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Sample records for affects vascular function

  1. Hindlimb unweighting affects rat vascular capacitance function

    NASA Technical Reports Server (NTRS)

    Dunbar, S. L.; Tamhidi, L.; Berkowitz, D. E.; Shoukas, A. A.

    2001-01-01

    Microgravity is associated with an impaired stroke volume and, therefore, cardiac output response to orthostatic stress. We hypothesized that a decreased venous filling pressure due to increased venous compliance may be an important contributing factor in this response. We used a constant flow, constant right atrial pressure cardiopulmonary bypass procedure to measure total systemic vascular compliance (C(T)), arterial compliance (C(A)), and venous compliance (C(V)) in seven control and seven 21-day hindlimb unweighted (HLU) rats. These compliance values were calculated under baseline conditions and during an infusion of 0.2 microg*kg(-1)*min(-1) norepinephrine (NE). The change in reservoir volume, which reflects changes in unstressed vascular volume (DeltaV(0)) that occurred upon infusion of NE, was also measured. C(T) and C(V) were larger in HLU rats both at baseline and during the NE infusion (P < 0.05). Infusion of NE decreased C(T) and C(V) by 20% in both HLU and control rats (P < 0.01). C(A) was also significantly decreased in both groups of rats by NE (P < 0.01), but values of C(A) were similar between HLU and control rats both at baseline and during the NE infusion. Additionally, the NE-induced DeltaV(0) was attenuated by 53% in HLU rats compared with control rats (P < 0.05). The larger C(V) and attenuated DeltaV(0) in HLU rats could contribute to a decreased filling pressure during orthostasis and thus may partially underlie the mechanism leading to the exaggerated fall in stroke volume and cardiac output seen in astronauts during an orthostatic stress after exposure to microgravity.

  2. Grape polyphenols do not affect vascular function in healthy men.

    PubMed

    van Mierlo, Linda A J; Zock, Peter L; van der Knaap, Henk C M; Draijer, Richard

    2010-10-01

    Data suggest that polyphenol-rich products may improve endothelial function and other cardiovascular health risk factors. Grape and wine contain high amounts of polyphenols, but effects of these polyphenols have hardly been investigated in isolation in randomized controlled studies. Our objective in this study was to test the chronic effect of polyphenol-rich solids derived from either a wine grape mix or grape seed on flow-mediated dilation (FMD). Blood pressure and other vascular function measures, platelet function, and blood lipids were secondary outcomes. Thirty-five healthy males were randomized in a double-blind, placebo-controlled crossover study consisting of three 2-wk intervention periods separated by 1-wk washout periods. The test products, containing 800 mg of polyphenols, were consumed as capsules. At the end of each intervention period, effects were measured after consumption of a low-fat breakfast (~751 kJ, 25% fat) and a high-fat lunch (~3136 kJ, 78% fat). After the low-fat breakfast, the treatments did not significantly affect FMD. The absolute difference after the wine grape solid treatment was -0.4% (95% CI = -1.8 to 0.9; P = 0.77) and after grape seed solids, 0.2% (95% CI = -1.2 to 1.5; P = 0.94) compared with after the placebo treatment. FMD effects after the high-fat lunch and effects on secondary outcomes also showed no consistent differences between both of the grape solids and placebo treatment. In conclusion, consumption of grape polyphenols has no major impact on FMD in healthy men. Future studies should address whether grape polyphenols can improve FMD and other cardiovascular health risk factors in populations with increased cardiovascular risk. PMID:20702747

  3. Right ventricular diastolic function in dialysis patients could be affected by vascular access.

    PubMed

    Di Lullo, Luca; Floccari, Fulvio; Polito, Pasquale

    2011-01-01

    Tricuspid annular plane excursion (TAPSE) measurement in echocardiography is a measure of heart diastolic distensibility: a low TAPSE indicates reduced ventricular distensibility leading to diastolic dysfunction. It is a good prognostic index for cardiac mortality risk in congestive heart failure patients, adding significant prognostic information to the NYHA clinical classification. Our study was designed to evaluate the effect of a single hemodialysis (HD) session on diastolic function and TAPSE, focusing on the effects of vascular access typology. Twenty chronically uremic patients (age 51 ± 10 years, dialytic age 24 ± 8 months), without overt heart disease, underwent conventional two-dimensional and Doppler echocardiography immediately before starting and 15 min after ending a mid-week HD session. Ten patients had distal radiocephalic arterovenous fistula (AVF), and 10 had permanent central venous catheters (CVC). The amount of fluid removed by HD was 2,706 ± 1,047 g/session. HD led to a reduction in TAPSE, left ventricle end-diastole volume, left ventricle end-systole volume, right ventricle end-diastole diameter, peak early transmitral flow velocity, and the ratio of early to late Doppler velocities of diastolic mitral flow. AVF patients showed greater right ventricle diameters versus CVC patients, while TAPSE appeared higher in the latter. Only the AVF patient group showed TAPSE values <15 mm. Our data confirm the effects of terminal uremia on right ventricle function (chamber dilation, impaired diastolic function), showing that these abnormalities are more frequent in AVF patients as opposed to CVC patients. It is reasonable to explain these clinical features as the effect of preload increase operated by AVF. PMID:21196771

  4. SIRT1 reduces endothelial activation without affecting vascular function in ApoE-/- mice

    PubMed Central

    Stein, Sokrates; Schäfer, Nicola; Breitenstein, Alexander; Besler, Christian; Winnik, Stephan; Lohmann, Christine; Heinrich, Kathrin; Brokopp, Chad E.; Handschin, Christoph; Landmesser, Ulf; Tanner, Felix C.; Lüscher, Thomas F.; Matter, Christian M.

    2010-01-01

    Excessive production of reactive oxygen species (ROS) contributes to progression of atherosclerosis, at least in part by causing endothelial dysfunction and inflammatory activation. The class III histone deacetylase SIRT1 has been implicated in extension of lifespan. In the vasculature,SIRT1 gain-of-function using SIRT1 overexpression or activation has been shown to improve endothelial function in mice and rats via stimulation of endothelial nitric oxide (NO) synthase (eNOS). However, the effects of SIRT1 loss-of-function on the endothelium in atherosclerosis remain to be characterized. Thus, we have investigated the endothelial effects of decreased endogenous SIRT1 in hypercholesterolemic ApoE-/- mice. We observed no difference in endothelial relaxation and eNOS (Ser1177) phosphorylation between 20-week old male atherosclerotic ApoE-/- SIRT1+/- and ApoE-/- SIRT1+/+ mice. However, SIRT1 prevented endothelial superoxide production, inhibited NF-κB signaling, and diminished expression of adhesion molecules. Treatment of young hypercholesterolemic ApoE-/- SIRT1+/- mice with lipopolysaccharide to boost NF-κB signaling led to a more pronounced endothelial expression of ICAM-1 and VCAM-1 as compared to ApoE-/- SIRT1+/+ mice. In conclusion, endogenous SIRT1 diminishes endothelial activation in ApoE-/- mice, but does not affect endothelium-dependent vasodilatation. PMID:20606253

  5. Regulatory RNAs controlling vascular (dys)function by affecting TGF-ß family signalling

    PubMed Central

    Kurakula, Kondababu; Goumans, Marie-Jose; ten Dijke, Peter

    2015-01-01

    Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. Over the last few years, microRNAs (miRNAs) have emerged as master regulators of gene expression in cardiovascular biology and disease. miRNAs are small endogenous non-coding RNAs that usually bind to 3′ untranslated region (UTR) of their target mRNAs and inhibit mRNA stability or translation of their target genes. miRNAs play a dynamic role in the pathophysiology of many CVDs through their effects on target mRNAs in vascular cells. Recently, numerous miRNAs have been implicated in the regulation of the transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signalling pathway which plays crucial roles in diverse biological processes, and is involved in pathogenesis of many diseases including CVD. This review gives an overview of current literature on the role of miRNAs targeting TGF-β/BMP signalling in vascular cells, including endothelial cells and smooth muscle cells. We also provide insight into how this miRNA-mediated regulation of TGF-β/BMP signalling might be used to harness CVD. PMID:26862319

  6. Short-Term Exposure to Ozone Does Not Impair Vascular Function or Affect Heart Rate Variability in Healthy Young Men

    PubMed Central

    Barath, Stefan; Langrish, Jeremy P.; Blomberg, Anders

    2013-01-01

    Air pollution exposure is associated with cardiovascular morbidity and mortality, yet the role of individual pollutants remains unclear. In particular, there is uncertainty regarding the acute effect of ozone exposure on cardiovascular disease. In these studies, we aimed to determine the effect of ozone exposure on vascular function, fibrinolysis, and the autonomic regulation of the heart. Thirty-six healthy men were exposed to ozone (300 ppb) and filtered air for 75min on two occasions in randomized double-blind crossover studies. Bilateral forearm blood flow (FBF) was measured using forearm venous occlusion plethysmography before and during intra-arterial infusions of vasodilators 2–4 and 6–8h after each exposure. Heart rhythm and heart rate variability (HRV) were monitored during and 24h after exposure. Compared with filtered air, ozone exposure did not alter heart rate, blood pressure, or resting FBF at either 2 or 6h. There was a dose-dependent increase in FBF with all vasodilators that was similar after both exposures at 2–4h. Ozone exposure did not impair vasomotor or fibrinolytic function at 6–8h but rather increased vasodilatation to acetylcholine (p = .015) and sodium nitroprusside (p = .005). Ozone did not affect measures of HRV during or after the exposure. Our findings do not support a direct rapid effect of ozone on vascular function or cardiac autonomic control although we cannot exclude an effect of chronic exposure or an interaction between ozone and alternative air pollutants that may be responsible for the adverse cardiovascular health effects attributed to ozone. PMID:23872581

  7. Exercise and Vascular Function – How Much is too Much?

    PubMed Central

    Durand, Matthew J.; Gutterman, David D.

    2015-01-01

    Exercise is a powerful therapy for preventing the onset and slowing the progression of cardiovascular disease. Increased shear stress during exercise improves vascular homeostasis by both decreasing reactive oxygen species and increasing nitric oxide bioavailability in the endothelium. While these observations are well accepted as they apply to individuals at risk for cardiovascular disease, less is known about how exercise, especially intense exercise, affects vascular function in healthy individuals. This review highlights examples of how vascular function can paradoxically be impaired in otherwise healthy individuals by extreme levels of exercise, with a focus on the causative role that reactive oxygen species play in this impairment. PMID:24873760

  8. Vascular Function in Alzheimer's Disease and Vascular Dementia.

    PubMed

    Tachibana, Hisatsugu; Washida, Kazuo; Kowa, Hisatomo; Kanda, Fumio; Toda, Tatsushi

    2016-08-01

    We investigated vascular functioning in patients with a clinical and radiological diagnosis of either Alzheimer's disease (AD) or vascular dementia (VaD) and examined a possible relationship between vascular function and cognitive status. Twenty-seven patients with AD, 23 patients with VaD, and 26 healthy control patients underwent measurements of flow-mediated dilation (FMD), ankle-brachial index (ABI), cardioankle vascular index (CAVI), and intima-media thickness (IMT). The FMD was significantly lower in patients with AD or VaD compared to controls. There were no significant differences in ABI, CAVI, or IMT among the 3 groups. A significant correlation was found between Mini-Mental State Examination (MMSE) scores and FMD. Furthermore, a multiple regression analysis revealed that FMD was significantly predicted by MMSE scores. These results suggest that endothelial involvement plays a role in AD pathogenesis, and FMD may be more sensitive than other surrogate methods (ABI, CAVI, and IMT) for detecting early-stage atherosclerosis and/or cognitive decline. PMID:27284205

  9. Reduction of homocysteine in elderly with heart failure improved vascular function and blood pressure control but did not affect inflammatory activity.

    PubMed

    Andersson, Sven E; Edvinsson, Marie-Louise; Edvinsson, Lars

    2005-11-01

    We have previously shown that hyperhomocysteinaemia is common in elderly heart failure patients, and is associated with endothelial dysfunction, impaired vasodilatory capacity and a low-grade inflammation. In the present study we examined if supplementation with B6, B12 and folate could normalize the hyperhomocysteinaemia and if so, in turn, would improve the associated parameters. This was an open study without placebo control on heart failure patients with plasma homocysteine > 15 microM. Measurements of cutaneous vascular reactivity, blood pressure, inflammatory activity and endothelial function were performed before and after intervention with intra-individual comparisons. The treatment reduced homocysteine to near normal values and enhanced the hyperaemic response to acetylcholine related to the response to heat. The mean arterial blood pressure and pulse rate was reduced. There was no effect on inflammatory activity, plasma levels of von Willebrand factor, subjective health quality or the hyperaemic responses to sodium nitroprusside or local warming. Hyperhomocysteinaemia in heart failure patients is multifactorial in origin. Folate deficiency, inflammatory activity and reduced renal function could be contributing. It is suggested that supplementation with B-vitamins can improve the vasodilatory capacity and reduce the blood pressure but additional studies are required to confirm this. PMID:16236143

  10. Testosterone and Vascular Function in Aging

    PubMed Central

    Lopes, Rhéure A. M.; Neves, Karla B.; Carneiro, Fernando S.; Tostes, Rita C.

    2012-01-01

    Androgen receptors are widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Through classic cytosolic androgen receptors or membrane receptors, testosterone induces genomic and non-genomic effects, respectively. Testosterone interferes with the vascular function by increasing the production of pro-inflammatory cytokines and arterial thickness. Experimental evidence indicates that sex steroid hormones, such as testosterone modulate the synthesis and bioavailability of NO and, consequently, endothelial function, which is key for a healthy vasculature. Of interest, aging itself is accompanied by endothelial and vascular smooth muscle dysfunction. Aging-associated decline of testosterone levels is accompanied by age-related diseases, such as metabolic and cardiovascular diseases, indicating that very low levels of androgens may contribute to cardiovascular dysfunction observed in these age-related disorders or, in other words, that testosterone may have beneficial effects in the cardiovascular system. However, testosterone seems to play a negative role in the severity of renal disease. In this mini-review, we briefly comment on the interplay between aging and testosterone levels, the vascular actions of testosterone and its implications for vascular aging. Renal effects of testosterone and the use of testosterone to prevent vascular dysfunction in elderly are also addressed. PMID:22514541

  11. Vascular dysregulation in normal-tension glaucoma is not affected by structure and function of the microcirculation or macrocirculation at rest: a case-control study.

    PubMed

    Bossuyt, Jelle; Vandekerckhove, Gwendolijn; De Backer, Tine L M; Van de Velde, Sandrien; Azermai, Majda; Stevens, Anna-Maria; Kestelyn, Philippe; Raemdonck, Tia; Segers, Patrick; Vanmolkot, Floris; Van Bortel, Luc M

    2015-01-01

    In normal-tension glaucoma (NTG), optic nerve damage occurs despite a normal intraocular pressure. Studies implicating systemic blood pressure or, more recently, arterial stiffness in the pathophysiology of NTG have produced conflicting results. Our aim was to investigate whether NTG is associated with alterations in the macrocirculation or microcirculation, cardiac function, and peripheral and central hemodynamics. Thirty patients with NTG (mean age 65 years, range 46-79) and 33 healthy subjects (mean age 67 years, range 42-79) matched for age and sex were included in the study. Exclusion criteria (for both cases and controls) were history of cardiovascular disease, diabetes mellitus, severe hypertension, and hypercholesterolemia. Aortic stiffness was measured using carotid-femoral pulse wave velocity (PWV), central hemodynamics using carotid artery applanation tonometry, and diameter, stiffness, and intima-media thickness (IMT) of the carotid and femoral artery using echo-tracking. Total peripheral resistance index (TPRI) was derived from mean arterial pressure and cardiac index, measured using ultrasound. There were no statistically significant differences in arterial structure nor function between NTG patients and age and sex-matched controls. NTG versus controls, respectively: brachial blood pressure 126 ± 15/77 ± 8 versus 127 ± 16/76 ± 7 mm Hg, P = 0.81; carotid-femoral PWV 9.8 ± 2.1 versus 10.1 ± 1.9 m/s, P = 0.60; TPRI 1833 ± 609 versus 1779 ± 602 dyne.s/cm5/m2, P = 0.79; and carotid IMT 0.65 ± 0.14 versus 0.68 ± 0.13 mm, P = 0.39. This study could not show an association of NTG with altered IMT, arterial stiffness, total peripheral resistance, cardiac output, and peripheral or central hemodynamics at rest. Although the majority of these NTG patients do exhibit symptoms of vascular dysregulation, in the present study this was not translated into alterations in the microcirculation or macrocirculation at rest. PMID:25590850

  12. In vitro assessment of mouse fetal abdominal aortic vascular function

    PubMed Central

    Dilworth, Mark R.; Greenwood, Susan L.; Sibley, Colin P.; Wareing, Mark

    2014-01-01

    Fetal growth restriction (FGR) affects 3–8% of human pregnancies. Mouse models have provided important etiological data on FGR; they permit the assessment of treatment strategies on the physiological function of both mother and her developing offspring. Our study aimed to 1) develop a method to assess vascular function in fetal mice and 2) as a proof of principle ascertain whether a high dose of sildenafil citrate (SC; Viagra) administered to the pregnant dam affected fetal vascular reactivity. We developed a wire myography methodology for evaluation of fetal vascular function in vitro using the placenta-specific insulin-like growth factor II (Igf2) knockout mouse (P0; a model of FGR). Vascular function was determined in abdominal aortas isolated from P0 and wild-type (WT) fetuses at embryonic day (E) 18.5 of gestation. A subset of dams received SC 0.8 mg/ml via drinking water from E12.5; data were compared with water-only controls. Using wire myography, we found that fetal aortic rings exhibited significant agonist-induced contraction, and endothelium-dependent and endothelium-independent relaxation. Sex-specific alterations in reactivity were noted in both strains. Maternal treatment with SC significantly attenuated endothelium-dependent and endothelium-independent relaxation of fetal aortic rings. Mouse fetal abdominal aortas reproducibly respond to vasoactive agents. Study of these vessels in mouse genetic models of pregnancy complications may 1) help to delineate early signs of abnormal vascular reactivity and 2) inform whether treatments given to the mother during pregnancy may impact upon fetal vascular function. PMID:25056105

