercise could improve the function of EPCs in DM patients, but the underling mechanism was unclear. Irisin, a newly identified myokine, was induced by exercise and has been demonstrated to mediate some of the positive effects of exercise. In this study, we hypothesize that irisin may have direct effects on EPC function in DM mice. These data showed for the first time that irisin increased the number of EPCs in peripheral blood of DM mice and improved the function of EPCs derived from DM mice bone marrow. The mechanism for the effect of irisin is related to the PI3K/Akt/eNOS pathway. Furthermore, irisin was demonstrated to improve endothelial repair in DM mice that received EPC transplants after carotid artery injury. The results of this study indicate a novel effect of irisin in regulating the number and function of EPCs via the PI3K/Akt/eNOS pathway, suggesting a potential for the administration of exogenous irisin as a succedaneum to improve EPC function in diabetic patients who fail to achieve such improvements through regular exercise. PMID:27002278

  14. Endothelial lipid phosphate phosphatase-3 deficiency that disrupts the endothelial barrier function is a modifier of cardiovascular development

    PubMed Central

    Chatterjee, Ishita; Baruah, Jugajyoti; Lurie, Erin E.; Wary, Kishore K.

    2016-01-01

    Aims Lipid phosphate phosphatase-3 (LPP3) is expressed at high levels in endothelial cells (ECs). Although LPP3 is known to hydrolyse the phosphate group from lysolipids such as spingosine-1-phosphate and its structural homologues, the function of Lpp3 in ECs is not completely understood. In this study, we investigated how tyrosine-protein kinase receptor (TEK or Tie2) promoter–dependent deletion of Lpp3 alters EC activities. Methods and results Lpp3fl/fl mice were crossed with the tg.Tie2Cre transgenic line. Vasculogenesis occurred normally in embryos with Tie2Cre-mediated deletion of Lpp3 (called Lpp3ECKO), but embryonic lethality occurred in two waves, the first wave between E8.5 and E10.5, while the second between E11.5 and E13.5. Lethality in Lpp3ECKO embryos after E11.5 was accompanied by vascular leakage and haemorrhage, which likely resulted in insufficient cardiovascular development. Analyses of haematoxylin- and eosin-stained heart sections from E11.5 Lpp3ECKO embryos showed insufficient heart growth associated with decreased trabeculation, reduced growth of the compact wall, and absence of cardiac cushions. Staining followed by microscopic analyses of Lpp3ECKO embryos revealed the presence of apoptotic ECs. Furthermore, Lpp3-deficient ECs showed decreased gene expression and protein levels of Cyclin-D1, VE-cadherin, Fibronectin, Klf2, and Klf4. To determine the underlying mechanisms of vascular leakage and barrier disruption, we performed knockdown and rescue experiments in cultured ECs. LPP3 knockdown decreased transendothelial electrical resistance and increased permeability. Re-expression of β-catenin cDNA in LPP3-knockdown ECs partially restored the effect of the LPP3 loss, whereas re-expression of p120ctn cDNA did not. Conclusion These findings demonstrate the essential roles of LPP3 in the maturation of EC barrier integrity and normal cardiovascular development. PMID:27125875

  15. Endothelial Mineralocorticoid Receptors Differentially Contribute to Coronary and Mesenteric Vascular Function Without Modulating Blood Pressure.

    PubMed

    Mueller, Katelee Barrett; Bender, Shawn B; Hong, Kwangseok; Yang, Yan; Aronovitz, Mark; Jaisser, Frederic; Hill, Michael A; Jaffe, Iris Z

    2015-11-01

    Arteriolar vasoreactivity tightly regulates tissue-specific blood flow and contributes to systemic blood pressure (BP) but becomes dysfunctional in the setting of cardiovascular disease. The mineralocorticoid receptor (MR) is known to regulate BP via the kidney and by vasoconstriction in smooth muscle cells. Although endothelial cells (EC) express MR, the contribution of EC-MR to BP and resistance vessel function remains unclear. To address this, we created a mouse with MR specifically deleted from EC (EC-MR knockout [EC-MR-KO]) but with intact leukocyte MR expression and normal renal MR function. Telemetric BP studies reveal no difference between male EC-MR-KO mice and MR-intact littermates in systolic, diastolic, circadian, or salt-sensitive BP or in the hypertensive responses to aldosterone±salt or angiotensin II±l-nitroarginine methyl ester. Vessel myography demonstrated normal vasorelaxation in mesenteric and coronary arterioles from EC-MR-KO mice. After exposure to angiotensin II-induced hypertension, impaired endothelial-dependent relaxation was prevented in EC-MR-KO mice in mesenteric vessels but not in coronary vessels. Mesenteric vessels from angiotensin II-exposed EC-MR-KO mice showed increased maximum responsiveness to acetylcholine when compared with MR-intact vessels, a difference that is lost with indomethacin+l-nitroarginine methyl ester pretreatment. These data support that EC-MR plays a role in regulating endothelial function in hypertension. Although there was no effect of EC-MR deletion on mesenteric vasoconstriction, coronary arterioles from EC-MR-KO mice showed decreased constriction to endothelin-1 and thromboxane agonist at baseline and also after exposure to hypertension. These data support that EC-MR participates in regulation of vasomotor function in a vascular bed-specific manner that is also modulated by risk factors, such as hypertension.

  16. Oral trehalose supplementation improves resistance artery endothelial function in healthy middle-aged and older adults

    PubMed Central

    Kaplon, Rachelle E.; Hill, Sierra D.; Bispham, Nina Z.; Santos-Parker, Jessica R.; Nowlan, Molly J.; Snyder, Laura L.; Chonchol, Michel; LaRocca, Thomas J.; McQueen, Matthew B.; Seals, Douglas R.

    2016-01-01

    We hypothesized that supplementation with trehalose, a disaccharide that reverses arterial aging in mice, would improve vascular function in middle-aged and older (MA/O) men and women. Thirty-two healthy adults aged 50-77 years consumed 100 g/day of trehalose (n=15) or maltose (n=17, isocaloric control) for 12 weeks (randomized, double-blind). In subjects with Δbody mass<2.3kg (5 lb.), resistance artery endothelial function, assessed by forearm blood flow to brachial artery infusion of acetylcholine (FBFACh), increased ∼30% with trehalose (13.3±1.0 vs. 10.5±1.1 AUC, P=0.02), but not maltose (P=0.40). This improvement in FBFACh was abolished when endothelial nitric oxide (NO) production was inhibited. Endothelium-independent dilation, assessed by FBF to sodium nitroprusside (FBFSNP), also increased ∼30% with trehalose (155±13 vs. 116±12 AUC, P=0.03) but not maltose (P=0.92). Changes in FBFACh and FBFSNP with trehalose were not significant when subjects with Δbody mass≥2.3kg were included. Trehalose supplementation had no effect on conduit artery endothelial function, large elastic artery stiffness or circulating markers of oxidative stress or inflammation (all P>0.1) independent of changes in body weight. Our findings demonstrate that oral trehalose improves resistance artery (microvascular) function, a major risk factor for cardiovascular diseases, in MA/O adults, possibly through increasing NO bioavailability and smooth muscle sensitivity to NO. PMID:27208415

  17. Oral trehalose supplementation improves resistance artery endothelial function in healthy middle-aged and older adults.

    PubMed

    Kaplon, Rachelle E; Hill, Sierra D; Bispham, Nina Z; Santos-Parker, Jessica R; Nowlan, Molly J; Snyder, Laura L; Chonchol, Michel; LaRocca, Thomas J; McQueen, Matthew B; Seals, Douglas R

    2016-06-01

    We hypothesized that supplementation with trehalose, a disaccharide that reverses arterial aging in mice, would improve vascular function in middle-aged and older (MA/O) men and women. Thirty-two healthy adults aged 50-77 years consumed 100 g/day of trehalose (n=15) or maltose (n=17, isocaloric control) for 12 weeks (randomized, double-blind). In subjects with Δbody mass less than 2.3kg (5 lb.), resistance artery endothelial function, assessed by forearm blood flow to brachial artery infusion of acetylcholine (FBFACh), increased ~30% with trehalose (13.3±1.0 vs. 10.5±1.1 AUC, P=0.02), but not maltose (P=0.40). This improvement in FBFACh was abolished when endothelial nitric oxide (NO) production was inhibited. Endothelium-independent dilation, assessed by FBF to sodium nitroprusside (FBFSNP), also increased ~30% with trehalose (155±13 vs. 116±12 AUC, P=0.03) but not maltose (P=0.92). Changes in FBFACh and FBFSNP with trehalose were not significant when subjects with Δbody mass ≥ 2.3kg were included. Trehalose supplementation had no effect on conduit artery endothelial function, large elastic artery stiffness or circulating markers of oxidative stress or inflammation (all P>0.1) independent of changes in body weight. Our findings demonstrate that oral trehalose improves resistance artery (microvascular) function, a major risk factor for cardiovascular diseases, in MA/O adults, possibly through increasing NO bioavailability and smooth muscle sensitivity to NO. PMID:27208415

  18. Microheterogeneity of antithrombin III: effect of single amino acid substitutions and relationship with functional abnormalities.

    PubMed

    De Stefano, V; Leone, G; Mastrangelo, S; Lane, D A; Girolami, A; de Moerloose, P; Sas, G; Abildgaard, U; Blajchman, M; Rodeghiero, F

    1994-02-01

    Microheterogeneity of antithrombin III (AT-III) was investigated by crossed immunoelectrofocusing (CIEF) on eleven molecular variants. A normal pattern was found in five variants while two different abnormal CIEF patterns were found in the other four and two variants, respectively. Point mutations causing a major pI change (exceeding 4.0) of the amino acid substituted lead to alterations in the overall microheterogeneity. The variants thus substituted share a first type of abnormal CIEF pattern with alterations throughout the pH range, regardless of the location of the mutation (reactive site and adjacent regions or heparin binding region). Minor amino acid pI changes in these regions do not alter the AT-III overall microheterogeneity, whatever the resulting functional defect. However, if the mutation is placed in the region around positions 404 or 429, then even minor changes of the amino acid pI seem able to alter the overall charge, leading to a second type of abnormal CIEF pattern with the main alteration at pH 4.8-4.6. Neuraminidase treatment leads to disappearance of microheterogeneity except for the variants with the Arg393 to Cys substitution. Addition of thrombin induces CIEF modifications specifically related to the functional defect. A normal formation of thrombin-antithrombin complexes induces a shift towards the more acid pH range, whereas in the variants substituted at the reactive site the CIEF pattern is substantially unaffected by thrombin; variants substituted at positions 382-384 show a maximal thrombin-induced increase of the isoforms at pI 4.8-4.6. Therefore mutant antithrombins with different functional abnormalities but sharing a common CIEF pattern were well distinguished.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8180341

  19. Decreased Endothelial Nitric Oxide Bioavailability, Impaired Microvascular Function, and Increased Tissue Oxygen Consumption in Children with Falciparum Malaria

    PubMed Central

    Yeo, Tsin W.; Lampah, Daniel A.; Kenangalem, Enny; Tjitra, Emiliana; Weinberg, J. Brice; Granger, Donald L.; Price, Ric N.; Anstey, Nicholas M.

    2014-01-01

    Endothelial nitric oxide (NO) bioavailability, microvascular function, and host oxygen consumption have not been assessed in pediatric malaria. We measured NO-dependent endothelial function by using peripheral artery tonometry to determine the reactive hyperemia index (RHI), and microvascular function and oxygen consumption (VO2) using near infrared resonance spectroscopy in 13 Indonesian children with severe falciparum malaria and 15 with moderately severe falciparum malaria. Compared with 19 controls, children with severe malaria and those with moderately severe malaria had lower RHIs (P = .03); 12% and 8% lower microvascular function, respectively (P = .03); and 29% and 25% higher VO2, respectively. RHIs correlated with microvascular function in all children with malaria (P < .001) and all with severe malaria (P < .001). Children with malaria have decreased endothelial and microvascular function and increased oxygen consumption, likely contributing to the pathogenesis of the disease. PMID:24879801

  20. Decreased endothelial nitric oxide bioavailability, impaired microvascular function, and increased tissue oxygen consumption in children with falciparum malaria.

    PubMed

    Yeo, Tsin W; Lampah, Daniel A; Kenangalem, Enny; Tjitra, Emiliana; Weinberg, J Brice; Granger, Donald L; Price, Ric N; Anstey, Nicholas M

    2014-11-15

    Endothelial nitric oxide (NO) bioavailability, microvascular function, and host oxygen consumption have not been assessed in pediatric malaria. We measured NO-dependent endothelial function by using peripheral artery tonometry to determine the reactive hyperemia index (RHI), and microvascular function and oxygen consumption (VO2) using near infrared resonance spectroscopy in 13 Indonesian children with severe falciparum malaria and 15 with moderately severe falciparum malaria. Compared with 19 controls, children with severe malaria and those with moderately severe malaria had lower RHIs (P = .03); 12% and 8% lower microvascular function, respectively (P = .03); and 29% and 25% higher VO2, respectively. RHIs correlated with microvascular function in all children with malaria (P < .001) and all with severe malaria (P < .001). Children with malaria have decreased endothelial and microvascular function and increased oxygen consumption, likely contributing to the pathogenesis of the disease.

  1. In vitro modeling of endothelial interaction with macrophages and pericytes demonstrates Notch signaling function in the vascular microenvironment.

    PubMed

    Tattersall, Ian W; Du, Jing; Cong, Zhuangzhuang; Cho, Bennet S; Klein, Alyssa M; Dieck, Chelsea L; Chaudhri, Reyhaan A; Cuervo, Henar; Herts, James H; Kitajewski, Jan

    2016-04-01

    Angiogenesis is regulated by complex interactions between endothelial cells and support cells of the vascular microenvironment, such as tissue myeloid cells and vascular mural cells. Multicellular interactions during angiogenesis are difficult to study in animals and challenging in a reductive setting. We incorporated stromal cells into an established bead-based capillary sprouting assay to develop assays that faithfully reproduce major steps of vessel sprouting and maturation. We observed that macrophages enhance angiogenesis, increasing the number and length of endothelial sprouts, a property we have dubbed "angiotrophism." We found that polarizing macrophages toward a pro-inflammatory profile further increased their angiotrophic stimulation of vessel sprouting, and this increase was dependent on macrophage Notch signaling. To study endothelial/pericyte interactions, we added vascular pericytes directly to the bead-bound endothelial monolayer. These pericytes formed close associations with the endothelial sprouts, causing increased sprout number and vessel caliber. We found that Jagged1 expression and Notch signaling are essential for the growth of both endothelial cells and pericytes and may function in their interaction. We observed that combining endothelial cells with both macrophages and pericytes in the same sprouting assay has multiplicative effects on sprouting. These results significantly improve bead-capillary sprouting assays and provide an enhanced method for modeling interactions between the endothelium and the vascular microenvironment. Achieving this in a reductive in vitro setting represents a significant step toward a better understanding of the cellular elements that contribute to the formation of mature vasculature.

  2. Cord blood-derived endothelial colony-forming cell function is disrupted in congenital diaphragmatic hernia.

    PubMed

    Fujinaga, Hideshi; Fujinaga, Hiroko; Watanabe, Nobuyuki; Kato, Tomoko; Tamano, Moe; Terao, Miho; Takada, Shuji; Ito, Yushi; Umezawa, Akihiro; Kuroda, Masahiko

    2016-06-01

    Vascular growth is necessary for normal lung development. Although endothelial progenitor cells (EPCs) play an important role in vascularization, little is known about EPC function in congenital diaphragmatic hernia (CDH), a severe neonatal condition that is associated with pulmonary hypoplasia. We hypothesized that the function of endothelial colony-forming cells (ECFCs), a type of EPC, is impaired in CDH. Cord blood (CB) was collected from full-term CDH patients and healthy controls. We assessed CB progenitor cell populations as well as plasma vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1α (SDF1α) levels. CB ECFC clonogenicity; growth kinetics; migration; production of VEGF, SDF1α, and nitric oxide (NO); vasculogenic capacity; and mRNA expression of VEGF-A, fms-related tyrosine kinase 1 (FLT1), kinase insert domain receptor (KDR), nitric oxide synthase (NOS) 1-3, SDF1, and chemokine (C-X-C motif) receptor 4 (CXCR4) were also assessed. Compared with controls, CB ECFCs were decreased in CDH. CDH ECFCs had reduced potential for self-renewal, clonogenicity, proliferation, and migration. Their capacity for NO production was enhanced but their response to VEGF was blunted in CDH ECFCs. In vivo potential for de novo vasculogenesis was reduced in CDH ECFCs. There was no difference in CB plasma VEGF and SDF1α concentrations, VEGF and SDF1α production by ECFCs, and ECFC mRNA expression of VEGF-A, FLT1, KDR, NOS1-3, SDF1, and CXCR4 between CDH and control subjects. In conclusion, CB ECFC function is disrupted in CDH, but these changes may be caused by mechanisms other than alteration of VEGF-NO and SDF1-CXCR4 signaling. PMID:27130531

  3. Stretching exercises enhance vascular endothelial function and improve peripheral circulation in patients with acute myocardial infarction.

    PubMed

    Hotta, Kazuki; Kamiya, Kentaro; Shimizu, Ryosuke; Yokoyama, Misako; Nakamura-Ogura, Misao; Tabata, Minoru; Kamekawa, Daisuke; Akiyama, Ayako; Kato, Michitaka; Noda, Chiharu; Matsunaga, Atsuhiko; Masuda, Takashi

    2013-01-01

    The purpose of this study was to clarify the acute effects of a single session of stretching exercises on vascular endothelial function and peripheral circulation in patients with acute myocardial infarction. This study evaluated 32 patients (mean age, 66 ± 9 years) who received phase I cardiac rehabilitation after acute myocardial infarction. Five types of stretching exercises were performed on the floor: wrist dorsiflexion, close-legged trunk flexion, open-legged trunk flexion, open-legged lateral trunk bending, and cross-legged trunk flexion. Each exercise entailed a 30-second stretching followed by a 30-second relaxation, and was repeated twice. Low- and high-frequency components (LF and HF) of heart rate variability (LF, 0.04-0.15 Hz; HF, 0.15-0.40 Hz) were analyzed, and HF and LF/HF were used as indices of parasympathetic and sympathetic nervous activities, respectively. Reactive hyperemia peripheral arterial tonometry (RH-PAT) index was measured and used as a parameter for vascular endothelial function. Transcutaneous oxygen pressure (tcPO2) on the right foot and chest was also measured, and the Foot-tcPO2/Chest-tcPO2 ratio was used as a parameter for peripheral circulation. The HF, RH-PAT index, and Foot-tcPO2/Chest-tcPO2 ratio were significantly higher after the exercises than before (P < 0.05, P < 0.01, and P < 0.05, respectively). There was no significant difference in the LF/HF ratio measured before and after stretching exercises. These findings demonstrate that stretching exercises improve vascular endothelial function and peripheral circulation in patients with acute myocardial infarction.

  4. Positive influence of aspirin on coronary endothelial function: Importance of the dose

    PubMed Central

    Teragawa, Hiroki; Mitsuba, Naoya; Ishibashi, Ken; Kurisu, Satoshi; Kihara, Yasuki

    2013-01-01

    AIM: To investigate the effects of different doses of aspirin on coronary endothelial function. METHODS: The study included 139 Japanese subjects (mean age, 60 years; 53 women) with angiographically normal coronary arteries. Patients were distributed into Group I (n = 63), who was administered aspirin and Group II (n = 76), the control, who were not administered aspirin. Group I was further divided into Group Ia (n = 50, low-dose aspirin, 100 mg) and Group Ib (n = 13, high-dose aspirin, 500 mg). After a routine coronary angiography, acetylcholine (ACh; 3 and 30 μg/min successively) and nitroglycerin (NTG) were infused into the left coronary ostium over 2 min. The change in the diameter of the coronary artery in response to each drug was expressed as the percentage change from baseline values. RESULTS: The patient characteristics did not differ between the two groups. The change in coronary diameter in response to ACh was greater in Group I than in Group II (P = 0.0043), although the NTG-induced coronary vasodilation was similar between groups. ACh-induced dilation was greater in Group Ia than in Group Ib (P = 0.0231). Multivariate regression analysis showed that a low-dose of aspirin (P = 0.0004) was one of the factors associated with ACh-induced dilation at 30 μg/min. CONCLUSION: In subjects with angiographically normal coronary arteries, aspirin only had a positive influence on coronary endothelial function at the low dose of 100 mg. This improvement of coronary endothelial function may be involved in the preventive effect of aspirin against future coronary events. PMID:24340141

  5. Time Rate of Blood Pressure Variation Is Associated With Endothelial Function in Patients With Metabolic Syndrome.

    PubMed

    Ruan, Yanping; Wei, Wanlin; Yan, Jianhua; Sun, Lixian; Lian, Hui; Zhao, Xiaoyi; Liang, Ruijuan; Xiaole, Liu; Fan, Zhongjie

    2016-01-01

    The time rate of blood pressure (BP) variation indicates the speed of BP fluctuations. Previous studies have demonstrated that the time rate of BP variation was associated with target organ damage. However, the association between time rate of BP variation and endothelial function has not been evaluated.24-hour ambulatory blood pressure monitoring (ABPM) was performed in 61 patients with metabolic syndrome. Time rate of BP variation was calculated from BP recordings of ABPM. Endothelial function was assessed using reactive hyperemia-peripheral arterial tonometry index (RHI) by EndoPat2000. Multiple linear regression models were used to detect the association between time rate of BP variation and RHI.Among all the subjects (n = 61), the multiple linear regression models revealed that the daytime rate of systolic blood pressure (SBP) variation was independently associated with RHI (β = -0.334, P = 0.008). A 0.1 mmHg/minute increase in the daytime rate of SBP variation correlated with a decline of 0.20 in RHI. The same effect was also found in the subjects with eGFR ≥ 60 mL/ (minute*1.73 m(2)). A greater association was found in those who were not taking a statin, β-blocker, ACEI/ARB, or diuretic and those without diabetes compared with those with any antihypertensive medication or with diabetes. Other ambulatory blood pressure parameters and central hemodynamics were not found to be associated with RHI.Our findings have shown that the daytime rate of SBP variation was associated with endothelial function in patients with metabolic syndrome, independent of other BP parameters and central hemodynamics.

  6. Q192R Paraoxonase (PON)1 Polymorphism, Insulin Sensitivity, and Endothelial Function in Essential Hypertensive Men

    PubMed Central

    Dell’Omo, Giulia; Penno, Giuseppe; Pucci, Laura; Lucchesi, Daniela; Prato, Stefano Del; Pedrinelli, Roberto

    2014-01-01

    AIMS Essential hypertension is characterized by increased reactive oxygen species (ROS) generation harmful for insulin sensitivity and nitric oxide (NO)-mediated vasomotor function, a noxious effect that paraoxonase (PON)1, an antioxidant circulating high-density lipoprotein (HDL)-bound esterase, may counteract. The PON1 gene contains several polymorphisms including a glutamine (Q) to arginine (R) transition at position 192 encoding circulating allozymes with higher antioxidant activity that might influence both parameters. METHODS Q192R was determined by polymerase chain reaction in 72 never-treated, glucose-tolerant, uncomplicated essential hypertensive men. Insulin sensitivity was assessed by homeostasis model assessment (HOMA) and endothelial function by forearm vasodilation (strain-gage venous plethysmography) to intra-arterial acetylcholine (ACH) with sodium nitroprusside (NIP) as a NO-independent control. Additional evaluation variables included 24-hour blood pressure (BP), lipids, BMI, smoking status, and metabolic syndrome (MetS) by Adult Treatment Panel (ATP)-III criteria. R192 was considered as the rare allele, and its associations analyzed by dominant models (Q/Q vs. Q/R + R/R). RESULTS Genotype frequencies were consistent with the Hardy–Weinberg equilibrium. HOMA was lower and insulin resistance (the upper fourth of HOMA values distribution) less prevalent in Q/R + R/R carriers in whom ACH-mediated vasodilatation was greater and endothelial dysfunction (the bottom fourth of ACHAUC values distribution) less frequent than in Q/Q homozygotes. Q192R polymorphism and MetS were unrelated parameters despite their common association with insulin resistance. 24-hour BP, BMI, lipids, and smoking habits were homogeneously distributed across genotypes. CONCLUSIONS Q192R polymorphism associates differentially with insulin sensitivity and endothelial function in essential hypertensive men. PMID:25089090

  7. Wine polyphenols improve endothelial function in large vessels of female spontaneously hypertensive rats.

    PubMed

    López-Sepúlveda, Rocío; Jiménez, Rosario; Romero, Miguel; Zarzuelo, Maria José; Sánchez, Manuel; Gómez-Guzmán, Manuel; Vargas, Félix; O'Valle, Francisco; Zarzuelo, Antonio; Pérez-Vizcaíno, Francisco; Duarte, Juan

    2008-04-01

    Red wine polyphenols (RWPs) have been reported to prevent hypertension and endothelial dysfunction. Several individual RWPs exert estrogenic effects. We analyzed the possible in vivo protective effects on blood pressure and endothelial function of RWPs in female spontaneously hypertensive rats (SHR) and its relationship with ovarian function. RWPs (40 mg/kg by gavage) were orally administered for 5 weeks. Ovariectomized rats showed both increased isoprostaglandin F(2alpha) excretion and aortic superoxide production and reduced relaxant response to acetylcholine and contraction to the endothelial nitric oxide synthase (eNOS) inhibitor l-NAME measured in the aorta but similar blood pressure, as compared with sham-operated rats. Moreover, in ovariectomized rats aortic eNOS expression was unchanged, whereas caveolin-1, angiotensin II receptor (AT)-1, and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p22(phox) and p47(phox) expression was increased compared with sham-operated rats. In both ovariectomized and sham-operated SHR, RWPs reduced systolic blood pressure, urinary isoprostaglandin F(2alpha) excretion, and aortic O(2)(-) production, improving the endothelium-dependent relaxant response to acetylcholine in SHR. These changes were associated with unchanged aortic eNOS expression, whereas caveolin-1 was increased and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p22(phox) and p47(phox) expression was reduced. RWPs had no effect on the AT-1 overexpression found in ovariectomized animals. All these results suggest that a chronic treatment with RWPs reduces hypertension and vascular dysfunction through reduction in vascular oxidative stress in female SHR in a manner independent of the ovarian function.

  8. Successive deep dives impair endothelial function and enhance oxidative stress in man.

    PubMed

    Obad, Ante; Marinovic, Jasna; Ljubkovic, Marko; Breskovic, Toni; Modun, Darko; Boban, Mladen; Dujic, Zeljko

    2010-11-01

    The aim of this study was to assess the effects of successive deep dives on endothelial function of large conduit arteries and plasma pro-oxidant and antioxidant activity. Seven experienced divers performed six dives in six consecutive days using a compressed mixture of oxygen, helium and nitrogen (trimix) with diving depths ranging from 55 to 80 m. Before and after first, third and sixth dive, venous gas emboli formation and brachial artery function (flow-mediated dilation, FMD) was assessed by ultrasound. In addition, plasma antioxidant capacity (AOC) was measured by ferric reducing antioxidant power, and the level of oxidative stress was assessed by thiobarbituric acid-reactive substances (TBARS) method. Although the FMD was reduced to a similar extent after each dive, the comparison of predive FMD showed a reduction from 8.6% recorded before the first dive to 6.3% before the third (P = 0.03) and 5.7% before the sixth dive (P = 0.003). A gradual shift in baseline was also detected with TBARS assay, with malondialdehyde values increasing from 0.10 ± 0.02 μmol l⁻¹ before the first dive to 0.16 ± 0.03 before the sixth (P = 0.005). Predive plasma AOC values also showed a decreasing trend from 0.67 ± 0.20 mmol l⁻¹ trolox equivalents (first day) to 0.56 ± 0.12 (sixth day), although statistical significance was not reached (P = 0.08). This is the first documentation of acute endothelial dysfunction in the large conduit arteries occurring after successive deep trimix dives. Both endothelial function and plasma pro-oxidant and antioxidant activity did not return to baseline during the course of repetitive dives, indicating possible cumulative and longer lasting detrimental effects.

  9. Abnormalities in personal space and parietal-frontal function in schizophrenia.

    PubMed

    Holt, Daphne J; Boeke, Emily A; Coombs, Garth; DeCross, Stephanie N; Cassidy, Brittany S; Stufflebeam, Steven; Rauch, Scott L; Tootell, Roger B H

    2015-01-01

    Schizophrenia is associated with subtle abnormalities in day-to-day social behaviors, including a tendency in some patients to "keep their distance" from others in physical space. The neural basis of this abnormality, and related changes in social functioning, is unknown. Here we examined, in schizophrenic patients and healthy control subjects, the functioning of a parietal-frontal network involved in monitoring the space immediately surrounding the body ("personal space"). Using fMRI, we found that one region of this network, the dorsal intraparietal sulcus (DIPS), was hyper-responsive in schizophrenic patients to face stimuli appearing to move towards the subjects, intruding into personal space. This hyper-responsivity was predicted both by the size of personal space (which was abnormally elevated in the schizophrenia group) and the severity of negative symptoms. In contrast, in a second study, the activity of two lower-level visual areas that send information to DIPS (the fusiform face area and middle temporal area) was normal in schizophrenia. Together, these findings suggest that changes in parietal-frontal networks that support the sensory-guided initiation of behavior, including actions occurring in the space surrounding the body, contribute to social dysfunction and negative symptoms in schizophrenia. PMID:26484048

  10. Abnormalities in personal space and parietal-frontal function in schizophrenia.

    PubMed

    Holt, Daphne J; Boeke, Emily A; Coombs, Garth; DeCross, Stephanie N; Cassidy, Brittany S; Stufflebeam, Steven; Rauch, Scott L; Tootell, Roger B H

    2015-01-01

    Schizophrenia is associated with subtle abnormalities in day-to-day social behaviors, including a tendency in some patients to "keep their distance" from others in physical space. The neural basis of this abnormality, and related changes in social functioning, is unknown. Here we examined, in schizophrenic patients and healthy control subjects, the functioning of a parietal-frontal network involved in monitoring the space immediately surrounding the body ("personal space"). Using fMRI, we found that one region of this network, the dorsal intraparietal sulcus (DIPS), was hyper-responsive in schizophrenic patients to face stimuli appearing to move towards the subjects, intruding into personal space. This hyper-responsivity was predicted both by the size of personal space (which was abnormally elevated in the schizophrenia group) and the severity of negative symptoms. In contrast, in a second study, the activity of two lower-level visual areas that send information to DIPS (the fusiform face area and middle temporal area) was normal in schizophrenia. Together, these findings suggest that changes in parietal-frontal networks that support the sensory-guided initiation of behavior, including actions occurring in the space surrounding the body, contribute to social dysfunction and negative symptoms in schizophrenia.

  11. Abnormalities in personal space and parietal–frontal function in schizophrenia

    PubMed Central

    Holt, Daphne J.; Boeke, Emily A.; Coombs, Garth; DeCross, Stephanie N.; Cassidy, Brittany S.; Stufflebeam, Steven; Rauch, Scott L.; Tootell, Roger B.H.

    2015-01-01

    Schizophrenia is associated with subtle abnormalities in day-to-day social behaviors, including a tendency in some patients to “keep their distance” from others in physical space. The neural basis of this abnormality, and related changes in social functioning, is unknown. Here we examined, in schizophrenic patients and healthy control subjects, the functioning of a parietal–frontal network involved in monitoring the space immediately surrounding the body (“personal space”). Using fMRI, we found that one region of this network, the dorsal intraparietal sulcus (DIPS), was hyper-responsive in schizophrenic patients to face stimuli appearing to move towards the subjects, intruding into personal space. This hyper-responsivity was predicted both by the size of personal space (which was abnormally elevated in the schizophrenia group) and the severity of negative symptoms. In contrast, in a second study, the activity of two lower-level visual areas that send information to DIPS (the fusiform face area and middle temporal area) was normal in schizophrenia. Together, these findings suggest that changes in parietal–frontal networks that support the sensory-guided initiation of behavior, including actions occurring in the space surrounding the body, contribute to social dysfunction and negative symptoms in schizophrenia. PMID:26484048

  12. Functional Characterization and Expression Profiling of Human Induced Pluripotent Stem Cell- and Embryonic Stem Cell-Derived Endothelial Cells

    PubMed Central

    Li, Zongjin; Hu, Shijun; Ghosh, Zhumur; Han, Zhongchao

    2011-01-01

    With regard to human induced pluripotent stem cells (hiPSCs), in which adult cells are reprogrammed into embryonic-like cells using defined factors, their functional and transcriptional expression pattern during endothelial differentiation has yet to be characterized. In this study, hiPSCs and human embryonic stem cells (hESCs) were differentiated using the embryoid body method, and CD31+ cells were sorted. Fluorescence activated cell sorting analysis of hiPSC-derived endothelial cells (hiPSC-ECs) and hESC-derived endothelial cells (hESC-ECs) demonstrated similar endothelial gene expression patterns. We showed functional vascular formation by hiPSC-ECs in a mouse Matrigel plug model. We compared the gene profiles of hiPSCs, hESCs, hiPSC-ECs, hESC-ECs, and human umbilical vein endothelial cells (HUVECs) using whole genome microarray. Our analysis demonstrates that gene expression variation of hiPSC-ECs and hESC-ECs contributes significantly to biological differences between hiPSC-ECs and hESC-ECs as well as to the “distances” among hiPSCs, hESCs, hiPSC-ECs, hESC-ECs, and HUVECs. We further conclude that hiPSCs can differentiate into functional endothelial cells, but with limited expansion potential compared with hESC-ECs; thus, extensive studies should be performed to explore the cause and extent of such differences before clinical application of hiPSC-ECs can begin. PMID:21235328

  13. Abnormalities in large scale functional networks in unmedicated patients with schizophrenia and effects of risperidone

    PubMed Central

    Kraguljac, Nina Vanessa; White, David Matthew; Hadley, Jennifer Ann; Visscher, Kristina; Knight, David; ver Hoef, Lawrence; Falola, Blessing; Lahti, Adrienne Carol

    2015-01-01

    Objective To describe abnormalities in large scale functional networks in unmedicated patients with schizophrenia and to examine effects of risperidone on networks. Material and methods 34 unmedicated patients with schizophrenia and 34 matched healthy controls were enrolled in this longitudinal study. We collected resting state functional MRI data with a 3T scanner at baseline and six weeks after they were started on risperidone. In addition, a group of 19 healthy controls were scanned twice six weeks apart. Four large scale networks, the dorsal attention network, executive control network, salience network, and default mode network were identified with seed based functional connectivity analyses. Group differences in connectivity, as well as changes in connectivity over time, were assessed on the group's participant level functional connectivity maps. Results In unmedicated patients with schizophrenia we found resting state connectivity to be increased in the dorsal attention network, executive control network, and salience network relative to control participants, but not the default mode network. Dysconnectivity was attenuated after six weeks of treatment only in the dorsal attention network. Baseline connectivity in this network was also related to clinical response at six weeks of treatment with risperidone. Conclusions Our results demonstrate abnormalities in large scale functional networks in patients with schizophrenia that are modulated by risperidone only to a certain extent, underscoring the dire need for development of novel antipsychotic medications that have the ability to alleviate symptoms through attenuation of dysconnectivity. PMID:26793436

  14. Endothelial nitric oxide synthase in red blood cells: key to a new erythrocrine function?

    PubMed

    Cortese-Krott, Miriam M; Kelm, Malte

    2014-01-01

    Red blood cells (RBC) have been considered almost exclusively as a transporter of metabolic gases and nutrients for the tissues. It is an accepted dogma that RBCs take up and inactivate endothelium-derived NO via rapid reaction with oxyhemoglobin to form methemoglobin and nitrate, thereby limiting NO available for vasodilatation. Yet it has also been shown that RBCs not only act as "NO sinks", but exert an erythrocrine function - i.e an endocrine function of RBC - by synthesizing, transporting and releasing NO metabolic products and ATP, thereby potentially controlling systemic NO bioavailability and vascular tone. Recent work from our and others laboratory demonstrated that human RBCs carry an active type 3, endothelial NO synthase (eNOS), constitutively producing NO under normoxic conditions, the activity of which is compromised in patients with coronary artery disease. In this review we aim to discuss the potential role of red cell eNOS in RBC signaling and function, and to critically revise evidence to this date showing a role of non-endothelial circulating eNOS in cardiovascular pathophysiology.

  15. Effect of Ivabradine on Endothelial Function in Diastolic and Right Heart Failure Patients

    PubMed Central

    Orea-Tejeda, Arturo; Balderas-Muñoz, Karla; Castillo-Martínez, Lilia; Infante-Vázquez, Oscar; Martínez Memije, Raúl; Keirns-Davis, Candace; Dorantes-García, Joel; Narváez-David, René; Vázquez-Ortíz, Zuilma

    2013-01-01

    Background. Ivabradine is an If ion current inhibitor that has proved to reduce mortality in patients with systolic heart failure by slowing heart rate without decreasing myocardial contractility. Photoplethysmography is a simple, low-cost optical technique that can evaluate vascular function and detect changes in blood flow, pulse, and swelling of tissular microvascular space. Objective. To evaluate the effect of ivabradine on endothelial function by photoplethysmography in diastolic and right heart failure patients. Methodology. 15 patients were included (mean age of 78.1 ± 9.2 years) with optimally treated diastolic and right heart failure. They underwent photoplethysmography before and after induced ischemia to evaluate the wave blood flow on the finger, using the maximum amplitude time/total time (MAT/TT) index. Two measurements were made before and after oral Ivabradine (mean 12.5 mg a day during 6 months of followup). Results. In the study group, the MAT/TT index was 29.1 ± 2.2 versus 24.3 ± 3.2 (P = 0.05) in basal recording and 30.4 ± 2.1 versus 23.3 ± 2.9 (P = 0.002), before versus after ischemia and before versus after Ivabradine intervention, respectively. Conclusions. Ivabradine administration improves endothelial function (shear stress) in diastolic and right heart failure patients. PMID:24222884

  16. Inflammatory bowel disease, liver diseases and endothelial function: is there a linkage?

    PubMed

    Ciccone, Marco Matteo; Principi, Mariabeatrice; Ierardi, Enzo; Di Leo, Alfredo; Ricci, Gabriella; Carbonara, Santa; Gesualdo, Michele; Devito, Fiorella; Zito, Annapaola; Cortese, Francesca; Scicchitano, Pietro

    2015-01-01

    Atherosclerosis is a systemic inflammatory disease able to deeply worsen the outcome of patients because of its serious clinical consequences. The complex inflammatory background underlining such a disease makes atherosclerosis linked to several systemic inflammatory conditions able to impair endothelial function and morphology. Inflammatory bowel diseases are a group of gastrointestinal diseases including Crohn's disease and ulcerative colitis, that is, syndromes characterized by changes in mucosal immunity and gastrointestinal physiology, which could negatively influence the vascular endothelial function and structure. Hepatitis (i.e. inflammatory diseases of the liver mainly due to viral infections) and nonalcoholic fatty liver disease could be aligned to inflammatory bowel disease in such an induction of atherosclerosis disease.Many studies tried to point out the relationship between bowel and liver inflammatory diseases and early vascular changes, considered the first step for atherosclerosis development.The aim of such a narrative review is to explain the relationship between inflammatory bowel disease, hepatitis and nonalcoholic fatty liver disease and their role in increasing cardiovascular risk profile due to early impairment in vascular function and morphology.

  17. Tesmilifene modifies brain endothelial functions and opens the blood-brain/blood-glioma barrier.

    PubMed

    Walter, Fruzsina R; Veszelka, Szilvia; Pásztói, Mária; Péterfi, Zoltán A; Tóth, András; Rákhely, Gábor; Cervenak, László; Ábrahám, Csongor S; Deli, Mária A

    2015-09-01

    Tesmilifene, a tamoxifen analog with antihistamine action, has chemopotentiating properties in experimental and clinical cancer studies. In our previous works, tesmilifene increased the permeability of the blood-brain barrier (BBB) in animal and culture models. Our aim was to investigate the effects of tesmilifene on brain microvessel permeability in the rat RG2 glioma model and to reveal its mode of action in brain endothelial cells. Tesmilifene significantly increased fluorescein extravasation in the glioma. Short-term treatment with tesmilifene reduced the resistance and increased the permeability for marker molecules in a rat triple co-culture BBB model. Tesmilifene also affected the barrier integrity in brain endothelial cells co-cultured with RG2 glioblastoma cells. Tesmilifene inhibited the activity of P-glycoprotein and multidrug resistance-associated protein-1 efflux pumps and down-regulated the mRNA expression of tight junction proteins, efflux pumps, solute carriers, and metabolic enzymes important for BBB functions. Among the possible signaling pathways that regulate BBB permeability, tesmilifene activated the early nuclear translocation of NFκB. The MAPK/ERK and PI3K/Akt kinase pathways were also involved. We demonstrate for the first time that tesmilifene increases permeability marker molecule extravasation in glioma and inhibits efflux pump activity in brain endothelial cells, which may have therapeutic relevance. Tesmilifene, a chemopotentiator in experimental and clinical cancer studies increases vascular permeability in RG2 glioma in rats and permeability for marker molecules in a culture model of the blood-brain barrier. Tesmilifene inhibits the activity of efflux pumps and down-regulates the mRNA expression of tight junction proteins, transporters, and metabolic enzymes important for the blood-brain barrier functions, which may have therapeutic relevance.

  18. Nobiletin, a citrus polymethoxyflavonoid, suppresses multiple angiogenesis-related endothelial cell functions and angiogenesis in vivo.

    PubMed

    Kunimasa, Kazuhiro; Ikekita, Masahiko; Sato, Mayumi; Ohta, Toshiro; Yamori, Yukio; Ikeda, Megumi; Kuranuki, Sachi; Oikawa, Tsutomu

    2010-11-01

    Nobiletin is a citrus polymethoxyflavonoid that suppresses tumor growth and metastasis, both of which depend on angiogenesis. We recently identified nobiletin as a cell differentiation modulator. Because cell differentiation is a critical event in angiogenesis, it might be possible that nobiletin could exhibit antiangiogenic activity, resulting in suppression of these tumor malignant properties. To verify this possibility, we examined the antiangiogenic effects of nobiletin in vitro and in vivo. Nobiletin had concentration-dependent inhibitory effects on multiple functions of angiogenesis-related endothelial cells (EC); it suppressed the proliferation, migration and tube formation on matrigel of human umbilical vein EC (HUVEC) stimulated with endothelial cell growth supplement (ECGS), a mixture of acidic and basic fibroblast growth factors (FGFs). Gelatin zymography and northern blotting revealed that nobiletin suppressed pro-matrix metalloproteinase-2 (proMMP-2) production and MMP-2 mRNA expression in ECGS-stimulated HUVEC. Nobiletin also downregulated cell-associated plasminogen activator (PA) activity and urokinase-type PA mRNA expression. Furthermore, nobiletin inhibited angiogenic differentiation induced by vascular endothelial growth factor and FGF, an in vitro angiogenesis model. This inhibition was accompanied by downregulation of angiogenesis-related signaling molecules, such as extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase, and transcriptional factors (c-Jun and signal transducer and activator of transcription 3), and activation of the caspase pathway. In a chick embryo chorioallantoic membrane assay, nobiletin showed an antiangiogenic activity, the ID(50) value being 10μg (24.9nmol) per egg. These results indicate that nobiletin is a novel antiangiogenic compound that exhibits its activity through combined inhibition of multiple angiogenic EC functions.