  13. Diacylglycerol Kinase Inhibition and Vascular Function.

    PubMed

    Choi, Hyehun; Allahdadi, Kyan J; Tostes, Rita C A; Webb, R Clinton

    2009-01-01

    Diacylglycerol kinases (DGKs), a family of lipid kinases, convert diacylglycerol (DG) to phosphatidic acid (PA). Acting as a second messenger, DG activates protein kinase C (PKC). PA, a signaling lipid, regulates diverse functions involved in physiological responses. Since DGK modulates two lipid second messengers, DG and PA, regulation of DGK could induce related cellular responses. Currently, there are 10 mammalian isoforms of DGK that are categorized into five groups based on their structural features. These diverse isoforms of DGK are considered to activate distinct cellular functions according to extracellular stimuli. Each DGK isoform is thought to play various roles inside the cell, depending on its subcellular localization (nuclear, ER, Golgi complex or cytoplasm). In vascular smooth muscle, vasoconstrictors such as angiotensin II, endothelin-1 and norepinephrine stimulate contraction by increasing inositol trisphosphate (IP(3)), calcium, DG and PKC activity. Inhibition of DGK could increase DG availability and decrease PA levels, as well as alter intracellular responses, including calcium-mediated and PKC-mediated vascular contraction. The purpose of this review is to demonstrate a role of DGK in vascular function. Selective inhibition of DGK isoforms may represent a novel therapeutic approach in vascular dysfunction. PMID:21547002

  14. Poldip2 sustains vascular structure and function

    PubMed Central

    Sutliff, Roy L.; Hilenski, Lula L.; Amanso, Angélica M.; Parastatidis, Ioannis; Dikalova, Anna E.; Hansen, Laura; Datla, Srinivasa Raju; Long, James S.; El-Ali, Alexander M.; Joseph, Giji; Gleason, Rudolph L.; Taylor, W. Robert; Hart, C. Michael; Griendling, Kathy K.; Lassègue, Bernard

    2013-01-01

    Objective Based on previous evidence that polymerase delta interacting protein 2 (Poldip2) increases NADPH oxidase 4 (Nox4) activity in vascular smooth muscle cells (VSMC), we hypothesized that in vivo knockdown of Poldip2 would inhibit reactive oxygen species (ROS) production and alter vascular function. Approach and Results Because homozygous Poldip2 deletion is lethal, Poldip2+/− mice were employed. Poldip2 mRNA and protein levels were reduced by about 50% in Poldip2+/− aorta, with no change in p22phox, Nox1, Nox2 and Nox4 mRNAs. NADPH oxidase activity was also inhibited in Poldip2+/− tissue. Isolated aortas from Poldip2+/− mice demonstrated impaired phenylephrine and potassium chloride-induced contractions, increased stiffness and reduced compliance, associated with disruption of elastic lamellae and excessive extracellular matrix deposition. Collagen I secretion was elevated in cultured VSMC from Poldip2+/− mice and restored by H2O2 supplementation, suggesting that this novel function of Poldip2 is mediated by reactive oxygen species. Furthermore, Poldip2+/− mice were protected against aortic dilatation in a model of experimental aneurysm, an effect consistent with increased collagen secretion. Conclusions Poldip2 knockdown reduces H2O2 production in vivo, leading to increases in extracellular matrix, greater vascular stiffness and impaired agonist-mediated contraction. Thus, unaltered expression of Poldip2 is necessary for vascular integrity and function. PMID:23825363

  15. Endothelial microparticles: Sophisticated vesicles modulating vascular function

    PubMed Central

    Curtis, Anne M; Edelberg, Jay; Jonas, Rebecca; Rogers, Wade T; Moore, Jonni S; Syed, Wajihuddin; Mohler, Emile R

    2015-01-01

    Endothelial microparticles (EMPs) belong to a family of extracellular vesicles that are dynamic, mobile, biological effectors capable of mediating vascular physiology and function. The release of EMPs can impart autocrine and paracrine effects on target cells through surface interaction, cellular fusion, and, possibly, the delivery of intra-vesicular cargo. A greater understanding of the formation, composition, and function of EMPs will broaden our understanding of endothelial communication and may expose new pathways amenable for therapeutic manipulation. PMID:23892447

  16. Exercise training improves vascular mitochondrial function.

    PubMed

    Park, Song-Young; Rossman, Matthew J; Gifford, Jayson R; Bharath, Leena P; Bauersachs, Johann; Richardson, Russell S; Abel, E Dale; Symons, J David; Riehle, Christian

    2016-04-01

    Exercise training is recognized to improve cardiac and skeletal muscle mitochondrial respiratory capacity; however, the impact of chronic exercise on vascular mitochondrial respiratory function is unknown. We hypothesized that exercise training concomitantly increases both vascular mitochondrial respiratory capacity and vascular function. Arteries from both sedentary (SED) and swim-trained (EX, 5 wk) mice were compared in terms of mitochondrial respiratory function, mitochondrial content, markers of mitochondrial biogenesis, redox balance, nitric oxide (NO) signaling, and vessel function. Mitochondrial complex I and complex I + II state 3 respiration and the respiratory control ratio (complex I + II state 3 respiration/complex I state 2 respiration) were greater in vessels from EX relative to SED mice, despite similar levels of arterial citrate synthase activity and mitochondrial DNA content. Furthermore, compared with the SED mice, arteries from EX mice displayed elevated transcript levels of peroxisome proliferative activated receptor-γ coactivator-1α and the downstream targets cytochrome c oxidase subunit IV isoform 1,isocitrate dehydrogenase(Idh)2, and Idh3a, increased manganese superoxide dismutase protein expression, increased endothelial NO synthase phosphorylation (Ser(1177)), and suppressed reactive oxygen species generation (all P< 0.05). Although there were no differences in EX and SED mice concerning endothelium-dependent and endothelium-independent vasorelaxation, phenylephrine-induced vasocontraction was blunted in vessels from EX compared with SED mice, and this effect was normalized by NOS inhibition. These training-induced increases in vascular mitochondrial respiratory capacity and evidence of improved redox balance, which may, at least in part, be attributable to elevated NO bioavailability, have the potential to protect against age- and disease-related challenges to arterial function. PMID:26825520

  17. Regulation of thrombosis and vascular function by protein methionine oxidation.

    PubMed

    Gu, Sean X; Stevens, Jeff W; Lentz, Steven R

    2015-06-18

    Redox biology is fundamental to both normal cellular homeostasis and pathological states associated with excessive oxidative stress. Reactive oxygen species function not only as signaling molecules but also as redox regulators of protein function. In the vascular system, redox reactions help regulate key physiologic responses such as cell adhesion, vasoconstriction, platelet aggregation, angiogenesis, inflammatory gene expression, and apoptosis. During pathologic states, altered redox balance can cause vascular cell dysfunction and affect the equilibrium between procoagulant and anticoagulant systems, contributing to thrombotic vascular disease. This review focuses on the emerging role of a specific reversible redox reaction, protein methionine oxidation, in vascular disease and thrombosis. A growing number of cardiovascular and hemostatic proteins are recognized to undergo reversible methionine oxidation, in which methionine residues are posttranslationally oxidized to methionine sulfoxide. Protein methionine oxidation can be reversed by the action of stereospecific enzymes known as methionine sulfoxide reductases. Calcium/calmodulin-dependent protein kinase II is a prototypical methionine redox sensor that responds to changes in the intracellular redox state via reversible oxidation of tandem methionine residues in its regulatory domain. Several other proteins with oxidation-sensitive methionine residues, including apolipoprotein A-I, thrombomodulin, and von Willebrand factor, may contribute to vascular disease and thrombosis. PMID:25900980

  18. Regulation of thrombosis and vascular function by protein methionine oxidation

    PubMed Central

    Gu, Sean X.; Stevens, Jeff W.

    2015-01-01

    Redox biology is fundamental to both normal cellular homeostasis and pathological states associated with excessive oxidative stress. Reactive oxygen species function not only as signaling molecules but also as redox regulators of protein function. In the vascular system, redox reactions help regulate key physiologic responses such as cell adhesion, vasoconstriction, platelet aggregation, angiogenesis, inflammatory gene expression, and apoptosis. During pathologic states, altered redox balance can cause vascular cell dysfunction and affect the equilibrium between procoagulant and anticoagulant systems, contributing to thrombotic vascular disease. This review focuses on the emerging role of a specific reversible redox reaction, protein methionine oxidation, in vascular disease and thrombosis. A growing number of cardiovascular and hemostatic proteins are recognized to undergo reversible methionine oxidation, in which methionine residues are posttranslationally oxidized to methionine sulfoxide. Protein methionine oxidation can be reversed by the action of stereospecific enzymes known as methionine sulfoxide reductases. Calcium/calmodulin-dependent protein kinase II is a prototypical methionine redox sensor that responds to changes in the intracellular redox state via reversible oxidation of tandem methionine residues in its regulatory domain. Several other proteins with oxidation-sensitive methionine residues, including apolipoprotein A-I, thrombomodulin, and von Willebrand factor, may contribute to vascular disease and thrombosis. PMID:25900980

  19. Influence of vascular function and pulsatile hemodynamics on cardiac function.

    PubMed

    Bell, Vanessa; Mitchell, Gary F

    2015-09-01

    Interactions between cardiac and vascular structure and function normally are optimized to ensure delivery of cardiac output with modest pulsatile hemodynamic overhead. Aortic stiffening with age or disease impairs optimal ventricular-vascular coupling, increases pulsatile load, and contributes to left ventricular (LV) hypertrophy, reduced systolic function, and impaired diastolic relaxation. Aortic pulse pressure and timing of peak systolic pressure are well-known measures of hemodynamic ventricular-vascular interaction. Recent work has elucidated the importance of direct, mechanical coupling between the aorta and the heart. LV systolic contraction results in displacement of aortic and mitral annuli, thereby producing longitudinal stretch in the ascending aorta and left atrium, respectively. Force associated with longitudinal stretch increases systolic load on the LV. However, the resulting energy stored in the elastic elements of the proximal aorta during systole facilitates early diastolic LV recoil and rapid filling. This review discusses current views on hemodynamics and mechanics of ventricular-vascular coupling. PMID:26164466

  20. VASCULAR ACTIONS OF ESTROGENS: FUNCTIONAL IMPLICATIONS

    PubMed Central

    Miller, Virginia M.; Duckles, Sue P.

    2009-01-01

    The impact of estrogen exposure in preventing or treating cardiovascular disease is controversial. But it is clear that estrogen has important effects on vascular physiology and pathophysiology, with potential therapeutic implications. Therefore, it is the goal of this review to summarize, using an integrated approach, current knowledge of the vascular effects of estrogen, both in humans and in experimental animals. Aspects of estrogen synthesis and receptors, as well as general mechanisms of estrogenic action are reviewed with an emphasis on issues particularly relevant to the vascular system. Recent understanding of the impact of estrogen on mitochondrial function suggests that the longer lifespan of women compared to men may depend in part on the ability of estrogen to decrease production of reactive oxygen species in mitochondria. Mechanisms by which estrogen increases endothelial vasodilator function, promotes angiogenesis and modulates autonomic function are summarized. Key aspects of the relevant pathophysiology of inflammation, atherosclerosis, stroke, migraine and thrombosis are reviewed concerning current knowledge of estrogenic effects. A number of emerging concepts are addressed throughout. These include the importance of estrogenic formulation and route of administration and the impact of genetic polymorphisms, either in estrogen receptors or in enzymes responsible for estrogen metabolism, on responsiveness to hormone treatment. The importance of local metabolism of estrogenic precursors and the impact of timing for initiation of treatment and its duration are also considered. While consensus opinions are emphasized, controversial views are presented in order to stimulate future research. PMID:18579753

  1. Aging and vascular endothelial function in humans

    PubMed Central

    SEALS, Douglas R.; JABLONSKI, Kristen L.; DONATO, Anthony J.

    2012-01-01

    Advancing age is the major risk factor for the development of CVD (cardiovascular diseases). This is attributable, in part, to the development of vascular endothelial dysfunction, as indicated by reduced peripheral artery EDD (endothelium-dependent dilation) in response to chemical [typically ACh (acetylcholine)] or mechanical (intravascular shear) stimuli. Reduced bioavailability of the endothelium-synthesized dilating molecule NO (nitric oxide) as a result of oxidative stress is the key mechanism mediating reduced EDD with aging. Vascular oxidative stress increases with age as a consequence of greater production of reactive oxygen species (e.g. superoxide) without a compensatory increase in antioxidant defences. Sources of increased superoxide production include up-regulation of the oxidant enzyme NADPH oxidase, uncoupling of the normally NO-producing enzyme, eNOS (endothelial NO synthase) (due to reduced availability of the cofactor tetrahydrobiopterin) and increased mitochondrial synthesis during oxidative phosphorylation. Increased bioactivity of the potent endothelial-derived constricting factor ET-1 (endothelin-1), reduced endothelial production of/responsiveness to dilatory prostaglandins, the development of vascular inflammation, formation of AGEs (advanced glycation end-products), an increased rate of endothelial apoptosis and reduced expression of oestrogen receptor α (in postmenopausal females) also probably contribute to impaired EDD with aging. Several lifestyle and biological factors modulate vascular endothelial function with aging, including regular aerobic exercise, dietary factors (e.g. processed compared with non-processed foods), body weight/fatness, vitamin D status, menopause/oestrogen deficiency and a number of conventional and non-conventional risk factors for CVD. Given the number of older adults now and in the future, more information is needed on effective strategies for the prevention and treatment of vascular endothelial aging. PMID

  2. Mechanisms of Microgravity Effect on Vascular Function

    NASA Technical Reports Server (NTRS)

    Purdy, Ralph E.

    1995-01-01

    The overall goal of the project is to characterize the effects of simulated microgravity on vascular function. Microgravity is simulated using the hindlimb unweighted (HU) rat, and the following vessels are removed from HU and paired control rats for in vitro analysis: abdominal aorta, carotid and femoral arteries, jugular and femoral veins. These vessels are cut into 3 mm long rings and mounted in tissue baths for the measurement of either isometric contraction, or relaxation of pre- contracted vessels. The isolated mesenteric vascular bed is perfused for the measurement of changes in perfusion pressure as an index of arteriolar constriction or dilation. This report presents, in addition to the statement of the overall goal of the project, a summary list of the specific hypotheses to be tested. These are followed by sections on results, conclusions, significance and plans for the next year.

  3. Image-Based Evaluation of Vascular Function and Hemodynamics

    PubMed Central

    Lee, Jongmin

    2013-01-01

    The noticeable characteristics of the blood vascular structure are the inconsistent viscosity of blood and the stiffness of the vascular wall. If we can control these two factors, we can solve more problems related to hemodynamics and vascular wall function. Understanding the properties of hemodynamics and vascular wall function may provide more information applicable to clinical practice for cardiovascular disease. The bedside techniques evaluating vascular function usually measure indirect parameters. In contrast, some medical imaging techniques provide clear and direct depictions of functional cardiovascular characteristics. In this review, image-based evaluation of hemodynamic and vascular wall functions is discussed from the perspective of blood flow velocity, flow volume, flow pattern, peripheral vascular resistance, intraluminal pressure, vascular wall stress, and wall stiffness. PMID:26587430

  4. Vascular function and ocular involvement in sarcoidosis.

    PubMed

    Siasos, Gerasimos; Paraskevopoulos, Theodoros; Gialafos, Elias; Rapti, Aggeliki; Oikonomou, Evangelos; Zaromitidou, Marina; Mourouzis, Konstantinos; Siasou, Georgia; Gouliopoulos, Nikolaos; Tsalamandris, Sotiris; Vlasis, Konstantinos; Stefanadis, Christodoulos; Papavassiliou, Athanasios G; Tousoulis, Dimitris

    2015-07-01

    Ocular involvement occurs in sarcoidosis (Sar) patients mainly in the form of uveitis. This study was designed to determine if uveitis in Sar patients is associated with vascular impairment. We enrolled 82 Sar patients and 77, age and sex matched, control subjects (Cl). Sar patients were divided into those with ocular sarcoidosis (OS) and those without ocular sarcoidosis (WOS). Endothelial function was evaluated by flow-mediated dilation (FMD). Pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as a measure of arterial wave reflections. Although there was no significant difference in sex, age and mean arterial pressure, patients with OS compared to WOS patients and Cl subjects had impaired FMD (p<0.001), increased AIx (p=0.02) and increased PWV (p=0.001). Interestingly, impaired FMD in Sar patients was independently, from possible covariates (age, sex, smoking habits, arterial hypertension, dyslipidemia), associated with increased odds of ocular involvement (odds ratio=1.69, p=0.001). More precisely ROC curve analysis revealed that FMD had a significant diagnostic ability for the detection of OS (AUC=0.77, p<0.001) with a sensitivity of 79% and a specificity of 68% for an FMD value below 6.00%. To conclude in the present study we have shown that ocular involvement in Sar patients is associated with impaired endothelial function and increased arterial stiffness. These results strengthen the vascular theory which considers uveitis a consequence of vascular dysfunction in Sar patients and reveals a possible clinical importance of the use of endothelial function tests. PMID:25937082

  5. Functional preservation of vascular smooth muscle tissue

    NASA Technical Reports Server (NTRS)

    Alexander, W. C.; Hutchins, P. M.; Kimzey, S. L.

    1973-01-01

    The ionic and cellular feedback relationships operating to effect the vascular decompensatory modifications were examined to reveal procedures for implementing protective measures guarding against vascular collapse when returning from a weightless environment to that of the earth's gravity. The surgical procedures for preparing the rat cremaster, and the fixation methods are described. Abstracts of publications resulting from this research are included.

  6. Endothelial Outgrowth Cells: Function and Performance in Vascular Grafts

    PubMed Central

    Glynn, Jeremy J.

    2014-01-01

    The clinical need for vascular grafts continues to grow. Tissue engineering strategies have been employed to develop vascular grafts for patients lacking sufficient autologous vessels for grafting. Restoring a functional endothelium on the graft lumen has been shown to greatly improve the long-term patency of small-diameter grafts. However, obtaining an autologous source of endothelial cells for in vitro endothelialization is invasive and often not a viable option. Endothelial outgrowth cells (EOCs), derived from circulating progenitor cells in peripheral blood, provide an alternative cell source for engineering an autologous endothelium. This review aims at highlighting the role of EOCs in the regulation of processes that are central to vascular graft performance. To characterize EOC performance in vascular grafts, this review identifies the characteristics of EOCs, defines functional performance criteria for EOCs in vascular grafts, and summarizes the existing work in developing vascular grafts with EOCs. PMID:24004404

  7. Melamine Impairs Renal and Vascular Function in Rats.

    PubMed

    Tian, Xiao Yu; Wong, Wing Tak; Lau, Chi Wai; Wang, Yi-Xiang; Cheang, Wai San; Liu, Jian; Lu, Ye; Huang, Huihui; Xia, Yin; Chen, Zhen Yu; Mok, Chuen-Shing; Lau, Chau-Ming; Huang, Yu

    2016-01-01

    Melamine incident, linked to nephrotoxicity and kidney stone in infants previously exposed to melamine-contaminated milk products, was unprecedentedly grave in China in 2008 as little was known about the mechanistic process leading to renal dysfunction in affected children. This study investigates whether neonatal ingestion of melamine leads to renal and vascular dysfunction in adulthood; and whether ingestion of melamine in pregnant rats leads to renal dysfunction in their offspring. A combination of approaches employed includes functional studies in rat renal arteries, renal blood flow measurement by functional magnetic resonance imaging, assay for pro-inflammatory and fibrotic biomarkers, immunohistochemistry, and detection of plasma and renal melamine. We provide mechanistic evidence showing for the first time that melamine reduces renal blood flow and impairs renal and vascular function associated with overexpression of inflammatory markers, transforming growth factor-β1, bone morphogenic protein 4 and cyclooxygenase-2 in kidney and renal vasculature. Melamine also induces renal inflammation and fibrosis. More importantly, melamine causes nephropathies in offsprings from pregnant rat exposed to melamine during pregnancy, as well as in neonatal rat exposed to melamine afterbirth, thus supporting the clinical observations of kidney stone and acute renal failure in infants consuming melamine-contaminated milk products. PMID:27324576

  8. Melamine Impairs Renal and Vascular Function in Rats

    PubMed Central

    Tian, Xiao Yu; Wong, Wing Tak; Lau, Chi Wai; Wang, Yi-Xiang; Cheang, Wai San; Liu, Jian; Lu, Ye; Huang, Huihui; Xia, Yin; Chen, Zhen Yu; Mok, Chuen-Shing; Lau, Chau-Ming; Huang, Yu

    2016-01-01

    Melamine incident, linked to nephrotoxicity and kidney stone in infants previously exposed to melamine-contaminated milk products, was unprecedentedly grave in China in 2008 as little was known about the mechanistic process leading to renal dysfunction in affected children. This study investigates whether neonatal ingestion of melamine leads to renal and vascular dysfunction in adulthood; and whether ingestion of melamine in pregnant rats leads to renal dysfunction in their offspring. A combination of approaches employed includes functional studies in rat renal arteries, renal blood flow measurement by functional magnetic resonance imaging, assay for pro-inflammatory and fibrotic biomarkers, immunohistochemistry, and detection of plasma and renal melamine. We provide mechanistic evidence showing for the first time that melamine reduces renal blood flow and impairs renal and vascular function associated with overexpression of inflammatory markers, transforming growth factor-β1, bone morphogenic protein 4 and cyclooxygenase-2 in kidney and renal vasculature. Melamine also induces renal inflammation and fibrosis. More importantly, melamine causes nephropathies in offsprings from pregnant rat exposed to melamine during pregnancy, as well as in neonatal rat exposed to melamine afterbirth, thus supporting the clinical observations of kidney stone and acute renal failure in infants consuming melamine-contaminated milk products. PMID:27324576

  9. PDMS content affects in vitro hemocompatibility of synthetic vascular grafts.

    PubMed

    Spiller, Dario; Losi, Paola; Briganti, Enrica; Sbrana, Silverio; Kull, Silvia; Martinelli, Ilaria; Soldani, Giorgio

    2007-06-01

    An unsolved problem when employing small-diameter vascular grafts for aorto-coronary by-pass and peripheral reconstruction is the early thrombotic occlusion. The PEtU-PDMS is a new elastomeric material, composed of poly(ether)urethane and polydimethylsiloxane, synthesized to realize grafts with improved hemocompatibility characteristics. In order to investigate the effect of PDMS content on hemocompatibility, three different percentages of PDMS containing grafts (10, 25 and 40) were evaluated. Grafts realized with Estane 5714-F1 and silicone medical grade tubes were used as references. The hemocompatibility was investigated by an in vitro circuit in which human anticoagulated blood was circulated into grafts by a peristaltic pump modified to obtain a passive flow. For each experiment, 40 cm length graft was closed into a circular loop and put in rotation for 2 h at 37 degrees C. At the end of the experiments different parameters regarding platelet adhesion and activation were evaluated: circulating platelets count, beta-thromboglobulin release, platelet CD62P expression and amount of monocyte-platelet conjugates. PEtU-PDMS grafts with 25 and 40% of PDMS induced the lowest platelet adhesion, plasma level of beta-TG and amount of monocyte-platelet conjugates. No significative variations were observed in CD62P expression. In conclusion, PDMS content significatively affects blood-graft surface interaction, in fact higher PDMS percentage containing grafts showed the best in vitro hemocompatibility. PMID:17268875

  10. Vascular precursors: origin, regulation and function

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this miniseries, we discuss the phenotype, origin, and specialized microenvironment (niche) of distinct populations of stem and progenitor cells that exhibit vascular potential. Their usefulness and effectiveness for clinical therapies are also described. We have learned a great deal about post...

  11. 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.

  12. Effects of estradiol on uterine perfusion in anesthetized cyclic mares affected with uterine vascular elastosis.

    PubMed

    Esteller-Vico, A; Liu, I K M; Vaughan, B; Steffey, E P; Brosnan, R J

    2016-01-01

    Uterine vascular elastosis in mares is characterized by degeneration of uterine vasculature through thickening of the elastin layers. Factors commonly associated with this degeneration include age, parity, and chronic uterine endometritis. Affected mares have also been shown to exhibit decreases in uterine blood flow and perfusion of the uterus. Due to the increased thickness of the elastin layers, we hypothesize that vasodilatation of the uterine vasculature is also impaired. To test the functionality of these vessels, we evaluated the vasodilatory effects of estradiol on the uterine vascular bed in mares with normal vasculature and mares with severe elastosis. Both groups were tested in estrus and diestrus. Fluorescent microspheres were used to determine basal blood perfusion, followed by the intravenous administration of 1.0 μg/kg of 17β-estradiol. After 90 min, perfusion was measured once again to determine the vascular response to estradiol. Control mares in estrus displayed a significant increase in total uterine blood flow after the administration of estradiol when compared to baseline levels. No other group had a significant increase in total blood flow and perfusion after estradiol administration. The administration of estradiol in control mares induced regional increases in perfusion in the uterine horns and uterine body during estrus and only in the uterine horns during diestrus. Mares affected by elastosis exhibited no regional differences in perfusion levels post-estradiol administration. The difference in the vasodilatory response induced by estradiol between reproductively healthy mares and mares affected with elastosis indicates that the functionality of the affected vessels is compromised. PMID:26642749

  13. Host tree phenology affects vascular epiphytes at the physiological, demographic and community level

    PubMed Central

    Einzmann, Helena J. R.; Beyschlag, Joachim; Hofhansl, Florian; Wanek, Wolfgang; Zotz, Gerhard

    2015-01-01

    The processes that govern diverse tropical plant communities have rarely been studied in life forms other than trees. Structurally dependent vascular epiphytes, a major part of tropical biodiversity, grow in a three-dimensional matrix defined by their hosts, but trees differ in their architecture, bark structure/chemistry and leaf phenology. We hypothesized that the resulting seasonal differences in microclimatic conditions in evergreen vs. deciduous trees would affect epiphytes at different levels, from organ physiology to community structure. We studied the influence of tree leaf phenology on vascular epiphytes on the Island of Barro Colorado, Panama. Five tree species were selected, which were deciduous, semi-deciduous or evergreen. The crowns of drought-deciduous trees, characterized by sunnier and drier microclimates, hosted fewer individuals and less diverse epiphyte assemblages. Differences were also observed at a functional level, e.g. epiphyte assemblages in deciduous trees had larger proportions of Crassulacean acid metabolism species and individuals. At the population level a drier microclimate was associated with lower individual growth and survival in a xerophytic fern. Some species also showed, as expected, lower specific leaf area and higher δ13C values when growing in deciduous trees compared with evergreen trees. As hypothesized, host tree leaf phenology influences vascular epiphytes at different levels. Our results suggest a cascading effect of tree composition and associated differences in tree phenology on the diversity and functioning of epiphyte communities in tropical lowland forests. PMID:25392188

  14. Development affects in vitro vascular tone and calcium sensitivity in ovine cerebral arteries

    PubMed Central

    Geary, Greg G; Osol, George J; Longo, Lawrence D

    2004-01-01

    We have shown recently that development from neonatal to adult life affects cerebrovascular tone of mouse cerebral arteries through endothelium-derived vasodilatory mechanisms. The current study tested the hypothesis that development from fetal to adult life affects cerebral artery vascular smooth muscle (VSM) [Ca2+]i sensitivity and tone through a mechanism partially dependent upon endothelium-dependent signalling. In pressurized resistance sized cerebral arteries (∼150 μm) from preterm (95 ± 2 days gestation (95 d)) and near-term (140 ± 2 days gestation (140 d)) fetuses, and non-pregnant adults, we measured vascular diameter (μm) and [Ca2+]i (nm) as a function of intravascular pressure. We repeated these studies in the presence of inhibition of nitric oxide synthase (NOS; with l-NAME), cyclo-oxygenase (COX; with indomethacin) and endothelium removal (E–). Cerebrovasculature tone (E+) was greater in arteries from 95 d fetuses and adults compared to 140 d sheep. Ca2+ sensitivity was similar in 95 d fetuses and adults, but much lower in 140 d fetuses. Removal of endothelium resulted in a reduction in lumen diameter as a function of pressure (greater tone) in all treatment groups. [Ca2+]i sensitivity differences among groups were magnified after E–. NOS inhibition decreased diameter as a function of pressure in each age group, with a significant increase in [Ca2+]i to pressure ratio only in the 140 d fetuses. Indomethacin increased tone and increased [Ca2+]i in the 140 d fetuses, but not the other age groups. Development from near-term to adulthood uncovered an interaction between NOS- and COX-sensitive substances that functioned to modulate artery diameter but not [Ca2+]i. This study suggests that development is associated with significant alterations in cerebral vascular smooth muscle (VSM), endothelium, NOS and COX responses to intravascular pressure. We speculate that these changes have important implications in the regulation of cerebral blood flow in

  15. The Adventitia: Essential Regulator of Vascular Wall Structure and Function

    PubMed Central

    Stenmark, Kurt R.; Yeager, Michael E.; El Kasmi, Karim C.; Nozik-Grayck, Eva; Gerasimovskaya, Evgenia V.; Li, Min; Riddle, Suzette R.; Frid, Maria G.

    2013-01-01

    The vascular adventitia acts as a biological processing center for the retrieval, integration, storage, and release of key regulators of vessel wall function. It is the most complex compartment of the vessel wall and is comprised of a variety of cells including fibroblasts, immunomodulatory cells (dendritic and macrophages), progenitor cells, vasa vasorum endothelial cells and pericytes, and adrenergic nerves. In response to vascular stress or injury, resident adventitial cells are often the first to be activated and re-programmed to then influence tone and structure of the vessel wall, to initiate and perpetuate chronic vascular inflammation, and to act to stimulate expansion of the vasa vasorum, which can act as a conduit for continued inflammatory and progenitor cell delivery to the vessel wall. This review presents the current evidence demonstrating that the adventitia acts as a key regulator of vascular wall function and structure from the “outside-in.” PMID:23216413

  16. The adventitia: essential regulator of vascular wall structure and function.

    PubMed

    Stenmark, Kurt R; Yeager, Michael E; El Kasmi, Karim C; Nozik-Grayck, Eva; Gerasimovskaya, Evgenia V; Li, Min; Riddle, Suzette R; Frid, Maria G

    2013-01-01

    The vascular adventitia acts as a biological processing center for the retrieval, integration, storage, and release of key regulators of vessel wall function. It is the most complex compartment of the vessel wall and is composed of a variety of cells, including fibroblasts, immunomodulatory cells (dendritic cells and macrophages), progenitor cells, vasa vasorum endothelial cells and pericytes, and adrenergic nerves. In response to vascular stress or injury, resident adventitial cells are often the first to be activated and reprogrammed to influence the tone and structure of the vessel wall; to initiate and perpetuate chronic vascular inflammation; and to stimulate expansion of the vasa vasorum, which can act as a conduit for continued inflammatory and progenitor cell delivery to the vessel wall. This review presents the current evidence demonstrating that the adventitia acts as a key regulator of vascular wall function and structure from the outside in. PMID:23216413

  17. Macrophages in Vascular Inflammation: Origins and Functions.

    PubMed

    Decano, Julius L; Mattson, Peter C; Aikawa, Masanori

    2016-06-01

    Macrophages influence various processes of cardiovascular inflammation. Whether they are of embryonic or post-natal hematopoietic origin, their balance in differential activation may direct the course of inflammation. Accelerated macrophage activation and accumulation through a pro-inflammatory signaling pathway may result in extensive tissue damage, adverse repair, and worsened clinical outcomes. Attenuation of such a mechanism and/or promotion of the anti-inflammatory macrophage activation may lead to early resolution of inflammation. Elucidating multiple novel mechanisms of monocyte and macrophage activation leads to a better understanding of their roles in vascular inflammation. In turn, this begets better therapeutic target identification and biomarker discovery. Combined with increasingly sensitive and specific imaging techniques, we continue to push back early detection and monitoring to provide us with a greater window for disease modification. The potential success of cytokine-targeted therapy will be solid proof of the inflammatory hypothesis of atherothrombosis. PMID:27125207

  18. Systemic vascular function is associated with muscular power in adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Age-associated loss of muscular strength and muscular power are critical determinants of loss of physical function and progression to disability in older adults. In this study, we examined the association of systemic vascular function and measures of muscle strength and power in older adults. Measu...

  19. Functional Human Vascular Network Generated in Photocrosslinkable Gelatin Methacrylate Hydrogels.

    PubMed

    Chen, Ying-Chieh; Lin, Ruei-Zeng; Qi, Hao; Yang, Yunzhi; Bae, Hojae; Melero-Martin, Juan M; Khademhosseini, Ali

    2012-05-23

    The generation of functional, 3D vascular networks is a fundamental prerequisite for the development of many future tissue engineering-based therapies. Current approaches in vascular network bioengineering are largely carried out using natural hydrogels as embedding scaffolds. However, most natural hydrogels present a poor mechanical stability and a suboptimal durability, which are critical limitations that hamper their widespread applicability. The search for improved hydrogels has become a priority in tissue engineering research. Here, the suitability of a photopolymerizable gelatin methacrylate (GelMA) hydrogel to support human progenitor cell-based formation of vascular networks is demonstrated. Using GelMA as the embedding scaffold, it is shown that 3D constructs containing human blood-derived endothelial colony-forming cells (ECFCs) and bone marrow-derived mesenchymal stem cells (MSCs) generate extensive capillary-like networks in vitro. These vascular structures contain distinct lumens that are formed by the fusion of ECFC intracellular vacuoles in a process of vascular morphogenesis. The process of vascular network formation is dependent on the presence of MSCs, which differentiate into perivascular cells occupying abluminal positions within the network. Importantly, it is shown that implantation of cell-laden GelMA hydrogels into immunodeficient mice results in a rapid formation of functional anastomoses between the bioengineered human vascular network and the mouse vasculature. Furthermore, it is shown that the degree of methacrylation of the GelMA can be used to modulate the cellular behavior and the extent of vascular network formation both in vitro and in vivo. These data suggest that GelMA hydrogels can be used for biomedical applications that require the formation of microvascular networks, including the development of complex engineered tissues. PMID:22907987

  20. Functional Human Vascular Network Generated in Photocrosslinkable Gelatin Methacrylate Hydrogels

    PubMed Central

    Chen, Ying-Chieh; Lin, Ruei-Zeng; Qi, Hao; Yang, Yunzhi; Bae, Hojae

    2012-01-01

    The generation of functional, 3D vascular networks is a fundamental prerequisite for the development of many future tissue engineering-based therapies. Current approaches in vascular network bioengineering are largely carried out using natural hydrogels as embedding scaffolds. However, most natural hydrogels present a poor mechanical stability and a suboptimal durability, which are critical limitations that hamper their widespread applicability. The search for improved hydrogels has become a priority in tissue engineering research. Here, the suitability of a photopolymerizable gelatin methacrylate (GelMA) hydrogel to support human progenitor cell-based formation of vascular networks is demonstrated. Using GelMA as the embedding scaffold, it is shown that 3D constructs containing human blood-derived endothelial colony-forming cells (ECFCs) and bone marrow-derived mesenchymal stem cells (MSCs) generate extensive capillary-like networks in vitro. These vascular structures contain distinct lumens that are formed by the fusion of ECFC intracellular vacuoles in a process of vascular morphogenesis. The process of vascular network formation is dependent on the presence of MSCs, which differentiate into perivascular cells occupying abluminal positions within the network. Importantly, it is shown that implantation of cell-laden GelMA hydrogels into immunodeficient mice results in a rapid formation of functional anastomoses between the bioengineered human vascular network and the mouse vasculature. Furthermore, it is shown that the degree of methacrylation of the GelMA can be used to modulate the cellular behavior and the extent of vascular network formation both in vitro and in vivo. These data suggest that GelMA hydrogels can be used for biomedical applications that require the formation of microvascular networks, including the development of complex engineered tissues. PMID:22907987

  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. Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone.

    PubMed

    Busija, David W; Rutkai, Ibolya; Dutta, Somhrita; Katakam, Prasad V

    2016-01-01

    Mitochondria not only produce energy in the form of ATP to support the activities of cells comprising the neurovascular unit, but mitochondrial events, such as depolarization and/or ROS release, also initiate signaling events which protect the endothelium and neurons against lethal stresses via pre-/postconditioning as well as promote changes in cerebral vascular tone. Mitochondrial depolarization in vascular smooth muscle (VSM), via pharmacological activation of the ATP-dependent potassium channels on the inner mitochondrial membrane (mitoKATP channels), leads to vasorelaxation through generation of calcium sparks by the sarcoplasmic reticulum and subsequent downstream signaling mechanisms. Increased release of ROS by mitochondria has similar effects. Relaxation of VSM can also be indirectly achieved via actions of nitric oxide (NO) and other vasoactive agents produced by endothelium, perivascular and parenchymal nerves, and astroglia following mitochondrial activation. Additionally, NO production following mitochondrial activation is involved in neuronal preconditioning. Cerebral arteries from female rats have greater mitochondrial mass and respiration and enhanced cerebral arterial dilation to mitochondrial activators. Preexisting chronic conditions such as insulin resistance and/or diabetes impair mitoKATP channel relaxation of cerebral arteries and preconditioning. Surprisingly, mitoKATP channel function after transient ischemia appears to be retained in the endothelium of large cerebral arteries despite generalized cerebral vascular dysfunction. Thus, mitochondrial mechanisms may represent the elusive signaling link between metabolic rate and blood flow as well as mediators of vascular change according to physiological status. Mitochondrial mechanisms are an important, but underutilized target for improving vascular function and decreasing brain injury in stroke patients. © 2016 American Physiological Society. Compr Physiol 6:1529-1548, 2016. PMID:27347901

  3. Vascular function in diabetic individuals in association with particulate matter

    EPA Science Inventory

    Rationale: Exposure to ambient air pollution has been shown to be associated with cardiovascular effects, especially in people with chronic diseases such as diabetes. The purpose of this study was to analyze the short-term effects of air pollution on vascular function in two pane...