  19. Effect of the transdermal low-level laser therapy on endothelial function.

    PubMed

    Szymczyszyn, Alicja; Doroszko, Adrian; Szahidewicz-Krupska, Ewa; Rola, Piotr; Gutherc, Radosław; Jasiczek, Jakub; Mazur, Grzegorz; Derkacz, Arkadiusz

    2016-09-01

    The effect of low-level laser therapy (LLLT) on the cardiovascular system is not fully established. Since the endothelium is an important endocrine element, establishing the mechanisms of LLLT action is an important issue.The aim of the study was to evaluate the effect of transdermal LLLT on endothelial function.In this study, healthy volunteers (n = 40, age = 20-40 years) were enrolled. N = 30 (14 female, 16 male, mean age 30 ± 5 years) constituted the laser-irradiated group (LG). The remaining 10 subjects (6 women, 4 men, mean age 28 ± 5 years) constituted the control group (CG). Participants were subjected to LLLT once a day for three consecutive days. Blood for biochemical assessments was drawn before the first irradiation and 24 h after the last session. In the LG, transdermal illumination of radial artery was conducted (a semiconductor laser λ = 808 nm, irradiation 50 mW, energy density 1.6 W/cm(2) and a dose 20 J/day, a total dose of 60 J). Biochemical parameters (reflecting angiogenesis: vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), angiostatin; antioxidative status: glutathione (GSH) and the nitric oxide metabolic pathway: symmetric dimethylarginine (SDMA), asymmetric dimethylarginine (ADMA) and L-arginine) were assessed. In the LG, a significant increase in GSH levels and considerable decrease in angiostatin concentration following the LLLT were observed. No significant differences in levels of the VEGF, FGF, SDMA, ADMA were observed.LLLT modifies vascular endothelial function by increasing its antioxidant and angiogenic potential. We found no significant differences in levels of the nitric oxide pathway metabolites within 24 h following the LLLT irradiation. PMID:27299570

  20. Angiotensin II Receptor Blockers Improve Peripheral Endothelial Function: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Li, Shuang; Wu, Yan; Yu, Ge; Xia, Qing; Xu, Yawei

    2014-01-01

    Objective(s) Several studies have assessed the effect of angiotensin II receptor blockers (ARBs) on peripheral endothelial dysfunction as measured by flow-mediated vasodilatation (FMD), a widely-used indicator for endothelial function. We conducted a meta-analysis to investigate the effect in comparison to placebo or no treatment and other antihypertensives. Methods MEDLINE, Cochrane library and EMBASE were searched to September 2013 for randomized controlled trials (RCTs) that assessed the effect of ARBs versus placebo or no treatment and other antihypertensives (angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), β-blockers, diuretics) by forearm FMD. Furthermore, we also use meta-regression to analyze the relationship between the endothelial function and the duration of ARBs treatments. Results In 11 trials including 590 patients, ARBs (n = 315) significantly improved FMD (1.36%, 95% confidence internal [CI]:1.28 to 1.44) versus placebo or no treatment (n = 275). In 16 trials that included 1028 patients, ARBs (n = 486) had a significant effect (0.59%, 95% CI: 0.25 to 0.94) on FMD when compared with other antihypertensives (n = 542). In 8 trials, ARBs (n = 174) had no significant effect (−0.14%, 95% CI: −0.32 to 0.03) compared with ACEI (n = 173). Compared with others, the benefits of ARBs, respectively, were 1.67% (95% CI: 0.65 to 0.93) in 7 trials with CCBs, 0.79% (95% CI: 0.42 to 1.01) with β-blockers in 3 trials and 0.9% (95% CI: 0.77 to 1.03) with diuretics in 3 trials. Importantly, we found ARBs were less effective in a long time span (95% CI: −1.990 to −0.622) than the first 6 months (95% CI: −0.484 to 0.360). Conclusions This study shows that ARBs improve peripheral endothelial function and are superior to CCBs, β-blockers and diuretics. However, the effect couldn't be maintained for a long time. In addition, there was no significant difference between ARBs and ACEI. PMID:24595033

  1. The research on endothelial function in women and men at risk for cardiovascular disease (REWARD) study: methodology

    PubMed Central

    2011-01-01

    Background Endothelial function has been shown to be a highly sensitive marker for the overall cardiovascular risk of an individual. Furthermore, there is evidence of important sex differences in endothelial function that may underlie the differential presentation of cardiovascular disease (CVD) in women relative to men. As such, measuring endothelial function may have sex-specific prognostic value for the prediction of CVD events, thus improving risk stratification for the overall prediction of CVD in both men and women. The primary objective of this study is to assess the clinical utility of the forearm hyperaemic reactivity (FHR) test (a proxy measure of endothelial function) for the prediction of CVD events in men vs. women using a novel, noninvasive nuclear medicine -based approach. It is hypothesised that: 1) endothelial dysfunction will be a significant predictor of 5-year CVD events independent of baseline stress test results, clinical, demographic, and psychological variables in both men and women; and 2) endothelial dysfunction will be a better predictor of 5-year CVD events in women compared to men. Methods/Design A total of 1972 patients (812 men and 1160 women) undergoing a dipyridamole stress testing were recruited. Medical history, CVD risk factors, health behaviours, psychological status, and gender identity were assessed via structured interview or self-report questionnaires at baseline. In addition, FHR was assessed, as well as levels of sex hormones via blood draw. Patients will be followed for 5 years to assess major CVD events (cardiac mortality, non-fatal MI, revascularization procedures, and cerebrovascular events). Discussion This is the first study to determine the extent and nature of any sex differences in the ability of endothelial function to predict CVD events. We believe the results of this study will provide data that will better inform the choice of diagnostic tests in men and women and bring the quality of risk stratification in

  2. The relationship between white matter abnormalities and cognitive functions in new-onset juvenile myoclonic epilepsy.

    PubMed

    Ekmekci, Burcu; Bulut, Hacı Taner; Gümüştaş, Funda; Yıldırım, Adem; Kuştepe, Ali

    2016-09-01

    Diffusion tensor imaging (DTI) has revealed evidence of subcortical white matter abnormalities in the frontal area in juvenile myoclonic epilepsy (JME). Decreased fractional anisotropy (FA) and increased mean diffusivity (MD) in the corticothalamic pathway have been detected in adult patients with JME. It has been demonstrated that, in adult patients with JME, frontal dysfunction is related to subcortical white matter damage and decreased volume in frontal cortical gray matter and the thalamus. Many studies have focused on adult patients. Twenty-four patients and 28 controls were evaluated. The group with JME had significantly worse results for the word fluency, trail-B, and Stroop tests that assessed executive functions. A significant decrease in FA values in the dorsolateral prefrontal cortex (DLPFC), the supplementary motor area (SMA), the right thalamus, the posterior cingulate, the corpus callosum anterior, the corona radiata, and the middle frontal white matter (MFWM) and an increase in ADC values in patients with JME were detected. The correlation between FA values in DLPFC and the letter fluency test results was positive, and the correlation with the Stroop and trail-B test results was negative. We found a negative correlation between SMA, anterior thalamus, and MFWM FA values and the trail-B test results and a positive correlation between the SMA, anterior thalamus, and MFWM FA values and the letter fluency test results. We detected white matter and gray matter abnormalities in patients with new-onset JME using DTI. In addition, we determined the relationship between cognitive deficit and microstructural abnormalities by evaluating the correlation between the neuropsychological test battery results and DTI parameters. We evaluated newly diagnosed patients with JME in our study. That leads us to believe that microstructural abnormalities exist from the very beginning of the disease and that they result from the genetic basis of the disease.

  3. Abnormal function of the corpus luteum in some ewes with phyto-oestrogenic infertility.

    PubMed

    Adams, N R; Hearnshaw, H; Oldham, C M

    1981-01-01

    Ewes with permanent phyto-estrogenic infertility show oestrus less regularly than normal ewes, and the present study examines the extent to which this results from abnormal ovarian function. Forty-nine affected ewes and 53 controls were run with rams fitted with marking crayons and harnesses, and crayon marks were recorded and laparoscopy performed at weekly intervals for 3 weeks. Fewer affected ewes showed oestrus accompanied by ovulation (28 v. 49, P less than 0.001), and four of these affected ewes had a second ovulation during the experiment. More of the ovulations observed in affected ewes were unaccompanied by behavioural oestrus than in controls (8 out of 38 v. 2 out of 50; P less than 0.05). Six affected ewes had no corpus luteum or oestrus, and five of these had adhesions over the genitalia. Hydrops uteri in five other affected ewes was accompanied by prolonged maintenance of the corpus luteum. Some other abnormalities were also observed. In a second study, plasma progesterone concentrations were measured twice daily in 12 affected ewes which were run with rams. Five ewes had oestrous cycles of abnormal duration (two of more than 23 days, two of 21 days, and one of 11 days), and these were accompanied by plasma progesterone patterns different from those of the ewes with an oestrous cycle duration of 16-18 days. It is concluded that the irregular oestrous cycles in affected ewes are due mainly to abnormal life span and progesterone secretion by the corpus luteum, which in turn largely result from changes in the uterus. PMID:7196218

  4. Coffee polyphenols improve peripheral endothelial function after glucose loading in healthy male adults.

    PubMed

    Ochiai, Ryuji; Sugiura, Yoko; Shioya, Yasushi; Otsuka, Kazuhiro; Katsuragi, Yoshihisa; Hashiguchi, Teruto

    2014-02-01

    Brewed coffee is a widely consumed beverage, and many studies have examined its effects on human health. We investigated the vascular effects of coffee polyphenols (CPPs), hypothesizing that a single ingestion of CPP during glucose loading would improve endothelial function. To test this hypothesis, we conducted a randomized acute clinical intervention study with crossover design and measured reactive hyperemia index (RHI) to assess the acute effects of a 75-g glucose load with CPP in healthy, nondiabetic adult men. Blood glucose and insulin levels were elevated after glucose loading with and without CPP, with no significant differences between treatments. The RHI did not significantly decrease after glucose loading without CPP. With CPP, however, RHI significantly (P < .05) increased over baseline after glucose loading. The difference between treatments was statistically significant (P < .05). No significant changes were observed in an oxidative stress marker after glucose loading with or without CPP. These findings suggest that a single ingestion of CPP improves peripheral endothelial function after glucose loading in healthy subjects.

  5. Effects of Exercise Intensity on Postexercise Endothelial Function and Oxidative Stress

    PubMed Central

    McClean, Conor; Harris, Ryan A.; Brown, Malcolm; Brown, John C.; Davison, Gareth W.

    2015-01-01

    Purpose. To measure endothelial function and oxidative stress immediately, 90 minutes, and three hours after exercise of varying intensities. Methods. Sixteen apparently healthy men completed three exercise bouts of treadmill running for 30 minutes at 55% V˙O2max (mild); 20 minutes at 75% V˙O2max (moderate); or 5 minutes at 100% V˙O2max (maximal) in random order. Brachial artery flow-mediated dilation (FMD) was assessed with venous blood samples drawn for measurement of endothelin-1 (ET-1), lipid hydroperoxides (LOOHs), and lipid soluble antioxidants. Results. LOOH increased immediately following moderate exercise (P < 0.05). ET-1 was higher immediately after exercise and 3 hours after exercise in the mild trial compared to maximal one (P < 0.05). Transient decreases were detected for ΔFMD/ShearAUC from baseline following maximal exercise, but it normalised at 3 hours after exercise (P < 0.05). Shear rate was higher immediately after exercise in the maximal trial compared to mild exercise (P < 0.05). No changes in baseline diameter, peak diameter, absolute change in diameter, or FMD were observed following any of the exercise trials (P > 0.05). Conclusions. Acute exercise at different intensities elicits varied effects on oxidative stress, shear rate, and ET-1 that do not appear to mediate changes in endothelial function measured by FMD. PMID:26583061

  6. AMP-ACTIVATED PROTEIN KINASE ACTIVATION AS A STRATEGY FOR PROTECTING VASCULAR ENDOTHELIAL FUNCTION

    PubMed Central

    Zou, Ming-Hui; Wu, Yong

    2010-01-01

    SUMMARY 1. AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase involved in the regulation of cellular and organismal metabolism. AMPK has a heterotrimeric structure, consisting of a catalytic α-subunit and regulatory β- and γ-subunits, each of which has two or more isoforms that are differentially expressed in various tissues and that arise from distinct genes. The AMPK system acts as a sensor of cellular energy status that is conserved in all eukaryotic cells. In addition, AMPK is activated by physiological stimuli and oxidants. 2. The importance of AMPK in cardiovascular functions is best demonstrated by recent studies showing that widely used drugs, including statins, metformin and rosiglitazone, execute cardiovascular protective effects at least partly through the activation of AMPK. As a consequence, AMPK has been proposed as a candidate target for therapeutic intervention in the treatment of both Type 2 diabetes and metabolic syndrome owing to its central role in the regulation of energy balance; it may also have a role in weight control. 3. In the present brief review, we summarize the recent progress of AMPK signalling and regulation focusing on vascular endothelial cells. We further hypothesize that AMPK is a dual sensor for energy and redox status within a cell and AMPK may be a therapeutic target for protecting vascular endothelial function. PMID:18177481

  7. Immortalized functional endothelial progenitor cell lines from umbilical cord blood for vascular tissue engineering.

    PubMed

    Sobhan, Praveen K; Seervi, Mahendra; Joseph, Jeena; Varghese, Saneesh; Pillai, Prakash Rajappan; Sivaraman, Divya Mundackal; James, Jackson; George, Roshin Elizabeth; Elizabeth, K E; Santhoshkumar, T R; Pillai, M Radhakrishna

    2012-11-01

    Endothelial progenitor cells (EPCs) play a significant role in multiple biological processes such as vascular homeostasis, regeneration, and tumor angiogenesis. This makes them a promising cell of choice for studying a variety of biological processes, toxicity assays, biomaterial-cell interaction studies, as well as in tissue-engineering applications. In this study, we report the generation of two clones of SV40-immortalized EPCs from umbilical cord blood. These cells retained most of the functional features of mature endothelial cells and showed no indication of senescence after repeated culture for more than 240 days. Extensive functional characterization of the immortalized cells by western blot, flow cytometry, and immunofluorescence studies substantiated that these cells retained their ability to synthesize nitric oxide, von Willebrand factor, P-Selectin etc. These cells achieved unlimited proliferation potential subsequent to inactivation of the cyclin-dependent kinase inhibitor p21, but failed to form colonies on soft agar. We also show their enhanced growth and survival on vascular biomaterials compared to parental cultures in late population doubling. These immortalized EPCs can be used as a cellular model system for studying the biology of these cells, gene manipulation experiments, cell-biomaterial interactions, as well as a variety of tissue-engineering applications.

  8. Characterization of endothelial function in the brachial artery via affine registration of ultrasonographic image sequences

    NASA Astrophysics Data System (ADS)

    Lamata, Pablo; Laclaustra, Martin; Frangi, Alejandro F.

    2003-05-01

    The assessment and characterization of the endothelial function is a current research topic as it may play an important role in the diagnosis of cardiovascular diseases. Flow mediated dilatation may be used to investigate endothelial function, and B-mode ultrasonography is a cheap and non-invasive way to assess the vasodilation response. Computerized analysis techniques are very desirable to give higher accuracy and objectivity to the measurements. A new method is presented that solves some limitations of existing methods, which in general depend on accurate edge detection of the arterial wall. This method is based on a global image analysis strategy. The arterial vasodilation between two frames is modeled by a superposition of a rigid motion model and a stretching perpendicular to the artery. Both transformation models are recovered using an image registration algorithm based on normalized mutual information and a multi-resolution search framework. Temporal continuity of in the variation of the registration parameters is enforced with a Kalman filter, since the dilation process is known to be a gradual and continuous physiological phenomenon. The proposed method presents a negligible bias when compared with manual assessment. It also eliminates artifacts introduced by patient and probe motion, thus improving the accuracy of the measurements. Finally, it is also robust to typical problems of ultrasound, like speckle noise and poor image quality.

  9. The effect of liraglutide on endothelial function in patients with type 2 diabetes.

    PubMed

    Nandy, Debashis; Johnson, Christopher; Basu, Rita; Joyner, Michael; Brett, Jason; Svendsen, Claus Bo; Basu, Ananda

    2014-11-01

    This single-centre, 12-week, double-blind, placebo-controlled trial assessed how the human glucagon-like-peptide 1 analogue liraglutide impacted endothelial function in adult patients (n = 49) with type 2 diabetes and no overt cardiovascular disease. Patients were randomized to liraglutide, placebo or glimepiride. At baseline and Week 12, venous occlusion plethysmography was used to measure forearm blood flow (FBF) in response to acetylcholine (ACh) and sodium nitroprusside (SNP) before and after (L)-N(G)-monomethyl arginine (L-NMMA) infusion. At Week 12, ACh-mediated FBF increased with liraglutide and decreased with placebo; however, the between-treatment difference was not significant (p = 0.055). Inhibition of ACh-mediated FBF after L-NMMA infusion increased with liraglutide and decreased with placebo; this between-treatment difference was also not significant (p = 0.149). No change in FBF was observed with SNP. Liraglutide did not significantly impact endothelium-dependent vasodilation after 12 weeks; however, additional investigations looking at the effect of liraglutide on endothelial function in alternative vasculature and during the postprandial period are warranted. PMID:25212693

  10. Immortalized Functional Endothelial Progenitor Cell Lines from Umbilical Cord Blood for Vascular Tissue Engineering

    PubMed Central

    Sobhan, Praveen K.; Seervi, Mahendra; Joseph, Jeena; Varghese, Saneesh; Pillai, Prakash Rajappan; Sivaraman, Divya Mundackal; James, Jackson; George, Roshin Elizabeth; Elizabeth, K.E.; Pillai, M. Radhakrishna

    2012-01-01

    Endothelial progenitor cells (EPCs) play a significant role in multiple biological processes such as vascular homeostasis, regeneration, and tumor angiogenesis. This makes them a promising cell of choice for studying a variety of biological processes, toxicity assays, biomaterial–cell interaction studies, as well as in tissue-engineering applications. In this study, we report the generation of two clones of SV40-immortalized EPCs from umbilical cord blood. These cells retained most of the functional features of mature endothelial cells and showed no indication of senescence after repeated culture for more than 240 days. Extensive functional characterization of the immortalized cells by western blot, flow cytometry, and immunofluorescence studies substantiated that these cells retained their ability to synthesize nitric oxide, von Willebrand factor, P-Selectin etc. These cells achieved unlimited proliferation potential subsequent to inactivation of the cyclin-dependent kinase inhibitor p21, but failed to form colonies on soft agar. We also show their enhanced growth and survival on vascular biomaterials compared to parental cultures in late population doubling. These immortalized EPCs can be used as a cellular model system for studying the biology of these cells, gene manipulation experiments, cell–biomaterial interactions, as well as a variety of tissue-engineering applications. PMID:22889128

  11. Effect of repeated sprints on postprandial endothelial function and triacylglycerol concentrations in adolescent boys.

    PubMed

    Sedgwick, Matthew J; Morris, John G; Nevill, Mary E; Barrett, Laura A

    2015-01-01

    This study investigated whether repeated, very short duration sprints influenced endothelial function (indicated by flow-mediated dilation) and triacylglycerol concentrations following the ingestion of high-fat meals in adolescent boys. Nine adolescent boys completed two, 2-day main trials (control and exercise), in a counter-balanced, cross-over design. Participants were inactive on day 1 of the control trial but completed 40 × 6 s maximal cycle sprints on day 1 of the exercise trial. On day 2, capillary blood samples were collected and flow-mediated dilation measured prior to, and following, ingestion of a high-fat breakfast and lunch. Fasting flow-mediated dilation and plasma triacylglycerol concentration were similar in the control and exercise trial (P > 0.05). In the control trial, flow-mediated dilation was reduced by 20% and 27% following the high-fat breakfast and lunch; following exercise these reductions were negated (main effect trial, P < 0.05; interaction effect trial × time, P < 0.05). The total area under the plasma triacylglycerol concentration versus time curve was 13% lower on day 2 in the exercise trial compared to the control trial (8.65 (0.97) vs. 9.92 (1.16) mmol · l(-1) · 6.5 h, P < 0.05). These results demonstrate that repeated 6 s maximal cycle sprints can have beneficial effects on postprandial endothelial function and triacylglycerol concentrations in adolescent boys.

  12. Functional changes are associated with tracheal structural abnormalities in patients with acromegaly

    PubMed Central

    Camilo, Gustavo Bittencourt; Guimarães, Fernando Silva; Mogami, Roberto; Faria, Alvaro Camilo Dias; Melo, Pedro Lopes

    2016-01-01

    Introduction Although impaired pulmonary function and respiratory sleep disorders are described as responsible for increased mortality in acromegalic patients, little is known about the tracheal abnormalities in this group of patients. Thus, the objectives of this study were to describe the tracheal structural abnormalities and correlate these changes with the respiratory function and clinical data of acromegalic patients. Material and methods This is a cross-sectional study that was carried out at two university hospitals. Twenty acromegalic patients underwent spirometry, forced oscillation technique, and computed tomography (CT) assessments. Dyspnea and daytime sleepiness were assessed using the Modified Medical Research Council (MMRC) scale and the Epworth Sleepiness Scale (ESS), respectively. Forty matched subjects served as controls. Results The acromegalic patients exhibited larger median ratios between forced expiratory flow and forced inspiratory flow at 50% of the forced vital capacity (FEF50%/FIF50%) (2.05 vs. 1.06, p = 0.0001) compared with healthy volunteers. In the CT analysis, acromegalic patients exhibited larger median differences between their cervical and thoracic tracheal diameters (Δ tracheal diameters) (3 vs. 1 mm; p = 0.003). An association was found between FEF50%/FIF50% and the following variables: mean resistance (Rm), cervical tracheal diameter, and Δ tracheal diameters. Rm also exhibited a negative correlation with cervical tracheal diameter. Neither the MMRC scale nor the ESS exhibited any significant correlation with large airway obstruction (LAO) indices or with the measured tracheal diameters. Conclusions Acromegalic patients have tracheal structural abnormalities which are associated with functional indicators of LAO but not with clinical data. PMID:26925121

  13. Sparstolonin B Inhibits Pro-Angiogenic Functions and Blocks Cell Cycle Progression in Endothelial Cells

    PubMed Central

    Bateman, Henry R.; Liang, Qiaoli; Fan, Daping; Rodriguez, Vanessa; Lessner, Susan M.

    2013-01-01

    Sparstolonin B (SsnB) is a novel bioactive compound isolated from Sparganium stoloniferum, an herb historically used in Traditional Chinese Medicine as an anti-tumor agent. Angiogenesis, the process of new capillary formation from existing blood vessels, is dysregulated in many pathological disorders, including diabetic retinopathy, tumor growth, and atherosclerosis. In functional assays, SsnB inhibited endothelial cell tube formation (Matrigel method) and cell migration (Transwell method) in a dose-dependent manner. Microarray experiments with human umbilical vein endothelial cells (HUVECs) and human coronary artery endothelial cells (HCAECs) demonstrated differential expression of several hundred genes in response to SsnB exposure (916 and 356 genes, respectively, with fold change ≥2, p<0.05, unpaired t-test). Microarray data from both cell types showed significant overlap, including genes associated with cell proliferation and cell cycle. Flow cytometric cell cycle analysis of HUVECs treated with SsnB showed an increase of cells in the G1 phase and a decrease of cells in the S phase. Cyclin E2 (CCNE2) and Cell division cycle 6 (CDC6) are regulatory proteins that control cell cycle progression through the G1/S checkpoint. Both CCNE2 and CDC6 were downregulated in the microarray data. Real Time quantitative PCR confirmed that gene expression of CCNE2 and CDC6 in HUVECs was downregulated after SsnB exposure, to 64% and 35% of controls, respectively. The data suggest that SsnB may exert its anti-angiogenic properties in part by downregulating CCNE2 and CDC6, halting progression through the G1/S checkpoint. In the chick chorioallantoic membrane (CAM) assay, SsnB caused significant reduction in capillary length and branching number relative to the vehicle control group. Overall, SsnB caused a significant reduction in angiogenesis (ANOVA, p<0.05), demonstrating its ex vivo efficacy. PMID:23940584

  14. Abnormal functional architecture of amygdala-centered networks in adolescent posttraumatic stress disorder.

    PubMed

    Aghajani, Moji; Veer, Ilya M; van Hoof, Marie-José; Rombouts, Serge A R B; van der Wee, Nic J; Vermeiren, Robert R J M

    2016-03-01

    Posttraumatic stress disorder (PTSD) is a prevalent, debilitating, and difficult to treat psychiatric disorder. Very little is known of how PTSD affects neuroplasticity in the developing adolescent brain. Whereas multiple lines of research implicate amygdala-centered network dysfunction in the pathophysiology of adult PTSD, no study has yet examined the functional architecture of amygdala subregional networks in adolescent PTSD. Using intrinsic functional connectivity analysis, we investigated functional connectivity of the basolateral (BLA) and centromedial (CMA) amygdala in 19 sexually abused adolescents with PTSD relative to 23 matched controls. Additionally, we examined whether altered amygdala subregional connectivity coincides with abnormal grey matter volume of the amygdaloid complex. Our analysis revealed abnormal amygdalar connectivity and morphology in adolescent PTSD patients. More specifically, PTSD patients showed diminished right BLA connectivity with a cluster including dorsal and ventral portions of the anterior cingulate and medial prefrontal cortices (p < 0.05, corrected). In contrast, PTSD patients showed increased left CMA connectivity with a cluster including the orbitofrontal and subcallosal cortices (p < 0.05, corrected). Critically, these connectivity changes coincided with diminished grey matter volume within BLA and CMA subnuclei (p < 0.05, corrected), with CMA connectivity shifts additionally relating to more severe symptoms of PTSD. These findings provide unique insights into how perturbations in major amygdalar circuits could hamper fear regulation and drive excessive acquisition and expression of fear in PTSD. As such, they represent an important step toward characterizing the neurocircuitry of adolescent PTSD, thereby informing the development of reliable biomarkers and potential therapeutic targets.

  15. Selective functional connectivity abnormality of the transition zone of the inferior parietal lobule in schizophrenia.

    PubMed

    Liu, Xingyun; Zhuo, Chuanjun; Qin, Wen; Zhu, Jiajia; Xu, Lixue; Xu, Yongjie; Yu, Chunshui

    2016-01-01

    Structural and functional alterations in the inferior parietal lobule (IPL) in schizophrenia have been frequently reported; however, the IPL connectivity changes in schizophrenia remain largely unknown. Based on heterogeneity of the IPL in structure, connection and function, we hypothesize that the resting-state functional connectivities (rsFCs) of the IPL subregions are differentially affected in schizophrenia. This study included 95 schizophrenia patients and 104 healthy controls. The IPL subregions were defined according to a previous in vivo connection-based parcellation study. We calculated the rsFC of each IPL subregion and compared them between the two groups while controlling for the effects of age, gender, and grey matter volume. Among the six subregions of the left IPL and the five subregions of the right IPL, only the bilateral PFm (a transition zone of the IPL) subregions exhibited abnormal rsFC in schizophrenia. Specifically, the left PFm showed increased rsFC with the bilateral lingual gyri in schizophrenia patients than in healthy controls. The right PFm exhibited increased rsFC with the right lingual gyrus and inferior occipital gyrus, and bilateral mid-cingulate and sensorimotor cortices in schizophrenia patients. These findings suggest a selective rsFC abnormality in the IPL subregions in schizophrenia, characterized by the increased rsFC between the PFm subregion of the IPL and the visual and sensorimotor areas. PMID:27354957

  16. Circadian Variability of Fibrinolytic Markers and Endothelial Function in Patients with Obstructive Sleep Apnea

    PubMed Central

    Bagai, Kanika; Muldowney, James A. S.; Song, Yanna; Wang, Lily; Bagai, Jayant; Artibee, Kay J.; Vaughan, Douglas E.; Malow, Beth A.

    2014-01-01

    Study Objectives: Obstructive sleep apnea (OSA) is strongly associated with cardiovascular disease, including stroke and acute coronary syndromes. Plasminogen activator inhibitor-1 (PAI-1), the principal inhibitor of tissue-type plasminogen activator (t-PA), has a pronounced circadian rhythm and is elevated in both OSA and cardiovascular disease and may be an important link between the two conditions. Endothelial dysfunction is one of the underlying pathophysiological mechanisms of cardiovascular disease, and may be altered in OSA. Our primary aim was to compare circadian variability of PAI-1 and t-PA in patients with OSA and normal controls by determining the amplitude (peak level) and mesor (rhythm adjusted mean) of PAI-1 and t-PA in serial blood samples over a 24-h period. The secondary aim was to measure markers of endothelial function (brachial and radial artery flow) in patients with OSA compared with normal controls. Setting: Cross-sectional cohort study. Patients or Participants: Subjects age 18 y or older, with a body mass index of 25-45 kg/m2, with or without evidence of untreated OSA. Interventions: Plasma samples were collected every 2 h, in OSA patients and matched controls, over a 24-h period. PAI-1 and t-PA antigen and activity were measured. The presence or absence of OSA (apnea-hypopnea index of 5 or greater) was confirmed by overnight polysomnography. Endothelial function was measured via brachial artery flow mediated vasodilatation and computerized arterial pulse waveform analysis. Measurements and Results: The rhythm-adjusted mean levels of PAI-1 antigen levels in the OSA group (21.8 ng/mL, 95% confidence level [CI], 18 to 25.7) were significantly higher as compared to the non-OSA group (16 ng/mL, 95% CI, 12.2 to 19.8; P = 0.03). The rhythm-adjusted mean levels of PAI-1 activity levels in the OSA group (23.9 IU/mL, 95% CI, 21.4 to 26.5) were also significantly higher than in the non-OSA group (17.2 IU/ mL, 95% CI, 14.6 to 19.9; P < 0.001).There

  17. A Novel Molecular and Functional Stemness Signature Assessing Human Cord Blood-Derived Endothelial Progenitor Cell Immaturity

    PubMed Central

    Pascaud, Juliette; Driancourt, Catherine; Boyer-Di-Ponio, Julie; Uzan, Georges

    2016-01-01

    Endothelial Colony Forming Cells (ECFCs), a distinct population of Endothelial Progenitor Cells (EPCs) progeny, display phenotypic and functional characteristics of endothelial cells while retaining features of stem/progenitor cells. Cord blood-derived ECFCs (CB-ECFCs) have a high clonogenic and proliferative potentials and they can acquire different endothelial phenotypes, this requiring some plasticity. These properties provide angiogenic and vascular repair capabilities to CB-ECFCs for ischemic cell therapies. However, the degree of immaturity retained by EPCs is still confused and poorly defined. Consequently, to better characterize CB-ECFC stemness, we quantified their clonogenic potential and demonstrated that they were reprogrammed into induced pluripotent stem cells (iPSCs) more efficiently and rapidly than adult endothelial cells. Moreover, we analyzed the transcriptional profile of a broad gene panel known to be related to stem cells. We showed that, unlike mature endothelial cells, CB-ECFCs expressed genes involved in the maintenance of embryonic stem cell properties such as DNMT3B, GDF3 or SOX2. Thus, these results provide further evidence and tools to appreciate EPC-derived cell stemness. Moreover this novel stem cell transcriptional signature of ECFCs could help better characterizing and ranging EPCs according to their immaturity profile. PMID:27043207

  18. Abnormalities of functional brain networks in pathological gambling: a graph-theoretical approach

    PubMed Central

    Tschernegg, Melanie; Crone, Julia S.; Eigenberger, Tina; Schwartenbeck, Philipp; Fauth-Bühler, Mira; Lemènager, Tagrid; Mann, Karl; Thon, Natasha; Wurst, Friedrich M.; Kronbichler, Martin

    2013-01-01

    Functional neuroimaging studies of pathological gambling (PG) demonstrate alterations in frontal and subcortical regions of the mesolimbic reward system. However, most investigations were performed using tasks involving reward processing or executive functions. Little is known about brain network abnormalities during task-free resting state in PG. In the present study, graph-theoretical methods were used to investigate network properties of resting state functional magnetic resonance imaging data in PG. We compared 19 patients with PG to 19 healthy controls (HCs) using the Graph Analysis Toolbox (GAT). None of the examined global metrics differed between groups. At the nodal level, pathological gambler showed a reduced clustering coefficient in the left paracingulate cortex and the left juxtapositional lobe (supplementary motor area, SMA), reduced local efficiency in the left SMA, as well as an increased node betweenness for the left and right paracingulate cortex and the left SMA. At an uncorrected threshold level, the node betweenness in the left inferior frontal gyrus was decreased and increased in the caudate. Additionally, increased functional connectivity between fronto-striatal regions and within frontal regions has also been found for the gambling patients. These findings suggest that regions associated with the reward system demonstrate reduced segregation but enhanced integration while regions associated with executive functions demonstrate reduced integration. The present study makes evident that PG is also associated with abnormalities in the topological network structure of the brain during rest. Since alterations in PG cannot be explained by direct effects of abused substances on the brain, these findings will be of relevance for understanding functional connectivity in other addictive disorders. PMID:24098282

  19. Reduced endothelial function in the skin in Southeast Asians compared to Caucasians

    PubMed Central

    Petrofsky, Jerrold Sott; Alshammari, Faris; Lee, Haneul; Hamdan, Adel; Yim, Jong Eun; Shetye, Gauri; Neupane, Sushma; Somanaboina, Karunakar; Pathak, Kunal; Shenoy, Samruddha; Dave, Bhargav; Cho, Sungkwan; Chen, Wei-Ti; Nevgi, Bhakti; Moniz, Harold; Alshaharani, Mastour; Malthane, Swapnil; Desai, Rajavi

    2012-01-01

    Summary Background The reaction of vascular endothelial cells to occlusion and heat in Southeast Asian Indians (SAI) compared to Caucasians (C) has not been studied, although genetic differences are found in endothelial cells between the races. Material/Methods Ten C and Ten SAI (<35 years old) male and female subjects participated. There was no difference in the demographics of the subjects except that the SAI group had been in the United States for 6 months; C was natives to the US. Endothelial function was assessed by the response of the circulation (BF) to local heating and the response to vascular occlusion. The effects of local heat on circulation in the skin on the forearm was assessed by applying heat for 6 minutes at temperatures, 38, 40 and 42°C on 3 separate days. On different days, vascular occlusion was applied for 4 minutes to the same arm and skin blood flow was measured for 2 minutes after occlusion; skin temperature was either 31°C or 42°C. Results When occlusion was applied at a skin temperature of 31°C, the BF response to occlusion was significantly lower in the SAI cohort compared to C (peak BF C=617±88.2 flux, SAE=284±73 flux). The same effect was seen at skin temperatures of 42°C. The circulatory response to heat was also significantly less in SAI compared to C at each temperature examined (p<0.05)(for temperatures of 38, 40 and 42°C, peak blood flow for C was 374.7±81.2, 551.9±91.3 and 725.9±107 flux respectively and 248.5±86.2, 361.4±104.3 and 455.3±109.7 flux respectively for SAI. (p<0.05). Conclusions Thus there seems to be big differences in these 2 populations in endothelial response to these stressors. The difference may be due to genetic variations between the 2 groups of subjects. PMID:22207113

  20. Tetrahydrobiopterin improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women

    PubMed Central

    Meditz, Amie; Deane, Kevin D.; Kohrt, Wendy M.

    2012-01-01

    The mechanisms mediating arterial stiffening with aging and menopause are not completely understood. We determined whether administration of tetrahydrobiopterin (BH4), a critical cofactor for endothelial nitric oxide synthase to produce nitric oxide, would increase vascular endothelial-dependent vasodilatory tone and decrease arterial stiffness in estrogen-deficient postmenopausal women. Additionally, we examined whether the beneficial effects of estrogen on vascular function were possibly related to BH4. Arterial stiffness (carotid artery compliance) and endothelial-dependent vasodilation [brachial artery flow-mediated dilation (FMD)] were measured in postmenopausal (n = 24; 57 ± 1 yr, mean ± SE) and eumenorrheic premenopausal (n = 9; 33 ± 2 yr) women before and 3 h after the oral administration of BH4. Subsequently, in postmenopausal women, vascular testing (before and after BH4) was repeated following randomization to either 2 days of transdermal estradiol or placebo. Baseline carotid artery compliance and brachial artery FMD were lower in postmenopausal than in premenopausal women (P < 0.0001). BH4 administration increased carotid artery compliance (0.61 ± 0.05 to 0.73 ± 0.04 mm2·mmHg−1·10−1 vs. baseline, P < 0.0001) and brachial artery FMD (P < 0.001) in postmenopausal women but had no effect in premenopausal women (P = 0.62). Carotid artery compliance (0.59 ± 0.05 to 0.78 ± 0.06 mm2·mmHg−1·10−1, P < 0.001) and FMD increased in postmenopausal women in response to estradiol (P = 0.02) but were not further improved with the coadministration of BH4, possibly because estrogen increased BH4 bioavailability. Carotid artery compliance and FMD increased with BH4 in the placebo group (P = 0.02). Although speculative, these results suggest that reduced vascular BH4 may be an important contributor to arterial stiffening in estrogen-deficient postmenopausal women, related in part to reduced endothelial-dependent vasodilatory tone. PMID:22245769

  1. The role of endothelial cells on islet function and revascularization after islet transplantation

    PubMed Central

    Del Toro-Arreola, Alicia; Robles-Murillo, Ana Karina; Daneri-Navarro, Adrian; Rivas-Carrillo, Jorge David

    2016-01-01

    ABSTRACT Islet transplantation has become a widely accepted therapeutic option for selected patients with type 1 diabetes mellitus. However, in order to achieve insulin independence a great number of islets are often pooled from 2 to 4 pancreata donors. Mostly, it is due to the massive loss of islets immediately after transplant. The endothelium plays a key role in the function of native islets and during the revascularization process after islet transplantation. However, if a delayed revascularization occurs, even the remaining islets will also undergo to cell death and late graft dysfunction. Therefore, it is essential to understand how the signals are released from endothelial cells, which might regulate both differentiation of pancreatic progenitors and thereby maintenance of the graft function. New strategies to facilitate islet engraftment and a prompt revascularization could be designed to intervene and might lead to improve future results of islet transplantation. PMID:27002241

  2. Structural and functional brain abnormalities place phenocopy frontotemporal dementia (FTD) in the FTD spectrum

    PubMed Central

    Steketee, Rebecca M.E.; Meijboom, Rozanna; Bron, Esther E.; Osse, Robert Jan; de Koning, Inge; Jiskoot, Lize C.; Klein, Stefan; de Jong, Frank Jan; van der Lugt, Aad; van Swieten, John C.; Smits, Marion

    2016-01-01

    Purpose ‘Phenocopy’ frontotemporal dementia (phFTD) patients may clinically mimic the behavioral variant of FTD (bvFTD), but do not show functional decline or abnormalities upon visual inspection of routine neuroimaging. We aimed to identify abnormalities in gray matter (GM) volume and perfusion in phFTD and to assess whether phFTD belongs to the FTD spectrum. We compared phFTD patients with both healthy controls and bvFTD patients. Materials & methods Seven phFTD and 11 bvFTD patients, and 20 age-matched controls underwent structural T1-weighted magnetic resonance imaging (MRI) and 3D pseudo-continuous arterial spin labeling (pCASL) at 3T. Normalized GM (nGM) volumes and perfusion, corrected for partial volume effects, were quantified regionally as well as in the entire supratentorial cortex, and compared between groups taking into account potential confounding effects of gender and scanner. Results PhFTD patients showed cortical atrophy, most prominently in the right temporal lobe. Apart from this regional atrophy, GM volume was generally not different from either controls or from bvFTD. BvFTD however showed extensive frontotemporal atrophy. Perfusion was increased in the left prefrontal cortex compared to bvFTD and to a lesser extent to controls. Conclusion PhFTD and bvFTD show overlapping cortical structural abnormalities indicating a continuum of changes especially in the frontotemporal regions. Together with functional changes suggestive of a compensatory response to incipient pathology in the left prefrontal regions, these findings are the first to support a possible neuropathological etiology of phFTD and suggest that phFTD may be a neurodegenerative disease on the FTD spectrum. PMID:27222795

  3. Acute effects of different types of oil consumption on endothelial function, oxidative stress status and vascular inflammation in healthy volunteers.

    PubMed

    Tousoulis, Dimitris; Papageorgiou, Nikolaos; Antoniades, Charalambos; Giolis, Anastasios; Bouras, George; Gounari, Panagiota; Stefanadi, Elli; Miliou, Antigoni; Psaltopoulou, Theodora; Stefanadis, Christodoulos

    2010-01-01

    Consumption of different types of oil may have different effects on cardiovascular risk. The exact role of maize oil, cod liver oil, soya oil and extra virgin olive oil on endothelial function, oxidative stress and inflammation is unknown. We evaluated the effect of acute consumption of these types of oil on endothelial function, oxidative stress and inflammation in healthy adults. Thirty-seven healthy volunteers were randomised to receive an oral amount of each type of oil or water. Endothelial function was evaluated by gauge-strain plethysmography at baseline and 1, 2 and 3 h after consumption. Oxidative stress status was determined by total lipid peroxides (PEROX), while inflammatory process was estimated by measuring the soluble form of vascular adhesion molecule 1. Serum levels of the two previous markers were measured at baseline and 3 h after oil consumption. Reactive hyperaemia (RH) was significantly decreased after maize oil consumption compared with controls (P < 0.05). However, the consumption of cod liver oil and soya oil induced a significant improvement of RH after 1 h, compared with controls (P < 0.05). There was no significant effect of any type of oil consumption on endothelium-independent dilatation, total lipid PEROX and vascular adhesion molecule 1 serum levels. Consumption of maize oil leads to impaired endothelial function, while soya oil and cod liver oil slightly improve endothelial function. However, all types of oils did not affect inflammatory process and systemic oxidative stress, suggesting that their effect on endothelial function may not be mediated by free radicals bioavailability.

  4. Interactions between cocoa flavanols and inorganic nitrate: additive effects on endothelial function at achievable dietary amounts.

    PubMed

    Rodriguez-Mateos, Ana; Hezel, Michael; Aydin, Hilal; Kelm, Malte; Lundberg, Jon O; Weitzberg, Eddie; Spencer, Jeremy P E; Heiss, Christian

    2015-03-01

    Dietary intervention studies have shown that flavanols and inorganic nitrate can improve vascular function, suggesting that these two bioactives may be responsible for beneficial health effects of diets rich in fruits and vegetables. We aimed to study interactions between cocoa flavanols (CF) and nitrate, focusing on absorption, bioavailability, excretion, and efficacy to increase endothelial function. In a double-blind randomized, dose-response crossover study, flow-mediated dilation (FMD) was measured in 15 healthy subjects before and at 1, 2, 3, and 4 h after consumption of CF (1.4-10.9 mg/kg bw) or nitrate (0.1-10 mg/kg bw). To study flavanol-nitrate interactions, an additional intervention trial was performed with nitrate and CF taken in sequence at low and high amounts. FMD was measured before (0 h) and at 1h after ingestion of nitrate (3 or 8.5 mg/kg bw) or water. Then subjects received a CF drink (2.7 or 10.9 mg/kg bw) or a micro- and macronutrient-matched CF-free drink. FMD was measured at 1, 2, and 4 h thereafter. Blood and urine samples were collected and assessed for CF and nitric oxide (NO) metabolites with HPLC and gas-phase reductive chemiluminescence. Finally, intragastric formation of NO after CF and nitrate consumption was investigated. Both CF and nitrate induced similar intake-dependent increases in FMD. Maximal values were achieved at 1 h postingestion and gradually decreased to reach baseline values at 4 h. These effects were additive at low intake levels, whereas CF did not further increase FMD after high nitrate intake. Nitrate did not affect flavanol absorption, bioavailability, or excretion, but CF enhanced nitrate-related gastric NO formation and attenuated the increase in plasma nitrite after nitrate intake. Both flavanols and inorganic nitrate can improve endothelial function in healthy subjects at intake amounts that are achievable with a normal diet. Even low dietary intake of these bioactives may exert relevant effects on endothelial

  5. Comparison of Morphological and Functional Endothelial Cell Changes after Cataract Surgery: Phacoemulsification Versus Manual Small-Incision Cataract Surgery

    PubMed Central

    Ganekal, Sunil; Nagarajappa, Ashwini

    2014-01-01

    Purpose: To compare the morphological (cell density, coefficient of variation and standard deviation) and functional (central corneal thickness) endothelial changes after phacoemulsification versus manual small-incision cataract surgery (MSICS). Design: Prospective randomized control study. Materials and Methods: In this prospective randomized control study, patients were randomly allocated to undergo phacoemulsification (Group 1, n = 100) or MSICS (Group 2, n = 100) using a random number Table. The patients underwent complete ophthalmic evaluation and specular microscopy preoperatively and at 1and 6 weeks postoperatively. Functional and morphological endothelial evaluation was Noncon ROBO PACHY SP-9000 specular microscope. Phacoemulsification was performed, the chop technique and MSICS, by the viscoexpression technique. Results: The mean difference in central corneal thickness at baseline and 1 week between Group 1 and Group 2 was statistically significant (P = 0.027). However, this difference at baseline when compared to 6 week and 1 week, 6 weeks was not statistically significant (P > 0.05). The difference in mean endothelial cell density between groups at 1 week and 6 weeks was statistically significant (P = 0.016). The mean coefficient of variation and mean standard deviation between groups were not statistically significant (P > 0.05, both comparisons). Conclusion: The central corneal thickness, coefficient of variation, and standard deviation were maintained in both groups indicating that the function and morphology of endothelial cells was not affected despite an initial reduction in endothelial cell number in MSICS. Thus, MSICS remains a safe option in the developing world. PMID:24669147

  6. Calcium Channel Blockade and Peroxisome Proliferator Activated Receptor γ Agonism Diminish Cognitive Loss and Preserve Endothelial Function During Diabetes Mellitus.