  4. 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. PMID:26275663

  5. Functional imaging of tumor vascular network in small animal models

    NASA Astrophysics Data System (ADS)

    Kalchenko, Vyacheslav; Madar-Balakirski, Noa; Kuznetsov, Yuri; Meglinski, Igor; Harmelin, Alon

    2011-07-01

    In current report we present synchronized in vivo imaging of tumor vascular network and tumor microenvironment obtained by combined use of Dynamic Light Scattering Imaging, Spectrally Enhanced Microscopy, and Fluorescence Intravital Microscopy. Dynamic Light Scattering Imaging is used for functional imaging of the vascular network and blood microcirculation. Spectrally Enhanced Microscopy provides information regarding blood vessel topography. Fluorescence Intravital Microscopy is used for imaging of tumor microvasculature and tumor microenvironment. These well known modalities have been comprehensively validated in the past and are widely used in various bio-medical applications. As shown here, their combined application has great potential for studies of vascular biology. This multi-modal non-invasive diagnostic technique expands our current capacity to investigate blood microcirculation and tumor angiogenesis in vivo, thereby contributing to the development of cancer research and treatment.

  6. Vascular Tree Reconstruction by Minimizing A Physiological Functional Cost

    PubMed Central

    Jiang, Yifeng; Zhuang, Zhenwu; Sinusas, Albert J.; Papademetris, Xenophon

    2011-01-01

    The reconstruction of complete vascular trees from medical images has many important applications. Although vessel detection has been extensively investigated, little work has been done on how connect the results to reconstruct the full trees. In this paper, we propose a novel theoretical framework for automatic vessel connection, where the automation is achieved by leveraging constraints from the physiological properties of the vascular trees. In particular, a physiological functional cost for the whole vascular tree is derived and an efficient algorithm is developed to minimize it. The method is generic and can be applied to different vessel detection/segmentation results, e.g. the classic rigid detection method as adopted in this paper. We demonstrate the effectiveness of this method on both 2D and 3D data. PMID:21755061

  7. A Novel Protective Function of 5-Methoxytryptophan in Vascular Injury

    PubMed Central

    Ho, Yen-Chun; Wu, Meng-Ling; Su, Chen-Hsuan; Chen, Chung-Huang; Ho, Hua-Hui; Lee, Guan-Lin; Lin, Wei-Shiang; Lin, Wen-Yu; Hsu, Yu-Juei; Kuo, Cheng-Chin; Wu, Kenneth K.; Yet, Shaw-Fang

    2016-01-01

    5-Methoxytryptophan (5-MTP), a 5-methoxyindole metabolite of tryptophan metabolism, was recently shown to suppress inflammatory mediator-induced cancer cell proliferation and migration. However, the role of 5-MTP in vascular disease is unknown. In this study, we investigated whether 5-MTP protects against vascular remodeling following arterial injury. Measurements of serum 5-MTP levels in healthy subjects and patients with coronary artery disease (CAD) showed that serum 5-MTP concentrations were inversely correlated with CAD. To test the role of 5-MTP in occlusive vascular disease, we subjected mice to a carotid artery ligation model of neointima formation and treated mice with vehicle or 5-MTP. Compared with vehicle-treated mice, 5-MTP significantly reduced intimal thickening by 40% 4 weeks after ligation. BrdU incorporation assays revealed that 5-MTP significantly reduced VSMC proliferation both in vivo and in vitro. Furthermore, 5-MTP reduced endothelial loss and detachment, ICAM-1 and VCAM-1 expressions, and inflammatory cell infiltration in the ligated arterial wall, suggesting attenuation of endothelial dysfunction. Signaling pathway analysis indicated that 5-MTP mediated its effects predominantly via suppressing p38 MAPK signaling in endothelial and VSMCs. Our data demonstrate a novel vascular protective function of 5-MTP against arterial injury-induced intimal hyperplasia. 5-MTP might be a therapeutic target for preventing and/or treating vascular remodeling. PMID:27146795

  8. A Novel Protective Function of 5-Methoxytryptophan in Vascular Injury.

    PubMed

    Ho, Yen-Chun; Wu, Meng-Ling; Su, Chen-Hsuan; Chen, Chung-Huang; Ho, Hua-Hui; Lee, Guan-Lin; Lin, Wei-Shiang; Lin, Wen-Yu; Hsu, Yu-Juei; Kuo, Cheng-Chin; Wu, Kenneth K; Yet, Shaw-Fang

    2016-01-01

    5-Methoxytryptophan (5-MTP), a 5-methoxyindole metabolite of tryptophan metabolism, was recently shown to suppress inflammatory mediator-induced cancer cell proliferation and migration. However, the role of 5-MTP in vascular disease is unknown. In this study, we investigated whether 5-MTP protects against vascular remodeling following arterial injury. Measurements of serum 5-MTP levels in healthy subjects and patients with coronary artery disease (CAD) showed that serum 5-MTP concentrations were inversely correlated with CAD. To test the role of 5-MTP in occlusive vascular disease, we subjected mice to a carotid artery ligation model of neointima formation and treated mice with vehicle or 5-MTP. Compared with vehicle-treated mice, 5-MTP significantly reduced intimal thickening by 40% 4 weeks after ligation. BrdU incorporation assays revealed that 5-MTP significantly reduced VSMC proliferation both in vivo and in vitro. Furthermore, 5-MTP reduced endothelial loss and detachment, ICAM-1 and VCAM-1 expressions, and inflammatory cell infiltration in the ligated arterial wall, suggesting attenuation of endothelial dysfunction. Signaling pathway analysis indicated that 5-MTP mediated its effects predominantly via suppressing p38 MAPK signaling in endothelial and VSMCs. Our data demonstrate a novel vascular protective function of 5-MTP against arterial injury-induced intimal hyperplasia. 5-MTP might be a therapeutic target for preventing and/or treating vascular remodeling. PMID:27146795

  9. The plant vascular system: evolution, development and functions.

    PubMed

    Lucas, William J; Groover, Andrew; Lichtenberger, Raffael; Furuta, Kaori; Yadav, Shri-Ram; Helariutta, Ykä; He, Xin-Qiang; Fukuda, Hiroo; Kang, Julie; Brady, Siobhan M; Patrick, John W; Sperry, John; Yoshida, Akiko; López-Millán, Ana-Flor; Grusak, Michael A; Kachroo, Pradeep

    2013-04-01

    The emergence of the tracheophyte-based vascular system of land plants had major impacts on the evolution of terrestrial biology, in general, through its role in facilitating the development of plants with increased stature, photosynthetic output, and ability to colonize a greatly expanded range of environmental habitats. Recently, considerable progress has been made in terms of our understanding of the developmental and physiological programs involved in the formation and function of the plant vascular system. In this review, we first examine the evolutionary events that gave rise to the tracheophytes, followed by analysis of the genetic and hormonal networks that cooperate to orchestrate vascular development in the gymnosperms and angiosperms. The two essential functions performed by the vascular system, namely the delivery of resources (water, essential mineral nutrients, sugars and amino acids) to the various plant organs and provision of mechanical support are next discussed. Here, we focus on critical questions relating to structural and physiological properties controlling the delivery of material through the xylem and phloem. Recent discoveries into the role of the vascular system as an effective long-distance communication system are next assessed in terms of the coordination of developmental, physiological and defense-related processes, at the whole-plant level. A concerted effort has been made to integrate all these new findings into a comprehensive picture of the state-of-the-art in the area of plant vascular biology. Finally, areas important for future research are highlighted in terms of their likely contribution both to basic knowledge and applications to primary industry. PMID:23462277

  10. BP and Vascular Function Following Space Flight

    NASA Technical Reports Server (NTRS)

    Hatton, Daniel C.; Yue, Qi; Chapman, Justin; Xue, Hong; Dierickx, Jacqueline; Roullet, Chantal; Roullet, Jean-Baptiste; Phanouvong, Thongchanh; Watanabe, Mitsuaki; Otsuka, Keiichi; McCarron, David A.

    1997-01-01

    Blood pressure and mesenteric resistance artery function were assessed in 9-week-old spontaneously hypertensive rats following an 18 day shuttle flight on STS-80. Blood pressure was measured twice, first in conscious animals using a tail-cuff method and then while the animals were anesthetized with 2% halothane in O2. Isolated mesenteric resistance artery responses to cumulative additions of norepinephrine, acetylcholine, sodium nitroprusside, and calcium were measured within 17 hours of landing using wire myography. Blood pressure was slightly reduced in conscious animals following flight (p=0.056) but was significantly elevated (p less than.001) above vivarium control group values in anesthetized animals. Maximal contraction of mesenteric arteries to norepinephrine was attenuated in the flight animals (p less than.001)aswasrelaxationtoacetylcholine(p less than .001)andcalcium(p less than .05). There was no difference between flight and control animals in the vessel response to sodium nitroprusside (p greater than .05). The results suggest that there may have been an increase in synthesis and release of nitric oxide in the flight animals.

  11. Maternal Hyperleptinemia Is Associated with Male Offspring’s Altered Vascular Function and Structure in Mice

    PubMed Central

    Pollock, Kelly E.; Talton, Omonseigho O.; Foote, Christopher A.; Reyes-Aldasoro, Constantino C.; Wu, Ho-Hsiang; Ji, Tieming; Martinez-Lemus, Luis A.; Schulz, Laura C.

    2016-01-01

    Children of mothers with gestational diabetes have greater risk of developing hypertension but little is known about the mechanisms by which this occurs. The objective of this study was to test the hypothesis that high maternal concentrations of leptin during pregnancy, which are present in mothers with gestational diabetes and/or obesity, alter blood pressure, vascular structure and vascular function in offspring. Wildtype (WT) offspring of hyperleptinemic, normoglycemic, Leprdb/+ dams were compared to genotype matched offspring of WT-control dams. Vascular function was assessed in male offspring at 6, and at 31 weeks of age after half the offspring had been fed a high fat, high sucrose diet (HFD) for 6 weeks. Blood pressure was increased by HFD but not affected by maternal hyperleptinemia. On a standard diet, offspring of hyperleptinemic dams had outwardly remodeled mesenteric arteries and an enhanced vasodilatory response to insulin. In offspring of WT but not Leprdb/+ dams, HFD induced vessel hypertrophy and enhanced vasodilatory responses to acetylcholine, while HFD reduced insulin responsiveness in offspring of hyperleptinemic dams. Offspring of hyperleptinemic dams had stiffer arteries regardless of diet. Therefore, while maternal hyperleptinemia was largely beneficial to offspring vascular health under a standard diet, it had detrimental effects in offspring fed HFD. These results suggest that circulating maternal leptin concentrations may interact with other factors in the pre- and post -natal environments to contribute to altered vascular function in offspring of diabetic pregnancies. PMID:27187080

  12. Differential and synergistic effects of mechanical stimulation and growth factor presentation on vascular wall function

    PubMed Central

    Liang, Mao-Shih; Koobatian, Maxwell T.; Lei, Pedro; Swartz, Daniel D.; Andreadis, Stelios T.

    2013-01-01

    We investigated the hypothesis that immobilizing TGF-β1 within fibrin hydrogels may act in synergy with cyclic mechanical stimulation to enhance the properties of vascular grafts. To this end, we engineered a fusion TGF-β1 protein that can covalently anchor to fibrin during polymerization upon the action of factor XIII. We also developed a 24-well based bioreactor in which vascular constructs can be mechanically stimulated by distending the silastic mandrel in the middle of each well. TGF-β1 was either conjugated to fibrin or supplied in the culture medium and the fibrin based constructs were cultured statically for a week followed by cyclic distention for another week. The tissues were examined for myogenic differentiation, vascular reactivity, mechanical properties and ECM content. Our results showed that some aspects of vascular function were differentially affected by growth factor presentation vs. pulsatile force application, while others were synergistically enhanced by both. Overall, this two-prong biomimetic approach improved ECM secretion, vascular reactivity and mechanical properties of vascular constructs. These findings may be applied in other tissue engineering applications such as cartilage, tendon or cardiac regeneration where growth factors TGF-β1 and mechano-stimulation play critical roles. PMID:23810080

  13. Enzymatic regulation of functional vascular networks using gelatin hydrogels

    PubMed Central

    Chuang, Chia-Hui; Lin, Ruei-Zeng; Tien, Han-Wen; Chu, Ya-Chun; Li, Yen-Cheng; Melero-Martin, Juan M.; Chen, Ying-Chieh

    2015-01-01

    To manufacture tissue engineering-based functional tissues, scaffold materials that can be sufficiently vascularized to mimic the functionality and complexity of native tissues are needed. Currently, vascular network bioengineering is largely carried out using natural hydrogels as embedding scaffolds, but most natural hydrogels have poor mechanical stability and durability, factors that critically limit their widespread use. In this study, we examined the suitability of gelatin-phenolic hydroxyl (gelatin-Ph) hydrogels that can be enzymatically crosslinked, allowing tuning of the storage modulus and the proteolytic degradation rate, for use as injectable hydrogels to support the human progenitor cell-based formation of a stable and mature vascular network. Porcine gelatin-Ph hydrogels were found to be cytocompatible with human blood-derived endothelial colony-forming cells and white adipose tissue-derived mesenchymal stem cells, resulting in >87% viability, and cell proliferation and spreading could be modulated by using hydrogels with different proteolytic degradability and stiffness. In addition, gelatin was extracted from mouse dermis and murine gelatin-Ph hydrogels were prepared. Importantly, implantation of human cell-laden porcine or murine gelatin-Ph hydrogels into immunodeficient mice resulted in the rapid formation of functional anastomoses between the bioengineered human vascular network and the mouse vasculature. Furthermore, the degree of enzymatic crosslinking of the gelatin-Ph hydrogels could be used to modulate cell behavior and the extent of vascular network formation in vivo. Our report details a technique for the synthesis of gelatin-Ph hydrogels from allogeneic or xenogeneic dermal skin and suggests that these hydrogels can be used for biomedical applications that require the formation of microvascular networks, including the development of complex engineered tissues. PMID:25749296

  14. Preeclampsia and Vascular Function: A Window to Future Cardiovascular Disease Risk.

    PubMed

    Enkhmaa, Davaasambuu; Wall, Danielle; Mehta, Puja K; Stuart, Jennifer J; Rich-Edwards, Janet Wilson; Merz, C Noel Bairey; Shufelt, Chrisandra

    2016-03-01

    Preeclampsia affects ∼3%-7% of all pregnancies and is the third leading cause of maternal mortality globally. Growing evidence indicates that preeclampsia results from vascular dysfunction, which also increases the risk for future cardiovascular events. Until recently, preeclampsia was considered a disorder limited to pregnancy, which fully resolved with the delivery of the placenta; however, it is now clear that women with a history of preeclampsia have approximately double the risk of future cardiovascular events compared to women with normotensive pregnancies. The aims of this review were to describe the hemodynamic and vascular changes that occur in normal and preeclamptic pregnancies, to review noninvasive methods to test vascular function, and to discuss the associated increased cardiovascular disease risk related to preeclampsia. PMID:26779584

  15. Gender Differences in Bed Rest: Preliminary Analysis of Vascular Function

    NASA Technical Reports Server (NTRS)

    Platts, Steven H.; Stenger, Michael B.; Martin, David S.; Freeman-Perez, Sondra A.; Phillips, Tiffany; Ribeiro, L. Christine

    2008-01-01

    Orthostatic intolerance is a recognized consequence of spaceflight. Numerous studies have shown that women are more susceptible to orthostatic intolerance following spaceflight as well as bed rest, the most commonly used ground-based analog for spaceflight. One of the possible mechanisms proposed to account for this is a difference in vascular responsiveness between genders. We hypothesized that women and men would have differing vascular responses to 90 days of 6-degree head down tilt bed rest. Additionally, we hypothesized that vessels in the upper and lower body would respond differently, as has been shown in the animal literature. Thirteen subjects were placed in bedrest for 90 days (8 men, 5 women) at the Flight Analogs Unit, UTMB. Direct arterial and venous measurements were made with ultrasound to evaluate changes in vascular structure and function. Arterial function was assessed, in the arm and leg, during a reactive hyperemia protocol and during sublingual nitroglycerin administration to gauge the contributions of endothelial dependent and independent dilator function respectively. Venous function was assessed in dorsal hand and foot veins during the administration of pharmaceuticals to assess constrictor and dilator function. Both gender and day effects are seen in arterial dilator function to reactive hyperemia, but none are seen with nitroglycerin. There are also differences in the wall thickness in the arm vs the leg during bed rest, which return toward pre-bed rest levels by day 90. More subjects are required, especially females as there is not sufficient power to properly analyze venous function. Day 90 data are most underpowered.