    PubMed

    Jain, Swati; Sharma, B M; Sharma, Bhupesh

    2016-01-01

    Diabetes mellitus is considered as a main risk factor for vascular dementia. In the past, we have reported the induction of vascular dementia (VaD) by experimental diabetes. This study investigates the efficacy of a nifedipine, a calcium channel blocker and pioglitazone in the pharmacological interdiction of pancreatectomy diabetes (PaD) induced vascular endothelial dysfunction and subsequent VaD in rats. Attentional set shifting (ASST) and Morris water-maze (MWM) test were used for assessment of learning and memory. Vascular endothelial function, blood brain barrier permeability, serum glucose, serum nitrite/nitrate, oxidative stress (viz. aortic superoxide anion, brain thiobarbituric acid reactive species and brain glutathione), brain calcium and inflammation (myeloperoxidase) were also estimated. PaD rats have shown impairment of endothelial function, blood brain barrier permeability, learning and memory along with an increase in brain inflammation, oxidative stress and calcium. Administration of nifedipine and pioglitazone significantly attenuated PaD induced impairment of learning, memory, blood brain barrier permeability, endothelial function and biochemical parameters. It may be concluded that nifedipine, a calcium channel blocker may be considered as a potent pharmacological agent for the management of PaD induced endothelial dysfunction and subsequent VaD. PMID:26648342

  7. Inhibition of endothelial cell functions and of angiogenesis by the metastasis inhibitor NAMI-A

    PubMed Central

    Vacca, A; Bruno, M; Boccarelli, A; Coluccia, M; Ribatti, D; Bergamo, A; Garbisa, S; Sartor, L; Sava, G

    2002-01-01

    NAMI-A is a ruthenium-based compound with selective anti-metastasis activity in experimental models of solid tumours. We studied whether this activity was dependent on anti-angiogenic ability of NAMI-A. We thus investigated its in vitro effects on endothelial cell functions necessary for angiogenesis to develop, as well as its in vivo effects in the chick embryo chorioallantoic membrane model. Endothelial cell proliferation, chemotaxis, and secretion of the matrix-degrading enzyme metalloproteinase-2 were inhibited by NAMI-A in a dose-dependent manner, and without morphologic signs of cell apoptosis or necrosis. Lastly, NAMI-A displayed a dose-dependent in vivo anti-angiogenic activity in the chorioallantoic membrane model. These data suggest that the anti-angiogenic activity of NAMI-A can contribute to its anti-metastatic efficacy in mice bearing malignant solid tumours. British Journal of Cancer (2002) 86, 993–998. DOI: 10.1038/sj/bjc/6600176 www.bjcancer.com © 2002 Cancer Research UK PMID:11953835

  8. Platelet Consumption by Arterial Prostheses: The Effects of Endothelialization and Pharmacologic Inhibition of Platelet Function

    PubMed Central

    Harker, Laurence A.; Slichter, Sherrill J.; Sauvage, Lester R.

    1977-01-01

    The thrombogenic mechanism of arterial grafts has been studied by determining the relative utilization of platelets, fibrinogen and plasminogen by human arterial prostheses, and by direct examination of arterial grafts in a baboon model. Forty-one survival and turnover measurements of 51Crplatelets, 131I-fibrinogen and 125I-plasminogen in ten patients with aortofemoral knitted Dacron prostheses demonstrated platelet consumption after graft placement (platelet survival 4.2 days ± 0.5 and turnover 68,000 plat/ul/day ±10,000 compared with 8.2 days ± 0.3 and 35,000 plat/ul/day ± 5,000 respectively for control subjects with stable vascular disease, p < 0.01). In vitro platelet function test results were normal. Platelet consumption was interrupted by dipyridamole or a combination of dipyridamole and acetylsalicylic acid, and platelet survival normalized spontaneously during nine months postoperatively. No significantly increased consumption of fibrinogen or plasminogen was found in these patients with arterial grafts. Placement of impervious knitted Dacron velour aortic grafts in baboons reproduced platelet consumption that progressively normalized over six weeks postoperatively. Platelet survival measurements correlated directly with endothelial cell coverage of the graft luminal surface in these animals implying that endothelialization of the graft surface was also occurring postoperatively in patients. ImagesFig. 4.Fig. 5. PMID:411428

  9. Mutant LRP6 Impairs Endothelial Cell Functions Associated with Familial Normolipidemic Coronary Artery Disease

    PubMed Central

    Guo, Jian; Li, Yang; Ren, Yi-Hong; Sun, Zhijun; Dong, Jie; Yan, Han; Xu, Yujun; Wang, Dao Wen; Zheng, Gu-Yan; Du, Jie; Tian, Xiao-Li

    2016-01-01

    Mutations in the genes low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) and myocyte enhancer factor 2A (MEF2A) were reported in families with coronary artery disease (CAD). We intend to determine the mutational spectrum of these genes among hyperlipidemic and normolipidemic CAD families. Forty probands with early-onset CAD were recruited from 19 hyperlipidemic and 21 normolipidemic Chinese families. We sequenced all exons and intron-exon boundaries of LRP6 and MEF2A, and found a novel heterozygous variant in LRP6 from a proband with normolipidemic CAD. This variant led to a substitution of histidine to tyrosine (Y418H) in an evolutionarily conserved domain YWTD in exon 6 and was not found in 1025 unrelated healthy individuals. Co-segregated with CAD in the affected family, LRP6Y418H significantly debilitated the Wnt3a-associated signaling pathway, suppressed endothelial cell proliferation and migration, and decreased anti-apoptotic ability. However, it exhibited no influences on low-density lipoprotein cholesterol uptake. Thus, mutation Y418H in LRP6 likely contributes to normolipidemic familial CAD via impairing endothelial cell functions and weakening the Wnt3a signaling pathway. PMID:27455246

  10. Monitoring of pulmonary endothelial enzyme function: an animal model for a simplified clinically applicable procedure

    SciTech Connect

    Toivonen, H.J.; Makari, N.; Catravas, J.D.

    1988-01-01

    The authors present a simple and clinically applicable method for the serial monitoring of pulmonary microvascular enzyme function in vivo. This method requires the intravenous injection of trace amounts of a radiolabelled substrate and the collection of a single arterial blood sample. Simultaneous measurement of pulmonary blood flow, (e.g., by dye- or thermo-dilution) and the determination of blood hematocrit are also needed for the calculations. This method was compared to the multiple blood sample indicator dilution method in normal anesthesized rabbits. Both methods gave identical results for the metabolism of the synthetic, hemodynamically inactive tripeptide, /sup 3/H-benzoyl-Phe-Ala-Pro (/sup 3/H-BPAP), by pulmonary microvascular endothelial angiotensin converting enzyme. The parameters measured were: 1) substrate utilization, expressed linearly and logarithmically, and 2) the apparent first order reaction constant. The new method was also used for the simultaneous measurement of single pass, transpulmonary metabolism of /sup 3/H-BPAP by angiotensin converting enzyme and of 5'-adenosine monophosphate by 5'-nucleotidase in rabbits in vivo. The authors propose that similar enzyme kinetic measurements could be used in clinical studies to test their usefulness as an aid in the early diagnosis of incipient pulmonary endothelial dysfunction, e.g., adult respiratory distress syndrome.

  11. Effects of polydopamine functionalized titanium dioxide nanotubes on endothelial cell and smooth muscle cell.

    PubMed

    Zhong, Si; Luo, Rifang; Wang, Xin; Tang, Linlin; Wu, Jian; Wang, Jin; Huang, Runbo; Sun, Hong; Huang, Nan

    2014-04-01

    Previous investigations have demonstrated that TiO2 nanotubes (NTs) with particular structure cues could control the behavior of different types of cells, including endothelial cells (ECs) and smooth muscle cells (SMCs). Besides, polydopamine (PDA) modified surfaces were reported to be beneficial to increase the proliferation and viability of ECs and meanwhile could inhibit the proliferation of SMCs. The TiO2 nanotubes (NTs) were functionalized with polydopamine (PDA) (PDA/NTs) to study the synergetic effect of both nanotopography (NTs) and chemical cues (PDA) of TiO2 nanotubes on the regulation of cellular behavior of ECs and SMCs. The PDA-modified TiO2 nanotubes were subjected to field-emission scanning electron microscopy (FE-SEM), X-ray photoelectron spectroscopy (XPS), and water contact angle (WCA) analysis. In vitro cell culture tests confirmed that, comparing with flat titanium (Ti) and TiO2 nanotubes, PDA/NTs surface synergistically promoted ECs attachment, proliferation, migration and release of nitric oxide (NO). Meanwhile, the PDA/NTs performed well in reducing SMCs adhesion and proliferation. This novel approach might provide a new platform to investigate the synergistic effect of local chemistry and topography, as well as the applications for the development of titanium-based implants for enhanced endothelialization.

  12. Effects of polydopamine functionalized titanium dioxide nanotubes on endothelial cell and smooth muscle cell.

    PubMed

    Zhong, Si; Luo, Rifang; Wang, Xin; Tang, Linlin; Wu, Jian; Wang, Jin; Huang, Runbo; Sun, Hong; Huang, Nan

    2014-04-01

    Previous investigations have demonstrated that TiO2 nanotubes (NTs) with particular structure cues could control the behavior of different types of cells, including endothelial cells (ECs) and smooth muscle cells (SMCs). Besides, polydopamine (PDA) modified surfaces were reported to be beneficial to increase the proliferation and viability of ECs and meanwhile could inhibit the proliferation of SMCs. The TiO2 nanotubes (NTs) were functionalized with polydopamine (PDA) (PDA/NTs) to study the synergetic effect of both nanotopography (NTs) and chemical cues (PDA) of TiO2 nanotubes on the regulation of cellular behavior of ECs and SMCs. The PDA-modified TiO2 nanotubes were subjected to field-emission scanning electron microscopy (FE-SEM), X-ray photoelectron spectroscopy (XPS), and water contact angle (WCA) analysis. In vitro cell culture tests confirmed that, comparing with flat titanium (Ti) and TiO2 nanotubes, PDA/NTs surface synergistically promoted ECs attachment, proliferation, migration and release of nitric oxide (NO). Meanwhile, the PDA/NTs performed well in reducing SMCs adhesion and proliferation. This novel approach might provide a new platform to investigate the synergistic effect of local chemistry and topography, as well as the applications for the development of titanium-based implants for enhanced endothelialization. PMID:24637093

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

    PubMed

    Yiu, Kai-Hang; Tse, Hung-Fat

    2014-06-01

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

  14. PECAM-1 isoform-specific functions in PECAM-1-deficient brain microvascular endothelial cells.

    PubMed

    DiMaio, Terri A; Sheibani, Nader

    2008-03-01

    Platelet endothelial cell adhesion molecule-1 (PECAM-1) is alternatively spliced generating eight isoforms that only differ in the length of their cytoplasmic domain. Multiple isoforms of PECAM-1 are present in the endothelium and their expression levels are regulated during vascular development and angiogenesis. However, the functional significance of PECAM-1 isoforms during these processes remains largely unknown. We recently showed that mouse brain endothelial (bEND) cells prepared from PECAM-1-deficient (PECAM-1-/-) mice differ in their cell adhesive and migratory properties compared to PECAM-1+/+ bEND cells. Here we demonstrate that the restoration of PECAM-1 expression in these cells affects their adhesive and migratory properties in an isoform-specific manner. Expression of Delta14&15 PECAM-1, the predominant isoform present in the mouse endothelium, in PECAM-1-/- bEND cells activated MAPK/ERKs, disrupted adherens junctions, and enhanced cell migration and capillary morphogenesis in Matrigel. In contrast, expression of Delta15 PECAM-1 in PECAM-1-/- bEND cells had minimal effects on their activation of MAPK/ERKs, migration, and capillary morphogenesis. The effects of PECAM-1 on cell adhesive and migratory properties were mediated in an isoform-specific manner, at least in part, through its interactions with intracellular signaling proteins, including SHP-2 and Src. These results suggest that the impact of PECAM-1 on EC adhesion, migration, and capillary morphogenesis is modulated by alternative splicing of its cytoplasmic domain. PMID:18029285

  15. Vascular endothelial cells express a functional fas-receptor due to lack of hemodynamic forces.

    PubMed

    Freyberg, M A; Kaiser, D; Graf, R; Friedl, P

    2001-10-01

    The fas system is present in atherosclerotic lesions. However, its role in the initiation and progression is still unclear. Here we show that in endothelial cells (EC) the expression of the fas receptor is regulated by flow conditions. The EC of the vascular system are regularly exposed to a range of hemodynamic forces with great impact on cellular structures and functions. Recently it was reported that in endothelial cells the lack of hemodynamic forces as well as irregular flow conditions trigger apoptosis by induction of a mechanosensitive autocrine loop of thrombospondin-1 and the alpha(V)beta(3) integrin/integrin-associated protein complex. Here we show that EC cultivated under regular laminar flow conditions are devoid of the fas-receptor whereas cultivation under static conditions as well as under turbulence leads to its expression. Stimulation of the fas-receptor by its ligand increases the amount of apoptotic cells by twofold; the increase can be prevented by blocking the fas-receptor. The availability of the expressed fas receptor for stimulation by its ligand hints at a role as a tool for progression of atherosclerosis. PMID:11483857

  16. Equal modulation of endothelial cell function by four distinct tissue-specific mesenchymal stem cells.

    PubMed

    Lin, Ruei-Zeng; Moreno-Luna, Rafael; Zhou, Bin; Pu, William T; Melero-Martin, Juan M

    2012-09-01

    Mesenchymal stem cells (MSCs) can generate multiple end-stage mesenchymal cell types and constitute a promising population of cells for regenerative therapies. Additionally, there is increasing evidence supporting other trophic activities of MSCs, including the ability to enable formation of vasculature in vivo. Although MSCs were originally isolated from the bone marrow, the presence of these cells in the stromal vascular fraction of multiple adult tissues has been recently recognized. However, it is unknown whether the capacity to modulate vasculogenesis is ubiquitous to all MSCs regardless of their tissue of origin. Here, we demonstrated that tissue-resident MSCs isolated from four distinct tissues have equal capacity to modulate endothelial cell function, including formation of vascular networks in vivo. MSCs were isolated from four murine tissues, including bone marrow, white adipose tissue, skeletal muscle, and myocardium. In culture, all four MSC populations secreted a plethora of pro-angiogenic factors that unequivocally induced proliferation, migration, and tube formation of endothelial colony-forming cells (ECFCs). In vivo, co-implantation of MSCs with ECFCs into mice generated an extensive network of blood vessels with ECFCs specifically lining the lumens and MSCs occupying perivascular positions. Importantly, there were no differences among all four MSCs evaluated. Our studies suggest that the capacity to modulate the formation of vasculature is a ubiquitous property of all MSCs, irrespective of their original anatomical location. These results validate multiple tissues as potential sources of MSCs for future cell-based vascular therapies.

  17. Abnormal pulmonary function and associated risk factors in children and adolescents with sickle cell anemia.

    PubMed

    Arteta, Manuel; Campbell, Andrew; Nouraie, Mehdi; Rana, Sohail; Onyekwere, Onyinye C; Ensing, Gregory; Sable, Craig; Dham, Niti; Darbari, Deepika; Luchtman-Jones, Lori; Kato, Gregory J; Gladwin, Mark T; Castro, Oswaldo L; Minniti, Caterina P; Gordeuk, Victor R

    2014-04-01

    Obstructive and restrictive pulmonary changes develop in children with sickle cell disease, but reports conflict as to the type of change that predominates. We prospectively performed spirometry, plethysmography, and lung diffusing capacity in 146 children aged 7 to 20 years with hemoglobin SS or Sβ(0)-thalassemia. Nineteen percent of the patients had obstructive physiology as defined according to guidelines of the American Thoracic Society. In addition, 9% had restrictive physiology and 11% had abnormal but not categorized physiology. Increasing age, patient-reported or family-reported history of asthma or wheezing, and higher lactate dehydrogenase concentration were independent predictors of obstruction as reflected in lower forced expiratory volume in the first second/forced vital capacity. In conclusion, abnormal pulmonary function, most often obstructive, is common in children with hemoglobin SS and Sβ(0)-thalassemia. Full pulmonary function testing should be performed in children with hemoglobin SS or Sβ(0)-thalassemia, especially with history of asthma or wheezing and accentuated elevations in hemolytic markers.

  18. Abnormalities of brain function during a nonverbal theory of mind task in schizophrenia.

    PubMed

    Brunet, Eric; Sarfati, Yves; Hardy-Baylé, Marie-Christine; Decety, Jean

    2003-01-01

    Theory of mind (ToM), the specific ability to attribute thoughts and feelings to oneself and others is generally impaired in schizophrenia. Previous studies demonstrated a deficit of the attribution of intentions to others among patients having formal thought disorder. During nonverbal tasks, such a function requires both the visual perception of human figures and the understanding of their intentions. These processes are considered to involve the superior temporal sulcus and the medial prefrontal cortex, respectively. Are the functional patterns of activation associated with those processes abnormal in schizophrenia? Seven schizophrenic patients on medication performed a nonverbal attribution of intentions task as well as two matched physical logic tasks, with and without human figures, while H2O15 PET-scanning was performed. Data from the patients were compared to those of eight healthy controls matched for verbal IQ and sex. The experimental design allowed dissociating the effect of the perception of human figures from that of the attribution of intentions. During attribution of intentions, significant activations in the right prefrontal cortex were detected in the control subjects. Those activations were not found in the schizophrenic group. However, in both groups, the perception of human figure elicited bilateral activation of the occipitotemporal regions and of the posterior part of the superior temporal sulcus. Schizophrenic patients performing a nonverbal attribution of intentions task have an abnormal cerebral activity. PMID:12887982

  19. Influence of Adjuvant Therapy in Cancer Survivors on Endothelial Function and Skeletal Muscle Deoxygenation.

    PubMed

    Ederer, Austin K; Didier, Kaylin D; Reiter, Landon K; Brown, Michael; Hardy, Rachel; Caldwell, Jacob; Black, Christopher D; Larson, Rebecca D; Ade, Carl J

    2016-01-01

    The cardiotoxic effects of adjuvant cancer treatments (i.e., chemotherapy and radiation treatment) have been well documented, but the effects on peripheral cardiovascular function are still unclear. We hypothesized that cancer survivors i) would have decreased resting endothelial function; and ii) altered muscle deoxygenation response during moderate intensity cycling exercise compared to cancer-free controls. A total of 8 cancer survivors (~70 months post-treatment) and 9 healthy controls completed a brachial artery FMD test, an index of endothelial-dependent dilation, followed by an incremental exercise test up to the ventilatory threshold (VT) on a cycle ergometer during which pulmonary V̇O2 and changes in near-infrared spectroscopy (NIRS)-derived microvascular tissue oxygenation (TOI), total hemoglobin concentration ([Hb]total), and muscle deoxygenation ([HHb] ≈ fractional O2 extraction) were measured. There were no significant differences in age, height, weight, and resting blood pressure between cancer survivors and control participants. Brachial artery FMD was similar between groups (P = 0.98). During exercise at the VT, TOI was similar between groups, but [Hb]total and [HHb] were significantly decreased in cancer survivors compared to controls (P < 0.01) The rate of change for TOI (ΔTOIΔ/V̇O2) and [HHb] (Δ[HHb]/ΔV̇O2) relative to ΔV̇O2 were decreased in cancer survivors compared to controls (P = 0.02 and P = 0.03 respectively). In cancer survivors, a decreased skeletal muscle microvascular function was observed during moderate intensity cycling exercise. These data suggest that adjuvant cancer therapies have an effect on the integrated relationship between O2 extraction, V̇O2 and O2 delivery during exercise.

  20. Influence of Adjuvant Therapy in Cancer Survivors on Endothelial Function and Skeletal Muscle Deoxygenation.

    PubMed

    Ederer, Austin K; Didier, Kaylin D; Reiter, Landon K; Brown, Michael; Hardy, Rachel; Caldwell, Jacob; Black, Christopher D; Larson, Rebecca D; Ade, Carl J

    2016-01-01

    The cardiotoxic effects of adjuvant cancer treatments (i.e., chemotherapy and radiation treatment) have been well documented, but the effects on peripheral cardiovascular function are still unclear. We hypothesized that cancer survivors i) would have decreased resting endothelial function; and ii) altered muscle deoxygenation response during moderate intensity cycling exercise compared to cancer-free controls. A total of 8 cancer survivors (~70 months post-treatment) and 9 healthy controls completed a brachial artery FMD test, an index of endothelial-dependent dilation, followed by an incremental exercise test up to the ventilatory threshold (VT) on a cycle ergometer during which pulmonary V̇O2 and changes in near-infrared spectroscopy (NIRS)-derived microvascular tissue oxygenation (TOI), total hemoglobin concentration ([Hb]total), and muscle deoxygenation ([HHb] ≈ fractional O2 extraction) were measured. There were no significant differences in age, height, weight, and resting blood pressure between cancer survivors and control participants. Brachial artery FMD was similar between groups (P = 0.98). During exercise at the VT, TOI was similar between groups, but [Hb]total and [HHb] were significantly decreased in cancer survivors compared to controls (P < 0.01) The rate of change for TOI (ΔTOIΔ/V̇O2) and [HHb] (Δ[HHb]/ΔV̇O2) relative to ΔV̇O2 were decreased in cancer survivors compared to controls (P = 0.02 and P = 0.03 respectively). In cancer survivors, a decreased skeletal muscle microvascular function was observed during moderate intensity cycling exercise. These data suggest that adjuvant cancer therapies have an effect on the integrated relationship between O2 extraction, V̇O2 and O2 delivery during exercise. PMID:26807572

  1. Exercise improves endothelial function: a local analysis of production of nitric oxide and reactive oxygen species.

    PubMed

    Tanaka, Leonardo Yuji; Bechara, Luiz Roberto Grassmann; dos Santos, Adriana Marques; Jordão, Camila Paixão; de Sousa, Luís Gustavo Oliveira; Bartholomeu, Teresa; Ventura, Laura Inês; Laurindo, Francisco Rafael Martins; Ramires, Paulo Rizzo

    2015-02-15

    This study aimed at investigating the acute effects of aerobic exercise on endothelium-dependent vasomotor function of rat aorta, as well as mechanisms involved in endothelial nitric oxide (NO) bioactivity. Wistar rats were assigned to either a resting control (C, n = 21) or acutely exercised (E, n = 21) groups (60 min, 55-60% of maximum speed). After exercise, thoracic aorta was excised and cut into rings. Two rings were promptly applied to evaluate vasomotor function and the rest of aorta was used for additional measurements. Acute exercise significantly improved maximum ACh-induced relaxation (C, 91.6 ± 1.2 vs. E, 102.4 ± 1.7%, p < 0.001) and sensitivity to ACh (C, -7.3 ± 0.06 vs. E, -7.3 ± 0.02 log M, p < 0.01), and was accompanied by significantly increases on serine1177 eNOS phosphorylation, reflecting its enhanced activation. However, acute exercise also enhanced both superoxide and hydrogen peroxide production, as assayed by dihydroethidium oxidation, lucigenin chemiluminescence and Amplex Red assays. We also provided evidence for Nox2 NADPH oxidase (Nox) activation through gp91dstat-mediated inhibition of superoxide signals. Enhanced arterial relaxations associated with acute exercise were nearly-completely prevented by catalase, suggesting a role for paracrine hydrogen peroxide. Despite increased detectable oxidant generation, cellular oxidative stress was not evident, as suggested by unaltered GSH:GSSG ratio and lipid hydroperoxides. Collectively, these results demonstrate that one bout of moderate aerobic exercise improves endothelial function by increasing NO bioavailability, while superoxide and hydrogen peroxide are generated in a controlled fashion. PMID:25619203

  2. Hydrogen sulfide protects endothelial nitric oxide function under conditions of acute oxidative stress in vitro.

    PubMed

    Al-Magableh, Mohammad R; Kemp-Harper, Barbara K; Ng, Hooi H; Miller, Alyson A; Hart, Joanne L

    2014-01-01

    The aim of this study was to examine the ability of H2S, released from NaHS to protect vascular endothelial function under conditions of acute oxidative stress by scavenging superoxide anions (O2(-)) and suppressing vascular superoxide anion production. O2(-) was generated in Krebs' solution by reacting hypoxanthine with xanthine oxidase (Hx-XO) or with the O2(-) generator pyrogallol to model acute oxidative stress in vitro. O2(-) generation was measured by lucigenin-enhanced chemiluminescence. Functional responses in mouse aortic rings were assessed using a small vessel myograph. NaHS scavenged O2(-) in a concentration-dependent manner. Isolated aortic rings exposed to either Hx-XO or pyrogallol displayed significantly attenuated maximum vasorelaxation responses to the endothelium-dependent vasodilator acetylcholine, and significantly reduced NO bioavailability, which was completely reversed if vessels were pre-incubated with NaHS (100 μM). NADPH-stimulated aortic O2(-) production was significantly attenuated by the NADPH oxidase inhibitor diphenyl iodonium. Prior treatment of vessels with NaHS (100 nM-100 μM; 30 min) inhibited NADPH-stimulated aortic O2(-) production in a concentration-dependent manner. This effect persisted when NaHS was washed out prior to measuring NADPH-stimulated O2(-) production. These data show for the first time that NaHS directly scavenges O2(-) and suppresses vascular NADPH oxidase-derived O2(-) production in vitro. Furthermore, these properties protect endothelial function and NO bioavailability in an in vitro model of acute oxidative stress. These results suggest that H2S can elicit vasoprotection by both scavenging O2(-) and by reducing vascular NADPH oxidase-derived O2(-) production.

  3. Vitamin D improves endothelial dysfunction and restores myeloid angiogenic cell function via reduced CXCL-10 expression in systemic lupus erythematosus.

    PubMed

    Reynolds, John A; Haque, Sahena; Williamson, Kate; Ray, David W; Alexander, M Yvonne; Bruce, Ian N

    2016-01-01

    Patients with systemic lupus erythematosus (SLE) have accelerated cardiovascular disease and dysfunctional endothelial repair mechanisms. Myeloid angiogenic cells (MACs), derived from circulating monocytes, augment vascular repair by paracrine secretion of pro-angiogenic factors. We observed that SLE MACs are dysfunctional and secrete pro-inflammatory cytokines. We also found that the vitamin D receptor was transiently expressed during MAC differentiation and that in vitro, calcitriol increased differentiation of monocytes into MACs in both SLE and in a model using the prototypic SLE cytokine, interferon-alpha. The active form of vitamin D (calcitriol) restored the SLE MAC phenotype towards that of healthy subjects with reduced IL-6 secretion, and normalised surface marker expression. Calcitriol also augmented the angiogenic capacity of MACs via the down-regulation of CXCL-10. In SLE patients treated with cholecalciferol for 12 weeks, the improvement in endothelial function correlated with increase in serum 25(OH)D concentrations independently of disease activity. We also show that MACs were able to positively modulate eNOS expression in human endothelial cells in vitro, an effect further enhanced by calcitriol treatment of SLE MACs. The results demonstrate that vitamin D can positively modify endothelial repair mechanisms and thus endothelial function in a population with significant cardiovascular risk. PMID:26930567

  4. Role of Epac1, an Exchange Factor for Rap GTPases, in Endothelial Microtubule Dynamics and Barrier Function

    PubMed Central

    Sehrawat, Seema; Cullere, Xavier; Patel, Sunita; Italiano, Joseph

    2008-01-01

    Rap1 GTPase activation by its cAMP responsive nucleotide exchange factor Epac present in endothelial cells increases endothelial cell barrier function with an associated increase in cortical actin. Here, Epac1 was shown to be responsible for these actin changes and to colocalize with microtubules in human umbilical vein endothelial cells. Importantly, Epac activation with a cAMP analogue, 8-pCPT-2′O-Me-cAMP resulted in a net increase in the length of microtubules. This did not require cell–cell interactions or Rap GTPase activation, and it was attributed to microtubule growth as assessed by time-lapse microscopy of human umbilical vein endothelial cell expressing fluorophore-linked microtubule plus-end marker end-binding protein 3. An intact microtubule network was required for Epac-mediated changes in cortical actin and barrier enhancement, but it was not required for Rap activation. Finally, Epac activation reversed microtubule-dependent increases in vascular permeability induced by tumor necrosis factor-α and transforming growth factor-β. Thus, Epac can directly promote microtubule growth in endothelial cells. This, together with Rap activation leads to an increase in cortical actin, which has functional significance for vascular permeability. PMID:18172027

  5. Vitamin D improves endothelial dysfunction and restores myeloid angiogenic cell function via reduced CXCL-10 expression in systemic lupus erythematosus.

    PubMed

    Reynolds, John A; Haque, Sahena; Williamson, Kate; Ray, David W; Alexander, M Yvonne; Bruce, Ian N

    2016-03-01

    Patients with systemic lupus erythematosus (SLE) have accelerated cardiovascular disease and dysfunctional endothelial repair mechanisms. Myeloid angiogenic cells (MACs), derived from circulating monocytes, augment vascular repair by paracrine secretion of pro-angiogenic factors. We observed that SLE MACs are dysfunctional and secrete pro-inflammatory cytokines. We also found that the vitamin D receptor was transiently expressed during MAC differentiation and that in vitro, calcitriol increased differentiation of monocytes into MACs in both SLE and in a model using the prototypic SLE cytokine, interferon-alpha. The active form of vitamin D (calcitriol) restored the SLE MAC phenotype towards that of healthy subjects with reduced IL-6 secretion, and normalised surface marker expression. Calcitriol also augmented the angiogenic capacity of MACs via the down-regulation of CXCL-10. In SLE patients treated with cholecalciferol for 12 weeks, the improvement in endothelial function correlated with increase in serum 25(OH)D concentrations independently of disease activity. We also show that MACs were able to positively modulate eNOS expression in human endothelial cells in vitro, an effect further enhanced by calcitriol treatment of SLE MACs. The results demonstrate that vitamin D can positively modify endothelial repair mechanisms and thus endothelial function in a population with significant cardiovascular risk.

  6. Vitamin D improves endothelial dysfunction and restores myeloid angiogenic cell function via reduced CXCL-10 expression in systemic lupus erythematosus

    PubMed Central

    Reynolds, John A.; Haque, Sahena; Williamson, Kate; Ray, David W.; Alexander, M. Yvonne; Bruce, Ian N.

    2016-01-01

    Patients with systemic lupus erythematosus (SLE) have accelerated cardiovascular disease and dysfunctional endothelial repair mechanisms. Myeloid angiogenic cells (MACs), derived from circulating monocytes, augment vascular repair by paracrine secretion of pro-angiogenic factors. We observed that SLE MACs are dysfunctional and secrete pro-inflammatory cytokines. We also found that the vitamin D receptor was transiently expressed during MAC differentiation and that in vitro, calcitriol increased differentiation of monocytes into MACs in both SLE and in a model using the prototypic SLE cytokine, interferon-alpha. The active form of vitamin D (calcitriol) restored the SLE MAC phenotype towards that of healthy subjects with reduced IL-6 secretion, and normalised surface marker expression. Calcitriol also augmented the angiogenic capacity of MACs via the down-regulation of CXCL-10. In SLE patients treated with cholecalciferol for 12 weeks, the improvement in endothelial function correlated with increase in serum 25(OH)D concentrations independently of disease activity. We also show that MACs were able to positively modulate eNOS expression in human endothelial cells in vitro, an effect further enhanced by calcitriol treatment of SLE MACs. The results demonstrate that vitamin D can positively modify endothelial repair mechanisms and thus endothelial function in a population with significant cardiovascular risk. PMID:26930567

  7. Functional and Transcriptional Characterization of Human Embryonic Stem Cell-Derived Endothelial Cells for Treatment of Myocardial Infarction

    PubMed Central

    Li, Zongjin; Wilson, Kitchener D.; Smith, Bryan; Kraft, Daniel L.; Jia, Fangjun; Huang, Mei; Xie, Xiaoyan; Robbins, Robert C.; Gambhir, Sanjiv S.; Weissman, Irving L.; Wu, Joseph C.

    2009-01-01

    Background Differentiation of human embryonic stem cells into endothelial cells (hESC-ECs) has the potential to provide an unlimited source of cells for novel transplantation therapies of ischemic diseases by supporting angiogenesis and vasculogenesis. However, the endothelial differentiation efficiency of the conventional embryoid body (EB) method is low while the 2-dimensional method of co-culturing with mouse embryonic fibroblasts (MEFs) require animal product, both of which can limit the future clinical application of hESC-ECs. Moreover, to fully understand the beneficial effects of stem cell therapy, investigators must be able to track the functional biology and physiology of transplanted cells in living subjects over time. Methodology In this study, we developed an extracellular matrix (ECM) culture system for increasing endothelial differentiation and free from contaminating animal cells. We investigated the transcriptional changes that occur during endothelial differentiation of hESCs using whole genome microarray, and compared to human umbilical vein endothelial cells (HUVECs). We also showed functional vascular formation by hESC-ECs in a mouse dorsal window model. Moreover, our study is the first so far to transplant hESC-ECs in a myocardial infarction model and monitor cell fate using molecular imaging methods. Conclusion Taken together, we report a more efficient method for derivation of hESC-ECs that express appropriate patterns of endothelial genes, form functional vessels in vivo, and improve cardiac function. These studies suggest that hESC-ECs may provide a novel therapy for ischemic heart disease in the future. PMID:20046878

  8. Heat stress-induced disruption of endothelial barrier function is via PAR1 signaling and suppressed by Xuebijing injection.

    PubMed

    Xu, Qiulin; Liu, Jingxian; Wang, Zhenglian; Guo, Xiaohua; Zhou, Gengbiao; Liu, Yanan; Huang, Qiaobing; Su, Lei

    2015-01-01

    Increased vascular permeability leading to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is central to the pathogenesis of heatstroke. Protease-activated receptor 1 (PAR1), the receptor for thrombin, plays a key role in disruption of endothelial barrier function in response to extracellular stimuli. However, the role of PAR1 in heat stress-induced endothelial hyper-permeability is unknown. In this study, we measured PAR1 protein expression in heat-stressed human umbilical venous endothelial cells (HUVECs), investigated the influences of PAR1 on endothelial permeability, F-actin rearrangement, and moesin phosphorylation by inhibiting PAR1 with its siRNA, neutralizing antibody (anti-PAR1), specific inhibitor(RWJ56110), and Xuebijing injection (XBJ), a traditional Chinese medicine used for sepsis treatment, and evaluated the role of PAR1 in heatstroke-related ALI/ARDS in mice by suppressing PAR1 with RWJ56110, anti-PAR1and XBJ. We found that heat stress induced PAR1 protein expression 2h after heat stress in endothelial cells, caused the release of endothelial matrix metalloprotease 1, an activator of PAR1, after 60 or 120 min of heat stimulation, as well as promoted endothelial hyper-permeability and F-actin rearrangement, which were inhibited by suppressing PAR1 with RWJ56110, anti-PAR1 and siRNA. PAR1 mediated moesin phosphorylation, which caused F-actin rearrangement and disruption of endothelial barrier function. To corroborate findings from in vitro experiments, we found that RWJ56110 and the anti-PAR1 significantly decreased lung edema, pulmonary microvascular permeability, protein exudation, and leukocytes infiltrations in heatstroke mice. Additionally, XBJ was found to suppress PAR1-moesin signal pathway and confer protective effects on maintaining endothelial barrier function both in vitro and in vivo heat-stressed model, similar to those observed above with the inhibition of PAR1. These results suggest that PAR1 is a potential

  9. Predictors of endothelial function in employees with sedentary occupations in a worksite exercise program.

    PubMed

    Lippincott, Margaret F; Desai, Aditi; Zalos, Gloria; Carlow, Andrea; De Jesus, Janet; Blum, Arnon; Smith, Kevin; Rodrigo, Maria; Patibandla, Sushmitha; Chaudhry, Hira; Glaser, Alexander P; Schenke, William H; Csako, Gyorgy; Waclawiw, Myron A; Cannon, Richard O

    2008-10-01

    A sedentary workforce may be at increased risk for future cardiovascular disease. Exercise at the work site has been advocated, but effects on endothelium as a biomarker of risk and relation to weight loss, lipid changes, or circulating endothelial progenitor cells (EPCs) have not been reported. Seventy-two office and laboratory employees (58 women; average age 45 years, range 22 to 62; 26 with body mass index values >30 kg/m(2)) completed 3 months of participation in the National Heart, Lung, and Blood Institute's Keep the Beat program, with the determination of vital signs, laboratory data, and peak oxygen consumption (VO(2)) during treadmill exercise. Brachial artery endothelium was tested by flow-mediated dilation (FMD), which at baseline was inversely associated with Framingham risk score (r = -0.3689, p <0.0001). EPCs were quantified by colony assay. With exercise averaging 98 +/- 47 minutes each workweek, there was improvement in FMD (from 7.8 +/- 3.4% to 8.5 +/- 3.0%, p = 0.0096) and peak VO(2) (+1.2 +/- 3.1 ml O(2)/kg/min, p = 0.0028), with reductions in diastolic blood pressure (-2 +/- 8 mm Hg, p = 0.0478), total cholesterol (-8 +/- 25 mg/dl, p = 0.0131), and low-density lipoprotein cholesterol (-7 +/- 19 mg/dl, p = 0.0044) but with a marginal reduction in weight (-0.5 +/- 2.1 kg, p = 0.0565). By multiple regression modeling, lower baseline FMD, greater age, reductions in total and low-density lipoprotein cholesterol and diastolic blood pressure, and increases in EPC colonies and peak VO(2) were jointly statistically significant predictors of change in FMD and accounted for 47% of the variability in FMD improvement with program participation. Results were similar when modeling was performed for women only. In contrast, neither adiposity at baseline nor change in weight was a predictor of improved endothelial function. In conclusion, daily exercise achievable at their work sites by employees with sedentary occupations improves endothelial function, even

  10. Vascular endothelial growth factors: multitasking functionality in metabolism, health and disease.

    PubMed

    Smith, Gina A; Fearnley, Gareth W; Harrison, Michael A; Tomlinson, Darren C; Wheatcroft, Stephen B; Ponnambalam, Sreenivasan

    2015-07-01

    Vascular endothelial growth factors (VEGFs) bind to VEGF receptor tyrosine kinases (VEGFRs). The VEGF and VEGFR gene products regulate diverse regulatory pathways in mammalian development, health and disease. The interaction between a particular VEGF and its cognate VEGFR activates multiple signal transduction pathways which regulate different cellular responses including metabolism, gene expression, proliferation, migration, and survival. The family of VEGF isoforms regulate vascular physiology and promote tissue homeostasis. VEGF dysfunction is implicated in major chronic disease states including atherosclerosis, diabetes, and cancer. More recent studies implicate a strong link between response to VEGF and regulation of vascular metabolism. Understanding how this family of multitasking cytokines regulates cell and animal function has implications for treating many different diseases.

  11. Acute exercise improves endothelial function despite increasing vascular resistance during stress in smokers and nonsmokers.

    PubMed

    Rooks, Cherie R; McCully, Kevin K; Dishman, Rod K

    2011-09-01

    The present study examined the effect of acute exercise on flow mediated dilation (FMD) and reactivity to neurovascular challenges among female smokers and nonsmokers. FMD was determined by arterial diameter, velocity, and blood flow measured by Doppler ultrasonography after forearm occlusion. Those measures and blood pressure and heart rate were also assessed in response to forehead cold and the Stroop Color-Word Conflict Test (CWT) before and after 30 min of rest or an acute bout of cycling exercise (∼50% VO₂ peak). Baseline FMD and stress responses were not different between smokers and nonsmokers. Compared to passive rest, exercise increased FMD and decreased arterial velocity and blood flow responses during the Stroop CWT and forehead cold in both groups. Overall, acute exercise improved endothelial function among smokers and nonsmokers despite increasing vascular resistance and reducing limb blood flow during neurovascular stress. PMID:21457274

  12. Vascular endothelial growth factors: multitasking functionality in metabolism, health and disease.

    PubMed

    Smith, Gina A; Fearnley, Gareth W; Harrison, Michael A; Tomlinson, Darren C; Wheatcroft, Stephen B; Ponnambalam, Sreenivasan

    2015-07-01

    Vascular endothelial growth factors (VEGFs) bind to VEGF receptor tyrosine kinases (VEGFRs). The VEGF and VEGFR gene products regulate diverse regulatory pathways in mammalian development, health and disease. The interaction between a particular VEGF and its cognate VEGFR activates multiple signal transduction pathways which regulate different cellular responses including metabolism, gene expression, proliferation, migration, and survival. The family of VEGF isoforms regulate vascular physiology and promote tissue homeostasis. VEGF dysfunction is implicated in major chronic disease states including atherosclerosis, diabetes, and cancer. More recent studies implicate a strong link between response to VEGF and regulation of vascular metabolism. Understanding how this family of multitasking cytokines regulates cell and animal function has implications for treating many different diseases. PMID:25868665

  13. Highly active antiretroviral therapy-related mechanisms of endothelial and platelet function alterations.

    PubMed

    Gresele, Paolo; Falcinelli, Emanuela; Momi, Stefania; Francisci, Daniela; Baldelli, Franco

    2014-01-01

    Highly active antiretroviral therapy (HAART) has transformed human immunodeficiency virus (HIV) infection into a chronic condition, which has allowed the infected population to age and become prone to chronic degenerative diseases common to the general population, including atherosclerotic cardiovascular disease, and coronary artery disease (CAD). Possible causative mechanisms of HIV-associated CAD are related to classic cardiovascular risk factors, such as dyslipidemia, insulin resistance, and fat redistribution, which may be due to either HIV infection or to HAART-associated toxicity. However, other mechanisms are emerging as crucial for the cardiovascular complication of HIV and HAART. This article analyzes the effects of HIV and HAART on endothelial function, endothelium-leukocyte interactions, and platelets as possible mechanisms of enhanced cardiovascular risk.

  14. Abnormal functional connectivity in focal hand dystonia: Mutual information analysis in EEG

    PubMed Central

    Jin, Seung-Hyun; Lin, Peter; Auh, Sungyoung; Hallett, Mark

    2011-01-01

    The aim of the present study was to investigate functional connectivity (FC) in focal hand dystonia (FHD) patients to understand the pathophysiology underlying their abnormality in movement. We recorded EEG from 58 electrodes in 15 FHD patients and 15 healthy volunteers during rest and a simple finger-tapping task that did not induce any dystonic symptoms. We investigated the mutual information (MI), which provides a quantitative measure of linear and nonlinear coupling, in the alpha, beta and gamma bands. Mean MI of all 58 channels and mean of the channels of interest (COIs) representative of regional FC over sensorimotor areas (C3, CP3, C4, CP4, FCz and Cz) were evaluated. For both groups, we found enhanced MI during the task compared to the rest condition specifically in the beta and gamma bands for mean MI of all channels, and in all bands for mean MI of COIs. Comparing the FHD patients to the healthy volunteers, for both rest and task, there was reduced MI in the beta band for both mean MI of all channels and mean MI of COIs. Regarding the properties of the connectivity in the beta band, we found that the majority of the MI differences were from linear connectivity. The abnormal beta band FC in FHD patients suggests deficient brain connectivity. PMID:21506166

  15. Calorie Restriction Prevents Metabolic Aging Caused by Abnormal SIRT1 Function in Adipose Tissues.

    PubMed

    Xu, Cheng; Cai, Yu; Fan, Pengcheng; Bai, Bo; Chen, Jie; Deng, Han-Bing; Che, Chi-Ming; Xu, Aimin; Vanhoutte, Paul M; Wang, Yu

    2015-05-01

    Adipose tissue is a pivotal organ determining longevity, due largely to its role in maintaining whole-body energy homeostasis and insulin sensitivity. SIRT1 is a NAD-dependent protein deacetylase possessing antiaging activities in a wide range of organisms. The current study demonstrates that mice with adipose tissue-selective overexpression of hSIRT1(H363Y), a dominant-negative mutant that disrupts endogenous SIRT1 activity, show accelerated development of metabolic aging. These mice, referred to as Adipo-H363Y, exhibit hyperglycemia, dyslipidemia, ectopic lipid deposition, insulin resistance, and glucose intolerance at a much younger age than their wild-type littermates. The metabolic defects of Adipo-H363Y are associated with abnormal epigenetic modifications and chromatin remodeling in their adipose tissues, as a result of excess accumulation of biotin, which inhibits endogenous SIRT1 activity, leading to increased inflammation, cellularity, and collagen deposition. The enzyme acetyl-CoA carboxylase 2 plays an important role in biotin accumulation within adipose tissues of Adipo-H363Y. Calorie restriction prevents biotin accumulation, abolishes abnormal histone biotinylation, and completely restores the metabolic and adipose functions of Adipo-H363Y. The effects are mimicked by short-term restriction of biotin intake, an approach potentially translatable to humans for maintaining the epigenetic and chromatin remodeling capacity of adipose tissues and preventing aging-associated metabolic disorders.

  16. Functional and Structural Abnormalities in Deferoxamine Retinopathy: A Review of the Literature

    PubMed Central

    Di Nicola, Maura; Barteselli, Giulio; Dell'Arti, Laura; Ratiglia, Roberto; Viola, Francesco

    2015-01-01

    Deferoxamine mesylate (DFO) is the most commonly used iron-chelating agent to treat transfusion-related hemosiderosis. Despite the clear advantages for the use of DFO, numerous DFO-related systemic toxicities have been reported in the literature, as well as sight-threatening ocular toxicity involving the retinal pigment epithelium (RPE). The damage to the RPE can lead to visual field defects, color-vision defects, abnormal electrophysiological tests, and permanent visual deterioration. The purpose of this review is to provide an updated summary of the ocular findings, including both functional and structural abnormalities, in DFO-treated patients. In particular, we pay particular attention to analyzing results of multimodal technologies for retinal imaging, which help ophthalmologists in the early diagnosis and correct management of DFO retinopathy. Fundus autofluorescence, for example, is not only useful for screening patients at high-risk of DFO retinopathy, but is also a prerequisite for identify specific high-risk patterns of RPE changes that are relevant for the prognosis of the disease. In addition, optical coherence tomography may have a clinical usefulness in detecting extent and location of different retinal changes in DFO retinopathy. Finally, this review wants to underline the need for universally approved guidelines for screening and followup of this particular disease. PMID:26167477

  17. Positron Emission Tomography Reveals Abnormal Topological Organization in Functional Brain Network in Diabetic Patients

    PubMed Central

    Qiu, Xiangzhe; Zhang, Yanjun; Feng, Hongbo; Jiang, Donglang

    2016-01-01

    Recent studies have demonstrated alterations in the topological organization of structural brain networks in diabetes mellitus (DM). However, the DM-related changes in the topological properties in functional brain networks are unexplored so far. We therefore used fluoro-D-glucose positron emission tomography (FDG-PET) data to construct functional brain networks of 73 DM patients and 91 sex- and age-matched normal controls (NCs), followed by a graph theoretical analysis. We found that both DM patients and NCs had a small-world topology in functional brain network. In comparison to the NC group, the DM group was found to have significantly lower small-world index, lower normalized clustering coefficients and higher normalized characteristic path length. Moreover, for diabetic patients, the nodal centrality was significantly reduced in the right rectus, the right cuneus, the left middle occipital gyrus, and the left postcentral gyrus, and it was significantly increased in the orbitofrontal region of the left middle frontal gyrus, the left olfactory region, and the right paracentral lobule. Our results demonstrated that the diabetic brain was associated with disrupted topological organization in the functional PET network, thus providing functional evidence for the abnormalities of brain networks in DM. PMID:27303259

  18. Cognitive, neurophysiological, and functional correlates of proverb interpretation abnormalities in schizophrenia.

    PubMed

    Kiang, Michael; Light, Gregory A; Prugh, Jocelyn; Coulson, Seana; Braff, David L; Kutas, Marta

    2007-07-01

    A hallmark of schizophrenia is impaired proverb interpretation, which could be due to: (1) aberrant activation of disorganized semantic associations, or (2) working memory (WM) deficits. We assessed 18 schizophrenia patients and 18 normal control participants on proverb interpretation, and evaluated these two hypotheses by examining within patients the correlations of proverb interpretation with disorganized symptoms and auditory WM, respectively. Secondarily, we also explored the relationships between proverb interpretation and a spectrum of cognitive functions including auditory sensory-memory encoding (as indexed by the mismatch negativity (MMN) event-related brain potential (ERP)); executive function; and social/occupational function. As expected, schizophrenia patients produced less accurate and less abstract descriptions of proverbs than did controls. These proverb interpretation difficulties in patients were not significantly correlated with disorganization or other symptom factors, but were significantly correlated (p < .05) with WM impairment, as well as with impairments in sensory-memory encoding, executive function, and social/occupational function. These results offer no support for disorganized associations in abnormal proverb interpretation in schizophrenia, but implicate WM deficits, perhaps as a part of a syndrome related to generalized frontal cortical dysfunction. PMID:17521483

  19. Positron Emission Tomography Reveals Abnormal Topological Organization in Functional Brain Network in Diabetic Patients.

    PubMed

    Qiu, Xiangzhe; Zhang, Yanjun; Feng, Hongbo; Jiang, Donglang

    2016-01-01

    Recent studies have demonstrated alterations in the topological organization of structural brain networks in diabetes mellitus (DM). However, the DM-related changes in the topological properties in functional brain networks are unexplored so far. We therefore used fluoro-D-glucose positron emission tomography (FDG-PET) data to construct functional brain networks of 73 DM patients and 91 sex- and age-matched normal controls (NCs), followed by a graph theoretical analysis. We found that both DM patients and NCs had a small-world topology in functional brain network. In comparison to the NC group, the DM group was found to have significantly lower small-world index, lower normalized clustering coefficients and higher normalized characteristic path length. Moreover, for diabetic patients, the nodal centrality was significantly reduced in the right rectus, the right cuneus, the left middle occipital gyrus, and the left postcentral gyrus, and it was significantly increased in the orbitofrontal region of the left middle frontal gyrus, the left olfactory region, and the right paracentral lobule. Our results demonstrated that the diabetic brain was associated with disrupted topological organization in the functional PET network, thus providing functional evidence for the abnormalities of brain networks in DM. PMID:27303259

  20. Abnormal GABAergic Function and Face Processing in Schizophrenia: A Pharmacologic-fMRI Study

    PubMed Central

    Tso, Ivy F.; Fang, Yu; Phan, K. Luan; Welsh, Robert C.; Taylor, Stephan F.

    2015-01-01

    The involvement of the gamma-aminobutyric acid (GABA) system in schizophrenia is suggested by postmortem studies and the common use of GABA receptor-potentiating agents in treatment. In a recent study, we used a benzodiazepine challenge to demonstrate abnormal GABAergic function during processing of negative visual stimuli in schizophrenia. This study extended this investigation by mapping GABAergic mechanisms associated with face processing and social appraisal in schizophrenia using a benzodiazepine challenge. Fourteen stable, medicated schizophrenia/schizoaffective patients (SZ) and 13 healthy controls (HC) underwent functional MRI using the blood oxygenation level-dependent (BOLD) technique while they performed the Socio-emotional Preference Task (SePT) on emotional face stimuli (“Do you like this face?”). Participants received single-blinded intravenous saline and lorazepam (LRZ) in two separate sessions separated by 1-3 weeks. Both SZ and HC recruited medial prefrontal cortex/anterior cingulate during the SePT, relative to gender identification. A significant drug by group interaction was observed in the medial occipital cortex, such that SZ showed increased BOLD signal to LRZ challenge, while HC showed an expected decrease of signal; the interaction did not vary by task. The altered BOLD response to LRZ challenge in SZ was significantly correlated with increased negative affect across multiple measures. The altered response to LRZ challenge suggests that abnormal face processing and negative affect in SZ are associated with altered GABAergic function in the visual cortex, underscoring the role of impaired visual processing in socio-emotional deficits in schizophrenia. PMID:26363970

  1. Abnormal GABAergic function and face processing in schizophrenia: A pharmacologic-fMRI study.

    PubMed

    Tso, Ivy F; Fang, Yu; Phan, K Luan; Welsh, Robert C; Taylor, Stephan F

    2015-10-01

    The involvement of the gamma-aminobutyric acid (GABA) system in schizophrenia is suggested by postmortem studies and the common use of GABA receptor-potentiating agents in treatment. In a recent study, we used a benzodiazepine challenge to demonstrate abnormal GABAergic function during processing of negative visual stimuli in schizophrenia. This study extended this investigation by mapping GABAergic mechanisms associated with face processing and social appraisal in schizophrenia using a benzodiazepine challenge. Fourteen stable, medicated schizophrenia/schizoaffective patients (SZ) and 13 healthy controls (HC) underwent functional MRI using the blood oxygenation level-dependent (BOLD) technique while they performed the Socio-emotional Preference Task (SePT) on emotional face stimuli ("Do you like this face?"). Participants received single-blinded intravenous saline and lorazepam (LRZ) in two separate sessions separated by 1-3weeks. Both SZ and HC recruited medial prefrontal cortex/anterior cingulate during the SePT, relative to gender identification. A significant drug by group interaction was observed in the medial occipital cortex, such that SZ showed increased BOLD signal to LRZ challenge, while HC showed an expected decrease of signal; the interaction did not vary by task. The altered BOLD response to LRZ challenge in SZ was significantly correlated with increased negative affect across multiple measures. The altered response to LRZ challenge suggests that abnormal face processing and negative affect in SZ are associated with altered GABAergic function in the visual cortex, underscoring the role of impaired visual processing in socio-emotional deficits in schizophrenia. PMID:26363970

  2. Abnormal Functional Connectivity of Amygdala in Late-Onset Depression Was Associated with Cognitive Deficits

    PubMed Central

    Yue, Yingying; Yuan, Yonggui; Hou, Zhenghua; Jiang, Wenhao; Bai, Feng; Zhang, Zhijun

    2013-01-01

    Background Major depressive disorder (MDD) is associated with decreased function of cortico-limbic circuits, which play important roles in the pathogenesis of MDD. Abnormal functional connectivity (FC) with the amygdala, which is involved in cortico-limbic circuits, has also been observed in MDD. However, little is known about connectivity alterations in late-onset depression (LOD) or whether disrupted connectivity is correlated with cognitive impairment in LOD. Methods and Results A total of twenty-two LOD patients and twenty-two matched healthy controls (HC) underwent neuropsychological tests and resting state functional magnetic resonance imaging (rs-fMRI). Regional homogeneity (ReHo) and FC with bilateral amygdala seeds were used to analyze blood oxygen level-dependent fMRI data between two groups. Compared with HC, LOD patients showed decreased ReHo in the right middle frontal gyrus and left superior frontal gyrus. In the LOD group, the left amygdala had decreased FC with the right middle frontal gyrus and the left superior frontal gyrus in the amygdala positive network, and it had increased FC with the right post-central gyrus in the amygdala negative network. However, significantly reduced FC with the right amygdala was observed in the right middle occipital gyrus in the amygdala negative network. Further correlative analyses revealed that decreased FC between the amygdala and the right middle occipital gyrus was negatively correlated with the verbal fluency test (VFT, r = −0.485, P = 0.022) and the digit span test (DST, r = −0.561, P = 0.007). Conclusions Our findings of reduced activity of the prefrontal gyrus and abnormal FC with the bilateral amygdala may be key markers of cognitive dysfunction in LOD patients. PMID:24040385

  3. Kidney Function, Endothelial Activation and Atherosclerosis in Black and White Africans with Rheumatoid Arthritis

    PubMed Central

    Dessein, Patrick H.; Hsu, Hon-Chun; Tsang, Linda; Millen, Aletta M. E.; Woodiwiss, Angela J.; Norton, Gavin R.; Solomon, Ahmed; Gonzalez-Gay, Miguel A.

    2015-01-01

    Objective To determine whether kidney function independently relates to endothelial activation and ultrasound determined carotid atherosclerosis in black and white Africans with rheumatoid arthritis (RA). Methods We calculated the Jelliffe, 5 Cockcroft-Gault equations, Salazar-Corcoran, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (EGFR) equations in 233 (112 black) RA patients. Results The CKD-EPI eGFR was <90 ml/min/1.73m2 in 49.1% and 30.6% of black and white patients, respectively (odds ratio (95% confidence interval) = 2.19 (1.28–3.75), p = 0.004). EGFRs were overall consistently associated with monocyte chemoattractant protein-1 and angiopoietin 2 concentrations in white patients, and with carotid intima-media thickness and plaque in black participants. Amongst black patients, plaque prevalence was 36.7% and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was not associated with plaque presence for the MDRD equation (p = 0.3), whereas the respective relationship was significant or borderline significant (p = 0.003 to 0.08) and of similar extent (p>0.1 for comparisons of AUC (SE)) for the other 8 equations. Based on optimal eGFR cutoff values with sensitivities and specificities ranging from 42 to 60% and 70 to 91% respectively, as determined in ROC curve analysis, a low eGFR increased the odds ratio for plaque 2.2 to 4.0 fold. Conclusion Reduced kidney function is independently associated with atherosclerosis and endothelial activation in black and white Africans with RA, respectively. CKD is highly prevalent in black Africans with RA. Apart from the MDRD, eGFR equations are useful in predicting carotid plaque presence, a coronary heart disease equivalent, amongst black African RA patients. PMID:25806966

  4. Coffee polyphenol consumption improves postprandial hyperglycemia associated with impaired vascular endothelial function in healthy male adults.

    PubMed

    Jokura, Hiroko; Watanabe, Isamu; Umeda, Mika; Hase, Tadashi; Shimotoyodome, Akira

    2015-10-01

    Epidemiological studies indicate that habitual coffee consumption lowers the risk of diabetes and cardiovascular diseases. Postprandial hyperglycemia is a direct and independent risk factor for cardiovascular diseases. We previously demonstrated that coffee polyphenol ingestion increased secretion of Glucagon-like peptide 1 (GLP-1), which has been shown to exhibit anti-diabetic and cardiovascular effects. We hypothesized coffee polyphenol consumption may improve postprandial hyperglycemia and vascular endothelial function by increasing GLP-1 release and/or reducing oxidative stress. To examine this hypothesis, we conducted a randomized, acute, crossover, intervention study in healthy male adults, measuring blood parameters and flow-mediated dilation (FMD) after ingestion of a meal with or without coffee polyphenol extract (CPE). Nineteen subjects consumed a test meal with either a placebo- or CPE-containing beverage. Blood biomarkers and FMD were measured at fasting and up to 180 minutes postprandially. The CPE beverage led to a significantly lower peak postprandial increase in blood glucose and diacron-reactive oxygen metabolite, and significantly higher postprandial FMD than the placebo beverage. Postprandial blood GLP-1 increase tended to be higher after ingestion of the CPE beverage, compared with placebo. Subclass analysis revealed that the CPE beverage significantly improved postprandial blood GLP-1 response and reduced blood glucose increase in the subjects with a lower insulinogenic index. Correlation analysis showed postprandial FMD was negatively associated with blood glucose increase after ingestion of the CPE beverage. In conclusion, these results suggest that coffee polyphenol consumption improves postprandial hyperglycemia and vascular endothelial function, which is associated with increased GLP-1 secretion and decreased oxidative stress in healthy humans.

  5. First report on the association of drinking water hardness and endothelial function in children and adolescents

    PubMed Central

    Poursafa, Parinaz; Kelishadi, Roya; Hashemi, Mohammad; Amin, Maryam

    2014-01-01

    Introduction This study aims to investigate the relationship of water hardness and its calcium and magnesium content with endothelial function in a population-based sample of healthy children and adolescents. Material and methods This case-control study was conducted in 2012 among 90 individuals living in two areas with moderate and high water hardness in Isfahan County, Iran. The flow-mediated dilatation (FMD) of the brachial artery and the serum levels of soluble adhesion molecules (sICAM-1, sVCAM-1) were measured as surrogate markers of endothelial function, and high-sensitivity C-reactive protein (hs-CRP), as a marker of inflammation. Results Data of 89 participants (51% boys, mean age 14.75 (2.9) years) were complete. Those participants living in the area with high water hardness had higher FMD, hs-CRP, and soluble adhesion molecules (sICAM-1, sVCAM-1) than their counterparts living in the area with moderate water hardness. Multiple linear regression analysis showed that after adjustment for confounding factors of age, gender, body mass index, healthy eating index and physical activity level, total water hardness, as well as water content of calcium and magnesium, had a significant positive relationship with FMD. The corresponding associations were inverse and significant with soluble adhesion molecules (p < 0.05). Conclusions This study, which to the best of our knowledge is the first of its kind in the pediatric age group, suggests that water hardness, as well as its calcium and magnesium content, may have a protective role against early stages of atherosclerosis in children and adolescents. PMID:25276160

  6. Pentoxifylline, Inflammation, and Endothelial Function in HIV-Infected Persons: A Randomized, Placebo-Controlled Trial

    PubMed Central

    Gupta, Samir K.; Mi, Deming; Dubé, Michael P.; Saha, Chandan K.; Johnson, Raymond M.; Stein, James H.; Clauss, Matthias A.; Mather, Kieren J.; Desta, Zeruesenay; Liu, Ziyue

    2013-01-01

    Background Untreated HIV may increase the risk of cardiovascular events. Our preliminary in vitro and in vivo research suggests that pentoxifylline (PTX) reduces vascular inflammation and improves endothelial function in HIV-infected persons not requiring antiretroviral therapy. Methods We performed a randomized, placebo-controlled trial of PTX 400 mg orally thrice daily for 8 weeks in 26 participants. The primary endpoint was change in flow-mediated dilation (FMD) of the brachial artery after 8 weeks. Nitroglycerin-mediated dilation (NTGMD) and circulating markers of inflammation, cellular immune activation, coagulation, and metabolism were also assessed. Results The difference in mean absolute change (SD) in FMD after 8 weeks between the placebo [−1.06 (1.45)%] and PTX [−1.93 (3.03)%] groups was not significant (P = 0.44). No differences in NTGMD were observed. The only significant between-group difference in the changes in biomarkers from baseline to week 8 was in soluble tumor necrosis factor receptor-1 (sTNFRI) [−83.2 pg/mL in the placebo group vs. +65.9 pg/mL in the PTX group; P = 0.03]. PTX was generally well-tolerated. Conclusions PTX did not improve endothelial function and unexpectedly increased the inflammatory biomarker sTNFRI in HIV-infected participants not requiring antiretroviral therapy. Additional interventional research is needed to reduce inflammation and cardiovascular risk in this population. Trial Registration ClinicalTrials.gov NCT00796822 PMID:23593327

  7. Molecular cloning and functional analysis of SUT-1, a sulfate transporter from human high endothelial venules

    PubMed Central

    Girard, Jean-Philippe; Baekkevold, Espen S.; Feliu, Jacques; Brandtzaeg, Per; Amalric, François

    1999-01-01

    High endothelial venules (HEV) are specialized postcapillary venules found in lymphoid organs and chronically inflamed tissues that support high levels of lymphocyte extravasation from the blood. One of the major characteristics of HEV endothelial cells (HEVEC) is their capacity to incorporate large amounts of sulfate into sialomucin-type counter-receptors for the lymphocyte homing receptor L-selectin. Here, we show that HEVEC express two functional classes of sulfate transporters defined by their differential sensitivity to the anion-exchanger inhibitor 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS), and we report the molecular characterization of a DIDS-resistant sulfate transporter from human HEVEC, designated SUT-1. SUT-1 belongs to the family of Na+-coupled anion transporters and exhibits 40–50% amino acid identity with the rat renal Na+/sulfate cotransporter, NaSi-1, as well as with the human and rat Na+/dicarboxylate cotransporters, NaDC-1/SDCT1 and NaDC-3/SDCT2. Functional expression studies in cRNA-injected Xenopus laevis oocytes showed that SUT-1 mediates high levels of Na+-dependent sulfate transport, which is resistant to DIDS inhibition. The SUT-1 gene mapped to human chromosome 7q33. Northern blotting analysis revealed that SUT-1 exhibits a highly restricted tissue distribution, with abundant expression in placenta. Reverse transcription–PCR analysis indicated that SUT-1 and the diastrophic dysplasia sulfate transporter (DTD), one of the two known human DIDS-sensitive sulfate transporters, are coexpressed in HEVEC. SUT-1 and DTD could correspond, respectively, to the DIDS-resistant and DIDS-sensitive components of sulfate uptake in HEVEC. Together, these results demonstrate that SUT-1 is a distinct human Na+-coupled sulfate transporter, likely to play a major role in sulfate incorporation in HEV. PMID:10535998

  8. Long-term Successful Weight Loss Improves Vascular Endothelial Function in Severely Obese Individuals

    PubMed Central

    Bigornia, Sherman J.; Mott, Melanie M.; Hess, Donald T.; Apovian, Caroline M.; McDonnell, Marie E.; Duess, Mai-Ann; Kluge, Matthew A.; Fiscale, Antonino J.; Vita, Joseph A.; Gokce, Noyan

    2010-01-01

    Obesity is associated with increased cardiovascular risk. Although short-term weight loss improves vascular endothelial function, longer term outcomes have not been widely investigated. We examined brachial artery endothelium-dependent vasodilation and metabolic parameters in 29 severely obese subjects who lost ≥10% body weight (age 45 ± 13 years; BMI 48 ± 9 kg/m2) at baseline and after 12 months of dietary and/or surgical intervention. We compared these parameters to 14 obese individuals (age 49 ± 11 years; BMI 39 ± 7 kg/m2) who failed to lose weight. For the entire group, mean brachial artery flow-mediated dilation (FMD) was impaired at 6.7 ± 4.1%. Following sustained weight loss, FMD increased significantly from 6.8 ± 4.2 to 10.0 ± 4.7%, but remained blunted in patients without weight decline from 6.5 ± 4.0 to 5.7 ± 4.1%, P = 0.013 by ANOVA. Endothelium-independent, nitroglycerin-mediated dilation (NMD) was unaltered. BMI fell by 13 ± 7 kg/m2 following successful weight intervention and was associated with reduced total and low-density lipoprotein cholesterol, glucose, hemoglobin A1c, and high-sensitivity C-reactive protein (CRP). Vascular improvement correlated most strongly with glucose levels (r = −0.51, P = 0.002) and was independent of weight change. In this cohort of severely obese subjects, sustained weight loss at 1 year improved vascular function and metabolic parameters. The findings suggest that reversal of endothelial dysfunction and restoration of arterial homeostasis could potentially reduce cardiovascular risk. The results also demonstrate that metabolic changes in association with weight loss are stronger determinants of vascular phenotype than degree of weight reduction. PMID:20057371

  9. Endothelial Angiogenesis and Barrier Function in Response to Thrombin Require Ca2+ Influx through the Na+/Ca2+ Exchanger*

    PubMed Central

    Andrikopoulos, Petros; Kieswich, Julius; Harwood, Steven M.; Baba, Akemichi; Matsuda, Toshio; Barbeau, Olivier; Jones, Keith; Eccles, Suzanne A.; Yaqoob, Muhammad M.

    2015-01-01

    Thrombin acts on the endothelium by activating protease-activated receptors (PARs). The endothelial thrombin-PAR system becomes deregulated during pathological conditions resulting in loss of barrier function and a pro-inflammatory and pro-angiogenic endothelial phenotype. We reported recently that the ion transporter Na+/Ca2+ exchanger (NCX) operating in the Ca2+-influx (reverse) mode promoted ERK1/2 activation and angiogenesis in vascular endothelial growth factor-stimulated primary human vascular endothelial cells. Here, we investigated whether Ca2+ influx through NCX was involved in ERK1/2 activation, angiogenesis, and endothelial barrier dysfunction in response to thrombin. Reverse-mode NCX inhibitors and RNAi-mediated NCX1 knockdown attenuated ERK1/2 phosphorylation in response to thrombin or an agonist of PAR-1, the main endothelial thrombin receptor. Conversely, promoting reverse-mode NCX by suppressing Na+-K+-ATPase activity enhanced ERK1/2 activation. Reverse-mode NCX inhibitors and NCX1 siRNA suppressed thrombin-induced primary human vascular endothelial cell angiogenesis, quantified as proliferation and tubular differentiation. Reverse-mode NCX inhibitors or NCX1 knockdown preserved barrier integrity upon thrombin stimulation in vitro. Moreover, the reverse-mode NCX inhibitor SEA0400 suppressed Evans' blue albumin extravasation to the lung and kidneys and attenuated edema formation and ERK1/2 activation in the lungs of mice challenged with a peptide activator of PAR-1. Mechanistically, thrombin-induced ERK1/2 activation required NADPH oxidase 2-mediated reactive oxygen species (ROS) production, and reverse-mode NCX inhibitors and NCX1 siRNA suppressed thrombin-induced ROS production. We propose that reverse-mode NCX is a novel mechanism contributing to thrombin-induced angiogenesis and hyperpermeability by mediating ERK1/2 activation in a ROS-dependent manner. Targeting reverse-mode NCX could be beneficial in pathological conditions involving

  10. Abnormalities of Reproductive Function in Male Obesity Before and After Bariatric Surgery-A Comprehensive Review.

    PubMed

    Rosenblatt, Alberto; Faintuch, Joel; Cecconello, Ivan

    2015-07-01

    Young males represent one of the populations with the steepest increases in the incidence of obesity. They are also prone to significant derangements in sexual health and fertility. Despite a growing number of reports about female reproductive health, in the setting of bariatric surgery, males have received much less attention. In the current review of reproductive abnormalities in severe obese males before and after bariatric surgery, erectile function, hypothalamic-pituitary-gonadal axis status, sex hormones, semen quality, fertility and assisted reproductive techniques, along with analysis of adipokines, gut hormones, and environmental factors are addressed. Available evidence about weight loss benefits, both medical and surgical, are highlighted, along with perspectives for future investigations, which may be relevant for the patient, for the couple, and for the community alike.

  11. Structural and Functional Coronary Artery Abnormalities in Patients With Vasospastic Angina Pectoris.

    PubMed

    Ong, Peter; Aziz, Ahmed; Hansen, Henrik Steen; Prescott, Eva; Athanasiadis, Anastasios; Sechtem, Udo

    2015-01-01

    Coronary spasm is involved in many clinical scenarios, such as stable angina, acute coronary syndrome, sudden cardiac death, non-ischemic cardiomyopathy, arrhythmia and syncope. In recent years, imaging tools such as computerized tomographic angiography, intravascular ultrasound or optical coherence tomography have been applied to study the coronary pathology in patients with vasospastic angina. Patients with vasospastic angina represent a heterogeneous cohort of patients with regard to the extent of concomitant coronary atherosclerosis. They share the common pathophysiological phenomenon of vascular smooth muscle hyperreactivity leading to spasm caused by various factors that may also overlap. Focal coronary spasm is related to epicardial atherosclerosis and in the presence of obstructive coronary artery disease it may be useful to treat the lesion to prevent further spasm. The aim of this article is to review structural and functional coronary artery abnormalities in patients with vasospastic angina.

  12. Functional Connectivity Abnormalities of Brain Regions with Structural Deficits in Young Adult Male Smokers

    PubMed Central

    Bu, Limei; Yu, Dahua; Su, Shaoping; Ma, Yao; von Deneen, Karen M.; Luo, Lin; Zhai, Jinquan; Liu, Bo; Cheng, Jiadong; Guan, Yanyan; Li, Yangding; Bi, Yanzhi; Xue, Ting; Lu, Xiaoqi; Yuan, Kai

    2016-01-01

    Smoking is one of the most prevalent dependence disorders. Previous studies have detected structural and functional deficits in smokers. However, few studies focused on the changes of resting state functional connectivity (RSFC) of the brain regions with structural deficits in young adult smokers. Twenty-six young adult smokers and 26 well-matched healthy non-smokers participated in our study. Voxel-based morphometry (VBM) and RSFC were employed to investigate the structural and functional changes in young adult smokers. Compared with healthy non-smokers, young smokers showed increased gray matter (GM) volume in the left putamen and decreased GM volume in the left anterior cingulate cortex (ACC). Moreover, GM volume in the left ACC has a negative correlation trend with pack-years and GM volume in the left putamen was positively correlated with pack-years. The left ACC and putamen with abnormal volumes were chosen as the regions of interest (ROIs) for the RSFC analysis. We found that smokers showed increased RSFC between the left ACC and right amygdala and between the left putamen and right anterior insula. We revealed structural and functional deficits within the frontostriatal circuits in young smokers, which may shed new insights into the neural mechanisms of smoking. PMID:27757078

  13. Abnormalities in Parentally Rated Executive Function in Methamphetamine/Polysubstance Exposed Children

    PubMed Central

    Piper, Brian J.; Acevedo, Summer F.; Kolchugina, Galena K.; Butler, Robert W.; Corbett, Selena M.; Honeycutt, Elizabeth B.; Craytor, Michael J.; Raber, Jacob

    2011-01-01

    Methamphetamine/polysubstance abuse in women of childbearing age is a major concern because of the potential long-term detrimental effects on the brain function of the fetus following in utero exposure. A battery of established tests, including the Wechsler Abbreviated Scale of Intelligence, Conners’ Continuous Performance Test II, Behavioral Rating Inventory of Executive Function, the CMS Family Pictures and Dot Location tests, the Spatial Span test from the WISC-IV-Integrated, and a recently developed spatial learning and memory measure (Memory Island), was used to assess the effects of prenatal drug exposure on neurobehavioral performance. Participants were 7 to 9 year old children from similar socioeconomic backgrounds who either had (N = 31) or had not (N = 35) been exposed to methamphetamine/polysubstance during pregnancy. Compared to unexposed children, exposed children showed pronounced elevations (i.e. more problems) in parental ratings of executive function, including behavioral regulation and metacognition. Exposed children also exhibited subtle reductions in spatial performance in the Memory Island test. In contrast, IQ, Spatial Span, Family Pictures, Dot Location, and vigilance performance was unaffected by prenatal drug exposure history. Thus, children of women who reported using methamphetamine and other recreational drugs during pregnancy showed a selective profile of abnormalities in parentally rated executive function. PMID:21334365

  14. Abnormalities in parentally rated executive function in methamphetamine/polysubstance exposed children.

    PubMed

    Piper, Brian J; Acevedo, Summer F; Kolchugina, Galena K; Butler, Robert W; Corbett, Selena M; Honeycutt, Elizabeth B; Craytor, Michael J; Raber, Jacob

    2011-05-01

    Methamphetamine/polysubstance abuse in women of childbearing age is a major concern because of the potential long-term detrimental effects on the brain function of the fetus following in utero exposure. A battery of established tests, including the Wechsler Abbreviated Scale of Intelligence, Conners' Continuous Performance Test II, Behavioral Rating Inventory of Executive Function, the CMS Family Pictures and Dot Location tests, the Spatial Span test from the WISC-IV-Integrated, and a recently developed spatial learning and memory measure (Memory Island), was used to assess the effects of prenatal drug exposure on neurobehavioral performance. Participants were 7 to 9 year old children from similar socioeconomic backgrounds who either had (N=31) or had not (N=35) been exposed to methamphetamine/polysubstance during pregnancy. Compared to unexposed children, exposed children showed pronounced elevations (i.e. more problems) in parental ratings of executive function, including behavioral regulation and metacognition. Exposed children also exhibited subtle reductions in spatial performance in the Memory Island test. In contrast, IQ, Spatial Span, Family Pictures, Dot Location, and vigilance performance were unaffected by prenatal drug exposure history. Thus, children of women who reported using methamphetamine and other recreational drugs during pregnancy showed a selective profile of abnormalities in parentally rated executive function.

  15. Abnormal functional connectivity of the medial cortex in euthymic bipolar II disorder.

    PubMed

    Marchand, William R; Lee, James N; Johnson, Susanna; Gale, Phillip; Thatcher, John

    2014-06-01

    This project utilized functional MRI (fMRI) and a motor activation paradigm to investigate neural circuitry in euthymic bipolar II disorder. We hypothesized that circuitry involving the cortical midline structures (CMS) would demonstrate abnormal functional connectivity. Nineteen subjects with recurrent bipolar disorder and 18 controls were studied using fMRI and a motor activation paradigm. We used functional connectivity analyses to identify circuits with aberrant connectivity. We found increased functional connectivity among bipolar subjects compared to healthy controls in two CMS circuits. One circuit included the medial aspect of the left superior frontal gyrus and the dorsolateral region of the left superior frontal gyrus. The other included the medial aspect of the right superior frontal gyrus, the dorsolateral region of the left superior frontal gyrus and the right medial frontal gyrus and surrounding region. Our results indicate that CMS circuit dysfunction persists in the euthymic state and thus may represent trait pathology. Future studies should address whether these circuits contribute to relapse of illness. Our results also suggest the possibility that aberrations of superior frontal circuitry may impact default mode network and cognitive processes.

  16. Abnormal striatal resting-state functional connectivity in adolescents with obsessive-compulsive disorder.

    PubMed

    Bernstein, Gail A; Mueller, Bryon A; Schreiner, Melinda Westlund; Campbell, Sarah M; Regan, Emily K; Nelson, Peter M; Houri, Alaa K; Lee, Susanne S; Zagoloff, Alexandra D; Lim, Kelvin O; Yacoub, Essa S; Cullen, Kathryn R

    2016-01-30

    Neuroimaging research has implicated abnormalities in cortico-striatal-thalamic-cortical (CSTC) circuitry in pediatric obsessive-compulsive disorder (OCD). In this study, resting-state functional magnetic resonance imaging (R-fMRI) was used to investigate functional connectivity in the CSTC circuitry in adolescents with OCD. Imaging was obtained with the Human Connectome Project (HCP) scanner using newly developed pulse sequences which allow for higher spatial and temporal resolution. Fifteen adolescents with OCD and 13 age- and gender-matched healthy controls (ages 12-19) underwent R-fMRI on the 3T HCP scanner. Twenty-four minutes of resting-state scans (two consecutive 12-min scans) were acquired. We investigated functional connectivity of the striatum using a seed-based, whole brain approach with anatomically-defined seeds placed in the bilateral caudate, putamen, and nucleus accumbens. Adolescents with OCD compared with controls exhibited significantly lower functional connectivity between the left putamen and a single cluster of right-sided cortical areas including parts of the orbitofrontal cortex, inferior frontal gyrus, insula, and operculum. Preliminary findings suggest that impaired striatal connectivity in adolescents with OCD in part falls within the predicted CSTC network, and also involves impaired connections between a key CSTC network region (i.e., putamen) and key regions in the salience network (i.e., insula/operculum). The relevance of impaired putamen-insula/operculum connectivity in OCD is discussed. PMID:26674413

  17. Predictors of Endothelial Function in Employees with Sedentary Occupations in a Worksite Exercise Program

    PubMed Central

    Lippincott, Margaret F.; Desai, Aditi; Zalos, Gloria; Carlow, Andrea; De Jesus, Janet; Blum, Arnon; Smith, Kevin; Rodrigo, Maria; Patibandla, Sushmitha; Chaudhry, Hira; Glaser, Alexander P.; Schenke, William H.; Csako, Gyorgy; Waclawiw, Myron A.; Cannon, Richard O.

    2008-01-01

    A sedentary work force may be at increased risk of future cardiovascular disease. Exercise at the worksite has been advocated, but effects on endothelium as a biomarker of risk and relation to weight loss, lipid changes or circulating endothelial progenitor cells (EPCs) have not been reported. Seventy-two office and laboratory (26 with body-mass index [BMI] > 30 kg/m2) employees (58 women; average age 45 years; range: 22-62 years) completed 3 months of participation in the National Heart, Lung, and Blood Institute's “Keep the Beat” program, with determination of vital signs, laboratory data and peak oxygen consumption (VO2) during treadmill exercise. Brachial artery endothelium was tested by flow-mediated dilation (FMD), which at baseline was inversely associated with Framingham risk score (r=-0.3689, P<0.0001). EPCs were quantified by colony assay. With exercise averaging 98±47 (mean±SD) minutes each work week, there was improvement in FMD (from 7.8±3.4 to 8.5±3.0%, P=0.0096) and peak VO2 (+1.2±3.1 mL O2/kg/min; P=0.0028), with reduction in diastolic blood pressure (-2±8 mmHg; P=0.0478), total cholesterol (-8±25 mg/dL, P=0.0131), low-density lipoprotein (LDL) cholesterol (-7±19 mg/dL, P=0.0044), but with marginal reduction in weight (-0.5±2.1 kg, P=0.0565). By multiple regression modeling, lower baseline FMD, greater age, reductions in total and LDL cholesterol and diastolic blood pressure, and increases in EPC colonies and peak VO2 were jointly statistically significant predictors of change in FMD and accounted for 47% of the variability in FMD improvement with program participation. Results were similar when modeling was performed for women only. By contrast, neither adiposity at baseline nor change in weight were predictors of improved endothelial function. In conclusion, daily exercise achievable in the worksite by employees with sedentary occupations improves endothelial function—even with absence of weight loss--which may decrease

  18. Functional brain abnormalities in psychiatric disorders: neural mechanisms to detect and resolve cognitive conflict and interference.

    PubMed

    Melcher, Tobias; Falkai, Peter; Gruber, Oliver

    2008-11-01

    In the present article, we review functional neuroimaging studies on interference processing and performance monitoring in three groups of psychiatric disorders, (1) mood disorders, (2) schizophrenia, and (3) obsessive-compulsive disorder (OCD). Ad (1) Behavioral performance measures suggest an impaired interference resolution capability in symptomatic bipolar disorder patients. A series of neuroimaging analyses found alterations in the ACC-DLPFC system in mood disorder (unipolar depressed and bipolar) patients, putatively reflective of an abnormal interplay of monitoring and executive neurocognitive functions. Other studies of euthymic bipolar patients showed relatively decreased interference-related activation in rostroventral PFC which conceivably underlies defective inhibitory control. Ad (2) Behavioral Stroop studies revealed a specific performance pattern of schizophrenia patients (normal RT interference but increased error interference and RT facilitation) suggestive of a deficit in ignoring irrelevant (word) information. Moreover, reduced/absent behavioral post-error and post-conflict adaptation effects suggest alterations in performance monitoring and/or adjustment capability in these patients. Neuroimaging findings converge to suggest a disorder-related abnormal neurophysiology in ACC which consistently showed conflict- and error-related hypoactivation that, however, appeared to be modulated by different factors. Moreover, studies suggest a specific deficit in context processing in schizophrenia, evidently related to activation reduction in DLPFC. Ad (3) Behavioral findings provide evidence for impaired interference resolution in OCD. Neuroimaging results consistently showed conflict- and error-related ACC hyperactivation which--conforming OCD pathogenesis models--can be conclusively interpreted as reflecting overactive performance monitoring. Taken together, interference resolution and performance monitoring appeared to be fruitful concepts in the

  19. Abnormal activation of the motor cortical network in idiopathic scoliosis demonstrated by functional MRI.

    PubMed

    Domenech, Julio; García-Martí, G; Martí-Bonmatí, L; Barrios, C; Tormos, J M; Pascual-Leone, A

    2011-07-01

    The aetiology of idiopathic scoliosis (IS) remains unknown, but there is growing support for the possibility of an underlying neurological disorder. Functional magnetic resonance imaging (fMRI) can characterize the abnormal activation of the sensorimotor brain network in movement disorders and could provide further insights into the neuropathogenesis of IS. Twenty subjects were included in the study; 10 adolescents with IS (mean age of 15.2, 8 girls and 2 boys) and 10 age-matched healthy controls. The average Cobb angle of the primary curve in the IS patients was 35° (range 27°-55°). All participants underwent a block-design fMRI experiment in a 1.5-Tesla MRI scanner to explore cortical activation following a simple motor task. Rest periods alternated with activation periods during which participants were required to open and close their hand at an internally paced rate of approximately 1 Hz. Data were analyzed with Statistical Parametric Mapping (SPM5) including age, sex and laterality as nuisance variables to minimise the presence of bias in the results. Compared to controls, IS patients showed significant increases in blood oxygenation level dependent (BOLD) activity in contralateral supplementary motor area when performing the motor task with either hand. No significant differences were observed when testing between groups in the functional activation in the primary motor cortex, premotor cortex and somatosensory cortex. Additionally, the IS group showed a greater interhemispheric asymmetry index than the control group (0.30 vs. 0.13, p < 0.001). This study demonstrates an abnormal pattern of brain activation in secondary motor areas during movement execution in patients with IS. These findings support the hypothesis that a sensorimotor integration disorder underlies the pathogenesis of IS.

  20. Firewall function of the endothelial glycocalyx in the regulation of sodium homeostasis.

    PubMed

    Korte, Stefanie; Wiesinger, Anne; Straeter, Alexandra S; Peters, Wladimir; Oberleithner, Hans; Kusche-Vihrog, Kristina

    2012-02-01

    Plasma sodium, slightly above normal and in presence of aldosterone, stiffens vascular endothelium and reduces nitric oxide release with the consequence of endothelial dysfunction. This process is mediated by epithelial sodium channels (ENaC) and, most likely, the endothelial Na(+)/K(+)-ATPase. Both, ENaC and Na(+)/K(+)-ATPase, are located in the plasma membrane of endothelial cells and embedded in the endothelial glycocalyx (eGC). This negatively charged biopolymer is directly exposed to the blood stream and selectively buffers sodium ions. We hypothesize that the glycocalyx could interfere with endothelial sodium transport when extracellular sodium varies in the physiological range. Therefore, we modeled the endothelial cell as a pump-leak system measuring changes of intracellular sodium in cultured human endothelial cells. Experiments were performed under low/high extracellular sodium conditions before and after enzymatic eGC removal, and with inhibition of Na(+)/K(+)-ATPase and ENaC, respectively. Three major observations were made: (1) eGC removal by heparinase treatment facilitates sodium to enter/exit the endothelial cells. (2) The direction of net sodium movement across the endothelial plasma membrane depends on the concentration of extracellular sodium which regulates both the Na(+)/K(+)-ATPase and ENaC activity. (3) Removal of eGC and inhibition of sodium transport modify the electrical resistance of endothelial cells. We conclude that the eGC serves as a potential "firewall" preventing uncontrolled access of sodium to the pump-leak system of the endothelial cell. After eGC removal, sodium access to the system is facilitated. Thus the pump-leak system could be regulated by ambient sodium and control vascular permeability in pathophysiological conditions. PMID:22057584

  1. Gray Matter Abnormalities in Temporal Lobe Epilepsy: Relationships with Resting-State Functional Connectivity and Episodic Memory Performance

    PubMed Central

    Doucet, Gaelle E.; He, Xiaosong; Sperling, Michael; Sharan, Ashwini; Tracy, Joseph I.