  16. Impaired Right Ventricular-Pulmonary Vascular Function in Myeloproliferative Neoplasms

    PubMed Central

    Roach, Emir C.; Park, Margaret M.; Tang, W.H. Wilson; Thomas, James D.; Asosingh, Kewal; Kalaycio, Matt; Erzurum, Serpil C.; Farha, Samar

    2014-01-01

    Background Increased bone marrow hemangioblast numbers, alterations in erythroid/myeloid lineages, increased reticulin, and greater circulating bone marrow progenitor cells are present in patients with pulmonary arterial hypertension (PAH). The data suggest that myeloid progenitors contribute to the pathogenesis of PAH, but there is little data on prevalence of pulmonary vascular disease among different forms of myeloid diseases. We hypothesized that there would be a higher prevalence of pulmonary vascular disease in myeloproliferative neoplasms that have high circulating progenitor cells, such as myelofibrosis and chronic myelogenous leukemia (CML), as compared to those with low circulating progenitors, as in aplastic anemia. Methods Patients with myelofibrosis, CML and aplastic anemia who underwent echocardiographic evaluation of cardiac function in preparation for bone marrow transplantation at the Cleveland Clinic between 1997–2012 were identified using electronic medical records for demographic data, blood cell counts, and pulmonary function tests. All echocardiograms were uniformly analyzed in a blinded fashion by an advanced sonographer and cardiologist for measures of right and left ventricular function and estimation of pulmonary vascular disease. Results Gender and race distribution between disease groups were similar. Myelofibrosis [N=19] and aplastic anemia [N=30] had increased right ventricle (RV) wall thickness compared to CML [N=82] [RV Thickness (cm): aplastic anemia 0.7 ± 0.1, CML 0.5 ± 0.1 and myelofibrosis 0.7 ± 0.1; p = 0.02]. Patients with myelofibrosis had higher levels of estimated RV systolic pressure as compared to the other groups [RVSP (mmHg): aplastic anemia 29.9 ± 1.5, CML 26.2 ± 1.1 and myelofibrosis 36.7 ± 3.7; p < 0.01]. Conclusion The findings suggest an important role for myeloid progenitors in maintenance of pulmonary-vascular health, in which abnormal myeloproliferative progenitors are associated with right ventricle

  17. Complex treatment of trophic affections with vascular patients using monochromatic red light and hyperbaric oxygenation

    NASA Astrophysics Data System (ADS)

    Babkina, Zinaida M.; Vasilyev, Mikhail V.; Zakharov, Vyacheslav P.; Nikolayev, Viktor V.; Babkin, Vasily I.; Samoday, Valery G.; Zon, Boris A.; Pakhomov, Gennady V.; Naskidashvili, Vasily I.; Kumin, Anatoly A.

    1996-11-01

    Monochromatic red light irradiation therapy of trophic skin affections with vascular patients permits to receive positive results with small wounds. A combination of monochromatic red light and hyperbaric oxygenation is most perspective when conducting a complex therapy of trophic wounds not more than 40 mm2 and allows to diminish time of treatment almost two times.

  18. Assessment of vascular function in systemic onset juvenile idiopathic arthritis.

    PubMed

    Sozeri, Betul; Atikan, Basak Yildiz; Ozdemir, Kadriye; Mir, Sevgi

    2016-07-01

    and disease duration (p = 0.003, r = 0.45). Vascular function is impaired in patients with sJIA at a very young age. Vascular dysfunction may be partly attributed to the effects of disease-related characteristics (inflammation, disease activity, and medications). PMID:27075461

  19. Placebo Sleep Affects Cognitive Functioning

    ERIC Educational Resources Information Center

    Draganich, Christina; Erdal, Kristi

    2014-01-01

    The placebo effect is any outcome that is not attributed to a specific treatment but rather to an individual's mindset (Benson & Friedman, 1996). This phenomenon can extend beyond its typical use in pharmaceutical drugs to involve aspects of everyday life, such as the effect of sleep on cognitive functioning. In 2 studies examining whether…

  20. Maternal Copper Deficiency Perpetuates Altered Vascular Function in Sprague-Dawley Rat Offspring

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Little is known about the consequences of maternal Cu (Cu) deficiency on the vascular function of offspring or on perpetuation of vascular effects to a second generation. We examined vascular functional responses in mesenteric arteries from Cu-deficient Sprague-Dawley rat dams and from offspring dir...

  1. The functions of TRPP2 in the vascular system

    PubMed Central

    Du, Juan; Fu, Jie; Xia, Xian-ming; Shen, Bing

    2016-01-01

    TRPP2 (polycystin-2, PC2 or PKD2), encoded by the PKD2 gene, is a non-selective cation channel with a large single channel conductance and high Ca2+ permeability. In cell membrane, TRPP2, along with polycystin-1, TRPV4 and TRPC1, functions as a mechanotransduction channel. In the endoplasmic reticulum, TRPP2 modulates intracellular Ca2+ release associated with IP3 receptors and the ryanodine receptors. Noteworthily, TRPP2 is widely expressed in vascular endothelial and smooth muscle cells of all major vascular beds, and contributes to the regulation of vessel function. The mutation of the PKD2 gene is a major cause of autosomal dominant polycystic kidney disease (ADPKD), which is not only a common genetic disease of the kidney but also a systemic disorder associated with abnormalities in the vasculature; cardiovascular complications are the leading cause of mortality and morbidity in ADPKD patients. This review provides an overview of the current knowledge regarding the TRPP2 protein and its possible role in cardiovascular function and related diseases. PMID:26725733

  2. The functions of TRPP2 in the vascular system.

    PubMed

    Du, Juan; Fu, Jie; Xia, Xian-ming; Shen, Bing

    2016-01-01

    TRPP2 (polycystin-2, PC2 or PKD2), encoded by the PKD2 gene, is a non-selective cation channel with a large single channel conductance and high Ca(2+) permeability. In cell membrane, TRPP2, along with polycystin-1, TRPV4 and TRPC1, functions as a mechanotransduction channel. In the endoplasmic reticulum, TRPP2 modulates intracellular Ca(2+) release associated with IP3 receptors and the ryanodine receptors. Noteworthily, TRPP2 is widely expressed in vascular endothelial and smooth muscle cells of all major vascular beds, and contributes to the regulation of vessel function. The mutation of the PKD2 gene is a major cause of autosomal dominant polycystic kidney disease (ADPKD), which is not only a common genetic disease of the kidney but also a systemic disorder associated with abnormalities in the vasculature; cardiovascular complications are the leading cause of mortality and morbidity in ADPKD patients. This review provides an overview of the current knowledge regarding the TRPP2 protein and its possible role in cardiovascular function and related diseases. PMID:26725733

  3. Vascular function and brain-derived neurotrophic factor: The functional capacity factor.

    PubMed

    Alomari, Mahmoud A; Khabour, Omar F; Maikano, Abubakar; Alawneh, Khaldoon

    2015-12-01

    Brain-derived neurotrophic factor (BDNF) is essential for neurocognitive function. This study aims at establishing a plausible link between level of serum BDNF, functional capacity (FC), and vascular function in 181 young (age 25.5±9.1 years old), apparently healthy adults. Fasting blood samples were drawn from participants' antecubital veins into plain glass tubes while they were in a sitting position to evaluate serum BDNF using enzyme-linked immunosorbent assay (ELISA). Mercury-in-silastic strain-gauge plethysmography was used to determine arterial function indices, blood flow and vascular resistance at rest and following 5 minutes of arterial ischemia. The 6-minute walk distance (6MWD) test was used to determine FC, according to the American Thoracic Society Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories guidelines. It was conducted in an enclosed corridor on a flat surface with a circular track 33 meters long. The walking course was demarcated with bright colored cones. The 6MWD correlated with BDNF (r=0.3, p=0.000), as well as with forearm blood inflow (r=0.5, p=0.000) and vascular resistance (r = -0.4, p=0.000). Subsequent comparison showed that BDNF and blood inflow were greater (p<0.05) while vascular resistance was less (p<0.05) in participants who achieved a longer 6MWD. Similarly, BDNF correlated with forearm blood inflow (r=0.4, p=0.000) and vascular resistance (r = -0.4, p=0.000). Subsequent comparison showed improved vascular function (p<0.05) in the participants with greater BDNF. In conclusion, these findings might suggest that improved vascular function in individuals with greater FC is mediated, at least partially, by an enhanced serum BDNF level. PMID:26285588

  4. Silymarin improves vascular function of aged ovariectomized rats.

    PubMed

    Demirci, Buket; Dost, Turhan; Gokalp, Filiz; Birincioglu, Mustafa

    2014-06-01

    Both aging and estrogen depletion lead to endothelial dysfunction, which is the main reason of many cardiovascular diseases. Previous reports have shown that cell protective effect of silymarin (SM) depends on its antioxidant and phytoestrogenic properties. We investigated the effect of SM on vascular stiffness of aged menopausal rats and the involvement of estrogenic activity in this effect. Isolated rat aortas were obtained from 22-month-old rats, after 18 months of ovariectomy (OVX) follow-up. Each ring was incubated in tissue bath either with SM (50 mg/L) and 17β-estradiol (10 μM, E2) or in the presence of SM/fulvestrant (50 mg/L, 10 μM). Endothelium-intact rings were precontracted with phenylephrine (0.001-30 μM) or high potassium (40 mM); endothelium-dependent/independent relaxant responses were obtained using acetylcholine (0.001-30 μM) and sodium nitroprusside (0.0001-3 μM), respectively. While phenylephrine sensitivity was significantly increased in OVX rats, relaxations were significantly less in aged OVX rats compared with young rats. In spite of the presence of estrogen antagonist, immediate SM treatment restored the endothelial function and vascular tone better than estrogen replacement. Additionally, as a complementary and alternative medicine, it does not cause estrogenic side effects when taken acutely. PMID:24123505

  5. Massage Therapy Restores Peripheral Vascular Function following Exertion

    PubMed Central

    Franklin, Nina C.; Ali, Mohamed M.; Robinson, Austin T.; Norkeviciute, Edita; Phillips, Shane A.

    2014-01-01

    Objective To determine if lower extremity exercise-induced muscle injury (EMI) reduces vascular endothelial function of the upper extremity and if massage therapy (MT) improves peripheral vascular function after EMI. Design Randomized, blinded trial with evaluations at 90 minutes, 24 hours, 48 hours, and 72 hours. Setting Clinical research center at an academic medical center and laboratory Participants Thirty-six sedentary young adults were randomly assigned to one of three groups: 1) EMI + MT (n=15; mean age ± standard error (SE): 26.6±0.3), 2) EMI only (n=10; mean age ± SE: 23.6±0.4), and 3) MT only (n=11; mean age ± SE: 25.5 ± 0.4). Intervention Participants were assigned to either EMI only (a single bout of bilateral, eccentric leg-press exercise), MT only (30-minute lower extremity massage using Swedish technique), or EMI + MT. Main outcome measures Brachial artery flow-mediated dilation (FMD) was determined by ultrasound at each time point. Nitroglycerin-induced dilation was also assessed (NTG; 0.4 mg). Results Brachial FMD increased from baseline in the EMI + MT group and the MT only group (7.38±0.18 to 9.02±0.28%, p<0.05 and 7.77±0.25 to 10.20±0.22%, p < 0.05, respectively) at 90 minutes remaining elevated until 72 hrs. In the EMI only group FMD was reduced from baseline at 24 and 48 hrs (7.78±0.14 to 6.75±0.11%, p<0.05 and 6.53±0.11, p<0.05, respectively) returning to baseline after 72 hrs. Dilations to NTG were similar over time. Conclusions Our results suggest that MT attenuates impairment of upper extremity endothelial function resulting from lower extremity EMI in sedentary young adults. PMID:24583315

  6. The CRC orthologue from Pisum sativum shows conserved functions in carpel morphogenesis and vascular development

    PubMed Central

    Fourquin, Chloé; Primo, Amparo; Martínez-Fernández, Irene; Huet-Trujillo, Estefanía; Ferrándiz, Cristina

    2014-01-01

    Background and Aims CRABS CLAW (CRC) is a member of the YABBY family of transcription factors involved in carpel morphogenesis, floral determinacy and nectary specification in arabidopsis. CRC orthologues have been functionally characterized across angiosperms, revealing additional roles in leaf vascular development and carpel identity specification in Poaceae. These studies support an ancestral role of CRC orthologues in carpel development, while roles in vascular development and nectary specification appear to be derived. This study aimed to expand research on CRC functional conservation to the legume family in order to better understand the evolutionary history of CRC orthologues in angiosperms. Methods CRC orthologues from Pisum sativum and Medicago truncatula were identified. RNA in situ hybridization experiments determined the corresponding expression patterns throughout flower development. The phenotypic effects of reduced CRC activity were investigated in P. sativum using virus-induced gene silencing. Key Results CRC orthologues from P. sativum and M. truncatula showed similar expression patterns, mainly restricted to carpels and nectaries. However, these expression patterns differed from those of other core eudicots, most importantly in a lack of abaxial expression in the carpel and in atypical expression associated with the medial vein of the ovary. CRC downregulation in pea caused defects in carpel fusion and style/stigma development, both typically associated with CRC function in eudicots, but also affected vascular development in the carpel. Conclusions The data support the conserved roles of CRC orthologues in carpel fusion, style/stigma development and nectary development. In addition, an intriguing new aspect of CRC function in legumes was the unexpected role in vascular development, which could be shared by other species from widely diverged clades within the angiosperms, suggesting that this role could be ancestral rather than derived, as so far

  7. The KEEPS-Cognitive and Affective Study: Baseline Associations between Vascular Risk Factors and Cognition

    PubMed Central

    Wharton, Whitney; Gleason, Carey E.; Dowling, N. Maritza; Carlsson, Cynthia M.; Brinton, Eliot A.; Santoro, M. Nanette; Neal-Perry, Genevieve; Taylor, Hugh; Naftolin, Frederick; Lobo, Rogerio; Merriam, George; Manson, JoAnn E.; Cedars, Marcelle; Miller, Virginia M.; Black, Dennis M.; Budoff, Matthew; Hodis, Howard N.; Harman, Mitchell; Asthana, Sanjay

    2015-01-01

    Background Midlife vascular risk factors influence later cognitive decline and Alzheimer’s disease (AD). The decrease in serum estradiol levels during menopause has been associated with cognitive impairment and increased vascular risk, such as high blood pressure (BP), which independently contribute to cognitive dysfunction and AD. Methods We describe the extent to which vascular risk factors relate to cognition in healthy, middle–aged, recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Cognitive and Affective Study (KEEPS-Cog) at baseline. KEEPS-Cog is a double-blind, randomized, placebo-controlled, parallel group design, clinical trial, investigating the efficacy of low-dose, transdermal 17β-estradiol and oral conjugated equine estrogen on cognition. Results The KEEPS-Cog cohort (N=662) is healthy and free of cognitive dysfunction. Higher systolic BP was related to poorer performance in auditory working memory and attention (unadjusted p=0.004; adjusted p=0.10). This relationship was not associated with endogenous hormone levels. Conclusions Lower BP early in menopause may positively affect cognitive domains known to be associated with AD. PMID:24430001

  8. Cybersickness provoked by head-mounted display affects cutaneous vascular tone, heart rate and reaction time.

    PubMed

    Nalivaiko, Eugene; Davis, Simon L; Blackmore, Karen L; Vakulin, Andrew; Nesbitt, Keith V

    2015-11-01

    Evidence from studies of provocative motion indicates that motion sickness is tightly linked to the disturbances of thermoregulation. The major aim of the current study was to determine whether provocative visual stimuli (immersion into the virtual reality simulating rides on a rollercoaster) affect skin temperature that reflects thermoregulatory cutaneous responses, and to test whether such stimuli alter cognitive functions. In 26 healthy young volunteers wearing head-mounted display (Oculus Rift), simulated rides consistently provoked vection and nausea, with a significant difference between the two versions of simulation software (Parrot Coaster and Helix). Basal finger temperature had bimodal distribution, with low-temperature group (n=8) having values of 23-29 °C, and high-temperature group (n=18) having values of 32-36 °C. Effects of cybersickness on finger temperature depended on the basal level of this variable: in subjects from former group it raised by 3-4 °C, while in most subjects from the latter group it either did not change or transiently reduced by 1.5-2 °C. There was no correlation between the magnitude of changes in the finger temperature and nausea score at the end of simulated ride. Provocative visual stimulation caused prolongation of simple reaction time by 20-50 ms; this increase closely correlated with the subjective rating of nausea. Lastly, in subjects who experienced pronounced nausea, heart rate was elevated. We conclude that cybersickness is associated with changes in cutaneous thermoregulatory vascular tone; this further supports the idea of a tight link between motion sickness and thermoregulation. Cybersickness-induced prolongation of reaction time raises obvious concerns regarding the safety of this technology. PMID:26340855

  9. ELIMINATION OF VITAMIN D RECEPTOR IN VASCULAR ENDOTHELIAL CELLS ALTERS VASCULAR FUNCTION

    PubMed Central

    Ni, Wei; Watts, Stephanie W.; Ng, Michael; Chen, Songcang; Glenn, Denis J.; Gardner, David G.