    2016-01-01

    Temporal lobe epilepsy (TLE) affects multiple brain regions through evidence from both structural (gray matter; GM) and functional connectivity (FC) studies. We tested whether these structural abnormalities were associated with FC abnormalities, and assessed the ability of these measures to explain episodic memory impairments in this population. A resting-state and T1 sequences were acquired on 94 (45 with mesial temporal pathology) TLE patients and 50 controls, using magnetic resonance imaging (MRI) technique. A voxel-based morphometry analysis was computed to determine the GM volume differences between groups (right, left TLE, controls). Resting-state FC between the abnormal GM volume regions was computed, and compared between groups. Finally, we investigated the relation between EM, GM and FC findings. Patients with and without temporal pathology were analyzed separately. The results revealed reduced GM volume in multiple regions in the patients relative to the controls. Using FC, we found the abnormal GM regions did not display abnormal functional connectivity. Lastly, we found in left TLE patients, verbal episodic memory was associated with abnormal left posterior hippocampus volume, while in right TLE, non-verbal episodic memory was better predicted by resting-state FC measures. This study investigated TLE abnormalities using a multi-modal approach combining GM, FC and neurocognitive measures. We did not find that the GM abnormalities were functionally or abnormally connected during an inter-ictal resting state, which may reflect a weak sensitivity of functional connectivity to the epileptic network. We provided evidence that verbal and non-verbal episodic memory in left and right TLE patients may have distinct relationships with structural and functional measures. Lastly, we provide data suggesting that in the setting of occult, non-lesional right TLE pathology, a coupling of structural and functional abnormalities in extra-temporal/non-ictal regions is

  2. Association Between Peripheral Vascular Endothelial Function and Progression of Open-Angle Glaucoma.

    PubMed

    Liu, Chun-Hsiu; Su, Wei-Wen; Shie, Shian-Sen; Cheng, Shih-Tsung; Su, Cheng-Wen; Ho, Wang-Jing

    2016-03-01

    The aim of the study is to evaluate the relationship between Humphrey visual field progression and peripheral vascular endothelial function in patients with open-angle glaucoma (OAG), assessed by noninvasive endothelium-dependent flow-mediated vasodilation (FMD).Forty OAG patients, among which 22 had normal-tension glaucoma (NTG) and 18 had primary open-angle glaucoma (POAG) were enrolled. Each enrolled patient underwent a thorough ophthalmological examination including the Humphrey visual field test and measurement of FMD via high-resolution 2-dimensional ultrasonographic imaging of the brachial artery. Blood samples were evaluated for biochemistry and lipid profiles as well as levels of high-sensitivity C-reactive protein (hsCRP). The annual change of threshold sensitivity of the visual field in each test location were analyzed with pointwise linear regression. The correlation between long-term visual field progression and FMD was evaluated.A mean follow-up of 7.47 ± 1.84 years revealed a faster progression rate over the superior visual field in all 40 OAG patients (superior field -0.24 ± 0.67 dB/y, inferior field -0.10 ± 0.59 dB/y, P = 0.37). However, only the annual sensitivity change of the inferior peripheral field showed correlation with baseline FMD. There was no significant difference in the change slope of visual field between NTG and POAG patients.A correlation between baseline brachial artery FMD and visual field progression was observed in the inferior peripheral field in patients with NTG and POAG. This result suggests that peripheral vascular endothelial dysfunction may be related to glaucoma progression.

  3. Measurement of brachial artery endothelial function using a standard blood pressure cuff.

    PubMed

    Maltz, Jonathan S; Tison, Geoffrey H; Alley, Hugh F; Budinger, Thomas F; Owens, Christopher D; Olgin, Jeffrey

    2015-11-01

    The integrity of endothelial function in major arteries (EFMA) is a powerful independent predictor of heart attack and stroke. Existing ultrasound-based non-invasive assessment methods are technically challenging and suitable only for laboratory settings. EFMA, like blood pressure (BP), is both acutely and chronically affected by factors such as lifestyle and medication. Consequently, laboratory-based measurements cannot fully gauge the effects of medical interventions on EFMA. EFMA and BP have, arguably, comparable (but complementary) value in the assessment of cardiovascular health. Widespread deployment of EFMA assessment is thus a desirable clinical goal. To this end, we propose a device based on modifying the measurement protocol of a standard electronic sphygmomanometer. The protocol involves inflating the cuff to sub-diastolic levels to enable recording of the pulse waveform before and after vasodilatory stimulus. The mechanical unloading of the arterial wall provided by the cuff amplifies the distension that occurs with each pulse, which is measured as a pressure variation in the cuff. We show that the height of the rising edge of each pulse is proportional to the change in lumen area between diastole and systole. This allows the effect of vasodilatory stimuli on the artery to be measured with high sensitivity. We compare the proposed cuff flow-mediated dilation (cFMD) method to ultrasound flow-mediated dilation (uFMD). We find significant correlation (r = 0.55, p = 0.003, N = 27) between cFMD- and uFMD-based metrics obtained when the release of a 5 min cuff occlusion is employed to induce endothelial stimulus via reactive hyperemia. cFMD is approximately proportional to the square of uFMD, representing a typical increase in sensitivity to vasodilation of 300-600%. This study illustrates the potential for an individual to conveniently measure his/her EFMA by using a low-cost reprogrammed home sphygmomanometer. PMID:26393958

  4. Molecular and functional characterization of riboflavin specific transport system in rat brain capillary endothelial cells.

    PubMed

    Patel, Mitesh; Vadlapatla, Ramya Krishna; Pal, Dhananjay; Mitra, Ashim K

    2012-08-15

    Riboflavin is an important water soluble vitamin (B2) required for metabolic reactions, normal cellular growth, differentiation and function. Mammalian brain cells cannot synthesize riboflavin and must import from systemic circulation. However, the uptake mechanism, cellular translocation and intracellular trafficking of riboflavin in brain capillary endothelial cells are poorly understood. The primary objective of this study is to investigate the existence of a riboflavin-specific transport system and delineate the uptake and intracellular regulation of riboflavin in immortalized rat brain capillary endothelial cells (RBE4). The uptake of [3H]-riboflavin is sodium, temperature and energy dependent but pH independent. [3H]-Riboflavin uptake is saturable with K(m) and V(max) values of 19 ± 3 μM and 0.235 ± 0.012 pmol/min/mg protein, respectively. The uptake process is inhibited by unlabelled structural analogs (lumiflavin, lumichrome) but not by structurally unrelated vitamins. Ca(++)/calmodulin and protein kinase A (PKA) pathways are found to play an important role in the intracellular regulation of [3H]-riboflavin. Apical and baso-lateral uptake of [3H]-riboflavin clearly indicates that a riboflavin specific transport system is predominantly localized on the apical side of RBE4 cells. A 628 bp band corresponding to a riboflavin transporter is revealed in RT-PCR analysis. These findings, for the first time report the existence of a specialized and high affinity transport system for riboflavin in RBE4 cells. The blood-brain barrier (BBB) is a major obstacle limiting drug transport inside the brain as it regulates drug permeation from systemic circulation. This transporter can be utilized for targeted delivery in enhancing brain permeation of highly potent drugs on systemic administration.

  5. Measurement of brachial artery endothelial function using a standard blood pressure cuff

    PubMed Central

    Maltz, Jonathan S; Tison, Geoffrey H; Alley, Hugh F; Budinger, Thomas F; Owens, Christopher D; Olgin, Jeffrey

    2016-01-01

    The integrity of endothelial function in major arteries (EFMA) is a powerful independent predictor of heart attack and stroke. Existing ultrasound-based non-invasive assessment methods are technically challenging and suitable only for laboratory settings. EFMA, like blood pressure (BP), is both acutely and chronically affected by factors such as lifestyle and medication. Consequently, lab-based measurements cannot fully gauge the effects of medical interventions on EFMA. EFMA and BP have, arguably, comparable (but complementary) value in the assessment of cardiovascular health. Widespread deployment of EFMA assessment is thus a desirable clinical goal. To this end, we propose a device based on modifying the measurement protocol of a standard electronic sphygmomanometer. Methods The protocol involves inflating the cuff to sub-diastolic levels to enable recording of the pulse waveform before and after vasodilatory stimulus. The mechanical unloading of the arterial wall provided by the cuff amplifies the distension that occurs with each pulse, which is measured as a pressure variation in the cuff. We show that the height of the rising edge of each pulse is proportional to the change in lumen area between diastole and systole. This allows the effect of vasodilatory stimuli on the artery to be measured with high sensitivity. We compare the proposed cuff flow-mediated dilation (cFMD) method to ultrasound FMD (uFMD). Results We find significant correlation (r=0.55, p = 0.003, N=27) between cFMD- and uFMD-based metrics obtained when the release of a 5-minute cuff occlusion is employed to induce endothelial stimulus via reactive hyperemia. cFMD is approximately proportional to the square of uFMD, representing a typical increase in sensitivity to vasodilation of 300–600%. Conclusion This study illustrates the potential for an individual to conveniently measure his/her EFMA by using a low-cost reprogrammed home sphygmomanometer. PMID:26393958

  6. Association Between Peripheral Vascular Endothelial Function and Progression of Open-Angle Glaucoma.

    PubMed

    Liu, Chun-Hsiu; Su, Wei-Wen; Shie, Shian-Sen; Cheng, Shih-Tsung; Su, Cheng-Wen; Ho, Wang-Jing

    2016-03-01

    The aim of the study is to evaluate the relationship between Humphrey visual field progression and peripheral vascular endothelial function in patients with open-angle glaucoma (OAG), assessed by noninvasive endothelium-dependent flow-mediated vasodilation (FMD).Forty OAG patients, among which 22 had normal-tension glaucoma (NTG) and 18 had primary open-angle glaucoma (POAG) were enrolled. Each enrolled patient underwent a thorough ophthalmological examination including the Humphrey visual field test and measurement of FMD via high-resolution 2-dimensional ultrasonographic imaging of the brachial artery. Blood samples were evaluated for biochemistry and lipid profiles as well as levels of high-sensitivity C-reactive protein (hsCRP). The annual change of threshold sensitivity of the visual field in each test location were analyzed with pointwise linear regression. The correlation between long-term visual field progression and FMD was evaluated.A mean follow-up of 7.47 ± 1.84 years revealed a faster progression rate over the superior visual field in all 40 OAG patients (superior field -0.24 ± 0.67 dB/y, inferior field -0.10 ± 0.59 dB/y, P = 0.37). However, only the annual sensitivity change of the inferior peripheral field showed correlation with baseline FMD. There was no significant difference in the change slope of visual field between NTG and POAG patients.A correlation between baseline brachial artery FMD and visual field progression was observed in the inferior peripheral field in patients with NTG and POAG. This result suggests that peripheral vascular endothelial dysfunction may be related to glaucoma progression. PMID:26962832

  7. Relation of endothelial function to cardiovascular risk in women with sedentary occupations and without known cardiovascular disease.

    PubMed

    Lippincott, Margaret F; Carlow, Andrea; Desai, Aditi; Blum, Arnon; Rodrigo, Maria; Patibandla, Sushmitha; Zalos, Gloria; Smith, Kevin; Schenke, William H; Csako, Gyorgy; Waclawiw, Myron A; Cannon, Richard O

    2008-08-01

    Our purpose was to determine predictors of endothelial function and potential association with cardiovascular risk in women with sedentary occupations, in whom obesity-associated risk factors may contribute to excess morbidity and mortality. Ninety consecutive women (age range 22 to 63 years, 22 overweight (body mass index [BMI] > or =25 to 29.9 kg/m(2)) and 42 obese (BMI > or = 30 kg/m(2)), had vital signs, lipids, insulin, glucose, high-sensitivity C-reactive protein, and sex hormones measured. Endothelial function was determined using brachial artery flow-mediated dilation after 5 minutes of forearm ischemia. Treadmill stress testing was performed with gas exchange analysis at peak exercise (peak oxygen consumption [Vo(2)]) to assess cardiorespiratory fitness. Brachial artery reactivity was negatively associated with Framingham risk score (r = -0.3542, p = 0.0007). Univariate predictors of endothelial function included peak Vo(2) (r = 0.4483, p <0.0001), age (r = -0.3420, p = 0.0010), BMI (r = -0.3065, p = 0.0035), and high-sensitivity C-reactive protein (r = -0.2220, p = 0.0400). Using multiple linear regression analysis with stepwise modeling, peak Vo(2) (p = 0.0003) was the best independent predictor of brachial artery reactivity, with age as the only other variable reaching statistical significance (p = 0.0436) in this model. In conclusion, endothelial function was significantly associated with cardiovascular risk in women with sedentary occupations, who were commonly overweight or obese. Even in the absence of routine exercise, cardiorespiratory fitness, rather than conventional risk factors or body mass, is the dominant predictor of endothelial function and suggests a modifiable approach to risk.

  8. Expression of a functional extracellular calcium-sensing receptor in human aortic endothelial cells

    SciTech Connect

    Ziegelstein, Roy C.; Xiong Yali; He Chaoxia; Hu Qinghua . E-mail: qinghuaa@jhmi.edu

    2006-03-31

    Extracellular Ca{sup 2+} concentration ([Ca{sup 2+}]{sub o}) regulates the functions of many cell types through a G protein-coupled [Ca{sup 2+}]{sub o}-sensing receptor (CaR). Whether the receptor is functionally expressed in vascular endothelial cells is largely unknown. In cultured human aortic endothelial cells (HAEC), RT-PCR yielded the expected 555-bp product corresponding to the CaR, and CaR protein was demonstrated by fluorescence immunostaining and Western blot. RT-PCR also demonstrated the expression in HAEC of alternatively spliced variants of the CaR lacking exon 5. Although stimulation of fura 2-loaded HAEC by several CaR agonists (high [Ca{sup 2+}]{sub o}, neomycin, and gadolinium) failed to increase intracellular Ca{sup 2+} concentration ([Ca{sup 2+}]{sub i}), the CaR agonist spermine stimulated an increase in [Ca{sup 2+}]{sub i} that was diminished in buffer without Ca{sup 2+} and was abolished after depletion of an intracellular Ca{sup 2+} pool with thapsigargin or after blocking IP{sub 3}- and ryanodine receptor-mediated Ca{sup 2+} release with xestospongin C and with high concentration ryanodine, respectively. Spermine stimulated an increase in DAF-FM fluorescence in HAEC, consistent with NO production. Both the increase in [Ca{sup 2+}]{sub i} and in NO production were reduced or absent in HAEC transfected with siRNA specifically targeted to the CaR. HAEC express a functional CaR that responds to the endogenous polyamine spermine with an increase in [Ca{sup 2+}]{sub i}, primarily due to release of IP{sub 3}- and ryanodine-sensitive intracellular Ca{sup 2+} stores, leading to the production of NO. Expression of alternatively spliced variants of the CaR may result in the absence of a functional response to other known CaR agonists in HAEC.

  9. The effect of type 1 IFN on human aortic endothelial cell function in vitro: relevance to systemic lupus erythematosus.

    PubMed

    Reynolds, John A; Ray, David W; Zeef, Leo A H; O'Neill, Terence; Bruce, Ian N; Alexander, M Yvonne

    2014-05-01

    Cardiovascular disease (CVD) is an important cause of morbidity and mortality in patients with systemic lupus erythematosus. The etiopathogenesis of premature CVD is not fully understood, but recently interferon-alpha (IFNα) has been implicated as a contributing factor. Since IFNα has been associated with both disease activity and endothelial dysfunction in lupus patients, we aimed to determine whether IFNα has direct effects on human aortic endothelial cell (HAoEC) function in vitro. We studied the function of IFNα2b-treated HAoECs in terms of cell proliferation, capillary-like network formation, and nitric oxide (NO) generation. Changes in gene expression were also analyzed using an exon gene array. IFNα2b regulated the expression of 198 genes, including recognized interferon-stimulated genes (ISGs). Gene ontology analysis showed over-representation of genes involved in antigen presentation and host response to virus but no significant changes in clusters of genes recognized as important in endothelial cell activation or dysfunction. HAoEC proliferation, tubule formation, and NO bioavailability were unchanged, suggesting that IFNα in isolation does not have a direct impact on aortic endothelial cell function. PMID:24444308

  10. Neurological abnormalities and neurocognitive functions in healthy elder people: A structural equation modeling analysis

    PubMed Central

    2011-01-01

    Background/Aims Neurological abnormalities have been reported in normal aging population. However, most of them were limited to extrapyramidal signs and soft signs such as motor coordination and sensory integration have received much less attention. Very little is known about the relationship between neurological soft signs and neurocognitive function in healthy elder people. The current study aimed to examine the underlying relationships between neurological soft signs and neurocognition in a group of healthy elderly. Methods One hundred and eighty healthy elderly participated in the current study. Neurological soft signs were evaluated with the subscales of Cambridge Neurological Inventory. A set of neurocognitive tests was also administered to all the participants. Structural equation modeling was adopted to examine the underlying relationship between neurological soft signs and neurocognition. Results No significant differences were found between the male and female elder people in neurocognitive function performances and neurological soft signs. The model fitted well in the elderly and indicated the moderate associations between neurological soft signs and neurocognition, specifically verbal memory, visual memory and working memory. Conclusions The neurological soft signs are more or less statistically equivalent to capture the similar information done by conventional neurocognitive function tests in the elderly. The implication of these findings may serve as a potential neurological marker for the early detection of pathological aging diseases or related mental status such as mild cognitive impairment and Alzheimer's disease. PMID:21827719

  11. [Effect of sanatorium treatment on endothelial function in children with primary arterial hypertension].

    PubMed

    Ianina, T Iu

    2014-01-01

    To study the effect of sanatorium treatment (ST) using sodium chloride baths and metabolic drug mildronat on the dynamics of the ambulatory blood pressure monitoring (ABPM), markers of endothelial function in children with primary arterial hypertension (PAH). ABPM and held defined level of asymmetric dimethylarginine (ADMA), endothelin-1 (ET-1) and nitric oxide (NO) in the serum of 114 children with PAH aged 12-17. The positive dynamics of ABPM in all groups, but significantly (P < 0.05) decrease in mean BP was noted in the group with combined ST using sodium chloride baths. When analyzing the level of NO a positive trend (P < 0.01) in the group was using metabolic therapy, but significantly (P < 0.001) pronounced effect was observed when it is combined balneotherapy and metabolic therapy. Analysis of ET-1 and ADMA at ST in conjunction with therapy and metabolic rate of sodium chloride baths there was a significant (P < 0.01) decrease in these parameters in comparison with those before treatment. In children with PAH have been identified violations of the functional activity of the endothelium, which is reflected in increased levels of ET-1, ADMA and reducing NO. Conducting rehabilitation inclusion complex balneotherapy and metabolic therapy helps to reduce average daily blood pressure, normalization of functional activity of the endothelium as a normalization of the synthesis of NO (P < 0.,001), a significant decrease of ET-1 (P < 0.01) and ADMA (P < 0.01). PMID:24908958

  12. Endothelial Cell Death, Angiogenesis, and Microvascular Function after Castration in an Androgen-Dependent Tumor: Role of Vascular Endothelial Growth Factor

    NASA Astrophysics Data System (ADS)

    Jain, Rakesh K.; Safabakhsh, Nina; Sckell, Axel; Chen, Yi; Jiang, Ping; Benjamin, Laura; Yuan, Fan; Keshet, Eli

    1998-09-01

    The sequence of events that leads to tumor vessel regression and the functional characteristics of these vessels during hormone--ablation therapy are not known. This is because of the lack of an appropriate animal model and monitoring technology. By using in vivo microscopy and in situ molecular analysis of the androgen-dependent Shionogi carcinoma grown in severe combined immunodeficient mice, we show that castration of these mice leads to tumor regression and a concomitant decrease in vascular endothelial growth factor (VEGF) expression. Androgen withdrawal is known to induce apoptosis in Shionogi tumor cells. Surprisingly, tumor endothelial cells begin to undergo apoptosis before neoplastic cells, and rarefaction of tumor vessels precedes the decrease in tumor size. The regressing vessels begin to exhibit normal phenotype, i.e., lower diameter, tortuosity, vascular permeability, and leukocyte adhesion. Two weeks after castration, a second wave of angiogenesis and tumor growth begins with a concomitant increase in VEGF expression. Because human tumors often relapse following hormone--ablation therapy, our data suggest that these patients may benefit from combined anti-VEGF therapy.

  13. Functional behavior and gene expression of magnetic nanoparticle-loaded primary endothelial cells for targeting vascular stents

    PubMed Central

    Tuj Zohra, Fatema; Medved, Mikhail; Lazareva, Nina; Polyak, Boris

    2015-01-01

    Aim To assess functional competence and gene expression of magnetic nanoparticle (MNP)-loaded primary endothelial cells (ECs) as potential cell-based therapy vectors. Materials & methods A quantitative tube formation, nitric oxide and adhesion assays were conducted to assess functional potency of the MNP-loaded ECs. A quantitative real-time PCR was used to profile genes in both MNP-loaded at static conditions and in vitro targeted ECs. Results Functional behavior of MNP-loaded and unloaded cells was comparable. MNPs induce expression of genes involved in EC growth and survival, while repress genes involved in coagulation. Conclusion MNPs do not adversely affect cellular function. Gene expression indicates that targeting MNP-loaded ECs to vascular stents may potentially stimulate re-endothelialization of an implant and attenuate neointimal hyperplasia. PMID:25996117

  14. Histamine H2 receptor activation exacerbates myocardial ischemia/reperfusion injury by disturbing mitochondrial and endothelial function.

    PubMed

    Luo, Tao; Chen, Baihe; Zhao, Zonglei; He, Nvqin; Zeng, Zhi; Wu, Bing; Fukushima, Yasushi; Dai, Meng; Huang, Qiaobing; Xu, Dingli; Bin, Jianping; Kitakaze, Masafumi; Liao, Yulin

    2013-05-01

    There is evidence that H2R blockade improves ischemia/reperfusion (I/R) injury, but the underlying cellular mechanisms remain unclear. Histamine is known to increase vascular permeability and induce apoptosis, and these effects are closely associated with endothelial and mitochondrial dysfunction, respectively. Here, we investigated whether activation of the histamine H2 receptor (H2R) exacerbates myocardial I/R injury by increasing mitochondrial and endothelial permeability. Serum histamine levels were measured in patients with coronary heart disease, while the influence of H2R activation was assessed on mitochondrial and endothelial function in cultured cardiomyocytes or vascular endothelial cells, and myocardial I/R injury in mice. The serum histamine level was more than twofold higher in patients with acute myocardial infarction than in patients with angina or healthy controls. In neonatal rat cardiomyocytes, histamine dose-dependently reduced viability and induced apoptosis. Mitochondrial permeability and the levels of p-ERK1/2, Bax, p-DAPK2, and caspase 3 were increased by H2R agonists. In cultured human umbilical vein endothelial cells (HUVECs), H2R activation increased p-ERK1/2 and p-moesin levels and also enhanced permeability of HUVEC monolayer. All of these effects were abolished by the H2R blocker famotidine or the ERK inhibitor U0126. After I/R injury or permanent ischemia, the infarct size was reduced by famotidine and increased by an H2R agonist in wild-type mice. In H2R KO mice, the infarct size was smaller; myocardial p-ERK1/2, p-DAPK2, and mitochondrial Bax were downregulated. These findings indicate that H2R activation exaggerates myocardial I/R injury by promoting myocardial mitochondrial dysfunction and by increasing cardiac vascular endothelial permeability.

  15. Long-term effects of nasal continuous positive airway pressure on vasodilatory endothelial function in obstructive sleep apnea syndrome.

    PubMed

    Duchna, Hans-W; Orth, Maritta; Schultze-Werninghaus, Gerhard; Guilleminault, Christian; Stoohs, Riccardo A

    2005-09-01

    Obstructive sleep apnea syndrome (OSAS) is associated with a dysfunction of vascular endothelial cells. The aim of this study was to investigate long-term improvement of endothelial dysfunction in OSAS with nasal continuous positive airway pressure (nCPAP) treatment. We investigated endothelium-dependent and endothelium-independent vasodilatory function in patients with OSAS using the hand vein compliance technique. Dose-response curves to endothelium-dependent vasodilator bradykinin were obtained in 16 subjects with OSAS before and after 6 months of nCPAP therapy and in 12 control subjects without OSAS. Maximum dilation (Emax) to bradykinin, being impaired in all OSAS patients, was completely restored with nCPAP. Mean Emax to bradykinin rose from 54.9+/-18.5 to 108.2+/-28.7% with 164.4+/-90.0 nights of nCPAP therapy (p<0.0001; Emax healthy controls, 94.8+/-9.5%). At treatment follow-up, endothelium-dependent vasodilatory capacity was not significantly different in nCPAP-treated OSAS patients vs healthy controls. Mean vasodilation with endothelium independently acting nitroglycerin was not altered initially and did not change with nCPAP therapy indicating that nCPAP restored endothelial cell function and not unspecific, endothelium-independent factors. These results suggest that regular nocturnal nCPAP treatment leads to a sustained restoration of OSAS-induced impaired endothelium-dependent nitric oxide-mediated vasodilation, suggesting an improvement of systemic endothelial dysfunction in patients studied.

  16. Diastolic abnormalities in systemic sclerosis: evidence for associated defective cardiac functional reserve.

    PubMed Central

    Valentini, G; Vitale, D F; Giunta, A; Maione, S; Gerundo, G; Arnese, M; Tirri, E; Pelaggi, N; Giacummo, A; Tirri, G; Condorelli, M

    1996-01-01

    OBJECTIVE: To investigate the pattern of diastolic abnormalities in patients with systemic sclerosis (SSc) and the relationship between impaired ventricular filling and systolic function. METHODS: Twenty four patients with SSc underwent M-mode and two dimensional echocardiography using echo-Doppler and gated blood pool cardiac angiography, both at rest and after exercise. RESULTS: An impaired diastolic relaxation of the left ventricle was detected in 10 of the 24 patients with SSc. Left ventricular ejection fraction at rest in these 10 patients with impaired ventricular filling did not differ from that in the remaining 14 patients, but eight of the 10 failed to increase their ejection fraction during exercise, compared with two of the 14 with normal ventricular filling (p = 0.003). CONCLUSION: Impaired relaxation of the left ventricle is a recently described feature of scleroderma heart disease. Diastolic dysfunction in SSc could depend on myocardial fibrosis or myocardial ischaemia, or both. It was found to be associated with a defective cardiac functional reserve. However, its prognostic significance remains to be clarified. PMID:8774164

  17. Reward Abnormalities Among Women with Full and Subthreshold Bulimia Nervosa: A Functional Magnetic Resonance Imaging Study

    PubMed Central

    Bohon, Cara; Stice, Eric

    2010-01-01

    Objective To test the hypothesis that women with full and subthreshold bulimia nervosa show abnormal neural activation in response to food intake and anticipated food intake relative to healthy control women. Method Females with and without full/subthreshold bulimia nervosa recruited from the community (N = 26) underwent functional magnetic resonance imaging (fMRI) during receipt and anticipated receipt of chocolate milkshake and a tasteless control solution. Results Women with bulimia nervosa showed trends for less activation than healthy controls in the right anterior insula in response to anticipated receipt of chocolate milkshake (versus tasteless solution) and in the left middle frontal gyrus, right posterior insula, right precentral gyrus, and right mid dorsal insula in response to consumptions of milkshake (versus tasteless solution). Discussion Bulimia nervosa may be related to potential hypo-functioning of the brain reward system, which may lead these individuals to binge eat to compensate for this reward deficit, though the hypo-responsivity might be a result of a history of binge eating highly palatable foods. PMID:21997421

  18. Kinesin family 17 (osmotic avoidance abnormal-3) is dispensable for photoreceptor morphology and function.

    PubMed

    Jiang, Li; Tam, Beatrice M; Ying, Guoxing; Wu, Sen; Hauswirth, William W; Frederick, Jeanne M; Moritz, Orson L; Baehr, Wolfgang

    2015-12-01

    In Caenorhabditis elegans, homodimeric [kinesin family (KIF) 17, osmotic avoidance abnormal-3 (OSM-3)] and heterotrimeric (KIF3) kinesin-2 motors are required to establish sensory cilia by intraflagellar transport (IFT) where KIF3 and KIF17 cooperate to build the axoneme core and KIF17 builds the distal segments. However, the function of KIF17 in vertebrates is unresolved. We expressed full-length and motorless KIF17 constructs in mouse rod photoreceptors using adeno-associated virus in Xenopus laevis rod photoreceptors using a transgene and in ciliated IMCD3 cells. We found that tagged KIF17 localized along the rod outer segment axoneme when expressed in mouse and X. laevis photoreceptors, whereas KIF3A was restricted to the proximal axoneme. Motorless KIF3A and KIF17 mutants caused photoreceptor degeneration, likely through dominant negative effects on IFT. KIF17 mutant lacking the motor domain translocated to nuclei after exposure of a C-terminal nuclear localization signal. Germ-line deletion of Kif17 in mouse did not affect photoreceptor function. A rod-specific Kif3/Kif17 double knockout mouse demonstrated that KIF17 and KIF3 do not act synergistically and did not prevent rhodopsin trafficking to rod outer segments. In summary, the nematode model of KIF3/KIF17 cooperation apparently does not apply to mouse photoreceptors in which the photosensory cilium is built exclusively by KIF3. PMID:26229057

  19. Cytoarchitectural and Functional Abnormalities of the Inferior Colliculus in Sudden Unexplained Perinatal Death

    PubMed Central

    Lavezzi, Anna M.; Pusiol, Teresa; Matturri, Luigi

    2015-01-01

    Abstract The inferior colliculus is a mesencephalic structure endowed with serotonergic fibers that plays an important role in the processing of acoustic information. The implication of the neuromodulator serotonin also in the aetiology of sudden unexplained fetal and infant death syndromes and the demonstration in these pathologies of developmental alterations of the superior olivary complex (SOC), a group of pontine nuclei likewise involved in hearing, prompted us to investigate whether the inferior colliculus may somehow contribute to the pathogenetic mechanism of unexplained perinatal death. Therefore, we performed in a wide set of fetuses and infants, aged from 33 gestational weeks to 7 postnatal months and died of both known and unknown cause, an in-depth anatomopathological analysis of the brainstem, particularly of the midbrain. Peculiar neuroanatomical and functional abnormalities of the inferior colliculus, such as hypoplasia/structural disarrangement and immunonegativity or poor positivity of serotonin, were exclusively found in sudden death victims, and not in controls. In addition, these alterations were frequently related to dysgenesis of connected structures, precisely the raphé nuclei and the superior olivary complex, and to nicotine absorption in pregnancy. We propose, on the basis of these results, the involvement of the inferior colliculus in more important functions than those related to hearing, as breathing and, more extensively, all the vital activities, and then in pathological conditions underlying a sudden death in vulnerable periods of the autonomic nervous system development, particularly associated to harmful risk factors as cigarette smoking. PMID:25674737

  20. Functions of Müller cell-derived vascular endothelial growth factor in diabetic retinopathy

    PubMed Central

    Wang, Juan-Juan; Zhu, Meili; Le, Yun-Zheng

    2015-01-01

    Müller cells are macroglia and play many essential roles as supporting cells in the retina. To respond to pathological changes in diabetic retinopathy (DR), a major complication in the eye of diabetic patients, retinal Müller glia produce a high level of vascular endothelial growth factor (VEGF or VEGF-A). As VEGF is expressed by multiple retinal cell-types and Müller glia comprise only a small portion of cells in the retina, it has been a great challenge to reveal the function of VEGF or other globally expressed proteins produced by Müller cells. With the development of conditional gene targeting tools, it is now possible to dissect the function of Müller cell-derived VEGF in vivo. By using conditional gene targeting approach, we demonstrate that Müller glia are a major source of retinal VEGF in diabetic mice and Müller cell-derived VEGF plays a significant role in the alteration of protein expression and peroxynitration, which leads to retinal inflammation, neovascularization, vascular leakage, and vascular lesion, key pathological changes in DR. Therefore, Müller glia are a potential cellular target for the treatment of DR, a leading cause of blindness. PMID:26069721

  1. Electric Cell-substrate Impedance Sensing for the Quantification of Endothelial Proliferation, Barrier Function, and Motility

    PubMed Central

    Szulcek, Robert; Bogaard, Harm Jan; van Nieuw Amerongen, Geerten P.

    2014-01-01

    Electric Cell-substrate Impedance Sensing (ECIS) is an in vitro impedance measuring system to quantify the behavior of cells within adherent cell layers. To this end, cells are grown in special culture chambers on top of opposing, circular gold electrodes. A constant small alternating current is applied between the electrodes and the potential across is measured. The insulating properties of the cell membrane create a resistance towards the electrical current flow resulting in an increased electrical potential between the electrodes. Measuring cellular impedance in this manner allows the automated study of cell attachment, growth, morphology, function, and motility. Although the ECIS measurement itself is straightforward and easy to learn, the underlying theory is complex and selection of the right settings and correct analysis and interpretation of the data is not self-evident. Yet, a clear protocol describing the individual steps from the experimental design to preparation, realization, and analysis of the experiment is not available. In this article the basic measurement principle as well as possible applications, experimental considerations, advantages and limitations of the ECIS system are discussed. A guide is provided for the study of cell attachment, spreading and proliferation; quantification of cell behavior in a confluent layer, with regard to barrier function, cell motility, quality of cell-cell and cell-substrate adhesions; and quantification of wound healing and cellular responses to vasoactive stimuli. Representative results are discussed based on human microvascular (MVEC) and human umbilical vein endothelial cells (HUVEC), but are applicable to all adherent growing cells. PMID:24747269

  2. Protein phosphatase 2A activity is required for functional adherent junctions in endothelial cells.

    PubMed

    Kása, Anita; Czikora, István; Verin, Alexander D; Gergely, Pál; Csortos, Csilla

    2013-09-01

    Reversible Ser/Thr phosphorylation of cytoskeletal and adherent junction (AJ) proteins has a critical role in the regulation of endothelial cell (EC) barrier function. We have demonstrated earlier that protein phosphatase 2A (PP2A) activity is important in EC barrier integrity. In the present work, macro- and microvascular EC were examined and we provided further evidence on the significance of PP2A in the maintenance of EC cytoskeleton and barrier function with special focus on the Bα (regulatory) subunit of PP2A. Immunofluorescent staining revealed that the inhibition of PP2A results in changes in the organization of EC cytoskeleton as microtubule dissolution and actin re-arrangement were detected. Depletion of Bα regulatory subunit of PP2A had similar effect on the cytoskeleton structure of the cells. Furthermore, transendothelial electric resistance measurements demonstrated significantly slower barrier recovery of Bα depleted EC after thrombin treatment. AJ proteins, VE-cadherin and β-catenin, were detected along with Bα in pull-down assay. Also, the inhibition of PP2A (by okadaic acid or fostriecin) or depletion of Bα caused β-catenin translocation from the membrane to the cytoplasm in parallel with its phosphorylation on Ser552. In conclusion, our data suggest that the A/Bα/C holoenzyme form of PP2A is essential in EC barrier integrity both in micro- and macrovascular EC. PMID:23721711

  3. Abnormal functional specialization within medial prefrontal cortex in high-functioning autism: a multi-voxel similarity analysis

    PubMed Central

    Meuwese, Julia D.I.; Towgood, Karren J.; Frith, Christopher D.; Burgess, Paul W.

    2009-01-01

    Multi-voxel pattern analyses have proved successful in ‘decoding’ mental states from fMRI data, but have not been used to examine brain differences associated with atypical populations. We investigated a group of 16 (14 males) high-functioning participants with autism spectrum disorder (ASD) and 16 non-autistic control participants (12 males) performing two tasks (spatial/verbal) previously shown to activate medial rostral prefrontal cortex (mrPFC). Each task manipulated: (i) attention towards perceptual versus self-generated information and (ii) reflection on another person's mental state (‘mentalizing'versus ‘non-mentalizing’) in a 2 × 2 design. Behavioral performance and group-level fMRI results were similar between groups. However, multi-voxel similarity analyses revealed strong differences. In control participants, the spatial distribution of activity generalized significantly between task contexts (spatial/verbal) when examining the same function (attention/mentalizing) but not when comparing different functions. This pattern was disrupted in the ASD group, indicating abnormal functional specialization within mrPFC, and demonstrating the applicability of multi-voxel pattern analysis to investigations of atypical populations. PMID:19174370

  4. Effect of aspirin on acute changes in peripheral arterial stiffness and endothelial function following exertional heat stress in firefighters: The factorial group results of the Enhanced Firefighter Rehab Trial.

    PubMed

    Olafiranye, Oladipupo; Hostler, David; Winger, Daniel G; Wang, Li; Reis, Steven E

    2015-06-01

    Peripheral arterial stiffness and endothelial function, which are independent predictors of cardiac events, are abnormal in firefighters. We examined the effects of aspirin on peripheral arterial stiffness and endothelial function in firefighters. Fifty-two firefighters were randomized to receive daily 81 mg aspirin or placebo for 14 days before treadmill exercise in thermal protection clothing, and a single dose of 325 mg aspirin or placebo immediately following exertion. Peripheral arterial augmentation index adjusted for a heart rate of 75 (AI75) and reactive hyperemia index (RHI) were determined immediately before, and 30, 60, and 90 minutes after exertion. Low-dose aspirin was associated with lower AI75 (-15.25±9.25 vs -8.08±10.70, p=0.014) but not RHI. On repeated measures analysis, treatment with low-dose aspirin before, but not single-dose aspirin after exertion, was associated with lower AI75 following exertional heat stress (p=0.018). Low-dose aspirin improved peripheral arterial stiffness and wave reflection but not endothelial function in firefighters.

  5. Effects of black raspberry on lipid profiles and vascular endothelial function in patients with metabolic syndrome.

    PubMed

    Jeong, Han Saem; Hong, Soon Jun; Lee, Tae-Bum; Kwon, Ji-Wung; Jeong, Jong Tae; Joo, Hyung Joon; Park, Jae Hyoung; Ahn, Chul-Min; Yu, Cheol Woong; Lim, Do-Sun

    2014-10-01

    Black raspberry (Rubus occidentalis) has been known for its anti-inflammatory and anti-oxidant effects. However, short-term effects of black raspberry on lipid profiles and vascular endothelial function have not been investigated in patients with metabolic syndrome. Patients with metabolic syndrome (n = 77) were prospectively randomized into a group with black raspberry (n = 39, 750 mg/day) and a placebo group (n = 38) during a 12-week follow-up. Lipid profiles, brachial artery flow-mediated dilatation (baFMD), and inflammatory cytokines such as IL-6, TNF-α, C-reactive protein, adiponectin, sICAM-1, and sVCAM-1 were measured at the baseline and at the 12-week follow-up. Decreases from the baseline in the total cholesterol level (-22.8 ± 30.4 mg/dL vs. -1.9 ± 31.8 mg/dL, p < 0.05, respectively) and total cholesterol/HDL ratio (-0.31 ± 0.64 vs. 0.07 ± 0.58, p < 0.05, respectively) were significantly greater in the group with black raspberry than in the placebo group. Increases in baFMD at the 12-week follow-up were significantly greater in the group with black raspberry than in the placebo group (0.33 ± 0.44 mm vs. 0.10 ± 0.35 mm, p < 0.05, respectively). Decreases from the baseline in IL-6 (-0.4 ± 1.5 pg/mL vs. -0.1 ± 1.0 pg/mL, p < 0.05, respectively) and TNF-α (-2.9 ± 4.7 pg/mL vs. 0.1 ± 3.6 pg/mL, p < 0.05, respectively) were significantly greater in the group with black raspberry. The use of black raspberry significantly decreased serum total cholesterol level and inflammatory cytokines, thereby improving vascular endothelial function in patients with metabolic syndrome during the 12-week follow-up.

  6. Effect of antioxidant vitamin supplementation on endothelial function in type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials.

    PubMed

    Montero, D; Walther, G; Stehouwer, C D A; Houben, A J H M; Beckman, J A; Vinet, A

    2014-02-01

    Controversy exists among trials assessing whether prolonged antioxidant vitamin supplementation improves endothelial function in type 2 diabetes mellitus (T2DM) subjects. The aim of this study was to systematically review and quantify the effect of antioxidant vitamin supplementation on endothelial function in T2DM subjects. MEDLINE, Cochrane, Scopus and Web of Science were searched up to February 2013 for randomized controlled trials assessing the effect of antioxidant vitamin E and/or C supplementation on endothelial function in T2DM subjects. Ten randomized controlled trials comparing antioxidant vitamin-supplemented and control groups (overall n = 296) met the inclusion criteria. Post-intervention standardized mean difference (SMD) in endothelial function did not reach statistical significance between groups (0.35; 95% confidence interval = -0.17, 0.88; P = 0.18). In subgroup analysis, post-intervention endothelial function was significantly improved by antioxidant vitamin supplementation in T2DM subgroups with body mass index (BMI) ≤ 29.45 kg m(-2) (SMD = 1.02; P < 0.05), but not in T2DM subgroups with BMI > 29.45 kg m(-2) (SMD = -0.07; P = 0.70). In meta-regression, an inverse association was found between BMI and post-intervention SMD in endothelial function (B = -0.024, P = 0.02). Prolonged antioxidant vitamin E and/or C supplementation could be effective to improve endothelial function in non-obese T2DM subjects.

  7. Changes of Number and Function of Late Endothelial Progenitor Cells in Peripheral Blood of COPD Patients Combined with Pulmonary Hypertension.

    PubMed

    Liu, Pei; Zhang, Hongmei; Liu, Jianxin; Sheng, Chunfeng; Zhang, Linlin; Zeng, Yanjun

    2016-06-01

    Objective The objective of this study was to investigate the changes of number and function of late endothelial progenitor cells (EPCs) in peripheral blood of chronic obstructive pulmonary disease (COPD) patients combined with pulmonary hypertension. Subjects and Methods The study enrolled 120 cases including 40 non-COPD and pulmonary arterial hypertension (PAH) patients (non-COPD group), 40 COPD non-PAH patients (COPD group), and 40 COPD patients combined with PAH (COPD + PAH group). Peripheral blood mononuclear cells were separated by density gradient centrifugation, cultured for 21 days, and then identified as late endothelial progenitor cells. The cell colonies were counted. MTT assay, modified Boyden chamber assay, and human fibronectin plates were used to measure the proliferation, migration, and adhesion functions of the late endothelial progenitor cells, respectively. Results Compared with non-COPD and COPD groups, the number of peripheral blood late EPCs in COPD + PAH group was significantly reduced, and the proliferation, adhesion, and migration capacities were significantly lowered; the differences were statistically significant (p < 0.05). The number and function of late EPCs decreased with the increase of pulmonary artery pressure (p < 0.05). Conclusion The number of late EPCs in COPD patients combined with pulmonary hypertension was reduced, which implies the impaired cell functions. The changes of number and function were negatively correlated with the severity of pulmonary hypertension.

  8. Functional Imaging of Working Memory and Peripheral Endothelial Function in Middle-Aged Adults

    ERIC Educational Resources Information Center

    Gonzales, Mitzi M.; Tarumi, Takashi; Tanaka, Hirofumi; Sugawara, Jun; Swann-Sternberg, Tali; Goudarzi, Katayoon; Haley, Andreana P.

    2010-01-01

    The current study examined the relationship between a prognostic indicator of vascular health, flow-mediated dilation (FMD), and working memory-related brain activation in healthy middle-aged adults. Forty-two participants underwent functional magnetic resonance imaging while completing a 2-Back working memory task. Brachial artery…

  9. ZLM-7 exhibits anti-angiogenic effects via impaired endothelial cell function and blockade of VEGF/VEGFR-2 signaling

    PubMed Central

    Su, Min; Huang, Jingjia; Li, Jijia; Qin, Xiyuan; Tang, Xiaoning; Jin, Fang; Chen, Shali; Jiang, Chuanming; Zou, Zizheng; Peng, Kunjian; Nuruzzaman, Mohammed; Zhang, Jianting; Luo, Junli; Liu, Suyou; Luo, Zhiyong

    2016-01-01

    Inhibition of angiogenesis is a promising therapeutic strategy against cancer. In this study, we reported that ZLM-7, a combretastain A-4 (CA-4) derivative, exhibited anti-angiogenic activity in vitro and in vivo. In vitro, ZLM-7 induced microtubule cytoskeletal disassembly. It decreased VEGF-induced proliferation, migration, invasion and tube formation in endothelial cells, which are critical steps in angiogenesis. In vivo, ZLM-7 significantly inhibited neovascularization in a chicken chorioallantoic membrane (CAM) model and reduced the microvessel density in tumor tissues of MCF-7 xenograft mouse model. ZLM-7 also displayed comparable antiangiogenic and anti-tumor activities associated with the lead compound CA-4, but exhibited lower toxicity compared with CA-4. The anti-angiogenic effect of ZLM-7 was exerted via blockade of VEGF/VEGFR-2 signaling. ZLM-7 treatment suppressed the expression and secretion of VEGF in endothelial cells and MCF-7 cells under hypoxia. Further, ZLM-7 suppressed the VEGF-induced phosphorylation of VEGFR-2 and its downstream signaling mediators including activated AKT, MEK and ERK in endothelial cells. Overall, these results demonstrate that ZLM-7 exhibits anti-angiogenic activities by impairing endothelial cell function and blocking VEGF/VEGFR-2 signaling, suggesting that ZLM-7 might be a potential angiogenesis inhibitor. PMID:26967559

  10. Relationship of abnormal Tamm-Horsfall glycoprotein localization to renal morphology and function.

    PubMed

    Chambers, R; Groufsky, A; Hunt, J S; Lynn, K L; McGiven, A R

    1986-07-01

    Tamm-Horsfall glycoprotein (TH) distribution was studied using a biotin-avidin immunoperoxidase technique in renal biopsies from 166 consecutive patients and 8 normal kidneys. Tubulointerstitial damage was independently assessed and graded. In 109 patients TH antibodies were measured by ELISA and in 30 of these urinary TH and beta 2-microglobulin excretions were measured by radioimmunoassay. In 124 biopsies only distal tubular epithelium and casts were stained. Glomerular space (8) or interstitial (34) deposits were seen in 42 biopsies; 16/68 with glomerulonephritis, 4/14 with systemic vasculitis, 12/33 with chronic interstitial nephritis, 1/8 with acute interstitial nephritis, 9/43 with other nephropathies. There was no correlation between TH distribution and the degree of tubulointerstitial damage (p greater than 0.5), urinary TH excretion (p greater than 0.05), urinary beta 2-microglobulin excretion (p greater than 0.05), glomerular filtration rate, urinary concentrating ability, or the incidence of pyuria. TH antibodies did not correlate with TH distribution (p greater than 0.5) or the degree of tubulointerstitial damage. Abnormal TH distribution showed no statistical relationship to the degree of tubulointerstitial damage, changes in renal function or levels of TH antibodies.

  11. Claudin-16 Deficiency Impairs Tight Junction Function in Ameloblasts, Leading to Abnormal Enamel Formation.

    PubMed

    Bardet, Claire; Courson, Frédéric; Wu, Yong; Khaddam, Mayssam; Salmon, Benjamin; Ribes, Sandy; Thumfart, Julia; Yamaguti, Paulo M; Rochefort, Gael Y; Figueres, Marie-Lucile; Breiderhoff, Tilman; Garcia-Castaño, Alejandro; Vallée, Benoit; Le Denmat, Dominique; Baroukh, Brigitte; Guilbert, Thomas; Schmitt, Alain; Massé, Jean-Marc; Bazin, Dominique; Lorenz, Georg; Morawietz, Maria; Hou, Jianghui; Carvalho-Lobato, Patricia; Manzanares, Maria Cristina; Fricain, Jean-Christophe; Talmud, Deborah; Demontis, Renato; Neves, Francisco; Zenaty, Delphine; Berdal, Ariane; Kiesow, Andreas; Petzold, Matthias; Menashi, Suzanne; Linglart, Agnes; Acevedo, Ana Carolina; Vargas-Poussou, Rosa; Müller, Dominik; Houillier, Pascal; Chaussain, Catherine

    2016-03-01

    Claudin-16 protein (CLDN16) is a component of tight junctions (TJ) with a restrictive distribution so far demonstrated mainly in the kidney. Here, we demonstrate the expression of CLDN16 also in the tooth germ and show that claudin-16 gene (CLDN16) mutations result in amelogenesis imperfecta (AI) in the 5 studied patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). To investigate the role of CLDN16 in tooth formation, we studied a murine model of FHHNC and showed that CLDN16 deficiency led to altered secretory ameloblast TJ structure, lowering of extracellular pH in the forming enamel matrix, and abnormal enamel matrix protein processing, resulting in an enamel phenotype closely resembling human AI. This study unravels an association of FHHNC owing to CLDN16 mutations with AI, which is directly related to the loss of function of CLDN16 during amelogenesis. Overall, this study indicates for the first time the importance of a TJ protein in tooth formation and underlines the need to establish a specific dental follow-up for these patients.

  12. Neonatal lupus manifests as isolated neutropenia and mildly abnormal liver functions.

    PubMed

    Kanagasegar, Sivalingam; Cimaz, Rolando; Kurien, Biji T; Brucato, Antonio; Scofield, R Hal

    2002-01-01

    Neonatal lupus is characterized by typical clinical features and the presence of maternal autoantibodies. Mothers can have systemic lupus erythematosus (SLE) or Sjögren's syndrome, but are commonly not affected with any clinical disease. The major clinical manifestations in the infants are cardiac, dermatological and hepatic with rare instances of hemolytic anemia, thrombocytopenia or neutropenia. We describe an infant born to a mother with anti-Ro and anti-La, who had neutropenia and mildly abnormal liver functions without other major clinical features of neonatal lupus such as cardiac or dermatological manifestations. Neutropenia improved as maternal antibody was metabolized. Antibodies from both the infant and mother bound intact neutrophils, and this binding was inhibited by 60 kDa Ro. These data imply neutropenia may be an isolated manifestation of neonatal lupus. We studied the anti-Ro antibodies of 2 other mothers who gave birth to infants with complete congenital heart block and neutropenia. Their sera also bound neutrophils. Because healthy infants do not commonly undergo complete blood counts, the incidence of neutropenia among infants of anti-Ro-positive mothers may be much higher than previously recognized. Furthermore, although other factors may contribute, these data suggest that anti-60 kDa Ro is directly involved in the pathogenesis of neutropenia.

  13. Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function

    PubMed Central

    Margolis, Kara Gross; Li, Zhishan; Stevanovic, Korey; Saurman, Virginia; Anderson, George M.; Snyder, Isaac; Blakely, Randy D.; Gershon, Michael D.

    2016-01-01

    Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4–mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation. PMID:27111230

  14. Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function.

    PubMed

    Margolis, Kara Gross; Li, Zhishan; Stevanovic, Korey; Saurman, Virginia; Israelyan, Narek; Anderson, George M; Snyder, Isaac; Veenstra-VanderWeele, Jeremy; Blakely, Randy D; Gershon, Michael D

    2016-06-01

    Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4-mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation. PMID:27111230

  15. Influence of heavy ions on cell survival, cytogenetic damage and mitochondrial function of human endothelial cells

    NASA Astrophysics Data System (ADS)

    Ritter, Sylvia; Helm, Alexander; Lee, Ryonfa; Pollet, Dieter; Durante, Marco

    There is increasing evidence that there is an elevated risk of cardiovascular disease among atomic bomb survivors and radiotherapy patients, typically developing with a long latency. However, essentially no information is available on the potential cardiovascular risks associated with space radiation, in particular heavy ions. To address this issue, we have chosen human umbilical vein endothelial cells (HUVEC) as a model system. Cells at an early passage number were irradiated with 0.1 to 4 Gy of either 9.8 MeV/u C-ions (LET=170 keV/µm), 91 MeV/u C-ions (LET=29 keV/µm) or 250 kV X-rays. Cells were regularly subcultured up to 40 days (20 population doublings) post-irradiation. Immediately after exposure cell inactivation was deter-mined by the colony forming assay. Furthermore, at selected time-points cytogenetic damage (formation of micronuclei in binucleated cells) and the mitochondrial membrane potential ΨM (flow cytometric analysis following JC-1 staining) were assessed. Measurement of the directly induced radiation damage showed that 9.8 MeV/u and 91 MeV/u C-ions were more effective than X-rays (i.e. about 3 and 2 times, respectively) with respect to cell inactivation or the in-duction of cytogenetic damage. At the subsequent days in the irradiated cultures the number of cells with micronuclei declined to the control level (3-5Altogether our data indicate that under the applied radiation conditions the integrity of mitochondria which play a significant role in the regulation of cardiovascular cell function is not impaired. With respect to directly induced genetic damage C-ions are more effective than X-rays as observed in other cell systems. If the effectiveness of charged particles for the occurrence of late chromosomal damage in endothelial cells is higher than that of sparsely ionizing radiation needs further clarification. The data obtained up to now indicate that sophisticated cytogenetic techniques have to be applied in order to draw any firm

  16. [Effect of aspirin on function of human umbilical cord blood-derived late endothelial progenitor cells].

    PubMed

    Liu, Zhen-Zhen; Li, Guo-Qiang; Liu, Meng; Sun, Sheng-Xuan; An, Guan-Yu; Dong, Ning-Zheng

    2013-08-01

    This study was aimed to investigate whether aspirin has effect on function of late endothelial progenitor cells (EPC). Cord blood CD34(+) cells were purified using the ficoll density gradient centrifugation and human CD34 positive selection kit, then the cells were inoculated on fibronectin-coated culture plate. After culture for 2 weeks, adherent cells were identified as EPC by flow cytometry, immunofluorescence, RT-PCR, uptake of Dil-Ac-LDL and matrigel tube formation assay. EPC were treated with different concentrations of aspirin (0.1, 1, 10, 100, 1 000, 10 000 µmol/L) for 24 h, then the proliferation, adhesion and migration ability of these cells were analyzed by CCK-8 assay and transwell methods. The results indicated that the low concentrations of aspirin (0.1 and 1 000 µmol/L) promoted late EPC adhesive and migratory capacity, but no obvious effect on proliferation of late EPC were observed. On the other hand, the high concentrations of aspirin (10 000 µmol/L) inhibited proliferation and migratory capacity of EPC, but had no obvious effect on adhesive ability of EPC. It is concluded that low concentration of aspirin promotes migration and adhesion of late EPC, while the high concentration of aspirin decreases EPC proliferation and migratory capacity of EPC.

  17. Crosstalk between inflammation, iron metabolism and endothelial function in Behçet's disease.

    PubMed

    Oliveira, Rita; Napoleão, Patricia; Banha, João; Paixão, Eleonora; Bettencourt, Andreia; da Silva, Berta Martins; Pereira, Dina; Barcelos, Filipe; Teixeira, Ana; Patto, José Vaz; Viegas-Crespo, Ana Maria; Costa, Luciana

    2014-01-01

    Behçet's disease (BD) is a rare chronic vasculitis of unclear etiology. It has been suggested that inflammatory response has an important role in BD pathophysiology. Herein, we aimed to study the interplay between inflammation, iron metabolism and endothelial function in BD and search for its putative association with disease activity. Twenty five patients clinically diagnosed with BD were selected and twenty four healthy age-sex matched individuals participated as controls. Results showed an increase of total number of circulating white blood cells and neutrophils, serum transferrin, total iron binding capacity, mieloperoxidase (MPO), ceruloplasmin (Cp), C reactive protein, β2 microglobulin and Cp surface expression in peripheral blood monocytes in BD patients comparatively to healthy individuals (p < 0,05). Of notice, the alterations observed were associated to disease activity status. No significant differences between the two groups were found in serum nitric oxide concentration. The results obtained suggest an important contribution from innate immunity in the pathogenesis of this disease. In particular, surface expression of leukocyte-derived Cp may constitute a new and relevant biomarker to understand BD etiology.

  18. Occurring of In Vitro Functional Vasculogenic Pericytes from Human Circulating Early Endothelial Precursor Cell Culture.

    PubMed

    Cantoni, Silvia; Bianchi, Francesca; Galletti, Margherita; Olivi, Elena; Alviano, Francesco; Galiè, Nazzareno; Ventura, Carlo

    2015-01-01

    Pericytes are periendothelial cells of the microcirculation which contribute to tissue homeostasis and hemostasis by regulating microvascular morphogenesis and stability. Because of their multipotential ex vivo differentiation capabilities, pericytes are becoming very interesting in regenerative medicine field. Several studies address this issue by attempting to isolate pericyte/mesenchymal-like cells from peripheral blood; however the origin of these cells and their culture conditions are still debated. Here we showed that early Endothelial Progenitor Cells (EPCs) expressing CD45+/CD146+/CD31+ can be a source of cells with pericyte/mesenchymal phenotype and function, identified as human Progenitor Perivascular Cells (hPPCs). We provided evidence that hPPCs have an immunophenotype consistent with Mesenchymal Stem Cells (MSCs) from human adipose tissue (hASCs) and fetal membranes of term placenta (FM-hMSCs). In addition, hPPCs can be subcultured and exhibit expression of pluripotent genes (OCT-4, KLF-4, and NANOG) as well as a remarkable vasculogenic potential. Our findings could be helpful to develop innovative cell-based therapies for future clinical applications with distinct therapeutic purposes. PMID:26064139

  19. VEGF-functionalized dextran has longer intracellular bioactivity than VEGF in endothelial cells.

    PubMed

    Maia, João; Vazão, Helena; Pedroso, Dora C S; Jesus, Catarina S H; Brito, Rui M M; Grãos, Mário; Gil, Maria H; Ferreira, Lino

    2012-09-10

    Herein, we report that VEGF-functionalized dextran (dexOx-VEGF) is comparatively superior to free VEGF in prolonging the phosphorylation of VEGF receptor 2 (VEGFR-2). Both dexOx-VEGF and free VEGF activate VEGFR-2, and the complexes are internalized into early endosomes (EEA1(+) vesicles) and then transported to lysosomes (Rab7(+) vesicles). However, after cell activation, dexOx-VEGF is preferentially colocalized in early endosomes where VEGF signaling is still active while free VEGF is preferentially transported to late endosomes or lysosomes. We further show that dexOx-VEGF after phosphorylation of VEGF receptor 2 induces an increase of intracellular Ca(2+) and activates VEGF downstream effectors such as Akt and extracellular signal-regulated kinase (ERK1/2) proteins. Under specific conditions, the activation level is different from the one observed for free VEGF, thus suggesting mechanistic differences, which is illustrated by cell migration and cord-like formation studies. DexOx-VEGF can be cross-linked with adipic acid dihydrazide to form a degradable gel, which in turn can be incorporated in a fibrin gel containing endothelial cells (ECs) to modulate their activity. We envision that these constructs might be beneficial to extend the pro-angiogenic activity of VEGF in ischemic tissues and to modulate the biological activity of vascular cells. PMID:22901277

  20. Occurring of In Vitro Functional Vasculogenic Pericytes from Human Circulating Early Endothelial Precursor Cell Culture

    PubMed Central

    Bianchi, Francesca; Galletti, Margherita; Galiè, Nazzareno; Ventura, Carlo

    2015-01-01

    Pericytes are periendothelial cells of the microcirculation which contribute to tissue homeostasis and hemostasis by regulating microvascular morphogenesis and stability. Because of their multipotential ex vivo differentiation capabilities, pericytes are becoming very interesting in regenerative medicine field. Several studies address this issue by attempting to isolate pericyte/mesenchymal-like cells from peripheral blood; however the origin of these cells and their culture conditions are still debated. Here we showed that early Endothelial Progenitor Cells (EPCs) expressing CD45+/CD146+/CD31+ can be a source of cells with pericyte/mesenchymal phenotype and function, identified as human Progenitor Perivascular Cells (hPPCs). We provided evidence that hPPCs have an immunophenotype consistent with Mesenchymal Stem Cells (MSCs) from human adipose tissue (hASCs) and fetal membranes of term placenta (FM-hMSCs). In addition, hPPCs can be subcultured and exhibit expression of pluripotent genes (OCT-4, KLF-4, and NANOG) as well as a remarkable vasculogenic potential. Our findings could be helpful to develop innovative cell-based therapies for future clinical applications with distinct therapeutic purposes. PMID:26064139

  1. Vasopeptidase inhibition improves insulin sensitivity and endothelial function in the JCR:LA-cp rat.

    PubMed

    Russell, James C; Kelly, Sandra E; Schäfer, Stefan

    2004-08-01

    The insulin-resistant, hyperinsulinemic, normoglycemic, and obese JCR:LA-cp rat was used to study the effects of ramipril (an ACE inhibitor) and AVE7688 (a dual inhibitor of ACE and neutral endopeptidases) on insulin sensitivity and vascular function. Both compounds reduced the surge of plasma insulin in a meal tolerance test by approximately 50%. Ramipril had no effect on acetylcholine-induced relaxation but increased the sensitivity to sodium nitroprus-side at low concentrations. AVE7688 significantly reduced the EC50 for acetylcholine to relax phenylephrine-contracted aortic rings. None of the compounds affected the baseline coronary flow and reactive hyperemia. Coronary flow response to bradykinin in AVE7688- and ramipril-treated rat hearts showed a significantly lower EC50 than in control rats. Maximum flow rate was not different between groups. In summary, both ramipril and AVE7688 had significant hypoinsulinemic and insulin-sensitizing effects. Whereas ramipril had limited vascular effects, AVE7688 had more marked beneficial vascular effects, probably of endothelial origin and possibly related to lowered insulin levels.

  2. Functional Mineralocorticoid Receptors in Human Vascular Endothelial Cells Regulate ICAM-1 Expression and Promote Leukocyte Adhesion

    PubMed Central

    Caprio, Massimiliano; Newfell, Brenna G.; la Sala, Andrea; Baur, Wendy; Fabbri, Andrea; Rosano, Giuseppe; Mendelsohn, Michael E.; Jaffe, Iris Z.

    2008-01-01

    In clinical trials, aldosterone antagonists decrease cardiovascular mortality and ischemia by unknown mechanisms. The steroid hormone aldosterone acts by binding to the mineralocorticoid receptor (MR), a ligand-activated transcription factor. In humans, aldosterone causes MR-dependent endothelial cell (EC) dysfunction and in animal models, aldosterone increases vascular macrophage infiltration and atherosclerosis. MR antagonists inhibit these effects without changing blood pressure, suggesting a direct role for vascular MR in EC function and atherosclerosis. Whether human vascular EC express functional MR is not known. Here we show that human coronary artery and aortic EC express MR mRNA and protein and that EC MR mediates aldosterone-dependent gene transcription. Human EC also express the enzyme 11-beta hydroxysteroid dehydrogenase-2(11βHSD2) and inhibition of 11βHSD2 in aortic EC enhances gene transactivation by cortisol, supporting that EC 11βHSD2 is functional. Furthermore, aldosterone stimulates transcription of the proatherogenic leukocyte-EC adhesion molecule Intercellular Adhesion Molecule-1(ICAM1) gene and protein expression on human coronary artery EC, an effect inhibited by the MR antagonist spironolactone and by MR knock-down with siRNA. Cell adhesion assays demonstrate that aldosterone promotes leukocyte-EC adhesion, an effect that is inhibited by spironolactone and ICAM1 blocking antibody, supporting that aldosterone induction of EC ICAM1 surface expression via MR mediates leukocyte-EC adhesion. These data show that aldosterone activates endogenous EC MR and proatherogenic gene expression in clinically important human EC. These studies describe a novel mechanism by which aldosterone may influence ischemic cardiovascular events and support a new explanation for the decrease in ischemic events in patients treated with aldosterone antagonists. PMID:18467630

  3. Genetic and structure-function studies of missense mutations in human endothelial lipase.

    PubMed

    Razzaghi, Hamid; Tempczyk-Russell, Anna; Haubold, Kurt; Santorico, Stephanie A; Shokati, Touraj; Christians, Uwe; Churchill, Mair E A

    2013-01-01

    Endothelial lipase (EL) plays a pivotal role in HDL metabolism. We sought to characterize EL and its interaction with HDL as well as its natural variants genetically, functionally and structurally. We screened our biethnic population sample (n = 802) for selected missense mutations (n = 5) and identified T111I as the only common variant. Multiple linear regression analyses in Hispanic subjects revealed an unexpected association between T111I and elevated LDL-C (p-value = 0.012) and total cholesterol (p-value = 0.004). We examined lipase activity of selected missense mutants (n = 10) and found different impacts on EL function, ranging from normal to complete loss of activity. EL-HDL lipidomic analyses indicated that EL has a defined remodeling of HDL without exhaustion of the substrate and a distinct and preference for several fatty acids that are lipid mediators and known for their potent pro- and anti-inflammatory properties. Structural studies using homology modeling revealed a novel α/β motif in the C-domain, unique to EL. The EL dimer was found to have the flexibility to expand and to bind various sizes of HDL particles. The likely impact of the all known missense mutations (n = 18) on the structure of EL was examined using molecular modeling and the impact they may have on EL lipase activity using a novel structure-function slope based on their structural free energy differences. The results of this multidisciplinary approach delineated the impact of EL and its variants on HDL. Moreover, the results suggested EL to have the capacity to modulate vascular health through its role in fatty acid-based signaling pathways. PMID:23536757

  4. Analysis of functional abnormalities uncovered during preoperative evaluation of donor candidates for living-related liver transplantation.

    PubMed

    Morimoto, T; Awane, M; Tanaka, A; Ikai, I; Nakamura, Y; Yamamoto, Y; Takada, Y; Honda, K; Inamoto, T; Uemoto, S

    1995-02-01

    Functional abnormalities of the liver uncovered during preoperative routine evaluation were analyzed in 109 donor candidates for 100 cases of living-related liver transplantation (LRLT) performed during the period from June, 1990 to May, 1994 at the Second Department of Surgery, Kyoto University Hospital. High serum transaminase (GOT, GPT) levels were noted in 10 (9.2%) cases among 109 candidates, high alkaline phosphatase in 4 (3.7%), hyperbilirubinemia in 3 (2.8%), anemia in 3 and high choline esterase in 3 cases. Positive hepatitis C antibody (HCV) was also noted in 1 case. Fatty liver was detected in 10 (9.2%) cases, cholecystitis in 2 cases, 1 case each of cyst and calcification in the liver by diagnostic imaging (ultra sonograph and/or computed tomography). These abnormalities of the liver necessitated replacing the initial candidate with the other parent in 9 cases, including 1 case without any functional abnormality whose graft liver was too large to fit the recipient abdominal cavity. There were 14 cases of ABO blood type incompatible combination. Switching the initial candidate due to these abnormalities mentioned above resulted in incompatible combinations in 4 of these 14 cases. Although the advantages of the LRLT are the superior viability of the donor graft and the genetic histocompatibility between recipient and donor, to optimize the advantage of LRLT, all donor candidates should be strongly advised to make every effort preoperatively to improve their physical condition in preparation for the LRLT protocol, since many of these abnormalities are typically reversible.

  5. Abnormal functional global and local brain connectivity in female patients with anorexia nervosa

    PubMed Central

    Geisler, Daniel; Borchardt, Viola; Lord, Anton R.; Boehm, Ilka; Ritschel, Franziska; Zwipp, Johannes; Clas, Sabine; King, Joseph A.; Wolff-Stephan, Silvia; Roessner, Veit; Walter, Martin; Ehrlich, Stefan

    2016-01-01

    Background Previous resting-state functional connectivity studies in patients with anorexia nervosa used independent component analysis or seed-based connectivity analysis to probe specific brain networks. Instead, modelling the entire brain as a complex network allows determination of graph-theoretical metrics, which describe global and local properties of how brain networks are organized and how they interact. Methods To determine differences in network properties between female patients with acute anorexia nervosa and pairwise matched healthy controls, we used resting-state fMRI and computed well-established global and local graph metrics across a range of network densities. Results Our analyses included 35 patients and 35 controls. We found that the global functional network structure in patients with anorexia nervosa is characterized by increases in both characteristic path length (longer average routes between nodes) and assortativity (more nodes with a similar connectedness link together). Accordingly, we found locally decreased connectivity strength and increased path length in the posterior insula and thalamus. Limitations The present results may be limited to the methods applied during preprocessing and network construction. Conclusion We demonstrated anorexia nervosa–related changes in the network configuration for, to our knowledge, the first time using resting-state fMRI and graph-theoretical measures. Our findings revealed an altered global brain network architecture accompanied by local degradations indicating wide-scale disturbance in information flow across brain networks in patients with acute anorexia nervosa. Reduced local network efficiency in the thalamus and posterior insula may reflect a mechanism that helps explain the impaired integration of visuospatial and homeostatic signals in patients with this disorder, which is thought to be linked to abnormal representations of body size and hunger. PMID:26252451

  6. Pregnancy enhances sustained Ca2+ bursts and endothelial nitric oxide synthase activation in ovine uterine artery endothelial cells through increased connexin 43 function.

    PubMed

    Yi, Fu-Xian; Boeldt, Derek S; Gifford, Shannon M; Sullivan, Jeremy A; Grummer, Mary A; Magness, Ronald R; Bird, Ian M

    2010-01-01

    Endothelium-mediated vasodilation is specifically enhanced in uterine circulation during pregnancy, and production of nitric oxide (NO) is increased in response to a wide array of agonists. Uterine artery endothelial cells from nonpregnant (NP-UAECs) or pregnant (P-UAECs) ewes maintained in culture still show a pregnancy-enhanced difference in ATP-stimulated endothelial NO synthase (eNOS; official symbol NOS3) activation, even though NOS3 protein, purinergic receptors, and associated cell signaling proteins are expressed at equal levels. We have also shown that the pregnancy-enhanced endothelial cell NO response to ATP requires an enhanced and sustained capacitative entry phase that is likely mediated via canonical transient receptor potential protein/inositol 1,4,5-trisphosphate receptor type 2 interaction. In this study, we now show by simultaneous video imaging of individual Fura-2-loaded cells that the pregnancy-enhanced capacitative entry phase is not continuous and equal in all cells, but is in fact mediated as a series of periodic [Ca(2+)](i) bursts within individual cells. Not only does pregnancy increase the number of bursts over a longer time period in individual cells, but also a greater proportion of cells exhibit this burst activity, and at high cell density this occurs in a synchronous manner. The mediator of cell synchronization is connexin 43 (Cx43) gap junctions because 1) Cx43 is readily detectable by Western blot analysis in UAECs, whereas Cx40 and Cx37 are weakly detected or absent, and 2) pregnancy-specific enhancement of [Ca(2+)](i) bursts by ATP is blocked by inhibitory loop peptides selective to Cx43 ((43,37)GAP27) but not by a scrambled control peptide or (40)GAP27 or (40,37)GAP26 peptides, which are specific to Cx40 or Cx37. The relationship between Ca(2+) bursts and NOS3 activation is further established by the finding that (43,37)GAP27 inhibits ATP-stimulated NOS3 activation but has no effect on cell mitogenesis. We conclude that it is

  7. Endothelial Markers May Link Kidney Function to Cardiovascular Events in Type 2 Diabetes

    PubMed Central

    Maier, Christina; Clodi, Martin; Neuhold, Stephanie; Resl, Michael; Elhenicky, Marie; Prager, Rudolf; Moertl, Deddo; Strunk, Guido; Luger, Anton; Struck, Joachim; Pacher, Richard; Hülsmann, Martin

    2009-01-01

    OBJECTIVE The increased cardiovascular risk in diabetes has been linked to endothelial and renal dysfunction. The aim of this study was to investigate the role of stable fragments of the precursors of adrenomedullin, endothelin-1, vasopressin, and atrial natriuretic peptide in progression of cardiovascular disease in patients with diabetes. RESEARCH DESIGN AND METHODS This was a prospective, observational study design with a composite end point (death or unexpected admission to hospital due to a cardiovascular event) on 781 patients with type 2 diabetes (54 events, median duration of observation 15 months). The four stable precursor peptides midregional adrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), COOH-terminal proendothelin-1 (CT-proET-1), and COOH-terminal provasopressin or copeptin (CT-proAVP) were determined at baseline, and their association to renal function and cardiovascular events was studied using stepwise linear and Cox logistic regression analysis and receiver operating characteristic analysis, respectively. RESULTS MR-proADM, CT-proET-1, CT-proAVP, and MR-proANP were all elevated in patients with future cardiovascular events and independently correlated to serum creatinine. MR-proADM and MR-proANP were significant predictors of a future cardiovascular event, with MR-proANP being the stronger (area under the curve 0.802 ± 0.034, sensitivity 0.833, specificity 0.576, positive predictive value 0.132, and negative predictive value 0.978 with a cutoff value of 75 pmol/l). CONCLUSIONS The four serum markers of vasoactive and natriuretic peptides are related to both kidney function and cardiovascular events, thus linking two major complications of diabetes, diabetic nephropathy and cardiovascular disease. PMID:19564455

  8. A selective microRNA-based strategy inhibits restenosis while preserving endothelial function

    PubMed Central

    Santulli, Gaetano; Wronska, Anetta; Uryu, Kunihiro; Diacovo, Thomas G.; Gao, Melanie; Marx, Steven O.; Kitajewski, Jan; Chilton, Jamie M.; Akat, Kemal Marc; Tuschl, Thomas; Marks, Andrew R.; Totary-Jain, Hana

    2014-01-01

    Drugs currently approved to coat stents used in percutaneous coronary interventions do not discriminate between proliferating vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). This lack of discrimination delays reendothelialization and vascular healing, increasing the risk of late thrombosis following angioplasty. We developed a microRNA-based (miRNA-based) approach to inhibit proliferative VSMCs, thus preventing restenosis, while selectively promoting reendothelialization and preserving EC function. We used an adenoviral (Ad) vector that encodes cyclin-dependent kinase inhibitor p27Kip1 (p27) with target sequences for EC-specific miR-126-3p at the 3′ end (Ad-p27-126TS). Exogenous p27 overexpression was evaluated in vitro and in a rat arterial balloon injury model following transduction with Ad-p27-126TS, Ad-p27 (without miR-126 target sequences), or Ad-GFP (control). In vitro, Ad-p27-126TS protected the ability of ECs to proliferate, migrate, and form networks. At 2 and 4 weeks after injury, Ad-p27-126TS–treated animals exhibited reduced restenosis, complete reendothelialization, reduced hypercoagulability, and restoration of the vasodilatory response to acetylcholine to levels comparable to those in uninjured vessels. By incorporating miR-126-3p target sequences to leverage endogenous EC-specific miR-126, we overexpressed exogenous p27 in VSMCs, while selectively inhibiting p27 overexpression in ECs. Our proof-of-principle study demonstrates the potential of using a miRNA-based strategy as a therapeutic approach to specifically inhibit vascular restenosis while preserving EC function. PMID:25133430

  9. The effect of acute administration of Vitamin D on micro vascular endothelial function in Caucasians and South Asian Indians

    PubMed Central

    Petrofsky, Jerrold; Alshammari, Faris; Khowailed, Iman Akef; Rodrigues, Sophia; Potnis, Pooja; Akerkar, Siddhesh; Shah, Jinal; Chung, Guyeon; Save, Rakhi

    2013-01-01

    Background Vitamin D is a modulator of the immune system. There is some limited evidence that it also increases local blood flow in response to stress. Material/Methods In the present study, we examined 20 age matched subjects; 10 whom were from India and 10 Caucasians from the United States. Subjects were administered 4000 IU of Vitamin D3 for 3 weeks at breakfast. The function of the endothelial cells was evaluated in 2 ways; first, the response to 4 minutes of vascular occlusion was measured with a laser Doppler flow meter and second, the blood flow response to local heat at 42°C for 6 minutes. Results The results of the experiments showed that, as reported previously, the endothelial function in people from India was less than their Caucasian counterparts. The blood flow response to heat was reduced after 3 weeks administration of vitamin D in both groups and the response to vascular occlusion in the Caucasian group. But there was only a 20% reduction in the blood flow response to heat in the Caucasian group and a 50% reduction in the group from India. Conclusions Thus acute doses of vitamin D may increase vascular tone and reduce blood flow to tissue during stressors. Dosages administered for a longer duration may have beneficial effects on endothelial function but this was not examined here. PMID:23917403

  10. Novel Form of Curcumin Improves Endothelial Function in Young, Healthy Individuals: A Double-Blind Placebo Controlled Study.

    PubMed

    Oliver, Jonathan M; Stoner, Lee; Rowlands, David S; Caldwell, Aaron R; Sanders, Elizabeth; Kreutzer, Andreas; Mitchell, Joel B; Purpura, Martin; Jäger, Ralf

    2016-01-01

    Curcumin, a turmeric extract, may protect against cardiovascular diseases by enhancing endothelial function. In this randomized controlled double-blind parallel prospective study, fifty-nine healthy adults were assigned to placebo, 50 mg (50 mg), or 200 mg (200 mg) curcumin, for 8 weeks. The higher curcumin (200 mg) supplementation produced a dose-mediated improvement in endothelial function measured by flow-mediated dilation (FMD). The outcome was a clinically substantial 3.0% increase (90% CI 0.7 to 5.3%, p = 0.032; benefit : harm odds ratio 546 : 1) with the 200 mg dose, relative to placebo. The 50 mg dose also increased FMD relative to placebo by 1.7% (-0.6 to 4.0%, p = 0.23; 25 : 1), but the outcome was not clinically decisive. In apparently healthy adults, 8 weeks of 200 mg oral curcumin supplementation resulted in a clinically meaningful improvement in endothelial function as measured by FMD. Oral curcumin supplementation may present a simple lifestyle strategy for decreasing the risk of cardiovascular diseases. This trial was registered at ISRCTN registry (ISRCTN90184217). PMID:27630772

  11. Two angiotensin-converting enzyme-inhibitory peptides from almond protein and the protective action on vascular endothelial function.

    PubMed

    Liu, Rui-Lin; Ge, Xian-Li; Gao, Xiang-Yu; Zhan, Han-Ying; Shi, Ting; Su, Na; Zhang, Zhi-Qi

    2016-09-14

    This study aimed to discover and prepare novel angiotensin converting enzyme (ACE) inhibitory peptides from almond protein and further evaluate the effect on endothelial function of human umbilical vascular endothelial cells (HUVECs). Almond protein was hydrolyzed using a two-stage alcalase-protamex hydrolysis process, and the hydrolysates were subjected to a series of separations, ultrafiltration, gel filtration chromatography, and reversed-phased preparative chromatography, to obtain the active peptides. Seven ACE inhibitory fractions with the molecular weight below 1.5 kDa were isolated and prepared, and two purified ACE inhibitory peptides with the IC50 values of 67.52 ± 0.05 and 43.18 ± 0.07 μg mL(-1), were identified as Met-His-Thr-Asp-Asp and Gln-His-Thr-Asp-Asp, respectively. Then the effect of two ACE inhibitory peptides on the endothelial function of HUVECs was evaluated. Results showed that the two potent ACE inhibitory peptides significantly regulated the release of nitric oxide and endothelin in HUVECs. These results suggest that almond peptides have potential as an antihypertensive nutraceuticals or a functional food ingredient. PMID:27502043

  12. Chronic aerobic exercise training attenuates aortic stiffening and endothelial dysfunction through preserving aortic mitochondrial function in aged rats.

    PubMed

    Gu, Qi; Wang, Bing; Zhang, Xiao-Feng; Ma, Yan-Ping; Liu, Jian-Dong; Wang, Xiao-Ze

    2014-08-01

    Aging leads to large vessel arterial stiffening and endothelial dysfunction, which are important determinants of cardiovascular risk. The aim of present work was to assess the effects of chronic aerobic exercise training on aortic stiffening and endothelial dysfunction in aged rats and investigate the underlying mechanism about mitochondrial function. Chronic aerobic exercise training attenuated aortic stiffening with age marked by reduced collagen concentration, increased elastin concentration and reduced pulse wave velocity (PWV), and prevented aging-related endothelial dysfunction marked by improved endothelium-mediated vascular relaxation of aortas in response to acetylcholine. Chronic aerobic exercise training abated oxidative stress and nitrosative stress in aortas of aged rats. More importantly, we found that chronic aerobic exercise training in old rats preserved aortic mitochondrial function marked by reduced reactive oxygen species (ROS) formation and mitochondrial swelling, increased ATP formation and mitochondrial DNA content, and restored activities of complexes I and III and electron-coupling capacity between complexes I and III and between complexes II and III. In addition, it was found that chronic aerobic exercise training in old rats enhanced protein expression of uncoupling protein 2 (UCP-2), peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), manganese superoxide dismutase (Mn-SOD), aldehyde dehydrogenase 2 (ALDH-2), prohibitin (PHB) and AMP-activated kinase (AMPK) phosphorylation in aortas. In conclusion, chronic aerobic exercise training preserved mitochondrial function in aortas, which, at least in part, explained the aorta-protecting effects of exercise training in aging.

  13. Novel Form of Curcumin Improves Endothelial Function in Young, Healthy Individuals: A Double-Blind Placebo Controlled Study

    PubMed Central

    Stoner, Lee; Rowlands, David S.; Caldwell, Aaron R.; Sanders, Elizabeth; Kreutzer, Andreas; Mitchell, Joel B.; Purpura, Martin; Jäger, Ralf

    2016-01-01

    Curcumin, a turmeric extract, may protect against cardiovascular diseases by enhancing endothelial function. In this randomized controlled double-blind parallel prospective study, fifty-nine healthy adults were assigned to placebo, 50 mg (50 mg), or 200 mg (200 mg) curcumin, for 8 weeks. The higher curcumin (200 mg) supplementation produced a dose-mediated improvement in endothelial function measured by flow-mediated dilation (FMD). The outcome was a clinically substantial 3.0% increase (90% CI 0.7 to 5.3%, p = 0.032; benefit : harm odds ratio 546 : 1) with the 200 mg dose, relative to placebo. The 50 mg dose also increased FMD relative to placebo by 1.7% (−0.6 to 4.0%, p = 0.23; 25 : 1), but the outcome was not clinically decisive. In apparently healthy adults, 8 weeks of 200 mg oral curcumin supplementation resulted in a clinically meaningful improvement in endothelial function as measured by FMD. Oral curcumin supplementation may present a simple lifestyle strategy for decreasing the risk of cardiovascular diseases. This trial was registered at ISRCTN registry (ISRCTN90184217). PMID:27630772

  14. Novel Form of Curcumin Improves Endothelial Function in Young, Healthy Individuals: A Double-Blind Placebo Controlled Study.

    PubMed

    Oliver, Jonathan M; Stoner, Lee; Rowlands, David S; Caldwell, Aaron R; Sanders, Elizabeth; Kreutzer, Andreas; Mitchell, Joel B; Purpura, Martin; Jäger, Ralf

    2016-01-01

    Curcumin, a turmeric extract, may protect against cardiovascular diseases by enhancing endothelial function. In this randomized controlled double-blind parallel prospective study, fifty-nine healthy adults were assigned to placebo, 50 mg (50 mg), or 200 mg (200 mg) curcumin, for 8 weeks. The higher curcumin (200 mg) supplementation produced a dose-mediated improvement in endothelial function measured by flow-mediated dilation (FMD). The outcome was a clinically substantial 3.0% increase (90% CI 0.7 to 5.3%, p = 0.032; benefit : harm odds ratio 546 : 1) with the 200 mg dose, relative to placebo. The 50 mg dose also increased FMD relative to placebo by 1.7% (-0.6 to 4.0%, p = 0.23; 25 : 1), but the outcome was not clinically decisive. In apparently healthy adults, 8 weeks of 200 mg oral curcumin supplementation resulted in a clinically meaningful improvement in endothelial function as measured by FMD. Oral curcumin supplementation may present a simple lifestyle strategy for decreasing the risk of cardiovascular diseases. This trial was registered at ISRCTN registry (ISRCTN90184217).

  15. Effects of breed, gender, exercise and white-coat effect on markers of endothelial function in dogs.

    PubMed

    Moesgaard, S G; Holte, A V; Mogensen, T; Mølbak, J; Kristensen, A T; Jensen, A L; Teerlink, T; Reynolds, A J; Olsen, L H

    2007-06-01

    This study examines how systemic biomarkers of endothelial function and nitric oxide metabolism are affected by exercise in dogs. Furthermore, breed variation and white-coat effect have been tested by sampling three different dog breeds both in their home and in a clinical setting. Short-term exercise increased plasma nitrate and nitrite (NOx) and von Willebrand factor (vWf). There was significant difference between Pointers and the small dog breeds Cairn Terriers and Cavalier King Charles Spaniels in the general plasma levels of vWf and asymmetric dimethylarginine (ADMA). NOx and vWf were significantly higher when the sample was taken in the laboratory cf. at home, whereas ADMA and L-arginine were significantly lower. In conclusion, both short-term exercise and white-coat effect influence several plasma markers of endothelial function depending also on the breed and gender of the dogs. These findings should be considered in future studies concerning endothelial function in dogs. PMID:17092526

  16. Novel Form of Curcumin Improves Endothelial Function in Young, Healthy Individuals: A Double-Blind Placebo Controlled Study

    PubMed Central

    Stoner, Lee; Rowlands, David S.; Caldwell, Aaron R.; Sanders, Elizabeth; Kreutzer, Andreas; Mitchell, Joel B.; Purpura, Martin; Jäger, Ralf

    2016-01-01

    Curcumin, a turmeric extract, may protect against cardiovascular diseases by enhancing endothelial function. In this randomized controlled double-blind parallel prospective study, fifty-nine healthy adults were assigned to placebo, 50 mg (50 mg), or 200 mg (200 mg) curcumin, for 8 weeks. The higher curcumin (200 mg) supplementation produced a dose-mediated improvement in endothelial function measured by flow-mediated dilation (FMD). The outcome was a clinically substantial 3.0% increase (90% CI 0.7 to 5.3%, p = 0.032; benefit : harm odds ratio 546 : 1) with the 200 mg dose, relative to placebo. The 50 mg dose also increased FMD relative to placebo by 1.7% (−0.6 to 4.0%, p = 0.23; 25 : 1), but the outcome was not clinically decisive. In apparently healthy adults, 8 weeks of 200 mg oral curcumin supplementation resulted in a clinically meaningful improvement in endothelial function as measured by FMD. Oral curcumin supplementation may present a simple lifestyle strategy for decreasing the risk of cardiovascular diseases. This trial was registered at ISRCTN registry (ISRCTN90184217).

  17. Acute effects of an oral nitric oxide supplement on blood pressure, endothelial function, and vascular compliance in hypertensive patients.