    2014-01-01

    Vitamin D deficiency has been associated with cardiovascular dysfunction. We evaluated the role of the vitamin D receptor (VDR) in vascular endothelial function, a marker of cardiovascular health, at baseline and in the presence of angiotensin II, using an endothelial-specific knockout of the murine VDR gene. In the absence of endothelial VDR, acetylcholine-induced aortic relaxation was significantly impaired (maximal relaxation, endothelial-specific VDR knockout =58% vs. control=73%, p<0.05). This was accompanied by a reduction in eNOS expression and phospho-vasodilator-stimulated phosphoprotein levels in aortae from the endothelial-specific VDR knockout vs. control mice. While blood pressure levels at baseline were comparable at 12 and 24 weeks of age, the endothelial VDR knockout mice demonstrated increased sensitivity to the hypertensive effects of angiotensin II compared to control mice (after 1-week infusion: knockout = 155±15 mmHg vs. control = 133±7 mmHg, p<0.01; after 2-week infusion: knockout = 164±9 mmHg vs. control = 152±13 mmHg, p<0.05). By the end of two weeks, angiotensin II infusion-induced, hypertrophy-sensitive myocardial gene expression was higher in endothelial-specific VDR knockout mice (fold change compared to saline-infused control mice, ANP: knockout mice = 3.12 vs. control= 1.7, p<0.05; BNP: knockout mice= 4.72 vs. control= 2.68, p<0.05). These results suggest that endothelial VDR plays an important role in endothelial cell function and blood pressure control and imply a potential role for VDR agonists in the management of cardiovascular disease associated with endothelial dysfunction. PMID:25201890

  10. Vascular endothelial function of patients with stable coronary artery disease

    PubMed Central

    Wang, Zhe; Yang, Xinchun; Cai, Jun; Shi, Hui; Zhong, Guangzhen; Chi, Hongjie

    2015-01-01

    Objectives: To evaluate vascular endothelial function and contributing factors in coronary heart disease (CHD) patients. Methods: One hundred twenty six CHD outpatients were randomly recruited. Reactive hyperemia index (RHI) <1.67 indicates endothelial dysfunction. Correlation between RHI and different biochemical parameters was evaluated. Results: RHI in patients receiving statins treatment was significantly higher than patients without statins treatment (P<0.05). RHI in patients with more than 3 risk factors for CHD was also markedly lower than that in patients with ≤2 risk factors (P<0.05). Patients with lesions at several branches of coronary artery had a markedly lower RHI when compared with those with coronary lesions at a single branch (P<0.05). For patients without statins treatment, RHI increased significantly after statins treatment for 1 month (P=0.01). In patients with endothelial dysfunction, FBG, HbA1C, hs-CRP and Hcy were significantly higher than those in patients with normal endothelial function (P<0.05 for all). Smokers with CHD had a remarkably lower RHI when compared with non-smokers (P<0.05). Conclusions: Smoking, FBG, HbA1C, Hcy and hs-CRP are significantly associated with endothelial dysfunction. Endothelial dysfunction is also related to the numbers of risk factors for CHD, degree of coronary lesions and statins. Statins treatment may significantly improve the endothelial function of CHD patients. PMID:26150839

  11. Urinary Albumin Excretion and Vascular Function in Rheumatoid Arthritis

    PubMed Central

    2016-01-01

    Rheumatoid arthritis (RA) is associated with significant cardiovascular (CV) morbidity and mortality. Increased urinary albumin excretion is a marker of CV risk. There are only few data on urinary albumin excretion in RA patients. Aim of the present study was to investigate urinary albumin excretion in RA patients and analyze, whether there is an association between urinary albumin excretion and vascular function as measured by the augmentation index (AIx). In a total of 341 participants (215 with RA, 126 without RA) urinary albumin-creatinine ratio (ACR) was determined and the AIx was measured. The Kolmogorov-Smirnov-test was used to cluster patient groups whose distributions of ACR can be considered to be equal. A crude analysis showed a median ACR of 6.6 mg/g in the RA group and 5.7 mg/g in patients without RA (P > 0.05). In order to account for diabetes (DM) we formed 4 distinct patient groups. Group 1: RA-/DM- (n = 74); group 2: RA+/DM- (n = 195); group 3: RA-/DM+ (n = 52); group 4: RA+/DM+ (n = 20). Clustering of these groups revealed two distinct patient groups: those without RA and DM, and those with either RA or DM or both. The latter group showed statistically significant higher ACR (median 8.1 mg/g) as the former (median 4.5 mg/g). We found no significant correlation between AIx and ACR. Urinary albumin excretion in patients with RA or DM or both is higher than in subjects without RA and DM. This can be seen as a sign of vascular alteration and increased CV risk in these patients. PMID:26955238

  12. Urinary Albumin Excretion and Vascular Function in Rheumatoid Arthritis.

    PubMed

    Pieringer, Herwig; Brummaier, Tobias; Piringer, Bettina; Auer-Hackenberg, Lorenz; Hartl, Andreas; Puchner, Rudolf; Pohanka, Erich; Schmid, Michael

    2016-03-01

    Rheumatoid arthritis (RA) is associated with significant cardiovascular (CV) morbidity and mortality. Increased urinary albumin excretion is a marker of CV risk. There are only few data on urinary albumin excretion in RA patients. Aim of the present study was to investigate urinary albumin excretion in RA patients and analyze, whether there is an association between urinary albumin excretion and vascular function as measured by the augmentation index (AIx). In a total of 341 participants (215 with RA, 126 without RA) urinary albumin-creatinine ratio (ACR) was determined and the AIx was measured. The Kolmogorov-Smirnov-test was used to cluster patient groups whose distributions of ACR can be considered to be equal. A crude analysis showed a median ACR of 6.6 mg/g in the RA group and 5.7 mg/g in patients without RA (P > 0.05). In order to account for diabetes (DM) we formed 4 distinct patient groups. Group 1: RA-/DM- (n = 74); group 2: RA+/DM- (n = 195); group 3: RA-/DM+ (n = 52); group 4: RA+/DM+ (n = 20). Clustering of these groups revealed two distinct patient groups: those without RA and DM, and those with either RA or DM or both. The latter group showed statistically significant higher ACR (median 8.1 mg/g) as the former (median 4.5 mg/g). We found no significant correlation between AIx and ACR. Urinary albumin excretion in patients with RA or DM or both is higher than in subjects without RA and DM. This can be seen as a sign of vascular alteration and increased CV risk in these patients. PMID:26955238

  13. Dietary blueberry supplementation affects growth but not vascularization of neural transplants

    PubMed Central

    Willis, Lauren M; Small, Brent J; Bickford, Paula C; Umphlet, Claudia D; Moore, Alfred B; Granholm, Ann-Charlotte E

    2009-01-01

    Transplantation of neural tissue has been attempted as a treatment method for neurodegenerative disorders. Grafted neurons survive to a lesser extent into middle-aged or aged hosts, and survival rates of < 10% of grafted neurons is common. Antioxidant diets, such as blueberry, can exert powerful effects on developing neurons and blood vessels in vitro, but studies are lacking that examine the effects of these diets on transplanted tissues. In this study, we examined the effects of a blueberry diet on survival, growth, and vascularization of fetal hippocampal tissue to the anterior chamber of the eye of young or middle-aged female rats. Previous work from our group showed significant increase in neuronal survival and development with blueberry diet in grafts. However, the effects of antioxidant diet on vascular development in grafts have not been explored previously. The age of the host affected individual vessel morphology in that aged hosts contained grafts with thick, undeveloped walls, and wider lumen. The blood–brain barrier also appeared to be affected by the age of the host. The blueberry diet did not affect vessel morphology or density of vessel-associated protein markers but gave rise to significantly increased growth capacity, cytoarchitecture, and the final size of hippocampal grafts. PMID:18285804

  14. Alcohol and cardiovascular disease--modulation of vascular cell function.

    PubMed

    Cahill, Paul A; Redmond, Eileen M

    2012-04-01

    Alcohol is a commonly used drug worldwide. Epidemiological studies have identified alcohol consumption as a factor that may either positively or negatively influence many diseases including cardiovascular disease, certain cancers and dementia. Often there seems to be a differential effect of various drinking patterns, with frequent moderate consumption of alcohol being salutary and binge drinking or chronic abuse being deleterious to one's health. A better understanding of the cellular and molecular mechanisms mediating the many effects of alcohol consumption is beginning to emerge, as well as a clearer picture as to whether these effects are due to the direct actions of alcohol itself, or caused in part by its metabolites, e.g., acetaldehyde, or by incidental components present in the alcoholic beverage (e.g., polyphenols in red wine). This review will discuss evidence to date as to how alcohol (ethanol) might affect atherosclerosis that underlies cardiovascular and cerebrovascular disease, and the putative mechanisms involved, focusing on vascular endothelial and smooth muscle cell effects. PMID:22606372

  15. ALDOSTERONE DYSREGULATION WITH AGING PREDICTS RENAL-VASCULAR FUNCTION AND CARDIO-VASCULAR RISK

    PubMed Central

    Brown, Jenifer M.; Underwood, Patricia C.; Ferri, Claudio; Hopkins, Paul N.; Williams, Gordon H.; Adler, Gail K.; Vaidya, Anand

    2014-01-01

    Aging and abnormal aldosterone regulation are both associated with vascular disease. We hypothesized that aldosterone dysregulation influences the age-related risk of renal- and cardio-vascular disease. We conducted an analysis of 562 subjects who underwent detailed investigations under conditions of liberal and restricted dietary sodium intake (1,124 visits) in a Clinical Research Center. Aldosterone regulation was characterized by the ratio of maximal suppression-to-stimulation (supine serum aldosterone on a liberal sodium diet divided by the same measure on a restricted sodium diet). We previously demonstrated that higher levels of this Sodium-modulated Aldosterone Suppression-Stimulation Index (SASSI) indicate greater aldosterone dysregulation. Renal plasma flow (RPF) was determined via p-aminohippurate clearance to assess basal renal hemodynamics, and the renal-vascular responses to dietary sodium manipulation and angiotensin II (AngII) infusion. Cardiovascular risk was calculated using the Framingham Risk Score. In univariate linear regression, older age (β= -4.60, p<0.0001) and higher SASSI (β= -58.63, p=0.001) predicted lower RPF and a blunted RPF response to sodium loading and AngII infusion. We observed a continuous, independent, multivariate-adjusted interaction between age and SASSI, where the inverse relationship between SASSI and RPF was most apparent with older age (p<0.05). Higher SASSI and lower RPF independently predicted higher Framingham Risk Score (p<0.0001) and together displayed an additive effect. Aldosterone regulation and age may interact to mediate renal-vascular disease. Our findings suggest that the combination of aldosterone dysregulation and renal-vascular dysfunction could additively increase the risk of future cardiovascular outcomes; therefore, aldosterone dysregulation may represent a modifiable mechanism of age-related vascular disease. PMID:24664291

  16. Review of gestational diabetes mellitus effects on vascular structure and function.

    PubMed

    Jensen, Louise A; Chik, Constance L; Ryan, Edmond A

    2016-05-01

    Vascular dysfunction has been described in women with a history of gestational diabetes mellitus. Furthermore, previous gestational diabetes mellitus increases the risk of developing Type 2 diabetes mellitus, a risk factor for cardiovascular disease. Factors contributing to vascular changes remain uncertain. The aim of this review was to summarize vascular structure and function changes found to occur in women with previous gestational diabetes mellitus and to identify factors that contribute to vascular dysfunction. A systematic search of electronic databases yielded 15 publications from 1998 to March 2014 that met the inclusion criteria. Our review confirmed that previous gestational diabetes mellitus contributes to vascular dysfunction, and the most consistent risk factor associated with previous gestational diabetes mellitus and vascular dysfunction was elevated body mass index. Heterogeneity existed across studies in determining the relationship of glycaemic levels and insulin resistance to vascular dysfunction. PMID:26940821

  17. Regulation of Vascular and Renal Function by Metabolite Receptors.

    PubMed

    Peti-Peterdi, János; Kishore, Bellamkonda K; Pluznick, Jennifer L

    2016-01-01

    To maintain metabolic homeostasis, the body must be able to monitor the concentration of a large number of substances, including metabolites, in real time and to use that information to regulate the activities of different metabolic pathways. Such regulation is achieved by the presence of sensors, termed metabolite receptors, in various tissues and cells of the body, which in turn convey the information to appropriate regulatory or positive or negative feedback systems. In this review, we cover the unique roles of metabolite receptors in renal and vascular function. These receptors play a wide variety of important roles in maintaining various aspects of homeostasis-from salt and water balance to metabolism-by sensing metabolites from a wide variety of sources. We discuss the role of metabolite sensors in sensing metabolites generated locally, metabolites generated at distant tissues or organs, or even metabolites generated by resident microbes. Metabolite receptors are also involved in various pathophysiological conditions and are being recognized as potential targets for new drugs. By highlighting three receptor families-(a) citric acid cycle intermediate receptors, (b) purinergic receptors, and PMID:26667077

  18. Functional CB1 cannabinoid receptors in human vascular endothelial cells.

    PubMed Central

    Liu, J; Gao, B; Mirshahi, F; Sanyal, A J; Khanolkar, A D; Makriyannis, A; Kunos, G

    2000-01-01

    Cannabinoid CB1 receptor mRNA was detected using reverse transcription-polymerase chain reaction (RT-PCR) in endothelial cells from human aorta and hepatic artery and in the ECV304 cell line derived from human umbilical vein endothelial cells. CB1 receptor-binding sites were detected by the high-affinity antagonist radioligand [(125)I]AM-251. In ECV304 cells, both the highly potent synthetic cannabinoid agonist HU-210 and the endogenous ligand anandamide induce activation of mitogen-activated protein (MAP) kinase, and the effect of HU-210 was completely blocked, whereas the effect of anandamide was partially inhibited by SR141716A, a selective CB1 receptor antagonist. Transfection of ECV304 cells with CB1 receptor antisense, but not sense, oligonucleotides caused the same pattern of inhibition as SR141716A. This provides more definitive evidence for the involvement of CB1 receptors in MAP kinase activation and suggests that anandamide may also activate MAP kinase via an additional, CB1 receptor-independent, SR141716A-resistant mechanism. The MAP kinase activation by anandamide in ECV304 cells requires genistein-sensitive tyrosine kinases and protein kinase C (PKC), and anandamide also activates p38 kinase and c-Jun kinase. These findings indicate that CB1 receptors located in human vascular endothelium are functionally coupled to the MAP kinase cascade. Activation of protein kinase cascades by anandamide may be involved in the modulation of endothelial cell growth and proliferation. PMID:10698714

  19. Low-level X-radiation effects on functional vascular changes in Syrian hamster cheek pouch epithelium during hydrocarbon carcinogenesis

    SciTech Connect

    Lurie, A.G.; Coghill, J.E.; Rippey, R.M.

    1985-07-01

    Effects of repeated low-level X radiation on functional microvascular changes in hamster cheek pouch epithelium during and following carcinogenesis by 7,12-dimethylbenz(a)anthracene (DMBA) were studied. Hamsters were treated with either radiation, DMBA, radiation + DMBA, or no treatment. Animals were sacrificed at 3-week intervals from 0 to 39 weeks after treatments began. Pouch vascular volume and permeability changes were studied by fractional distributions of radiotracers and were analyzed by a variety of statistical methods which explored the vascular parameters, treatment types, elapsed time, presence of the carcinogen, and histopathologic changes. All treatments resulted in significant changes in vascular volume with time, while only DMBA treatments alone resulted in significant changes in vascular permeability with time. As in prior studies, there were significant vascular volume differences between DMBA and DMBA + radiation groups of tumor-bearing cheek pouches. Radiation significantly affected DMBA-associated vascular volume and permeability changes during carcinogenesis. Several possible explanations for the relationship of these changes to the enhancement of DMBA carcinogenesis are discussed.

  20. Differential and synergistic effects of mechanical stimulation and growth factor presentation on vascular wall function.

    PubMed

    Liang, Mao-Shih; Koobatian, Maxwell; Lei, Pedro; Swartz, Daniel D; Andreadis, Stelios T

    2013-10-01

    We investigated the hypothesis that immobilizing TGF-β1 within fibrin hydrogels may act in synergy with cyclic mechanical stimulation to enhance the properties of vascular grafts. To this end, we engineered a fusion TGF-β1 protein that can covalently anchor to fibrin during polymerization upon the action of factor XIII. We also developed a 24-well based bioreactor in which vascular constructs can be mechanically stimulated by distending the silastic mandrel in the middle of each well. TGF-β1 was either conjugated to fibrin or supplied in the culture medium and the fibrin-based constructs were cultured statically for a week followed by cyclic distention for another week. The tissues were examined for myogenic differentiation, vascular reactivity, mechanical properties and ECM content. Our results showed that some aspects of vascular function were differentially affected by growth factor presentation vs. pulsatile force application, while others were synergistically enhanced by both. Overall, this two-prong biomimetic approach improved ECM secretion, vascular reactivity and mechanical properties of vascular constructs. These findings may be applied in other tissue engineering applications such as cartilage, tendon or cardiac regeneration where growth factors TGF-β1 and mechano-stimulation play critical roles. PMID:23810080

  1. Loss-of-Function Mutations in ELMO2 Cause Intraosseous Vascular Malformation by Impeding RAC1 Signaling.

    PubMed

    Cetinkaya, Arda; Xiong, Jingwei Rachel; Vargel, İbrahim; Kösemehmetoğlu, Kemal; Canter, Halil İbrahim; Gerdan, Ömer Faruk; Longo, Nicola; Alzahrani, Ahmad; Camps, Mireia Perez; Taskiran, Ekim Zihni; Laupheimer, Simone; Botto, Lorenzo D; Paramalingam, Eeswari; Gormez, Zeliha; Uz, Elif; Yuksel, Bayram; Ruacan, Şevket; Sağıroğlu, Mahmut Şamil; Takahashi, Tokiharu; Reversade, Bruno; Akarsu, Nurten Ayse

    2016-08-01

    Vascular malformations are non-neoplastic expansions of blood vessels that arise due to errors during angiogenesis. They are a heterogeneous group of sporadic or inherited vascular disorders characterized by localized lesions of arteriovenous, capillary, or lymphatic origin. Vascular malformations that occur inside bone tissue are rare. Herein, we report loss-of-function mutations in ELMO2 (which translates extracellular signals into cellular movements) that are causative for autosomal-recessive intraosseous vascular malformation (VMOS) in five different families. Individuals with VMOS suffer from life-threatening progressive expansion of the jaw, craniofacial, and other intramembranous bones caused by malformed blood vessels that lack a mature vascular smooth muscle layer. Analysis of primary fibroblasts from an affected individual showed that absence of ELMO2 correlated with a significant downregulation of binding partner DOCK1, resulting in deficient RAC1-dependent cell migration. Unexpectedly, elmo2-knockout zebrafish appeared phenotypically normal, suggesting that there might be human-specific ELMO2 requirements in bone vasculature homeostasis or genetic compensation by related genes. Comparative phylogenetic analysis indicated that elmo2 originated upon the appearance of intramembranous bones and the jaw in ancestral vertebrates, implying that elmo2 might have been involved in the evolution of these novel traits. The present findings highlight the necessity of ELMO2 for maintaining vascular integrity, specifically in intramembranous bones. PMID:27476657

  2. Functional properties of ion channels and transporters in tumour vascularization

    PubMed Central

    Fiorio Pla, Alessandra; Munaron, Luca

    2014-01-01

    Vascularization is crucial for solid tumour growth and invasion, providing metabolic support and sustaining metastatic dissemination. It is now accepted that ion channels and transporters play a significant role in driving the cancer growth at all stages. They may represent novel therapeutic, diagnostic and prognostic targets for anti-cancer therapies. On the other hand, although the expression and role of ion channels and transporters in the vascular endothelium is well recognized and subject of recent reviews, only recently has their involvement in tumour vascularization been recognized. Here, we review the current literature on ion channels and transporters directly involved in the angiogenic process. Particular interest will be focused on tumour angiogenesis in vivo as well as in the different steps that drive this process in vitro, such as endothelial cell proliferation, migration, adhesion and tubulogenesis. Moreover, we compare the ‘transportome’ system of tumour vascular network with the physiological one. PMID:24493751

  3. Vascular Endothelial Growth Factor Modulates Skeletal Myoblast Function

    PubMed Central

    Germani, Antonia; Di Carlo, Anna; Mangoni, Antonella; Straino, Stefania; Giacinti, Cristina; Turrini, Paolo; Biglioli, Paolo; Capogrossi, Maurizio C.