    PubMed

    Houston, Mark; Hays, Laurie

    2014-07-01

    This blinded placebo-controlled crossover study evaluated the acute effects of an orally disintegrating lozenge that generates nitric oxide (NO) in the oral cavity on blood pressure (BP) response, endothelial function, and vascular compliance in unmedicated hypertensive patients. Thirty patients with clinical hypertension were recruited and enrolled in a blinded placebo-controlled clinical trial in an outpatient setting. Average baseline BP in 30 patients was 144±3/91±1 mm Hg. NO supplementation resulted in a significant decrease of 4 mm Hg in resting systolic BP (P<.003) and a significant decrease of 5 mm Hg in diastolic BP (P<.002) from baseline and placebo after 20 minutes. In addition, there was a further statistically significant reduction by 6 mm Hg in both systolic and diastolic pressure after 60 minutes (P<.0001 vs baseline). After a half hour of a single dose, there was a significant improvement in vascular compliance as measured by augmentation index and, after 4 hours, a statistically significant improvement in endothelial function as measured by the EndoPAT (Itamar Medical, Franklin, MA). A single administration of an oral active NO supplement appears to acutely lower BP, improve vascular compliance, and restore endothelial function in patients with hypertension. PMID:24962851

  18. Cigarette smoke exposure up-regulates endothelin receptor B in human pulmonary artery endothelial cells: molecular and functional consequences

    PubMed Central

    Milara, J; Ortiz, JL; Juan, G; Guijarro, R; Almudever, P; Martorell, M; Morcillo, EJ; Cortijo, J

    2010-01-01

    BACKGROUND AND PURPOSE Pulmonary arteries from smokers and chronic obstructive pulmonary disease patients show abnormal endothelium-dependent vascular reactivity. We studied the effect of cigarette smoke extract (CSE) on endothelin receptor B (ETB) expression in human pulmonary artery endothelial cells (HPAECs) and its role in endothelial dysfunction. EXPERIMENTAL APPROACH ETB receptor expression was measured by real time RT-PCR, Western blot and immunofluorescence. Cell contraction, intracellular Ca2+, F/G-actin, RhoA activity, myosin light chain phosphorylation, ET, NO, thromboxane (Tx)A2 and reactive oxygen species (ROS) were measured by traction microscopy, fluorescence microscopy, phalloidin fluorescence, colorimetric assay, Western blot, elisa and DCFDA fluorescence respectively. KEY RESULTS Cigarette smoke extract dose-dependently increased ETB receptor expression in HPAECs after 24 h incubation. CSE-induced ETB expression was attenuated by bosentan, the ETB receptor antagonist BQ788, the Rho kinase antagonist Y27632 and the antioxidant N-acetylcysteine. A monoclonal antibody to ET-1 prevented CSE-induced ETB receptor overexpression. Twenty-four hour exposure to ET-1 dose-dependently increased ETB receptor expression, mimicking the effect of CSE. CSE-induced ETB receptor overexpression caused greater cell contraction; increased intracellular Ca2+; increased F/G-actin and RhoA activity; increased myosin light chain phosphorylation; augmented TxA2 and ROS production; and decreased NO after acute ET-1 (10 nM). These effects were attenuated by bosentan, BQ788, Y27632 and N-acetylcysteine. CONCLUSIONS AND IMPLICATION Cigarette smoke extract induced ETB receptor overexpression by a feed forward mechanism mediated partly by ET release, promoting HPAEC dysfunction and attenuated by ETB receptor blockade, Rho kinase and ROS inhibition. These results provide support for the use of bosentan in CS-related endothelial dysfunction. PMID:20698855

  19. Abnormalities of motor function, transcription and cerebellar structure in mouse models of THAP1 dystonia.

    PubMed

    Ruiz, Marta; Perez-Garcia, Georgina; Ortiz-Virumbrales, Maitane; Méneret, Aurelie; Morant, Andrika; Kottwitz, Jessica; Fuchs, Tania; Bonet, Justine; Gonzalez-Alegre, Pedro; Hof, Patrick R; Ozelius, Laurie J; Ehrlich, Michelle E

    2015-12-20

    DYT6 dystonia is caused by mutations in THAP1 [Thanatos-associated (THAP) domain-containing apoptosis-associated protein] and is autosomal dominant and partially penetrant. Like other genetic primary dystonias, DYT6 patients have no characteristic neuropathology, and mechanisms by which mutations in THAP1 cause dystonia are unknown. Thap1 is a zinc-finger transcription factor, and most pathogenic THAP1 mutations are missense and are located in the DNA-binding domain. There are also nonsense mutations, which act as the equivalent of a null allele because they result in the generation of small mRNA species that are likely rapidly degraded via nonsense-mediated decay. The function of Thap1 in neurons is unknown, but there is a unique, neuronal 50-kDa Thap1 species, and Thap1 levels are auto-regulated on the mRNA level. Herein, we present the first characterization of two mouse models of DYT6, including a pathogenic knockin mutation, C54Y and a null mutation. Alterations in motor behaviors, transcription and brain structure are demonstrated. The projection neurons of the deep cerebellar nuclei are especially altered. Abnormalities vary according to genotype, sex, age and/or brain region, but importantly, overlap with those of other dystonia mouse models. These data highlight the similarities and differences in age- and cell-specific effects of a Thap1 mutation, indicating that the pathophysiology of THAP1 mutations should be assayed at multiple ages and neuronal types and support the notion of final common pathways in the pathophysiology of dystonia arising from disparate mutations. PMID:26376866

  20. Abnormalities of motor function, transcription and cerebellar structure in mouse models of THAP1 dystonia.

    PubMed

    Ruiz, Marta; Perez-Garcia, Georgina; Ortiz-Virumbrales, Maitane; Méneret, Aurelie; Morant, Andrika; Kottwitz, Jessica; Fuchs, Tania; Bonet, Justine; Gonzalez-Alegre, Pedro; Hof, Patrick R; Ozelius, Laurie J; Ehrlich, Michelle E

    2015-12-20

    DYT6 dystonia is caused by mutations in THAP1 [Thanatos-associated (THAP) domain-containing apoptosis-associated protein] and is autosomal dominant and partially penetrant. Like other genetic primary dystonias, DYT6 patients have no characteristic neuropathology, and mechanisms by which mutations in THAP1 cause dystonia are unknown. Thap1 is a zinc-finger transcription factor, and most pathogenic THAP1 mutations are missense and are located in the DNA-binding domain. There are also nonsense mutations, which act as the equivalent of a null allele because they result in the generation of small mRNA species that are likely rapidly degraded via nonsense-mediated decay. The function of Thap1 in neurons is unknown, but there is a unique, neuronal 50-kDa Thap1 species, and Thap1 levels are auto-regulated on the mRNA level. Herein, we present the first characterization of two mouse models of DYT6, including a pathogenic knockin mutation, C54Y and a null mutation. Alterations in motor behaviors, transcription and brain structure are demonstrated. The projection neurons of the deep cerebellar nuclei are especially altered. Abnormalities vary according to genotype, sex, age and/or brain region, but importantly, overlap with those of other dystonia mouse models. These data highlight the similarities and differences in age- and cell-specific effects of a Thap1 mutation, indicating that the pathophysiology of THAP1 mutations should be assayed at multiple ages and neuronal types and support the notion of final common pathways in the pathophysiology of dystonia arising from disparate mutations.

  1. A Comparison of Measures of Endothelial Function in Patients with Peripheral Arterial Disease and Age and Gender Matched Controls

    PubMed Central

    Allan, Richard B.; Vun, Simon V.; Spark, J. Ian

    2016-01-01

    This study compared flow-mediated dilatation (FMD), peripheral artery tonometry (PAT), and serum nitric oxide (NO) measures of endothelial function in patients with peripheral artery disease (PAD) against age/gender matched controls. 25 patients (mean age: 72.4 years, M : F 18 : 7) with established PAD and an age/gender matched group of 25 healthy controls (mean age: 72.4 years, M : F 18 : 7) were studied. Endothelial function was measured using the % FMD, reactive hyperemia index (RHI) using PAT and serum NO (μmol). Difference for each method between PAD and control patients and correlation between the methods were investigated. FMD and RHI were lower in patients with PAD (median FMD for PAD = 2.16% versus control = 3.77%, p = 0.034 and median RHI in PAD = 1.64 versus control = 1.92, p = 0.005). NO levels were not significantly different between the groups (PAD median = 7.70 μmol, control median = 13.05 μmol, p = 0.662). These results were obtained in elderly patients and cannot be extrapolated to younger individuals. FMD and PAT both demonstrated a lower hyperaemic response in patients with PAD; however, FMD results in PAD patients were unequivocally reduced whereas half the PAD patients had RHI values above the established threshold for endothelial dysfunction. This suggests that FMD is a more appropriate method for the measurement of NO-mediated endothelial function. PMID:26942010

  2. Effect of niacin on endothelial function: a systematic review and meta-analysis of randomized controlled trials.

    PubMed

    Sahebkar, Amirhossein

    2014-02-01

    Endothelial dysfunction is an independent predictor of incident atherosclerotic cardiovascular disease (ACVD). Niacin possesses high-density lipoprotein (HDL)-elevating, antioxidant and anti-inflammatory properties, all potentially contributing to the amelioration of endothelial function. However, controversies exist among trials reporting the effects of niacin on endothelium-dependent flow-mediated dilation (FMD) as a reliable surrogate of endothelial function. The objective of this study was to assess the effect of niacin on brachial artery FMD using a meta-analysis of available evidence. MEDLINE and Scopus databases were searched for randomized controlled trials investigating the impact of niacin therapy on brachial artery FMD. Meta-analysis of eligible studies was conducted using a random-effects model. Pooled effects were measured by weighted mean difference (WMD) and 95% confidence intervals (CIs). Quality assessment, and subgroup, meta-regression and sensitivity analyses were conducted using standard methods. Among 596 citations, 19 full-text articles were read and seven were found to be eligible for inclusion. Eligible studies involved 441 subjects comprising 228 in the niacin and 213 in the control groups. Niacin therapy significantly improved FMD (WMD: 1.98%; 95% CI: 0.91-3.05%; p = 0.0003) and this effect was robust in the sensitivity analysis. The effect size was greater in the subgroup of studies administering higher doses of niacin (≥ 2000 mg/day) as well as those studies administering niacin for primary prevention of ACVD. Meta-regression indicated no association between niacin-induced changes in FMD and changes in plasma HDL-cholesterol, low-density lipoprotein-cholesterol or triglycerides. None of the included studies could find any significant effect of niacin on nitroglycerin-mediated dilation. In conclusion, treatment with niacin improves endothelial function.

  3. Acid Sphingomyelinase-Derived Ceramide Regulates ICAM-1 Function during T Cell Transmigration across Brain Endothelial Cells.

    PubMed

    Lopes Pinheiro, Melissa A; Kroon, Jeffrey; Hoogenboezem, Mark; Geerts, Dirk; van Het Hof, Bert; van der Pol, Susanne M A; van Buul, Jaap D; de Vries, Helga E

    2016-01-01

    Multiple sclerosis (MS) is a chronic demyelinating disorder of the CNS characterized by immune cell infiltration across the brain vasculature into the brain, a process not yet fully understood. We previously demonstrated that the sphingolipid metabolism is altered in MS lesions. In particular, acid sphingomyelinase (ASM), a critical enzyme in the production of the bioactive lipid ceramide, is involved in the pathogenesis of MS; however, its role in the brain vasculature remains unknown. Transmigration of T lymphocytes is highly dependent on adhesion molecules in the vasculature such as intercellular adhesion molecule-1 (ICAM-1). In this article, we hypothesize that ASM controls T cell migration by regulating ICAM-1 function. To study the role of endothelial ASM in transmigration, we generated brain endothelial cells lacking ASM activity using a lentiviral shRNA approach. Interestingly, although ICAM-1 expression was increased in cells lacking ASM activity, we measured a significant decrease in T lymphocyte adhesion and consequently transmigration both in static and under flow conditions. As an underlying mechanism, we revealed that upon lack of endothelial ASM activity, the phosphorylation of ezrin was perturbed as well as the interaction between filamin and ICAM-1 upon ICAM-1 clustering. Functionally this resulted in reduced microvilli formation and impaired transendothelial migration of T cells. In conclusion, in this article, we show that ASM coordinates ICAM-1 function in brain endothelial cells by regulating its interaction with filamin and phosphorylation of ezrin. The understanding of these underlying mechanisms of T lymphocyte transmigration is of great value to develop new strategies against MS lesion formation. PMID:26597010

  4. Genetic engineering with endothelial nitric oxide synthase improves functional properties of endothelial progenitor cells from patients with coronary artery disease: an in vitro study.

    PubMed

    Kaur, Savneet; Kumar, T R Santhosh; Uruno, Akira; Sugawara, Akira; Jayakumar, Karunakaran; Kartha, Chandrasekharan Cheranellore

    2009-11-01

    Recent studies have reported a marked impairment in the number and functions of endothelial progenitor cells (EPCs) in patients with coronary artery disease (CAD). In view of an important role of eNOS in angiogenesis, in the present study, we evaluated the effects of eNOS gene transfer in ex vivo expanded EPCs isolated from patients with CAD. The expanded EPCs were transfected with mammalian expression vector pcDNA3.1-eNOS containing the full-length human eNOS gene using lipofectamine. About 35-40% of the eNOS-EPCs had higher expression of eNOS as compared to untransfected EPCs. EPCs transfected with pcDNA3.0-EGFP, the plasmid vector expressing green fluorescent protein (GFP) were used as control. The untransfected, GFP-transfected and eNOS-transfected EPCs were compared in terms of important functional attributes of angiogenesis such as proliferation, migration, differentiation and adhesion/integration into tube-like structures in vitro. Functional studies revealed that in the presence of defined growth conditions, compared to the untransfected and GFP-transfected cells, eNOS-EPCs from patients with CAD have a significant increase in [3H] thymidine-labeled DNA (P < 0.01), migration (14.6 +/- 1.8 and 16.5 +/- 1.9 vs. 23.5 +/- 3.4 cells/field, P < 0.01), ability to differentiate into endothelial-like spindle-shaped cells (46 +/- 4.5 and 56.5 +/- 2.1 vs. 93.2 +/- 6.6 cells/field, P < 0.001) and also incorporation into tube-like structures on the matrigel (GFP-EPCs: 21.25 +/- 2.9 vs. GFP-eNOS-EPCs: 34.5 +/- 5.5 cells/field, P < 0.05). We conclude that eNOS gene transfection is a valuable approach to augment angiogenic properties of ex vivo expanded EPCs and eNOS-modified EPCs may offer significant advantages than EPCs alone in terms of their clinical use in patients with myocardial ischemia.

  5. Disruption of Ah Receptor Signaling during Mouse Development Leads to Abnormal Cardiac Structure and Function in the Adult

    PubMed Central

    Carreira, Vinicius S.; Fan, Yunxia; Kurita, Hisaka; Wang, Qin; Ko, Chia-I; Naticchioni, Mindi; Jiang, Min; Koch, Sheryl; Zhang, Xiang; Biesiada, Jacek; Medvedovic, Mario; Xia, Ying; Rubinstein, Jack; Puga, Alvaro

    2015-01-01

    The Developmental Origins of Health and Disease (DOHaD) Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease. Interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent. Ten-months old adult Ahr-/- and in utero TCDD-exposed Ahr+/+ mice showed sexually dimorphic abnormal cardiovascular phenotypes characterized by echocardiographic findings of hypertrophy, ventricular dilation and increased heart weight, resting heart rate and systolic and mean blood pressure, and decreased exercise tolerance. Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. Cardiac dysfunction in mouse embryos resulting from AHR signaling disruption seems to progress into abnormal cardiac structure and function that predispose adults to cardiac disease, but while embryonic dysfunction is equally robust in males and females, the adult abnormalities are more prevalent in females, with the highest severity in Ahr-/- females. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease. PMID:26555816

  6. Surface modification of silicone tubes by functional carboxyl and amine, but not peroxide groups followed by collagen immobilization improves endothelial cell stability and functionality.

    PubMed

    Salehi-Nik, Nasim; Amoabediny, Ghassem; Shokrgozar, Mohammad Ali; Mottaghy, Khosrow; Klein-Nulend, Jenneke; Zandieh-Doulabi, Behrouz

    2015-03-02

    Surface modification by functional groups promotes endothelialization in biohybrid artificial lungs, but whether it affects endothelial cell stability under fluid shear stress, and the release of anti-thrombotic factors, e.g. nitric oxide (NO), is unknown. We aimed to test whether surface-modified silicone tubes containing different functional groups, but similar wettability, improve collagen immobilization, endothelialization, cell stability and cell-mediated NO-release. Peroxide, carboxyl, and amine-groups increased collagen immobilization (41-76%). Only amine-groups increased ultimate tensile strength (2-fold). Peroxide and amine enhanced (1.5-2.5 fold), but carboxyl-groups decreased (2.9-fold) endothelial cell number after 6 d. After collagen immobilization, cell numbers were enhanced by all group-modifications (2.8-3.8 fold). Cells were stable under 1 h-fluid shear stress on amine, but not carboxyl or peroxide-group-modified silicone (>50% cell detachment), while cells were also stable on carboxyl-group-modified silicone with immobilized collagen. NO-release was increased by peroxide and amine (1.1-1.7 fold), but decreased by carboxyl-group-modification (9.8-fold), while it increased by all group-modifications after collagen immobilization (1.8-2.8 fold). Only the amine-group-modification changed silicone stiffness and transparency. In conclusion, silicone-surface modification of blood-contacting parts of artificial lungs with carboxyl and amine, but not peroxide-groups followed by collagen immobilization allows the formation of a stable functional endothelial cell layer. Amine-group-modification seems undesirable since it affected silicone's physical properties.

  7. Effects of dark chocolate and cocoa consumption on endothelial function and arterial stiffness in overweight adults.

    PubMed

    West, Sheila G; McIntyre, Molly D; Piotrowski, Matthew J; Poupin, Nathalie; Miller, Debra L; Preston, Amy G; Wagner, Paul; Groves, Lisa F; Skulas-Ray, Ann C

    2014-02-01

    The consumption of cocoa and dark chocolate is associated with a lower risk of CVD, and improvements in endothelial function may mediate this relationship. Less is known about the effects of cocoa/chocolate on the augmentation index (AI), a measure of vascular stiffness and vascular tone in the peripheral arterioles. We enrolled thirty middle-aged, overweight adults in a randomised, placebo-controlled, 4-week, cross-over study. During the active treatment (cocoa) period, the participants consumed 37 g/d of dark chocolate and a sugar-free cocoa beverage (total cocoa = 22 g/d, total flavanols (TF) = 814 mg/d). Colour-matched controls included a low-flavanol chocolate bar and a cocoa-free beverage with no added sugar (TF = 3 mg/d). Treatments were matched for total fat, saturated fat, carbohydrates and protein. The cocoa treatment significantly increased the basal diameter and peak diameter of the brachial artery by 6% (+2 mm) and basal blood flow volume by 22%. Substantial decreases in the AI, a measure of arterial stiffness, were observed in only women. Flow-mediated dilation and the reactive hyperaemia index remained unchanged. The consumption of cocoa had no effect on fasting blood measures, while the control treatment increased fasting insulin concentration and insulin resistance (P= 0·01). Fasting blood pressure (BP) remained unchanged, although the acute consumption of cocoa increased resting BP by 4 mmHg. In summary, the high-flavanol cocoa and dark chocolate treatment was associated with enhanced vasodilation in both conduit and resistance arteries and was accompanied by significant reductions in arterial stiffness in women.

  8. Soya isoflavone-enriched cereal bars affect markers of endothelial function in postmenopausal women.

    PubMed

    Hallund, J; Bügel, S; Tholstrup, T; Ferrari, M; Talbot, D; Hall, W L; Reimann, M; Williams, C M; Wiinberg, N

    2006-06-01

    Soya isoflavones are thought to be cardioprotective due to their structural similarity to oestrogen. In order to investigate the effect of soya isoflavones on markers of endothelial function we conducted a randomised, double-blind, placebo-controlled, cross-over study with thirty healthy postmenopausal women. The women consumed cereal bars, with or without soya isoflavones (50 mg/d), for 8 weeks, separated by an 8-week washout period. Systemic arterial compliance (SAC), isobaric arterial compliance (IAC), flow-mediated endothelium-dependent vasodilation (FMD) and nitroglycerine-mediated endothelium-independent vasodilation (NMD) were measured at the beginning of the study and after each intervention period. Blood pressure (BP) and plasma concentrations of nitrite and nitrate (NOx) and endothelin-1 (ET-1) were measured at the beginning and end of each intervention period. NMD was 13.4 (SEM 2.0)% at baseline and 15.5 (SEM 1.1) % after isoflavone treatment compared with 12.4 (SEM 1.0)% after placebo treatment (P=0.03). NOx increased from 27.7 (SEM 2.7) to 31.1 (SEM 3.2) microM after isoflavones treatment compared with 25.4 (SEM 1.5) to 20.4 (SEM 1.1) microM after placebo treatment (P=0.003) and a significant increase in the NOx:ET-1 ratio (P=0.005) was observed after the isoflavone treatment compared with placebo. A significant difference in SAC after the isoflavone and placebo treatment was observed (P=0.04). No significant difference was found in FMD, IAC, BP and ET-1. In conclusion, 8 weeks' consumption of cereals bars enriched with 50 mg soya isoflavones/d increased plasma NOx concentrations and improved endothelium-independent vasodilation in healthy postmenopausal women. PMID:16768834

  9. Impaired function of bone marrow-derived endothelial progenitor cells in murine liver fibrosis.

    PubMed

    Shirakura, Katsuya; Masuda, Haruchika; Kwon, Sang-Mo; Obi, Syotaro; Ito, Rie; Shizuno, Tomoko; Kurihara, Yusuke; Mine, Tetsuya; Asahara, Takayuki

    2011-01-01

    Liver fibrosis (LF) caused by chronic liver damage has been considered as an irreversible disease. As alternative therapy for liver transplantation, there are high expectations for regenerative medicine of the liver. Bone marrow (BM)- or peripheral blood-derived stem cells, including endothelial progenitor cells (EPCs), have recently been used to treat liver cirrhosis. We investigated the biology of BM-derived EPC in a mouse model of LF. C57BL/6J mice were subcutaneously injected with carbon tetrachloride (CCl(4)) every 3 days for 90 days. Sacrificed 2 days after final injection, whole blood (WB) was collected for isolation of mononuclear cells (MNCs) and biochemical examination. Assessments of EPC in the peripheral blood and BM were performed by flow cytometry and EPC colony-forming assay, respectively, using purified MNCs and BM c-KIT(+), Sca-1(+), and Lin(-) (KSL) cells. Liver tissues underwent histological analysis with hematoxylin/eosin/Azan staining, and spleens were excised and weighed. CCl(4)-treated mice exhibited histologically bridging fibrosis, pseudolobular formation, and splenomegaly, indicating successful induction of LF. The frequency of definitive EPC-colony-forming-units (CFU) as well as total EPC-CFU at the equivalent cell number of 500 BM-KSL cells decreased significantly (p < 0.0001) in LF mice compared with control mice; no significant changes in primitive EPC-CFU occurred in LF mice. The frequency of WB-MNCs of definitive EPC-CFU decreased significantly (p < 0.01) in LF mice compared with control mice. Together, these findings indicated the existence of impaired EPC function and differentiation in BM-derived EPCs in LF mice and might be related to clinical LF.

  10. Resistance Exercise Restores Endothelial Function and Reduces Blood Pressure in Type 1 Diabetic Rats

    PubMed Central

    Mota, Marcelo Mendonça; da Silva, Tharciano Luiz Teixeira Braga; Fontes, Milene Tavares; Barreto, André Sales; Araújo, João Eliakim dos Santos; de Oliveira, Antônio Cesar Cabral; Wichi, Rogério Brandão; Santos, Márcio Roberto Viana

    2014-01-01

    Background Resistance exercise effects on cardiovascular parameters are not consistent. Objectives The effects of resistance exercise on changes in blood glucose, blood pressure and vascular reactivity were evaluated in diabetic rats. Methods Wistar rats were divided into three groups: control group (n = 8); sedentary diabetic (n = 8); and trained diabetic (n = 8). Resistance exercise was carried out in a squat device for rats and consisted of three sets of ten repetitions with an intensity of 50%, three times per week, for eight weeks. Changes in vascular reactivity were evaluated in superior mesenteric artery rings. Results A significant reduction in the maximum response of acetylcholine-induced relaxation was observed in the sedentary diabetic group (78.1 ± 2%) and an increase in the trained diabetic group (95 ± 3%) without changing potency. In the presence of NG-nitro-L-arginine methyl ester, the acetylcholine-induced relaxation was significantly reduced in the control and trained diabetic groups, but not in the sedentary diabetic group. Furthermore, a significant increase (p < 0.05) in mean arterial blood pressure was observed in the sedentary diabetic group (104.9 ± 5 to 126.7 ± 5 mmHg) as compared to that in the control group. However, the trained diabetic group showed a significant decrease (p < 0.05) in the mean arterial blood pressure levels (126.7 ± 5 to 105.1 ± 4 mmHg) as compared to the sedentary diabetic group. Conclusions Resistance exercise could restore endothelial function and prevent an increase in arterial blood pressure in type 1 diabetic rats. PMID:25120082

  11. Effects of disturbed blood flow during exercise on endothelial function: a time course analysis

    PubMed Central

    Paiva, F.M.; Vianna, L.C.; Fernandes, I.A.; Nóbrega, A.C.; Lima, R.M.

    2016-01-01

    This study aimed to examine the time course of endothelial function after a single handgrip exercise session combined with blood flow restriction in healthy young men. Nine participants (28±5.8 years) completed a single session of bilateral dynamic handgrip exercise (20 min with 60% of the maximum voluntary contraction). To induce blood flow restriction, a cuff was placed 2 cm below the antecubital fossa in the experimental arm. This cuff was inflated to 80 mmHg before initiation of exercise and maintained through the duration of the protocol. The experimental arm and control arm were randomly selected for all subjects. Brachial artery flow-mediated dilation (FMD) and blood flow velocity profiles were assessed using Doppler ultrasonography before initiation of the exercise, and at 15 and 60 min after its cessation. Blood flow velocity profiles were also assessed during exercise. There was a significant increase in FMD 15 min after exercise in the control arm compared with before exercise (64.09%±16.59%, P=0.001), but there was no change in the experimental arm (-12.48%±12.64%, P=0.252). FMD values at 15 min post-exercise were significantly higher for the control arm in comparison to the experimental arm (P=0.004). FMD returned to near baseline values at 60 min after exercise, with no significant difference between arms (P=0.424). A single handgrip exercise bout provoked an acute increase in FMD 15 min after exercise, returning to near baseline values at 60 min. This response was blunted by the addition of an inflated pneumatic cuff to the exercising arm. PMID:26909789

  12. [Endothelial cell adhesion molecules].

    PubMed

    Ivanov, A N; Norkin, I A; Puchin'ian, D M; Shirokov, V Iu; Zhdanova, O Iu

    2014-01-01

    The review presents current data concerning the functional role of endothelial cell adhesion molecules belonging to different structural families: integrins, selectins, cadherins, and the immunoglobulin super-family. In this manuscript the regulatory mechanisms and factors of adhesion molecules expression and distribution on the surface of endothelial cells are discussed. The data presented reveal the importance of adhesion molecules in the regulation of structural and functional state of endothelial cells in normal conditions and in pathology. Particular attention is paid to the importance of these molecules in the processes of physiological and pathological angiogenesis, regulation of permeability of the endothelial barrier and cell transmigration.

  13. Clinical trial to assess the effect of physical exercise on endothelial function and insulin resistance in pregnant women

    PubMed Central

    2009-01-01

    Background Preeclampsia (PE) is a common maternal disease that complicates 5 to 10% of pregnancies and remains as the major cause of maternal and neonatal mortality. Cost-effective interventions aimed at preventing the development of preeclampsia are urgently needed. However, the pathogenesis of PE is not well known. Multiple mechanisms such as oxidative stress, endothelial dysfunction and insulin resistance may contribute to its development. Regular aerobic exercise recovers endothelial function; improves insulin resistance and decreases oxidative stress. Therefore the purpose of this clinical trial is to determine the effect of regular aerobic exercise on endothelial function, on insulin resistance and on pregnancy outcome. Methods and design 64 pregnant women will be included in a blind, randomized clinical trial, and parallel assignment. The exercise group will do regular aerobic physical exercise: walking (10 minutes), aerobic exercise (30 minutes), stretching (10 minutes) and relaxation exercise (10 minutes) in three sessions per week. Control group will do the activities of daily living (bathing, dressing, eating, and walking) without counselling from a physical therapist. Trial registration NCT00741312. PMID:19919718

  14. Effects of 4-hydroxynonenal on vascular endothelial and smooth muscle cell redox signaling and function in health and disease☆

    PubMed Central

    Chapple, Sarah J.; Cheng, Xinghua; Mann, Giovanni E.

    2013-01-01

    4-hydroxynonenal (HNE) is a lipid hydroperoxide end product formed from the oxidation of n-6 polyunsaturated fatty acids. The relative abundance of HNE within the vasculature is dependent not only on the rate of lipid peroxidation and HNE synthesis but also on the removal of HNE adducts by phase II metabolic pathways such as glutathione-S-transferases. Depending on its relative concentration, HNE can induce a range of hormetic effects in vascular endothelial and smooth muscle cells, including kinase activation, proliferation, induction of phase II enzymes and in high doses inactivation of enzymatic processes and apoptosis. HNE also plays an important role in the pathogenesis of vascular diseases such as atherosclerosis, diabetes, neurodegenerative disorders and in utero diseases such as pre-eclampsia. This review examines the known production, metabolism and consequences of HNE synthesis within vascular endothelial and smooth muscle cells, highlighting alterations in mitochondrial and endoplasmic reticulum function and their association with various vascular pathologies. PMID:24024167

  15. Role of carbon monoxide in impaired endothelial function mediated by acute second-hand tobacco, incense, and candle smoke exposures.

    PubMed

    Weber, Lynn P; Al-Dissi, Ahmad; Marit, Jordan S; German, Timothy N; Terletski, Sharilyn D

    2011-05-01

    The aim of this study was to determine if carbon monoxide (CO) is responsible for acute adverse cardiovascular effects of different sources of smoke: second-hand tobacco smoke (SHS), incense and candle smoke. Endothelial function was tested using flow-mediated dilation (FMD) in pigs and was shown to be sensitive to nitric oxide synthase blockade. Subsequent experiments showed that FMD was significantly impaired compared to sham-exposed pigs at 30 min after a 30-min exposure to all three sources of smoke. In contrast, SHS significantly increased systolic, diastolic and pulse pressures compared to sham-exposure, while both incense and candle smoke exposure had no effect. The FMD impairment correlated well with CO levels in the exposure chamber, but not total particulates or venous CO-hemoglobin. Therefore, this study suggests a gas phase component of smoke that accompanies CO, but not CO itself, is responsible for acute endothelial dysfunction after SHS, incense or candle smoke exposure.

  16. Transcriptional and functional adaptations of human endothelial cells to physiological chronic low oxygen.

    PubMed

    Jiang, Yi-Zhou; Wang, Kai; Li, Yan; Dai, Cai-Feng; Wang, Ping; Kendziorski, Christina; Chen, Dong-Bao; Zheng, Jing

    2013-05-01

    Endothelial cells chronically reside in low-O2 environments in vivo (2%-13% O2), which are believed to be critical for cell homeostasis. To elucidate the roles of this physiological chronic normoxia in human endothelial cells, we examined transcriptomes of human umbilical vein endothelial cells (HUVECs), proliferation and migration of HUVECs in response to fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA), and underlying signaling mechanisms under physiological chronic normoxia. Immediately after isolation, HUVECs were cultured steadily under standard cell culture normoxia (SCN; 21% O2) or physiological chronic normoxia (PCN; 3% O2) up to 25 days. We found that PCN up-regulated 41 genes and down-regulated 21 genes, 90% of which differed from those previously reported from HUVECs cultured under SCN and exposed to acute low O2. Gene ontology analysis indicated that PCN-regulated genes were highly related to cell proliferation and migration, consistent with the results from benchtop assays that showed that PCN significantly enhanced FGF2- and VEGFA-stimulated cell proliferation and migration. Interestingly, preexposing the PCN cells to 21% O2 up to 5 days did not completely diminish PCN-enhanced cell proliferation and migration. These PCN-enhanced cell proliferations and migrations were mediated via augmented activation of MEK1/MEK2/ERK1/ERK2 and/or PI3K/AKT1. Importantly, these PCN-enhanced cellular responses were associated with an increase in activation of VEGFR2 but not FGFR1, without altering their expression. Thus, PCN programs endothelial cells to undergo dramatic changes in transcriptomes and sensitizes cellular proliferative and migratory responses to FGF2 and VEGFA. These PCN cells may offer a unique endothelial model, more closely mimicking the in vivo states.

  17. Chemical functionalization of bioceramics to enhance endothelial cells adhesion for tissue engineering.

    PubMed

    Borcard, Françoise; Staedler, Davide; Comas, Horacio; Juillerat, Franziska Krauss; Sturzenegger, Philip N; Heuberger, Roman; Gonzenbach, Urs T; Juillerat-Jeanneret, Lucienne; Gerber-Lemaire, Sandrine

    2012-09-27

    To control the selective adhesion of human endothelial cells and human serum proteins to bioceramics of different compositions, a multifunctional ligand containing a cyclic arginine-glycine-aspartate (RGD) peptide, a tetraethylene glycol spacer, and a gallate moiety was designed, synthesized, and characterized. The binding of this ligand to alumina-based, hydroxyapatite-based, and calcium phosphate-based bioceramics was demonstrated. The conjugation of this ligand to the bioceramics induced a decrease in the nonselective and integrin-selective binding of human serum proteins, whereas the binding and adhesion of human endothelial cells was enhanced, dependent on the particular bioceramics.

  18. κ-Opioid Receptor Stimulation Improves Endothelial Function via Akt-stimulated NO Production in Hyperlipidemic Rats

    PubMed Central

    Tian, Fei; Zheng, Xu-Yang; Li, Juan; Zhang, Shu-Miao; Feng, Na; Guo, Hai-Tao; Jia, Min; Wang, Yue-Min; Fan, Rong; Pei, Jian-Ming

    2016-01-01

    This study was designed to investigate the effect of U50,488H (a selective κ-opioid receptor agonist) on endothelial function impaired by hyperlipidemia and to determine the role of Akt-stimulated NO production in it. Hyperlipidemic model was established by feeding rats with a high-fat diet for 14 weeks. U50,488H and nor-BNI (a selective κ-opioid receptor antagonist) were administered intraperitoneally. In vitro, the involvement of the PI3K/Akt/eNOS pathway in the effect of U50,488H was studied using cultured endothelial cells subjected to artificial hyperlipidemia. Serum total cholesterol and low-density lipoprotein cholesterol concentrations dramatically increased after high-fat diet feeding. Administration of U50,488H significantly alleviated endothelial ultrastructural destruction and endothelium-dependent vasorelaxation impairment caused by hyperlipidemia. U50,488H also increased Akt/eNOS phosphorylation and serum/medium NO level both in vivo and in vitro. U50,488H increased eNOS activity and suppressed iNOS activity in vivo. The effects of U50,488H were abolished in vitro by siRNAs targeting κ-opioid receptor and Akt or PI3K/Akt/eNOS inhibitors. All effects of U50,488H were blocked by nor-BNI. These results demonstrate that κ-opioid receptor stimulation normalizes endothelial ultrastructure and function under hyperlipidemic condition. Its mechanism is related to the preservation of eNOS phosphorylation through activation of the PI3K/Akt signaling pathway and downregulation of iNOS expression/activity. PMID:27226238

  19. Pharmacological neutropenia prevents endothelial dysfunction but not smooth muscle functions impairment induced by middle cerebral artery occlusion

    PubMed Central

    Pétrault, Olivier; Ouk, Thavarak; Gautier, Sophie; Laprais, Maud; Gelé, Patrick; Bastide, Michèle; Bordet, Régis

    2005-01-01

    The polymorphonuclear neutrophils (PMN) activation and mobilization observed in acute cerebral infarction contribute to the brain tissue damage, but PMN could also be involved in postischemic functional injury of ischemied blood vessel. This study was undertaken to investigate whether pharmacological neutropenia could modify the postischemic endothelial dysfunction in comparison to smooth muscle whose impairment is likely more related to reperfusion and oxidative stress. A cerebral ischemia–reperfusion by endoluminal occlusion of right middle cerebral artery (MCA) was performed 4 days after intravenous administration of vinblastine or 12 h after RP-3 anti-rat neutrophils monoclonal antibody (mAb RP-3) injection into the peritoneal cavity, on male Wistar rats with 1-h ischemia then followed by 24-h reperfusion period. Brain infarct volume was measured by histomorphometric analysis and vascular endothelial and smooth muscle reactivity of MCA was analysed using Halpern myograph. Neutropenia induced a neuroprotective effect as demonstrated by a significant decrease of brain infarct size. In parallel to neuroprotection, neutropenia prevented postischemic impairment of endothelium-dependent relaxing response to acetylcholine. In contrast, smooth muscle functional alterations were not prevented by neutropenia. Ischemia–reperfusion-induced myogenic tone impairment remained unchanged in vinblastine and mAb RP-3-treated rats. Postischemic Kir2.x-dependent relaxation impairment was not prevented in neutropenic conditions. The fully relaxation of smooth muscle response to sodium nitroprusside was similar in all groups. Our results evidenced the dissociate prevention of pharmacologically induced neutropenia on postischemic vascular endothelial and smooth muscle impairment. The selective endothelial protection by neutropenia is parallel to a neuroprotective effect suggesting a possible relationship between the two phenomena. PMID:15700030

  20. Blueberries improve endothelial function, but not blood pressure, in adults with metabolic syndrome: a randomized, double-blind, placebo-controlled clinical trial.

    PubMed

    Stull, April J; Cash, Katherine C; Champagne, Catherine M; Gupta, Alok K; Boston, Raymond; Beyl, Robbie A; Johnson, William D; Cefalu, William T

    2015-05-27

    Blueberry consumption has been shown to have various health benefits in humans. However, little is known about the effect of blueberry consumption on blood pressure, endothelial function and insulin sensitivity in humans. The present study investigated the role of blueberry consumption on modifying blood pressure in subjects with metabolic syndrome. In addition, endothelial function and insulin sensitivity (secondary measurements) were also assessed. A double-blind and placebo-controlled study was conducted in 44 adults (blueberry, n = 23; and placebo, n = 21). They were randomized to receive a blueberry or placebo smoothie twice daily for six weeks. Twenty-four-hour ambulatory blood pressure, endothelial function and insulin sensitivity were assessed pre- and post-intervention. The blood pressure and insulin sensitivity did not differ between the blueberry and placebo groups. However, the mean change in resting endothelial function, expressed as reactive hyperemia index (RHI), was improved significantly more in the group consuming the blueberries versus the placebo group (p = 0.024). Even after adjusting for confounding factors, i.e., the percent body fat and gender, the blueberry group still had a greater improvement in endothelial function when compared to their counterpart (RHI; 0.32 ± 0.13 versus -0.33 ± 0.14; p = 0.0023). In conclusion, daily dietary consumption of blueberries did not improve blood pressure, but improved (i.e., increased) endothelial function over six weeks in subjects with metabolic syndrome.

  1. Blueberries Improve Endothelial Function, but Not Blood Pressure, in Adults with Metabolic Syndrome: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

    PubMed Central

    Stull, April J.; Cash, Katherine C.; Champagne, Catherine M.; Gupta, Alok K.; Boston, Raymond; Beyl, Robbie A.; Johnson, William D.; Cefalu, William T.

    2015-01-01

    Blueberry consumption has been shown to have various health benefits in humans. However, little is known about the effect of blueberry consumption on blood pressure, endothelial function and insulin sensitivity in humans. The present study investigated the role of blueberry consumption on modifying blood pressure in subjects with metabolic syndrome. In addition, endothelial function and insulin sensitivity (secondary measurements) were also assessed. A double-blind and placebo-controlled study was conducted in 44 adults (blueberry, n = 23; and placebo, n = 21). They were randomized to receive a blueberry or placebo smoothie twice daily for six weeks. Twenty-four-hour ambulatory blood pressure, endothelial function and insulin sensitivity were assessed pre- and post-intervention. The blood pressure and insulin sensitivity did not differ between the blueberry and placebo groups. However, the mean change in resting endothelial function, expressed as reactive hyperemia index (RHI), was improved significantly more in the group consuming the blueberries versus the placebo group (p = 0.024). Even after adjusting for confounding factors, i.e., the percent body fat and gender, the blueberry group still had a greater improvement in endothelial function when compared to their counterpart (RHI; 0.32 ± 0.13 versus −0.33 ± 0.14; p = 0.0023). In conclusion, daily dietary consumption of blueberries did not improve blood pressure, but improved (i.e., increased) endothelial function over six weeks in subjects with metabolic syndrome. PMID:26024297

  2. Zoledronate Inhibits Ischemia-Induced Neovascularization by Impairing the Mobilization and Function of Endothelial Progenitor Cells

    PubMed Central

    Tsai, Shih-Hung; Huang, Po-Hsun; Chang, Wei-Chou; Tsai, Hsiao-Ya; Lin, Chih-Pei; Leu, Hsin-Bang; Wu, Tao-Cheng; Chen, Jaw-Wen; Lin, Shing-Jong

    2012-01-01

    Background Bisphosphonates are a class of pharmacologic compounds that are commonly used to treat postmenopausal osteoporosis and malignant osteolytic processes. Studies have shown that bone marrow-derived endothelial progenitor cells (EPCs) play a significant role in postnatal neovascularization. Whether the nitrogen-containing bisphosphonate zoledronate inhibits ischemia-induced neovascularization by modulating EPC functions remains unclear. Methodology/Principal Findings Unilateral hindlimb ischemia was surgically induced in wild-type mice after 2 weeks of treatment with vehicle or zoledronate (low-dose: 30 μg/kg; high-dose: 100 μg/kg). Doppler perfusion imaging demonstrated that the ischemic limb/normal side blood perfusion ratio was significantly lower in wild-type mice treated with low-dose zoledronate and in mice treated with high-dose zoledronate than in controls 4 weeks after ischemic surgery (control vs. low-dose vs. high-dose: 87±7% vs. *61±18% vs. **49±17%, *p<0.01, **p<0.005 compared to control). Capillary densities were also significantly lower in mice treated with low-dose zoledronate and in mice treated with high-dose zoledronate than in control mice. Flow cytometry analysis showed impaired mobilization of EPC-like cells (Sca-1+/Flk-1+) after surgical induction of ischemia in mice treated with zoledronate but normal levels of mobilization in mice treated with vehicle. In addition, ischemic tissue from mice that received zoledronate treatment exhibited significantly lower levels of the active form of MMP-9, lower levels of VEGF, and lower levels of phosphorylated eNOS and phosphorylated Akt than ischemic tissue from mice that received vehicle. Results of the in vitro studies showed that incubation with zoledronate inhibited the viability, migration, and tube-forming capacities of EPC. Conclusions/Significance Zoledronate inhibited ischemia-induced neovascularization by impairing EPC mobilization and angiogenic functions. These findings suggest

  3. Abnormal resting-state functional connectivity of the nucleus accumbens in multi-year abstinent heroin addicts.

    PubMed

    Zou, Feng; Wu, Xinhuai; Zhai, Tianye; Lei, Yu; Shao, Yongcong; Jin, Xiao; Tan, Shuwen; Wu, Bing; Wang, Lubin; Yang, Zheng

    2015-11-01

    Functional neuroimaging studies suggest that abnormal brain functional connectivity may be the neural underpinning of addiction to illicit drugs and of relapse after successful cessation therapy. Aberrant brain networks have been demonstrated in addicted patients and in newly abstinent addicts. However, it is not known whether abnormal brain connectivity patterns persist after prolonged abstinence. In this cross-sectional study, whole-brain resting-state functional magnetic resonance images (8 min) were collected from 30 heroin-addicted individuals after a long period of abstinence (more than 3 years) and from 30 healthy controls. We first examined the group differences in the resting-state functional connectivity of the nucleus accumbens (NAc), a brain region implicated in relapse-related processes, including craving and reactivity to stress following acute and protracted withdrawal from heroin. We then examined the relation between the duration of abstinence and the altered NAc functional connectivity in the heroin group. We found that, compared with controls, heroin-dependent participants exhibited significantly greater functional connectivity between the right ventromedial prefrontal cortex and the NAc and weaker functional connectivity between the NAc and the left putamen, left precuneus, and supplementary motor area. However, with longer abstinence time, the strength of NAc functional connectivity with the left putamen increased. These results indicate that dysfunction of the NAc functional network is still present in long-term-abstinent heroin-dependent individuals. PMID:26280556

  4. Febuxostat improves endothelial function in hemodialysis patients with hyperuricemia: A randomized controlled study.

    PubMed

    Tsuruta, Yuki; Kikuchi, Kan; Tsuruta, Yukio; Sasaki, Yuko; Moriyama, Takahito; Itabashi, Mitsuyo; Takei, Takashi; Uchida, Keiko; Akiba, Takashi; Tsuchiya, Ken; Nitta, Kosaku

    2015-10-01

    Endothelial dysfunction is often found in both hyperuricemia and hemodialysis patients. Recent studies have shown that treating hyperuricemia with allopurinol improves endothelial dysfunction. This study is performed to assess the effect of febuxostat on endothelial dysfunction in hemodialysis patients with hyperuricemia. We randomly assigned 53 hemodialysis patients with hyperuricemia to a febuxostat (10 mg daily) group and a control group and measured flow-mediated dilation, serum uric acid (UA) levels, systolic and diastolic blood pressure, malondialdehyde-modified low-density lipoprotein (MDA-LDL), and highly sensitive C-reactive protein (hsCRP) at baseline and at the end of a 4-week study period. Flow-mediated dilation increased from 5.3% ± 2.4% to 8.9% ± 3.6% in the febuxostat group but did not change significantly in the control group. Treatment with febuxostat resulted in a significant decrease in serum UA level and a significant decrease in MDA-LDL compared with baseline, but no significant difference was observed in hsCRP level or blood pressure. No significant differences were observed in the control group. Febuxostat improved endothelial dysfunction and reduced serum UA levels and oxidative stress in hemodialysis patients with hyperuricemia.

  5. Physiologically Modeled Pulse Dynamics to Improve Function in In Vitro-Endothelialized Small-Diameter Vascular Grafts.

    PubMed

    Uzarski, Joseph S; Cores, Jhon; McFetridge, Peter S

    2015-11-01

    The lack of a functional endothelium on small-diameter vascular grafts leads to intimal hyperplasia and thrombotic occlusion. Shear stress conditioning through controlled hydrodynamics within in vitro perfusion bioreactors has shown promise as a mechanism to drive endothelial cell (EC) phenotype from an activated, pro-inflammatory wound state toward a quiescent functional state that inhibits responses that lead to occlusive failure. As part of an overall design strategy to engineer functional vascular grafts, we present a novel two-phase shear conditioning approach to improve graft endothelialization. Axial rotation was first used to seed uniform EC monolayers onto the lumenal surface of decellularized scaffolds derived from the human umbilical vein. Using computer-controlled perfusion circuits, a flow-ramping paradigm was applied to adapt endothelia to arterial levels of fluid shear stress and pressure without graft denudation. The effects of constant pulse frequencies (CF) on EC quiescence were then compared with pulse frequencies modeled from temporal fluctuations in blood flow observed in vivo, termed physiologically modeled pulse dynamics (PMPD). Constructs exposed to PMPD for 72 h expressed a more functional transcriptional profile, lower metabolic activity (39.8% ± 8.4% vs. 62.5% ± 11.5% reduction, p = 0.012), and higher nitric oxide production (80.42 ± 23.93 vs. 48.75 ± 6.93 nmol/10(5) cells, p = 0.028) than those exposed to CF. By manipulating in vitro flow conditions to mimic natural physiology, endothelialized vascular grafts can be stimulated to express a nonactivated phenotype that would better inhibit peripheral cell adhesion and smooth muscle cell hyperplasia, conditions that typically lead to occlusive failure. Development of robust, functional endothelia on vascular grafts by modulation of environmental conditions within perfusion bioreactors may ultimately improve clinical outcomes in vascular bypass grafting. PMID:25996580

  6. Hyaluronic acid concentration-mediated changes in structure and function of porous carriers for corneal endothelial cell sheet delivery.

    PubMed

    Lai, Jui-Yang

    2016-02-01

    In this study, the effects of hyaluronic acid (HA) concentrations (0.05-1.25wt.%) on the properties of porous carriers for corneal endothelial tissue engineering were investigated. The pore size and porosity gradually increased with decreasing solid content. However, at relatively low HA concentration (i.e., 0.05wt.%), the material samples contained small interior pores and a dense surface skin layer, probably due to no gas bubble effect on the stirring processing of porous microstructures of freeze-dried polysaccharide hydrogels. The carriers prepared from 0.25wt.% HA solution had the highest freezable water content and oxygen and glucose permeability among the samples evaluated. Results of cell viability assays and quantitative real-time reverse transcription polymerase chain reaction analyses showed that the HA concentration-related alteration of porous microstructure dictates the compatibility of biopolymer carriers with corneal endothelial cell (CEC) cultures. In vivo studies demonstrated that the CEC sheet/HA carrier construct implants are therapeutically efficacious in the reconstruction of endothelial scrape-wounded corneas. It is concluded that the polysaccharide concentration is the major factor for affecting the processing of carriers and their structure and function. Porous hydrogels prepared from 0.25wt.% HA solution are capable of delivering bioengineered CEC sheets to the posterior surface of cornea. PMID:26652391

  7. The effect of RGD fluorosurfactant polymer modification of ePTFE on endothelial cell adhesion, growth, and function

    PubMed Central

    Larsen, Coby C.; Kligman, Faina; Kottke-Marchant, Kandice; Marchant, Roger E.

    2007-01-01

    We have synthesized and characterized a novel peptide fluorosurfactant polymer (PFSP) modification that facilitates the adhesion and growth of endothelial cells on ePTFE vascular graft material. This PFSP consists of a poly(vinyl amine) (PVAm) backbone with integrin binding Arg-Gly-Asp (RGD) peptides and perfluorocarbon pendant branches for adsorption and stable adhesion to underlying ePTFE. Aqueous PFSP solution was used to modify the surface of fluorocarbon substrates. Following subconfluent seeding, endothelial cell (EC) adhesion and growth on PFSP was assessed by determining cell population at different time points. Spectroscopic results indicated successful synthesis of PFSP. PFSP modification of ePTFE reduced the receding water contact angle measurement from 120° to 6°, indicating successful surface modification. Quantification of cell population demonstrated reduced EC attachment efficiency but increased growth rate on RGD PFSP compared with fibronectin (FN). Actin staining revealed a well-developed cytoskeleton for ECs on RGD PFSP indicative of stable adhesion. Uptake of acetylated low-density lipoprotein and positive staining for VE-Cadherin confirm EC phenotype for adherent cells. Production of prostacyclin, a potent antiplatelet agent, was equivalent between ECs on FN and RGD PFSP surfaces. Our results indicate successful synthesis and surface modification with PFSP; this is a simple, quantitative, and effective approach to modifying ePTFE to encourage endothelial cell attachment, growth, and function. PMID:16762410

  8. Obesity-induced adipokine imbalance impairs mouse pulmonary vascular endothelial function and primes the lung for injury.

    PubMed

    Shah, Dilip; Romero, Freddy; Duong, Michelle; Wang, Nadan; Paudyal, Bishnuhari; Suratt, Benjamin T; Kallen, Caleb B; Sun, Jianxin; Zhu, Ying; Walsh, Kenneth; Summer, Ross

    2015-01-01

    Obesity is a risk factor for the development of acute respiratory distress syndrome (ARDS) but mechanisms mediating this association are unknown. While obesity is known to impair systemic blood vessel function, and predisposes to systemic vascular diseases, its effects on the pulmonary circulation are largely unknown. We hypothesized that the chronic low grade inflammation of obesity impairs pulmonary vascular homeostasis and primes the lung for acute injury. The lung endothelium from obese mice expressed higher levels of leukocyte adhesion markers and lower levels of cell-cell junctional proteins when compared to lean mice. We tested whether systemic factors are responsible for these alterations in the pulmonary endothelium; treatment of primary lung endothelial cells with obese serum enhanced the expression of adhesion proteins and reduced the expression of endothelial junctional proteins when compared to lean serum. Alterations in pulmonary endothelial cells observed in obese mice were associated with enhanced susceptibility to LPS-induced lung injury. Restoring serum adiponectin levels reversed the effects of obesity on the lung endothelium and attenuated susceptibility to acute injury. Our work indicates that obesity impairs pulmonary vascular homeostasis and enhances susceptibility to acute injury and provides mechanistic insight into the increased prevalence of ARDS in obese humans. PMID:26068229

  9. Early steatohepatitis in hyperlipidemic mice with endothelial-specific gain of TRPC3 function precedes changes in aortic atherosclerosis.

    PubMed

    Smedlund, Kathryn; Dube, Prabhatachandra; Vazquez, Guillermo

    2016-08-01

    Nonalcoholic fatty liver disease (NAFLD) and its more advanced form nonalcoholic steatohepatitis (NASH) are the most common chronic liver diseases in developed countries. Moreover, NAFLD and NASH are considerable risk factors for atherosclerosis, the most frequent vascular pathology in these and other metabolic diseases. Despite this strong connection, current knowledge of the relationship between NAFLD/NASH and atherosclerosis is scarce. Recently, we studied hyperlipidemic Apoe knockout mice with endothelial-specific gain of transient receptor potential canonical 3 channel function (TgESTRPC3/ApoeKO) and found that these animals had increased burden of advanced aortic atherosclerosis (16 wk on high-fat diet) compared with nontransgenic ApoeKO littermate controls (non-Tg/ApoeKO), whereas early lesions (10 wk on high-fat diet) were not different. Here, we report that at the early stage when differences in aortic atherosclerosis are not yet manifest, the livers of TgESTRPC3/ApoeKO mice show steatosis, fibrosis, and altered hepatic enzymes compared with non-Tg/ApoeKO animals. Because differences in liver pathology were noticeable long before differences in atherosclerosis were evident, our studies suggest that TRPC3-related endothelial mechanisms that promote steatohepatitis may also contribute to atherosclerosis progression. In vitro, downregulation of TRPC3 in liver sinusoid endothelial cells reduces their susceptibility to endoplasmic reticulum stress-induced apoptosis, suggesting that a proapoptotic effect of TRPC3 may add to other fibrogenic factors in vivo. These novel findings show a positive association between augmented expression of an endothelial TRPC channel, development of early steatohepatitis, and atherosclerotic burden in a hyperlipidemic mouse model of NAFLD fed conventional Western-type diet. PMID:27449657

  10. In Vitro Recapitulation of Functional Microvessels for the Study of Endothelial Shear Response, Nitric Oxide and [Ca2+]i

    PubMed Central

    He, Pingnian; Liu, Yuxin

    2015-01-01

    Microfluidic technologies enable in vitro studies to closely simulate in vivo microvessel environment with complexity. Such method overcomes certain constrains of the statically cultured endothelial monolayers and enables the cells grow under physiological range of shear flow with geometry similar to microvessels in vivo. However, there are still existing knowledge gaps and lack of convincing evidence to demonstrate and quantify key biological features of the microfluidic microvessels. In this paper, using advanced micromanufacturing and microfluidic technologies, we presented an engineered microvessel model that mimicked the dimensions and network structures of in vivo microvessels with a long-term and continuous perfusion capability, as well as high-resolution and real-time imaging capability. Through direct comparisons with studies conducted in intact microvessels, our results demonstrated that the cultured microvessels formed under perfused conditions recapitulated certain key features of the microvessels in vivo. In particular, primary human umbilical vein endothelial cells were successfully cultured the entire inner surfaces of the microchannel network with well-developed junctions indicated by VE-cadherin staining. The morphological and proliferative responses of endothelial cells to shear stresses were quantified under different flow conditions which was simulated with three-dimensional shear dependent numerical flow model. Furthermore, we successfully measured agonist-induced changes in intracellular Ca2+ concentration and nitric oxide production at individual endothelial cell levels using fluorescence imaging. The results were comparable to those derived from individually perfused intact venules. With in vivo validation of its functionalities, our microfluidic model demonstrates a great potential for biological applications and bridges the gaps between in vitro and in vivo microvascular research. PMID:25965067

  11. A detailed method for preparation of a functional and flexible blood-brain barrier model using porcine brain endothelial cells.

    PubMed

    Patabendige, Adjanie; Skinner, Robert A; Morgan, Louise; Abbott, N Joan

    2013-07-12

    The blood-brain barrier (BBB) is formed by the endothelial cells of cerebral microvessels and forms the critical interface regulating molecular flux between blood and brain. It contributes to homoeostasis of the microenvironment of the central nervous system and protection from pathogens and toxins. Key features of the BBB phenotype are presence of complex intercellular tight junctions giving a high transendothelial electrical resistance (TEER), and strongly polarised (apical:basal) localisation of transporters and receptors. In vitro BBB models have been developed from primary culture of brain endothelial cells of several mammalian species, but most require exposure to astrocytic factors to maintain the BBB phenotype. Other limitations include complicated procedures for isolation, poor yield and batch-to-batch variability. Some immortalised brain endothelial cell models have proved useful for transport studies but most lack certain BBB features and have low TEER. We have developed an in vitro BBB model using primary cultured porcine brain endothelial cells (PBECs) which is relatively simple to prepare, robust, and reliably gives high TEER (mean~800 Ω cm(2)); it also shows good functional expression of key tight junction proteins, transporters, receptors and enzymes. The model can be used either in monoculture, for studies of molecular flux including permeability screening, or in co-culture with astrocytes when certain specialised features (e.g. receptor-mediated transcytosis) need to be maximally expressed. It is also suitable for a range of studies of cell:cell interaction in normal physiology and in pathology. The method for isolating and growing the PBECs is given in detail to facilitate adoption of the model. This article is part of a Special Issue entitled Companion Paper. PMID:23603406

  12. Advanced glycation end products impair function of late endothelial progenitor cells through effects on protein kinase Akt and cyclooxygenase-2

    SciTech Connect

    Chen Qin; Dong Li; Wang Lian; Kang Lina; Xu Biao

    2009-04-03

    Endothelial progenitor cells (EPCs) exhibit impaired function in the context of diabetes, and advanced glycation end products (AGEs), which accumulate in diabetes, may contribute to this. In the present study, we investigated the mechanism by which AGEs impair late EPC function. EPCs from human umbilical cord blood were isolated, and incubated with AGE-modified albumin (AGE-albumin) at different concentrations found physiologically in plasma. Apoptosis, migration, and tube formation assays were used to evaluate EPC function including capacity for vasculogenesis, and expression of the receptor for AGEs (RAGE), Akt, endothelial nitric oxide synthase (eNOS), and cycloxygenase-2 (COX-2) were determined. Anti-RAGE antibody was used to block RAGE function. AGE-albumin concentration-dependently enhanced apoptosis and depressed migration and tube formation, but did not affect proliferation, of late EPCs. High AGE-albumin increased RAGE mRNA and protein expression, and decreased Akt and COX-2 protein expression, whilst having no effect on eNOS mRNA or protein in these cells. These effects were inhibited by co-incubation with anti-RAGE antibody. These results suggest that RAGE mediates the AGE-induced impairment of late EPC function, through down-regulation of Akt and COX-2 in these cells.

  13. The GST T1 and CYP2E1 genotypes are possible factors causing vinyl chloride induced abnormal liver function.

    PubMed

    Huang, C Y; Huang, K L; Cheng, T J; Wang, J D; Hsieh, L L

    1997-01-01

    Vinyl chloride monomer (VCM) is hepatotoxic as well as carcinogenic in humans. There are reports that exposure to VCM seems to induce abnormal liver function, liver fibrosis, cirrhosis, portal hypertension, and angiosarcoma of the liver. In vivo, VCM is metabolized by cytochrome P450 2E1 (CYP2E1) to form the electrophilic metabolites, chloroethylene oxide (CEO) and chloroacetaldehyde (CAA), which may either cause cell damage or be further metabolized and detoxified by glutathione S-transferases (GSTs). This study investigated whether or not the genotypes CYP2E1, glutathione S-transferase theta (GST T1) and mu (GST M1) correlated with abnormal liver function found in vinyl chloride exposed workers. For this study, 251 workers from five polyvinyl chloride plants were enrolled. The workers were classified into two exposure groups (high and low) and the degree of exposure was determined based on their job titles and airborne VCM concentration. The activity of serum alanine aminotransferase (ALT) was used as the parameter of liver function. The genotypes CYP2E1, GST T1 and GST M1 were determined by polymerase chain reaction and restriction fragment length polymorphism on peripheral white blood cell DNA. Other potential risk factors were also ascertained and the confounding effect was adjusted accordingly. Stratified analyses were used to explore the correlation between the alteration of liver function and the genotypes CYP2E1, GST T1 and GST M1 among the workers exposed to different levels of VCM. The following results were obtained (1) at low VCM exposure, the odds ratio (OR) of positive GST T1 on abnormal ALT was 3.8 (95% CI 1.2-14.5) but the CYP2E1 genotype was not associated with abnormal ALT. (2) At high VCM exposure, a c2c2 CYP2E1 genotype was associated with increased OR on abnormal ALT (OR 5.4, 95% CI 0.7-35.1) and positive GST T1 was significantly associated with decreased OR on abnormal ALT (OR 0.3, 95% CI 0.1-0.9). (3) Multiple linear and logistic regression

  14. Oxidative Stress-Dependent Cyclooxygenase-2-Derived Prostaglandin F2α Impairs Endothelial Function in Renovascular Hypertensive Rats

    PubMed Central

    Tian, Xiao Yu; Leung, Fung Ping; Zhang, Yang; Wang, Yi-Xiang; Lee, Hung Kay; Ng, Chi Fai; Chen, Zhen Yu; Yao, Xiaoqiang; Au, Chak Leung; Lau, Chi Wai; Vanhoutte, Paul M.; Cooke, John P.

    2012-01-01

    Abstract Aims: The role of endothelium-derived contracting factors (EDCFs) in regulating renovascular function is yet to be elucidated in renovascular hypertension (RH). The current study investigated whether oxidative stress-dependent cyclooxygenase (COX)-2-derived prostaglandin F2α (PGF2α) impairs endothelial function in renal arteries of renovascular hypertensive rats (RHR). Results: Renal hypertension was induced in rats by renal artery stenosis of both kidneys using the 2-kidney 2-clip model. Acute treatment with reactive oxygen species (ROS) scavengers, COX-2 inhibitors, and thromboxane-prostanoid receptor antagonists, but not COX-1 inhibitors, improved endothelium-dependent relaxations and eliminated endothelium-dependent contractions in RHR renal arteries. Five weeks of treatment with celecoxib or tempol reduced blood pressure, increased renal blood flow, and restored endothelial function in RHRs. Increased ROS production in RHR arteries was inhibited by ROS scavengers, but unaffected by COX-2 inhibitors; whereas increased PGF2α release was reduced by both ROS scavengers and COX-2 inhibitors. ROS also induced COX-2-dependent contraction in RHR renal arteries, which was accompanied by the release of COX-2-derived PGF2α. Further, chronic tempol treatment reduced COX-2 and BMP4 upregulation, p38MAPK phosphorylation, and the nitrotyrosine level in RHR renal arteries. Conclusion: These findings demonstrate the functional importance of oxidative stress, which serves as an initiator of increased COX-2 activity, and that COX-2-derived PGF2α plays an important role in mediating endothelial dysfunction in RH. Innovation: The current study, thus, suggests that drugs targeting oxidative stress-dependent COX-2-derived PGF2α may be useful in the prevention and management of RH. Antioxid. Redox Signal. 16, 363–373. PMID:21951274

  15. Impact of acute caffeine ingestion on endothelial function in subjects with and without coronary artery disease.

    PubMed

    Shechter, Michael; Shalmon, Guy; Scheinowitz, Mickey; Koren-Morag, Nira; Feinberg, Micha S; Harats, Dror; Sela, Ben Ami; Sharabi, Yehonatan; Chouraqui, Pierre

    2011-05-01

    Although coffee is a widely used, pharmacologically active beverage, its impact on the cardiovascular system is controversial. To explore the effect of acute caffeine ingestion on brachial artery flow-mediated dilation (FMD) in subjects without coronary artery disease (CAD; controls) and patients with CAD, we prospectively assessed brachial artery FMD in 40 controls and 40 age- and gender-matched patients with documented stable CAD on 2 separate mornings 1 week to 2 weeks apart. After overnight fasting, discontinuation of all medications for ≥12 hours, and absence of caffeine for >48 hours, participants received capsules with caffeine 200 mg or placebo. One hour after drug ingestion, participants underwent brachial artery FMD and nitroglycerin-mediated dilation (NTG) using high-resolution ultrasound. As expected, patients with CAD were more often diabetic, hypertensive, obese, dyslipidemic, and smoked more than controls (p <0.01 for all comparisons). Aspirin, Clopidogrel, angiotensin-converting enzyme inhibitors, β blockers, and statins were significantly more common in patients with CAD than in controls (p <0.01 for all comparisons). At baseline, FMD, but not NTG, was significantly lower in patients with CAD compared to controls. Acute caffeine ingestion significantly increased FMD (patients with CAD 5.6 ± 5.0% vs 14.6 ± 5.0%, controls 8.4 ± 2.9% vs 18.6 ± 6.8%, p <0.001 for all comparisons) but not NTG (patients with CAD 13.0 ± 5.2% vs 13.8 ± 6.1%, controls 12.9 ± 3.9% vs 13.9 ± 5.8%, p = NS for all comparisons) and significantly decreased high-sensitivity C-reactive protein (patients with CAD 2.6 ± 1.4 vs 1.4 ± 1.2 mg/L, controls 3.4 ± 3.0 vs 1.2 ± 1.0 mg/L, p <0.001 for all comparisons) in the 2 groups compared to placebo. In conclusion, acute caffeine ingestion significantly improved endothelial function assessed by brachial artery FMD in subjects with and without CAD and was associated with lower plasma markers of inflammation.

  16. Extended-release niacin/laropiprant improves endothelial function in patients after myocardial infarction.

    PubMed

    Bregar, Urska; Jug, Borut; Keber, Irena; Cevc, Matija; Sebestjen, Miran

    2014-05-01

    Raising high-density lipoprotein cholesterol (HDL-C) is an important strategy for reducing residual cardiovascular risk. In the present study, we sought to assess the effect of extended-release niacin/laropiprant on endothelial function in patients after a myocardial infarction with target low-density lipoprotein cholesterol (LDL-C). In this double-blind, placebo-controlled trial, 63 men (35-60 years of age) after a myocardial infarction were randomized to either niacin/laropiprant (1000/20 mg daily for 4 weeks and 2000/40 mg daily thereafter) or placebo. Flow-mediated dilation (FMD) and nitroglycerin-induced (GTN) dilation of the brachial artery, total cholesterol (TC), LDL-C, HDL-C, triglycerides (TG), lipoprotein(a) [Lp(a)], and apolipoprotein (Apo) A1/B were measured at baseline and after 12 weeks of intervention. FMD significantly increased (from 3.9 ± 5.1 to 9.8 ± 4.4%, p < 0.001) in the niacin/laropiprant group, but not in the placebo group (4.6 ± 4.4 to 6.1 ± 4.4%, p = 0.16) (p = 0.02 for comparison of interventions). GTN dilation also increased in the niacin/laropiprant group (from 12.5 ± 6.1 to 16.7 ± 4.8%, p = 0.02), but not in the placebo group (13.4 ± 5.0 to 15.1 ± 5.2%, p = 0.18), (p = 0.60 for comparison of interventions). Niacin/laropiprant reduced TC and LDL-C (p = 0.05 for both) and increased HDL-C (p < 0.001) without influencing TG, with no changes in the placebo group. Lp(a) (p = 0.026) and ApoB (p = 0.014) were significantly lower in the niacin/laropiprant group, with no difference in the placebo group. ApoA1 did not change in either of the groups (p = 0.13; p = 0.26). FMD and GTN dilation improvements did not correlate with changes in the lipid profile. Niacin/laropiprant improves endothelium-dependent and endothelium-independent dilation of the brachial artery. This improvement does not correlate with changes in lipid parameters.

  17. γ-Tocopherol-rich supplementation additively improves vascular endothelial function during smoking cessation.

    PubMed

    Mah, Eunice; Pei, Ruisong; Guo, Yi; Ballard, Kevin D; Barker, Tyler; Rogers, Victoria E; Parker, Beth A; Taylor, Alan W; Traber, Maret G; Volek, Jeff S; Bruno, Richard S

    2013-12-01

    Oxidative stress and inflammation persist years after smoking cessation thereby limiting the restoration of vascular endothelial function (VEF). Although short-term smoking cessation improves VEF, no studies have examined co-therapy of antioxidants in combination with smoking cessation to improve VEF. We hypothesized that improvements in γ-tocopherol (γ-T) status during smoking cessation would improve VEF beyond that from smoking cessation alone by decreasing oxidative stress and proinflammatory responses. A randomized, double-blind, placebo-controlled study was conducted in otherwise healthy smokers (22 ± 1 years; mean ± SEM) who quit smoking for 7 days with placebo (n=14) or γ-T-rich supplementation (n=16; 500 mg γ-T/day). Brachial artery flow-mediated dilation (FMD), cotinine, and biomarkers of antioxidant status, oxidative stress, and inflammation were measured before and after 7 days of smoking cessation. Smoking cessation regardless of supplementation similarly decreased plasma cotinine, whereas γ-T-rich supplementation increased plasma γ-T by seven times and its urinary metabolite γ-carboxyethyl hydroxychroman by nine times (P<0.05). Smoking cessation with γ-T-rich supplementation increased FMD responses by 1.3% (P<0.05) beyond smoking cessation alone (4.1 ± 0.6% vs 2.8 ± 0.3%; mean ± SEM). Although plasma malondialdehyde decreased similarly in both groups (P<0.05), plasma oxidized LDL and urinary F2-isoprostanes were unaffected by smoking cessation or γ-T-rich supplementation. Plasma TNF-α and myeloperoxidase decreased (P<0.05) only in those receiving γ-T-rich supplements and these were inversely related to FMD (P<0.05; R=-0.46 and -0.37, respectively). These findings demonstrate that short-term γ-T-rich supplementation in combination with smoking cessation improved VEF beyond that from smoking cessation alone in young smokers, probably by decreasing the proinflammatory mediators TNF-α and myeloperoxidase.

  18. Abnormal liver function in workers exposed to low levels of ethylene dichloride and vinyl chloride monomer.

    PubMed

    Cheng, T J; Huang, M L; You, N C; Du, C L; Chau, T T

    1999-12-01

    We investigated whether exposure to ethylene dichloride (EDC) and vinyl chloride monomer (VCM) resulted in increased risk of liver damage. Epidemiological information, including occupational, medical, smoking, and drinking history, was obtained by interview from 251 male workers. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) were used as indicators of liver damage. Exposure to moderate or low levels of ECD and VCM resulted in a higher risk of developing abnormal ALT levels than did exposure to lower levels of the chemicals. Results were similar for AST. GGT was not associated with EDC or VCM exposure. Combined exposure to EDC and VCM showed a dose-response relationship in association with abnormal ALT levels. We concluded that relatively low concentrations of VCM and EDC cause liver damage.

  19. Abnormal NF-kappa B function characterizes human type 1 diabetes dendritic cells and monocytes.

    PubMed

    Mollah, Zia U A; Pai, Saparna; Moore, Craig; O'Sullivan, Brendan J; Harrison, Matthew J; Peng, Judy; Phillips, Karen; Prins, Johannes B; Cardinal, John; Thomas, Ranjeny

    2008-03-01

    Dendritic cell (DC) differentiation is abnormal in type 1 diabetes mellitus (T1DM). However, the nature of the relationship between this abnormality and disease pathogenesis is unknown. We studied the LPS response in monocytes and monocyte-derived DCs isolated from T1DM patients and from non-T1DM controls. In T1DM patients, late LPS-mediated nuclear DNA binding by RelA, p50, c-Rel, and RelB was impaired as compared with type 2 DM, rheumatoid arthritis, and healthy subjects, associated with impaired DC CD40 and MHC class I induction but normal cytokine production. In TIDM monocytes, RelA and RelB were constitutively activated, and the src homology 2 domain-containing protein tyrosine phosphatase (SHP-1), a negative regulator of NF-kappaB, was overexpressed. Addition of sodium stibogluconate, a SHP-1 inhibitor, to DCs differentiating from monocyte precursors restored their capacity to respond to LPS in approximately 60% of patients. The monocyte and DC NF-kappaB response to LPS is thus a novel phenotypic and likely pathogenetic marker for human T1DM. SHP-1 is at least one NF-kappaB regulatory mechanism which might be induced as a result of abnormal inflammatory signaling responses in T1DM monocytes. PMID:18292540

  20. A single consumption of curry improved postprandial endothelial function in healthy male subjects: a randomized, controlled crossover trial

    PubMed Central

    2014-01-01

    Background Curry, one of the most popular foods in Japan, contains spices that are rich in potentially antioxidative compounds, such as curcumin and eugenol. Oxidative stress is thought to impair endothelial function associated with atherosclerosis, a leading cause of cardiovascular events. The aim of this study was to determine whether a single consumption of curry meal would improve endothelial function in healthy men. Methods Fourteen healthy male subjects (BMI 23.7 ± 2.7 kg/m2; age 45 ± 9 years) were given a single serving of curry meal or spice-free control meal (180 g of curry or control and 200 g of cooked rice; approximately 500 kcal in total) in a randomized, controlled crossover design. Before and 1 hr after the consumption, fasting and postprandial flow-mediated vasodilation (FMD) responses and other parameters were measured. Results The consumption of the control meal decreased FMD from 5.8 ± 2.4% to 5.1 ± 2.3% (P = 0.039). On the other hand, the consumption of the curry meal increased FMD from 5.2 ± 2.5% to 6.6 ± 2.0% (P = 0.001), and the postprandial FMD after the curry meal was higher than that after the control meal (P = 0.002). Presence of spices in the curry did not alter significantly the systemic and forearm hemodynamics, or any biochemical parameters including oxidative stress markers measured. Conclusions These findings suggest that the consumption of curry ameliorates postprandial endothelial function in healthy male subjects and may be beneficial for improving cardiovascular health. Trial registration UMIN Clinical Trials Registry 000012012. PMID:24972677

  1. MicroRNAs regulate tight junction proteins and modulate epithelial/endothelial barrier functions.

    PubMed

    Cichon, Christoph; Sabharwal, Harshana; Rüter, Christian; Schmidt, M Alexander

    2014-01-01

    Tightly controlled epithelial and endothelial barriers are a prerequisite for life as these barriers separate multicellular organisms from their environment and serve as first lines of defense. Barriers between neighboring epithelial cells are formed by multiple intercellular junctions including the 'apical junctional complex-AJC' with tight junctions (TJ), adherens junctions (AJ), and desmosomes. TJ consist of tetraspan transmembrane proteins like occludin, various claudins that directly control paracellular permeability, and the 'Junctional Adhesion Molecules' (JAMs). For establishing tight barriers TJ are essential but at the same time have to allow also selective permeability. For this, TJ need to be tightly regulated and controlled. This is organized by a variety of adaptor molecules, i.e., protein kinases, phosphatases and GTPases, which in turn are regulated and fine-tuned involving microRNAs (miRNAs). In this review we summarize available data on the role and targeting of miRNAs in the maintenance of epithelial and/or endothelial barriers.

  2. Associations Between Abnormal Rod-Mediated Dark Adaptation and Health and Functioning in Older Adults With Normal Macular Health

    PubMed Central

    Owsley, Cynthia; Huisingh, Carrie; Jackson, Gregory R.; Curcio, Christine A.; Szalai, Alexander J.; Dashti, Nassrin; Clark, Mark; Rookard, Kia; McCrory, Mark A.; Wright, Tyler T.; Callahan, Michael A.; Kline, Lanning B.; Witherspoon, C. Douglas; McGwin, Gerald

    2014-01-01

    Purpose. Delayed rod-mediated dark adaptation (DA) is characteristic of early age-related macular degeneration (AMD) and also can be observed in some older adults in normal macular health. We examine cross-sectional associations between rod-mediated DA and risk factors for AMD in older adults in normal macular health. Methods. The sample consisted of adults aged ≥60 years old in normal macular health per grading of fundus photos using an established disease classification system. Rod-mediated DA was measured psychophysically following a photobleach using a computer-automated dark adaptometer with targets centered at 5° on the inferior vertical meridian. The speed of DA was characterized by the rod-intercept value, with abnormal DA defined as rod-intercept ≥ 12.3 minutes. We assessed several health and functional characteristics that the literature has suggested increase AMD risk (e.g., smoking, alcohol use, inflammatory markers, apolipoproteins, low luminance visual acuity, chronic medical conditions, body mass, family history). Results. Among 381 participants (mean age, 68.5 years; SD, 5.5), 78% had normal and 22% had abnormal DA, with the prevalence of abnormal DA increasing with age. After age-adjustment, abnormal DA was associated with increased odds of elevated C-reactive protein (CRP), heavy use of or abstention from alcohol, high blood pressure, and drop in visual acuity under mesopic conditions. Conclusions. Despite having normal macular health according to accepted definitions of AMD presence, approximately one-quarter of older adults recruited from primary eye care clinics had abnormal DA, which was associated with known risk factors for AMD, including elevated CRP. PMID:24854857

  3. Combined Effects of Sleep Disordered Breathing and Metabolic Syndrome on Endothelial Function: The Wisconsin Sleep Cohort Study

    PubMed Central

    Korcarz, Claudia E.; Stein, James H.; Peppard, Paul E.; Young, Terry B.; Barnet, Jodi H.; Nieto, F. Javier

    2014-01-01

    Study Objectives: To examine the combined impact of sleep disordered breathing (SDB) and metabolic syndrome (MetS) in endothelial dysfunction. Design: Cross-sectional assessment of endothelial function, MetS and SDB status in a population-based sample. Setting: Community-based cohort. Participants: Participants (n = 431) from the Wisconsin Sleep Cohort were studied between 2004 and 2007. MetS was defined following the National Cholesterol Education Program criteria. SDB severity was defined by the apnea-hypopnea index ([AHI] events/h of sleep) during overnight polysomnography. Fasting lipids, glucose, and insulin were measured and homeostasis model assessment was calculated to quantify insulin resistance (HOMA-IR). Multivariable linear regression was used to assess associations of brachial artery flow-mediated dilation (FMD) with SDB, MetS, and their interaction. Intervention: None. Measurements and Results: Participants averaged 60.2 years of age (SD 7.8 years), 44% were female, and 97% Caucasian. MetS was present in 35%; 22% had AHI ≥ 15 events/hour. Of the no-MetS group, 7% had AHI ≥ 15 events/hour. FMD (mean 5.5%; SD 3.5%) was inversely associated with age (r = -0.16, P = 0.001) and mean brachial artery diameter (r = -0.29, P < 0.001). Multivariate linear models adjusted for CVD risk factors showed that the negative association between SDB and FMD was present among subjects with MetS (β FMDper unit log2(AHI+1) = -0.55%, P = 0.014), but not among subjects with normal metabolic function (β = 0.13, not significant), P for interaction = 0.011. Conclusion: Sleep disordered breathing and concurrent metabolic syndrome are synergistically associated with worse endothelial function. Individuals with both of these conditions appear to be at a significantly higher risk for cardiovascular disease complications. Citation: Korcarz CE, Stein JH, Peppard PE, Young TB, Barnet JH, Nieto FJ. Combined effects of sleep disordered breathing and metabolic syndrome on

  4. Can mild-to-moderate hyperhomocysteinaemia impair endothelial function in the absence of other risk factors for cardiovascular disease?

    PubMed

    Honing, Marina L H; Stehouwer, Coen D A

    2004-04-01

    The majority of clinical studies demonstrate that patients with hyperhomocysteinaemia have an increased risk of atherothrombotic events. However, there is a striking and poorly understood heterogeneity in the severity of clinical features in individuals with hyperhomocysteinaemia. This observation suggests that other factors must exist that modulate the relationship between hyperhomocysteinaemia and clinical disease. Therefore identifying factors that inhibit or enhance the vasculotoxic effects of homocysteine is important, as is elucidation of how homocysteine damages blood vessels. This comment discusses the study of Woodman and colleagues in this issue of Clinical Science in which they investigate the effects of hyperhomocysteinaemia on endothelial function.

  5. Effect of a Tibetan herbal mixture on microvascular endothelial function, heart rate variability and biomarkers of inflammation, clotting and coagulation.

    PubMed

    Schäfer, Daniela; Lambrecht, Julia; Radtke, Thomas; Wilhelm, Matthias; Saner, Hugo

    2015-08-01

    In this 6-week prospective, randomized, placebo-controlled and double-blind study, we investigated the effects of a natural herbal remedy based on a recipe from Tibet (Padma® 28), on microvascular endothelial function, heart rate variability and biomarkers of inflammation, clotting and coagulation in 80 coronary artery disease (CAD) patients (age 66 ± 8 years) on guideline-based medication for secondary prevention. We found no significant effects of Padma 28 and conclude that the addition of Padma 28 to guideline-based secondary prevention treatment of CAD did not lead to significant effects on important surrogate markers in elderly male CAD patients. PMID:25208904

  6. Aerobic exercise capacity remains normal despite impaired endothelial function in the micro- and macrocirculation of physically active IDDM patients.

    PubMed

    Veves, A; Saouaf, R; Donaghue, V M; Mullooly, C A; Kistler, J A; Giurini, J M; Horton, E S; Fielding, R A

    1997-11-01

    The aim of the present study was to examine if diabetes in the absence of neuropathy affects the exercising capacity of IDDM patients, and whether regular, intense training has a beneficial effect on endothelial function. Five groups of subjects were studied: 23 healthy control subjects who exercised regularly (age 33 +/- 6 years), 23 nonneuropathic type 1 diabetic patients who exercised regularly (age 33 +/- 6 years, IDDM duration 11 +/- 8 years), 7 neuropathic type 1 diabetic patients who exercised regularly (age 36 +/- 7 years, IDDM duration 22 +/- 8 years), 18 healthy subjects who did not exercise regularly (age 34 +/- 7 years), and 5 nonneuropathic type 1 diabetic patients who did not exercise regularly (age 31 +/- 4 years, IDDM duration 20 +/- 3 years). All groups were matched for age, sex, and body weight. No differences existed in the energy expenditure per week in physical activity among the three exercising groups or between the two nonexercising groups. The maximal oxygen uptake was similar between control and diabetic nonneuropathic exercisers, and among diabetic neuropathic exercisers, control nonexercisers, and diabetic nonexercisers; however, a significant difference existed between the first two and the last three groups (P < 0.0001). A stepwise increase was found in the resting heart rate among the groups, ranging from the lowest in control exercisers to the highest in diabetic nonexercisers, but the maximal heart rate was lower only in diabetic neuropathic exercisers compared with all other groups (P < 0.05). Assessments of endothelial function in both macro- and microcirculation were performed in 12 control exercisers, 10 diabetic nonneuropathic exercisers, 5 diabetic neuropathic exercisers, 17 control nonexercisers, and 4 diabetic nonexercisers. When all diabetic patients were considered as one group and all control subjects as another, the microcirculation endothelial function in the diabetic group was reduced compared with the control subjects

  7. Magnitude-dependent regulation of pulmonary endothelial cell barrier function by cyclic stretch.

    PubMed

    Birukov, Konstantin G; Jacobson, Jeffrey R; Flores, Alejandro A; Ye, Shui Q; Birukova, Anna A; Verin, Alexander D; Garcia, Joe G N

    2003-10-01

    Ventilator-induced lung injury syndromes are characterized by profound increases in vascular leakiness and activation of inflammatory processes. To explore whether excessive cyclic stretch (CS) directly causes vascular barrier disruption or enhances endothelial cell sensitivity to edemagenic agents, human pulmonary artery endothelial cells (HPAEC) were exposed to physiologically (5% elongation) or pathologically (18% elongation) relevant levels of strain. CS produced rapid (10 min) increases in myosin light chain (MLC) phosphorylation, activation of p38 and extracellular signal-related kinase 1/2 MAP kinases, and actomyosin remodeling. Acute (15 min) and chronic (48 h) CS markedly enhanced thrombin-induced MLC phosphorylation (2.1-fold and 3.2-fold for 15-min CS at 5 and 18% elongation and 2.1-fold and 3.1-fold for 48-h CS at 5 and 18% elongation, respectively). HPAEC preconditioned at 18% CS, but not at 5% CS, exhibited significantly enhanced thrombin-induced reduction in transendothelial electrical resistance but did not affect barrier protective effect of sphingosine-1-phosphate (0.5 microM). Finally, expression profiling analysis revealed a number of genes, including small GTPase rho, apoptosis mediator ZIP kinase, and proteinase activated receptor-2, to be regulated by CS in an amplitude-dependent manner. Thus our study demonstrates a critical role for the magnitude of CS in regulation of agonist-mediated pulmonary endothelial cell permeability and strongly suggests phenotypic regulation of HPAEC barrier properties by CS. PMID:12639843

  8. Hypoxia-Induced Endothelial Progenitor Cell Function Is Blunted in Angiotensinogen Knockout Mice

    PubMed Central

    Choi, Jin-Hwa; Nguyen, Minh-Phuong; Lee, Dongjin; Oh, Goo-Taeg; Lee, You-Mie

    2014-01-01

    Angiotensinogen (AGT), the precursor of angiotensin I, is known to be involved in tumor angiogenesis and associated with the pathogenesis of coronary atherosclerosis. This study was undertaken to determine the role played by AGT in endothelial progenitor cells (EPCs) in tumor progression and metastasis. It was found that the number of EPC colonies formed by AGT heterozygous knockout (AGT+/−) cells was less than that formed by wild-type (WT) cells, and that the migration and tube formation abilities of AGT+/− EPCs were significantly lower than those of WT EPCs. In addition, the gene expressions of vascular endothelial growth factor (VEGF), Flk1, angiopoietin (Ang)-1, Ang-2, Tie-2, stromal derived factor (SDF)-1, C-X-C chemokine receptor type 4 (CXCR4), and of endothelial nitric oxide synthase (eNOS) were suppressed in AGT+/− EPCs. Furthermore, the expressions of hypoxia-inducible factor (HIF)-1α and -2α were downregulated in AGT+/− early EPCs under hypoxic conditions, suggesting a blunting of response to hypoxia. Moreover, the activation of Akt/eNOS signaling pathways induced by VEGF, epithelial growth factor (EGF), or SDF-1α were suppressed in AGT+/− EPCs. In AGT+/− mice, the incorporation of EPCs into the tumor vasculature was significantly reduced, and lung tumor growth and melanoma metastasis were attenuated. In conclusion, AGT is required for hypoxia-induced vasculogenesis. PMID:24938229

  9. The Effect of Quercus salicina Leaf Extracts on Vascular Endothelial Function: Role of Nitric Oxide.

    PubMed

    Park, Sin-Hee; Kim, Hyun-Jung; Yoon, Jun-Seong; Lee, Hye-Won; Park, Gye-Choon; Yi, Eunyoung; Yoon, Goo; Schini-Kerth, Valérie B; Oak, Min-Ho

    2016-02-01

    Dysfunction of the vascular endothelium is reported as a hallmark of cardiovascular diseases. Many evidences suggest that polyphenols are associated with a decreased global mortality and might be involved in protection against cardiovascular risk. This beneficial effect of polyphenol may be due to many actions as antioxidant that increases bioavailability of nitric oxide, vasodilation or anti-hypertensive properties. To identify new natural medicine candidate for cardiovascular protection, plant extracts used in traditional medicine were evaluated by vascular reactivity system. Porcine coronary artery rings were suspended in organ chambers for the measurement of changes in isometric tension. Screening results indicated that the ethanolic extract of leaf from Quercus salicina (QSE) has been found to exhibit potent vasorelaxant activity. QSE dose-dependently induced endothelium-dependent relaxations, which were abolished by inhibitors of nitric oxide synthase (Nomega-nitro-L-arginine). In addition, QSE strongly and dose-dependently activate endothelial nitric oxide synthase (eNOS) in porcine coronary artery endothelial cell. Taken together, the present study has demonstrated that QSE is a powerful endothelium-dependentvasodilator and that this effect involves increased nitric oxide bioavailability. In conclusion, QSE could be a cardiovascular protective herbal medicine candidate associated with cardiovascular diseases and endothelial dysfunction. PMID:27433730

  10. Fenofibrate improves endothelial function in the brachial artery and forearm resistance arterioles of statin-treated Type 2 diabetic patients.

    PubMed

    Hamilton, Sandra J; Chew, Gerard T; Davis, Timothy M E; Watts, Gerald F

    2010-05-01

    Dyslipidaemia contributes to endothelial dysfunction and CVD (cardiovascular disease) in Type 2 diabetes mellitus. While statin therapy reduces CVD in these patients, residual risk remains high. Fenofibrate corrects atherogenic dyslipidaemia, but it is unclear whether adding fenofibrate to statin therapy lowers CVD risk. We investigated whether fenofibrate improves endothelial dysfunction in statin-treated Type 2 diabetic patients. In a cross-over study, 15 statin-treated Type 2 diabetic patients, with LDL (low-density lipoprotein)-cholesterol <2.6 mmol/l and endothelial dysfunction [brachial artery FMD (flow-mediated dilatation) <6.0%] were randomized, double-blind, to fenofibrate 145 mg/day or matching placebo for 12 weeks, with 4 weeks washout between treatment periods. Brachial artery FMD and endothelium-independent NMD (nitrate-mediated dilatation) were measured by ultrasonography at the start and end of each treatment period. PIFBF (post-ischaemic forearm blood flow), a measure of microcirculatory endothelial function, and serum lipids, lipoproteins and apo (apolipoprotein) concentrations were also measured. Compared with placebo, fenofibrate increased FMD (mean absolute 2.1+/-0.6 compared with -0.3+/-0.6%, P=0.04), but did not alter NMD (P=0.75). Fenofibrate also increased maximal PIFBF {median 3.5 [IQR (interquartile range) 5.8] compared with 0.3 (2.1) ml/100 ml/min, P=0.001} and flow debt repayment [median 1.0 (IQR 3.5) compared with -1.5 (3.0) ml/100 ml, P=0.01]. Fenofibrate lowered serum cholesterol, triacylgycerols (triglycerides), LDL-cholesterol, apoB-100 and apoC-III (P < or = 0.03), but did not alter HDL (high-density lipoprotein)-cholesterol or apoA-I. Improvement in FMD was inversely associated with on-treatment LDL-cholesterol (r=-0.61, P=0.02) and apoB-100 (r=-0.54, P=0.04) concentrations. Fenofibrate improves endothelial dysfunction in statin-treated Type 2 diabetic patients. This may relate partly to enhanced reduction in LDL-cholesterol and

  11. Abnormal aortic fatty acid composition and small artery function in offspring of rats fed a high fat diet in pregnancy

    PubMed Central

    Ghosh, P; Bitsanis, D; Ghebremeskel, K; Crawford, M A; Poston, L

    2001-01-01

    Disturbances of the in utero environment are associated with an increased risk of cardiovascular disease in adulthood. In this study we have determ