    2003-01-01

    Vascular endothelial growth factor (VEGF) expression is enhanced in ischemic skeletal muscle and is thought to play a key role in the angiogenic response to ischemia. However, it is still unknown whether, in addition to new blood vessel growth, VEGF modulates skeletal muscle cell function. In the present study immunohistochemical analysis showed that, in normoperfused mouse hindlimb, VEGF and its receptors Flk-1 and Flt-1 were expressed mostly in quiescent satellite cells. Unilateral hindlimb ischemia was induced by left femoral artery ligation. At day 3 and day 7 after the induction of ischemia, Flk-1 and Flt-1 were expressed in regenerating muscle fibers and VEGF expression by these fibers was markedly enhanced. Additional in vitro experiments showed that in growing medium both cultured satellite cells and myoblast cell line C2C12 expressed VEGF and its receptors. Under these conditions, Flk-1 receptor exhibited constitutive tyrosine phosphorylation that was increased by VEGF treatment. During myogenic differentiation Flk-1 and Flt-1 were down-regulated. In a modified Boyden Chamber assay, VEGF enhanced C2C12 myoblasts migration approximately fivefold. Moreover, VEGF administration to differentiating C2C12 myoblasts prevented apoptosis, while inhibition of VEGF signaling either with selective VEGF receptor inhibitors (SU1498 and CB676475) or a neutralizing Flk-1 antibody, enhanced cell death approximately 3.5-fold. Finally, adenovirus-mediated VEGF165 gene transfer inhibited ischemia-induced apoptosis in skeletal muscle. These results support a role for VEGF in myoblast migration and survival, and suggest a novel autocrine role of VEGF in skeletal muscle repair during ischemia. PMID:14507649

  4. Vascular permeability, vascular hyperpermeability and angiogenesis

    PubMed Central

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

    2008-01-01

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

  5. How mental stress affects endothelial function.

    PubMed

    Toda, Noboru; Nakanishi-Toda, Megumi

    2011-12-01

    Mental stress is an important factor contributing to recognized mechanisms underlying cardiovascular events. Among these, stress-related endothelial dysfunction is an early risk factor that predicts future development of severe cardiovascular disorders. Acute mental stress by a variety of tests impairs endothelial function in humans, although the opposite results have been reported by some investigators. Chronic stress always deteriorates endothelial function in humans and experimental animals. Stress hormones, such as glucocorticoids and pro-inflammatory cytokines, and endothelin-1 liberated in response to mental stress participate in endothelial dysfunction possibly via downregulation of endothelial nitric oxide synthase (eNOS) expression, eNOS inactivation, decreased nitric oxide (NO) actions, and increased NO degradation, together with vasoconstriction counteracting against NO-induced vasodilatation. Catecholamines do not directly affect endothelial function but impair its function when blood pressure elevation by the amines is sustained. Endogenous opioids favorably affect endothelial function, which counteract deteriorating effects of other stress hormones and mediators. Inhibition of cortisol and endothelin-1 production, prevention of pro-inflammatory mediator accumulation, hypnotics, mirthful laughter, humor orientation, and lifestyle modification would contribute to the prevention and treatment for stress-related endothelial dysfunction and future serious cardiovascular disease. PMID:21947555

  6. Time-of-day variation in vascular function.

    PubMed

    Rodrigo, G C; Denniff, M

    2016-08-01

    What is the topic of this review? This report looks at the role of endothelial nitric oxide signalling in the time-of-day variation in vasoconstriction of resistance vessels. What advances does it highlight? It highlights a time-of-day variation in contraction of mesenteric arteries, characterized by a reduced contractile response to either phenylephrine or high K(+) and increased relaxation in response to acetylcholine during the active period. This time-of-day variation in contraction results from a difference in endothelial nitric oxide synthase (eNOS) signalling that correlates with levels of eNOS expression, which peak during the active period and may have far reaching physiological consequences beyond regulation of blood pressure. There is a strong time-of-day variation in the vasoconstriction in response to sympathetic stimulation that may contribute to the time-of-day variation in blood pressure, which is characterized by a dip in blood pressure during the individual's rest period when sympathetic activity is low. Vasoconstriction is known to be regulated tightly by nitric oxide signalling from the endothelial cells, so we have looked at the effect of time-of-day on levels of endothelial nitric oxide synthase (eNOS) and vascular contractility. Mesenteric arteries isolated from the nocturnal rat exhibit a time-of-day variation in their contractile response to α1 -adrenoreceptor and muscarinic activation, which is characterized by a reduced vasoconstriction in response to phenylephrine and enhanced vasodilatation in response to acetylcholine during the rat's active period at night. An increase in eNOS signalling during the active period is responsible for this time-of-day difference in response to phenylephrine and acetylcholine and correlates with the large increase in eNOS expression (mRNA and protein) during the active period, possibly driven by the presence of a functioning peripheral circadian clock. This increase in eNOS signalling may function to

  7. Impairment of endothelial progenitor cell function and vascularization capacity by aldosterone in mice and humans

    PubMed Central

    Thum, Thomas; Schmitter, Kerstin; Fleissner, Felix; Wiebking, Volker; Dietrich, Bernd; Widder, Julian D.; Jazbutyte, Virginija; Hahner, Stefanie; Ertl, Georg; Bauersachs, Johann

    2011-01-01

    Aims Hyperaldosteronism is associated with vascular injury and increased cardiovascular events. Bone marrow-derived endothelial progenitor cells (EPCs) play an important role in endothelial repair and vascular homeostasis. We hypothesized that hyperaldosteronism impairs EPC function and vascularization capacity in mice and humans. Methods and results We characterized the effects of aldosterone and mineralocorticoid receptor (MR) blockade on EPC number and function as well as vascularization capacity and endothelial function. Treatment of human EPC with aldosterone induced translocation of the MR and impaired multiple cellular functions of EPC, such as differentiation, migration, and proliferation in vitro. Impaired EPC function was rescued by pharmacological blockade or genetic ablation of the MR. Aldosterone protein kinase A (PKA) dependently increased reactive oxygen species formation in EPC. Aldosterone infusion in mice impaired EPC function, EPC homing to vascular structures and vascularization capacity in a MR-dependent but blood pressure-independent manner. Endothelial progenitor cells from patients with primary hyperaldosteronism compared with controls of similar age displayed reduced migratory potential. Impaired EPC function was associated with endothelial dysfunction. MR blockade in patients with hyperaldosteronism improved EPC function and arterial stiffness. Conclusion Endothelial progenitor cells express a MR that mediates functional impairment by PKA-dependent increase of reactive oxygen species. Normalization of EPC function may represent a novel mechanism contributing to the beneficial effects of MR blockade in cardiovascular disease prevention and treatment. PMID:20926363

  8. 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

  9. The Restorative Effects of Eucommia ulmoides Oliver Leaf Extract on Vascular Function in Spontaneously Hypertensive Rats.

    PubMed

    Hosoo, Shingo; Koyama, Masahiro; Kato, Mai; Hirata, Tetsuya; Yamaguchi, Yasuyo; Yamasaki, Hiroo; Wada, Atsunori; Wada, Keiji; Nishibe, Sansei; Nakamura, Kozo

    2015-01-01

    Eucommia ulmoides Oliv. leaf is a traditional Chinese antihypertensive and antidiabetic medicine. We examined the effects of chronic Eucommia leaf extract (ELE) administration on artery function and morphology in spontaneously hypertensive rats (SHRs). ELE was orally administered via normal diet ad libitum to six-week-old male SHRs at a concentration of 5% for seven weeks. Acetylcholine (ACh)-induced endothelium-dependent relaxation, sodium nitroprusside (SNP)-induced endothelium-independent relaxation, plasma nitric oxide (NO) levels, and media thickness were assessed. ELE significantly improved ACh-induced aortic endothelium-dependent relaxation but did not affect SNP-induced endothelium-independent relaxation in the SHRs, as compared to the animals receiving normal diet. Plasma NO levels and media thickness were significantly increased and decreased, respectively, in the ELE-treated SHRs. Therefore, long-term ELE administration may effectively improve vascular function by increasing plasma NO levels and bioavailability, and by preventing vascular hypertrophy in the SHR aorta. PMID:26690110

  10. Omega-3 Polyunsaturated Fatty Acids: Structural and Functional Effects on the Vascular Wall

    PubMed Central

    Zanetti, Michela; Grillo, Andrea; Losurdo, Pasquale; Panizon, Emiliano; Mearelli, Filippo; Cattin, Luigi; Barazzoni, Rocco; Carretta, Renzo

    2015-01-01

    Omega-3 polyunsaturated fatty acids (n-3 PUFA) consumption is associated with reduced cardiovascular disease risk. Increasing evidence demonstrating a beneficial effect of n-3 PUFA on arterial wall properties is progressively emerging. We reviewed the recent available evidence for the cardiovascular effects of n-3 PUFA focusing on structural and functional properties of the vascular wall. In experimental studies and clinical trials n-3 PUFA have shown the ability to improve arterial hemodynamics by reducing arterial stiffness, thus explaining some of its cardioprotective properties. Recent studies suggest beneficial effects of n-3 PUFA on endothelial activation, which are likely to improve vascular function. Several molecular, cellular, and physiological pathways influenced by n-3 PUFA can affect arterial wall properties and therefore interfere with the atherosclerotic process. Although the relative weight of different physiological and molecular mechanisms and the dose-response on arterial wall properties have yet to be determined, n-3 PUFA have the potential to beneficially impact arterial wall remodeling and cardiovascular outcomes by targeting arterial wall stiffening and endothelial dysfunction. PMID:26301252

  11. Systemic Vascular Function Is Associated with Muscular Power in Older Adults

    PubMed Central

    Heffernan, Kevin S.; Chalé, Angela; Hau, Cynthia; Cloutier, Gregory J.; Phillips, Edward M.; Warner, Patrick; Nickerson, Heather; Reid, Kieran F.; Kuvin, Jeffrey T.; Fielding, Roger A.

    2012-01-01

    Age-associated loss of muscular strength and muscular power is a critical determinant of loss of physical function and progression to disability in older adults. In this study, we examined the association of systemic vascular function and measures of muscle strength and power in older adults. Measures of vascular endothelial function included brachial artery flow-mediated dilation (FMD) and the pulse wave amplitude reactive hyperemia index (PWA-RHI). Augmentation index (AIx) was taken as a measure of systemic vascular function related to arterial stiffness and wave reflection. Measures of muscular strength included one repetition maximum (1RM) for a bilateral leg press. Peak muscular power was measured during 5 repetitions performed as fast as possible for bilateral leg press at 40% 1RM. Muscular power was associated with brachial FMD (r = 0.43, P < 0.05), PWA-RHI (r = 0.42, P < 0.05), and AIx (r = −0.54, P < 0.05). Muscular strength was not associated with any measure of vascular function. In conclusion, systemic vascular function is associated with lower-limb muscular power but not muscular strength in older adults. Whether loss of muscular power with aging contributes to systemic vascular deconditioning or vascular dysfunction contributes to decrements in muscular power remains to be determined. PMID:22966457

  12. The plant vascular system: Evolution, development and functions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The emergence of the tracheophyte-based vascular system of land plants had major impacts on the evolution of terrestrial biology, in general, through its role in facilitating the development of plants with increased stature, photosynthetic output, and ability to colonize a greatly expanded range of ...

  13. Estrogen treatment affects brain functioning after menopause.

    PubMed

    Bayer, Ulrike; Hausmann, Markus

    2011-12-01

    Sex hormones have powerful neuromodulatory effects on functional brain organization and cognitive functioning. This paper reviews findings from studies investigating the influence of sex hormones in postmenopausal women with and without hormone therapy (HT). Functional brain organization was investigated using different behavioural tasks in postmenopausal women using either estrogen therapy or combined estrogen plus gestagen therapy and age- and IQ-matched postmenopausal women not taking HT. The results revealed HT-related modulations in specific aspects of functional brain organization including functional cerebral asymmetries and interhemispheric interaction. In contrast to younger women during the menstrual cycle, however, it seems that HT, and especially estrogen therapy, after menopause affects intrahemispheric processing rather than interhemispheric interaction. This might be explained by a faster and more pronounced age-related decline in intrahemispheric relative to interhemispheric functioning, which might be associated with higher sensitivity to HT. Taken together, the findings suggest that the female brain retains its plasticity even after reproductive age and remains susceptible to the effects of sex hormones throughout the lifetime, which might help to discover new clinical approaches in the hormonal treatment of neurological and psychiatric disorders. PMID:22120942

  14. Dual-mode imaging of cutaneous tissue oxygenation and vascular function.

    PubMed

    Xu, Ronald X; Huang, Kun; Qin, Ruogu; Huang, Jiwei; Xu, Jeff S; Ding, Liya; Gnyawali, Urmila S; Gordillo, Gayle M; Gnyawali, Surya C; Sen, Chandan K

    2010-01-01

    Accurate assessment of cutaneous tissue oxygenation and vascular function is important for appropriate detection, staging, and treatment of many health disorders such as chronic wounds. We report the development of a dual-mode imaging system for non-invasive and non-contact imaging of cutaneous tissue oxygenation and vascular function. The imaging system integrated an infrared camera, a CCD camera, a liquid crystal tunable filter and a high intensity fiber light source. A Labview interface was programmed for equipment control, synchronization, image acquisition, processing, and visualization. Multispectral images captured by the CCD camera were used to reconstruct the tissue oxygenation map. Dynamic thermographic images captured by the infrared camera were used to reconstruct the vascular function map. Cutaneous tissue oxygenation and vascular function images were co-registered through fiduciary markers. The performance characteristics of the dual-mode image system were tested in humans. PMID:21178967

  15. Characterization of vascular lesions in pigs affected by porcine circovirus type 2-systemic disease.

    PubMed

    Resendes, A R; Segalés, J

    2015-05-01

    Vascular lesions and their association with porcine circovirus type 2 (PCV2) were evaluated in multiple organs from 10 pigs affected with PCV2-systemic disease (PCV2-SD). Animals had vascular lesions in multiple organs, consisting of lymphohistiocytic lymphangitis and/or phlebitis, mild to severe necrotizing arteritis, and thrombosis within splenic arterioles and choroid plexus capillaries. Variable amounts of PCV2 nucleic acid detected by in situ hybridization were present within endothelial cells, tunica media myocytes, and perivascular and/or intralesional inflammatory cell infiltrates. PCV2 nucleic acid was detected within endothelial cells of both lymphatic and blood vessels without lesions in the associated tissues. Necrotizing arteritis was principally present in lymph nodes and kidney and consisted of degeneration, necrosis, and pyknosis of myocytes, often with intracytoplasmic, brightly eosinophilic inclusion bodies that were strongly positive for PCV2 nucleic acid. Segmental or circumferential fibrinoid necrosis was mainly present in vessels of the lymph node, spleen, and choroid plexus and was variably associated with PCV2 nucleic acid. Severe lymphangitis associated with strong intralesional PCV2 labeling was frequently detected within the mesenteric and mediastinal lymph nodes and the lamina propria of the ileum. In most tissues, medium and large lymphatics and/or veins often had disruption of the intima and mild mononuclear inflammatory cell infiltration that was variably associated with PCV2 nucleic acid. The present study indicates that vasculitis is a frequent finding in natural cases of PCV2-SD and that PCV2 may have a direct cytopathic effect on tunica media myocytes of small- and medium-sized arteries as well as endothelium. PMID:24963088

  16. Tie1 controls angiopoietin function in vascular remodeling and inflammation.

    PubMed

    Korhonen, Emilia A; Lampinen, Anita; Giri, Hemant; Anisimov, Andrey; Kim, Minah; Allen, Breanna; Fang, Shentong; D'Amico, Gabriela; Sipilä, Tuomas J; Lohela, Marja; Strandin, Tomas; Vaheri, Antti; Ylä-Herttuala, Seppo; Koh, Gou Young; McDonald, Donald M; Alitalo, Kari; Saharinen, Pipsa

    2016-09-01

    The angiopoietin/Tie (ANG/Tie) receptor system controls developmental and tumor angiogenesis, inflammatory vascular remodeling, and vessel leakage. ANG1 is a Tie2 agonist that promotes vascular stabilization in inflammation and sepsis, whereas ANG2 is a context-dependent Tie2 agonist or antagonist. A limited understanding of ANG signaling mechanisms and the orphan receptor Tie1 has hindered development of ANG/Tie-targeted therapeutics. Here, we determined that both ANG1 and ANG2 binding to Tie2 increases Tie1-Tie2 interactions in a β1 integrin-dependent manner and that Tie1 regulates ANG-induced Tie2 trafficking in endothelial cells. Endothelial Tie1 was essential for the agonist activity of ANG1 and autocrine ANG2. Deletion of endothelial Tie1 in mice reduced Tie2 phosphorylation and downstream Akt activation, increased FOXO1 nuclear localization and transcriptional activation, and prevented ANG1- and ANG2-induced capillary-to-venous remodeling. However, in acute endotoxemia, the Tie1 ectodomain that is responsible for interaction with Tie2 was rapidly cleaved, ANG1 agonist activity was decreased, and autocrine ANG2 agonist activity was lost, which led to suppression of Tie2 signaling. Tie1 cleavage also occurred in patients with hantavirus infection. These results support a model in which Tie1 directly interacts with Tie2 to promote ANG-induced vascular responses under noninflammatory conditions, whereas in inflammation, Tie1 cleavage contributes to loss of ANG2 agonist activity and vascular stability. PMID:27548530

  17. Antenatal Hypoxia and Pulmonary Vascular Function and Remodeling

    PubMed Central

    Papamatheakis, Demosthenes G.; Blood, Arlin B.; Kim, Joon H.; Wilson, Sean M.

    2015-01-01

    This review provides evidence that antenatal hypoxia, which represents a significant and worldwide problem, causes prenatal programming of the lung. A general overview of lung development is provided along with some background regarding transcriptional and signaling systems of the lung. The review illustrates that antenatal hypoxic stress can induce a continuum of responses depending on the species examined. Fetuses and newborns of certain species and specific human populations are well acclimated to antenatal hypoxia. However, antenatal hypoxia causes pulmonary vascular disease in fetuses and newborns of most mammalian species and humans. Disease can range from mild pulmonary hypertension, to severe vascular remodeling and dangerous elevations in pressure. The timing, length, and magnitude of the intrauterine hypoxic stress are important to disease development, however there is also a genetic-environmental relationship that is not yet completely understood. Determining the origins of pulmonary vascular remodeling and pulmonary hypertension and their associated effects is a challenging task, but is necessary in order to develop targeted therapies for pulmonary hypertension in the newborn due to antenatal hypoxia that can both treat the symptoms and curtail or reverse disease progression. PMID:24063380

  18. Vascular and cognitive functions associated with cardiovascular disease in the elderly

    PubMed Central

    Cohen, Ronald A.; Poppas, Athena; Forman, Daniel E.; Hoth, Karin F.; Haley, Andreana P.; Gunstad, John; Jefferson, Angela L.; Tate, David F.; Paul, Robert H.; Sweet, Lawrence H.; Ono, Mokato; Jerskey, Beth A.; Gerhard-Herman, Marie

    2009-01-01

    This study examines the relationship between systemic vascular function, neurocognitive performance, and structural brain abnormalities on magnetic resonance imaging (MRI) among geriatric outpatients with treated, stable cardiovascular disease and no history of neurological illness (n = 88, ages 56–85 years). Vascular function was assessed by cardiac ejection fraction and output, sequential systolic and diastolic blood pressures, flow mediated brachial artery reactivity (BAR), and carotid intima media thickness (IMT). White matter hyperintensities (WMH) on MRI were quantified and examined relative to cognitive and vascular function. Principal component analysis revealed two primary vascular components: one associated with cardiac function, the other with atherosclerotic burden/endothelial dysfunction. Both factors were significantly associated with cognitive function and WMH volume. Reduced systolic variability and increased IMT were most strongly related to reduced attention, executive function, and information-processing speed. These findings suggest the possibility that systemic vascular indices may provide proxy measures of cerebrovascular dysfunction and reinforce the importance of achieving greater understanding of interaction between systemic vascular disease and brain dysfunction among elderly people with cardiovascular disease. PMID:18608677

  19. Interference with PPARγ Function in Smooth Muscle Causes Vascular Dysfunction and Hypertension

    PubMed Central

    Halabi, Carmen M.; Beyer, Andreas M.; de Lange, Willem J.; Keen, Henry L.; Baumbach, Gary L.; Faraci, Frank M.; Sigmund, Curt D.

    2008-01-01

    Summary Peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand activated transcription factor playing a critical role in metabolism. Thiazolidinediones, high affinity PPARγ ligands used clinically to treat type-II diabetes, have been reported to lower blood pressure and provide other cardiovascular benefits. Some mutations in PPARγ cause type-II diabetes and severe hypertension. We tested the hypothesis that PPARγ in vascular muscle plays a role in the regulation of vascular tone and blood pressure. Transgenic mice expressing dominant negative mutations in PPARγ under the control of a smooth muscle-specific promoter exhibit a loss of responsiveness to nitric oxide and striking alterations in contractility in the aorta, hypertrophy and inward remodeling in the cerebral microcirculation, and systolic hypertension. These results identify PPARγ as pivotal in vascular muscle as a regulator of vascular structure, vascular function and blood pressure, potentially explaining some of the cardioprotective effects of thiazolidinediones. PMID:18316027

  20. Biomechanical regulation of vascular smooth muscle cell functions: from in vitro to in vivo understanding

    PubMed Central

    Qiu, Juhui; Zheng, Yiming; Hu, Jianjun; Liao, Donghua; Gregersen, Hans; Deng, Xiaoyan; Fan, Yubo; Wang, Guixue

    2014-01-01

    Vascular smooth muscle cells (VSMCs) have critical functions in vascular diseases. Haemodynamic factors are important regulators of VSMC functions in vascular pathophysiology. VSMCs are physiologically active in the three-dimensional matrix and interact with the shear stress sensor of endothelial cells (ECs). The purpose of this review is to illustrate how haemodynamic factors regulate VSMC functions under two-dimensional conditions in vitro or three-dimensional co-culture conditions in vivo. Recent advances show that high shear stress induces VSMC apoptosis through endothelial-released nitric oxide and low shear stress upregulates VSMC proliferation and migration through platelet-derived growth factor released by ECs. This differential regulation emphasizes the need to construct more actual environments for future research on vascular diseases (such as atherosclerosis and hypertension) and cardiovascular tissue engineering. PMID:24152813

  1. Creating Perfused Functional Vascular Channels Using 3D Bio-Printing Technology

    PubMed Central

    Lee, Vivian K.; Kim, Diana Y.; Ngo, Haygan; Lee, Young; Seo, Lan; Yoo, Seung-Schik; Vincent, Peter A.; Dai, Guohao

    2014-01-01

    We developed a methodology using 3D bio-printing technology to create a functional in vitro vascular channel with perfused open lumen using only cells and biological matrices. The fabricated vasculature has a tight, confluent endothelium lining, presenting barrier function for both plasma protein and high-molecular weight dextran molecule. The fluidic vascular channel is capable of supporting the viability of tissue up to 5mm in distance at 5 million cells/mL density under the physiological flow condition. In static-cultured vascular channels, active angiogenic sprouting from the vessel surface was observed whereas physiological flow strongly suppressed this process. Gene expression analysis were reported in this study to show the potential of this vessel model in vascular biology research. The methods have great potential in vascularized tissue fabrication using 3D bio-printing technology as the vascular channel is simultaneously created while cells and matrix are printed around the channel in desired 3D patterns. It can also serve as a unique experimental tool for investigating fundamental mechanisms of vascular remodeling with extracellular matrix and maturation process under 3D flow condition. PMID:24965886

  2. Creating perfused functional vascular channels using 3D bio-printing technology.

    PubMed

    Lee, Vivian K; Kim, Diana Y; Ngo, Haygan; Lee, Young; Seo, Lan; Yoo, Seung-Schik; Vincent, Peter A; Dai, Guohao

    2014-09-01

    We developed a methodology using 3D bio-printing technology to create a functional in vitro vascular channel with perfused open lumen using only cells and biological matrices. The fabricated vasculature has a tight, confluent endothelium lining, presenting barrier function for both plasma protein and high-molecular weight dextran molecule. The fluidic vascular channel is capable of supporting the viability of tissue up to 5 mm in distance at 5 million cells/mL density under the physiological flow condition. In static-cultured vascular channels, active angiogenic sprouting from the vessel surface was observed whereas physiological flow strongly suppressed this process. Gene expression analysis was reported in this study to show the potential of this vessel model in vascular biology research. The methods have great potential in vascularized tissue fabrication using 3D bio-printing technology as the vascular channel is simultaneously created while cells and matrix are printed around the channel in desired 3D patterns. It can also serve as a unique experimental tool for investigating fundamental mechanisms of vascular remodeling with extracellular matrix and maturation process under 3D flow condition. PMID:24965886

  3. Small-diameter biodegradable scaffolds for functional vascular tissue engineering in the mouse model.

    PubMed

    Roh, Jason D; Nelson, Gregory N; Brennan, Matthew P; Mirensky, Tamar L; Yi, Tai; Hazlett, Tyrone F; Tellides, George; Sinusas, Albert J; Pober, Jordan S; Saltzman, W M; Kyriakides, Themis R; Breuer, Christopher K

    2008-04-01

    The development of neotissue in tissue engineered vascular grafts remains poorly understood. Advances in mouse genetic models have been highly informative in the study of vascular biology, but have been inaccessible to vascular tissue engineers due to technical limitations on the use of mouse recipients. To this end, we have developed a method for constructing sub-1mm internal diameter (ID) biodegradable scaffolds utilizing a dual cylinder chamber molding system and a hybrid polyester sealant scaled for use in a mouse model. Scaffolds constructed from either polyglycolic acid or poly-l-lactic acid nonwoven felts demonstrated sufficient porosity, biomechanical profile, and biocompatibility to function as vascular grafts. The scaffolds implanted as either inferior vena cava or aortic interposition grafts in SCID/bg mice demonstrated excellent patency without evidence of thromboembolic complications or aneurysm formation. A foreign body immune response was observed with marked macrophage infiltration and giant cell formation by post-operative week 3. Organized vascular neotissue, consisting of endothelialization, medial generation, and collagen deposition, was evident within the internal lumen of the scaffolds by post-operative week 6. These results present the ability to create sub-1mm ID biodegradable tubular scaffolds that are functional as vascular grafts, and provide an experimental approach for the study of vascular tissue engineering using mouse models. PMID:18164056

  4. Serum Superoxide Dismutase Is Associated with Vascular Structure and Function in Hypertensive and Diabetic Patients.

    PubMed

    Gómez-Marcos, Manuel A; Blázquez-Medela, Ana M; Gamella-Pozuelo, Luis; Recio-Rodriguez, José I; García-Ortiz, Luis; Martínez-Salgado, Carlos

    2016-01-01

    Oxidative stress is associated with cardiac and vascular defects leading to hypertension and atherosclerosis, being superoxide dismutase (SOD) one of the main intracellular antioxidant defence mechanisms. Although several parameters of vascular function and structure have a predictive value for cardiovascular morbidity-mortality in hypertensive patients, there are no studies on the involvement of SOD serum levels with these vascular parameters. Thus, we assessed if SOD serum levels are correlated with parameters of vascular function and structure and with cardiovascular risk in hypertensive and type 2 diabetic patients. We enrolled 255 consecutive hypertensive and diabetic patients and 52 nondiabetic and nonhypertensive controls. SOD levels were measured with an enzyme-linked immunosorbent assay kit. Vascular function and structure were evaluated by pulse wave velocity, augmentation index, ambulatory arterial stiffness index, and carotid intima-media thickness. We detected negative correlations between SOD and pressure wave velocity, peripheral and central augmentation index and ambulatory arterial stiffness index, pulse pressure, and plasma HDL-cholesterol, as well as positive correlations between SOD and plasma uric acid and triglycerides. Our study shows that SOD is a marker of cardiovascular alterations in hypertensive and diabetic patients, since changes in its serum levels are correlated with alterations in vascular structure and function. PMID:26635913

  5. Serum Superoxide Dismutase Is Associated with Vascular Structure and Function in Hypertensive and Diabetic Patients

    PubMed Central

    Gómez-Marcos, Manuel A.; Blázquez-Medela, Ana M.; Gamella-Pozuelo, Luis; Recio-Rodriguez, José I.; García-Ortiz, Luis; Martínez-Salgado, Carlos

    2016-01-01

    Oxidative stress is associated with cardiac and vascular defects leading to hypertension and atherosclerosis, being superoxide dismutase (SOD) one of the main intracellular antioxidant defence mechanisms. Although several parameters of vascular function and structure have a predictive value for cardiovascular morbidity-mortality in hypertensive patients, there are no studies on the involvement of SOD serum levels with these vascular parameters. Thus, we assessed if SOD serum levels are correlated with parameters of vascular function and structure and with cardiovascular risk in hypertensive and type 2 diabetic patients. We enrolled 255 consecutive hypertensive and diabetic patients and 52 nondiabetic and nonhypertensive controls. SOD levels were measured with an enzyme-linked immunosorbent assay kit. Vascular function and structure were evaluated by pulse wave velocity, augmentation index, ambulatory arterial stiffness index, and carotid intima-media thickness. We detected negative correlations between SOD and pressure wave velocity, peripheral and central augmentation index and ambulatory arterial stiffness index, pulse pressure, and plasma HDL-cholesterol, as well as positive correlations between SOD and plasma uric acid and triglycerides. Our study shows that SOD is a marker of cardiovascular alterations in hypertensive and diabetic patients, since changes in its serum levels are correlated with alterations in vascular structure and function. PMID:26635913

  6. Chronic hypoxia in pregnancy affected vascular tone of renal interlobar arteries in the offspring.

    PubMed

    Tang, Jiaqi; Zhu, Zhoufeng; Xia, Shuixiu; Li, Na; Chen, Ningjing; Gao, Qinqin; Li, Lingjun; Zhou, Xiuwen; Li, Dawei; Zhu, Xiaolin; Tu, Qing; Li, Weisheng; Wu, Chonglong; Li, Jiayue; Zhong, Yuan; Li, Xiang; Mao, Caiping; Xu, Zhice

    2015-01-01

    Hypoxia during pregnancy could affect development of fetuses as well as cardiovascular systems in the offspring. This study was the first to demonstrate the influence and related mechanisms of prenatal hypoxia (PH) on renal interlobar arteries (RIA) in the 5-month-old male rat offspring. Following chronic hypoxia during pregnancy, phenylephrine induced significantly higher pressor responses and greater vasoconstrictions in the offspring. Nitric oxide mediated vessel relaxation was altered in the RIA. Phenylephrine-stimulated free intracellular calcium was significantly higher in the RIA of the PH group. The activity and expression of L-type calcium channel (Cav1.2), not T-type calcium channel (Cav3.2), was up-regulated. The whole-cell currents of calcium channels and the currents of Cav1.2 were increased compared with the control. In addition, the whole-cell K(+) currents were decreased in the offspring exposed to prenatal hypoxia. Activity of large-conductance Ca(2+)-activated K(+) channels and the expression of MaxiKα was decreased in the PH group. The results provide new information regarding the influence of prenatal hypoxia on the development of the renal vascular system, and possible underlying cellular and ion channel mechanisms involved. PMID:25983078

  7. Can lifestyle modification affect men's erectile function?

    PubMed

    Hehemann, Marah C; Kashanian, James A

    2016-04-01

    Erectile dysfunction (ED) is a common condition affecting millions of men worldwide. The pathophysiology and epidemiologic links between ED and risk factors for cardiovascular disease (CVD) are well-established. Lifestyle modifications such as smoking cessation, weight reduction, dietary modification, physical activity, and psychological stress reduction have been increasingly recognized as foundational to the prevention and treatment of ED. The aim of this review is to outline behavioral choices which may increase ones risk of developing ED, to present relevant studies addressing lifestyle factors correlated with ED, and to highlight proposed mechanisms for intervention aimed at improving erectile function in men with ED. These recommendations can provide a framework for counseling patients with ED about lifestyle modification. PMID:27141445

  8. Augmented EGF receptor tyrosine kinase activity impairs vascular function by NADPH oxidase-dependent mechanism in type 2 diabetic mouse.

    PubMed

    Kassan, Modar; Ait-Aissa, Karima; Ali, Maha; Trebak, Mohamed; Matrougui, Khalid

    2015-10-01

    We previously determined that augmented EGFR tyrosine kinase (EGFRtk) impairs vascular function in type 2 diabetic mouse (TD2). Here we determined that EGFRtk causes vascular dysfunction through NADPH oxidase activity in TD2. Mesenteric resistance arteries (MRA) from C57/BL6 and db-/db- mice were mounted in a wired myograph and pre-incubated for 1h with either EGFRtk inhibitor (AG1478) or exogenous EGF. The inhibition of EGFRtk did not affect the contractile response to phenylephrine-(PE) and thromboxane-(U46619) or endothelium-dependent relaxation (EDR) to acetylcholine in MRA from control group. However, in TD2 mice, AG1478 reduced the contractile response to U46619, improved vasodilatation and reduced p22phox-NADPH expression, but had no effect on the contractile response to PE. The incubation of MRA with exogenous EGF potentiated the contractile response to PE in MRA from control and diabetic mice. However, EGF impaired the EDR and potentiated the vasoconstriction to U46619 only in the control group. Interestingly, NADPH oxidase inhibition in the presence of EGF restored the normal contraction to PE and improved the EDR but had no effect on the potentiated contraction to U46619. Vascular function improvement was associated with the rescue of eNOS and Akt and reduction in phosphorylated Rho-kinase, NOX4 mRNA levels, and NADPH oxidase activity. MRA from p47phox-/- mice incubated with EGF potentiated the contraction to U46619 but had no effect to PE or ACh responses. The present study provides evidence that augmented EGFRtk impairs vascular function by NADPH oxidase-dependent mechanism. Therefore, EGFRtk and oxidative stress should be potential targets to treat vascular dysfunction in TD2. PMID:26036345

  9. Modular Small Diameter Vascular Grafts with Bioactive Functionalities

    PubMed Central

    Neufurth, Meik; Wang, Xiaohong; Tolba, Emad; Dorweiler, Bernhard; Schröder, Heinz C.; Link, Thorben; Diehl-Seifert, Bärbel; Müller, Werner E. G.

    2015-01-01

    We report the fabrication of a novel type of artificial small diameter blood vessels, termed biomimetic tissue-engineered blood vessels (bTEBV), with a modular composition. They are composed of a hydrogel scaffold consisting of two negatively charged natural polymers, alginate and a modified chitosan, N,O-carboxymethyl chitosan (N,O-CMC). Into this biologically inert scaffold two biofunctionally active biopolymers are embedded, inorganic polyphosphate (polyP) and silica, as well as gelatin which exposes the cell recognition signal, Arg-Gly-Asp (RGD). These materials can be hardened by exposure to Ca2+ through formation of Ca2+ bridges between the polyanions, alginate, N,O-CMC, and polyP (alginate-Ca2+-N,O-CMC-polyP). The bTEBV are formed by pressing the hydrogel through an extruder into a hardening solution, containing Ca2+. In this universal scaffold of the bTEBV biomaterial, polycations such as poly(l-Lys), poly(d-Lys) or a His/Gly-tagged RGD peptide (three RGD units) were incorporated, which promote the adhesion of endothelial cells to the vessel surface. The mechanical properties of the biopolymer material (alginate-Ca2+-N,O-CMC-polyP-silica) revealed a hardness (elastic modulus) of 475 kPa even after a short incubation period in CaCl2 solution. The material of the artificial vascular grafts (bTEBVs with an outer size 6 mm and 1.8 mm, and an inner diameter 4 mm and 0.8 mm, respectively) turned out to be durable in 4-week pulsatile flow experiments at an alternating pressure between 25 and 100 mbar (18.7 and 75.0 mm Hg). The burst pressure of the larger (smaller) vessels was 850 mbar (145 mbar). Incorporation of polycationic poly(l-Lys), poly(d-Lys), and especially the His/Gly-tagged RGD peptide, markedly increased the adhesion of human, umbilical vein/vascular endothelial cells, EA.HY926 cells, to the surface of the hydrogel. No significant effect of the polyP samples on the clotting of human plasma is measured. We propose that the metabolically degradable

  10. Differential Effects of Hormone Therapy on Serotonin, Vascular Function and Mood in the KEEPS

    PubMed Central

    Raz, Limor; Hunter, Larry; Dowling, N. Maritza; Wharton, Whitney; Gleason, Carey; Jayachandran, Muthuvel; Anderson, Layne; Asthana, Sanjay; Miller, Virginia

    2016-01-01

    Background Serotonin (5-hydroxytryptamine, 5-HT) is modulated by sex steroid hormones and affects vascular function and mood. In the Kronos Early Estrogen Prevention Cognitive and Affective Ancillary Study (KEEPS-Cog), women randomized to oral conjugated equine estrogens (oCEE) showed greater benefit on affective mood states than women randomized to transdermal 17β-estradiol (tE2) or placebo (PL). This study examined the effect of these treatments on the platelet content of 5-HT as a surrogate measure of 5-HT synthesis and uptake in the brain. Methods The following were measured in a subset (n = 79) of women enrolled in KEEPS-Cog: 5-HT by ELISA, carotid intima-medial thickness (CIMT) by ultrasound, endothelial function by reactive hyperemia index (RHI), and self-reported symptoms of affective mood states by the Profile of Mood States (POMS) questionnaire. Results Mean platelet content of 5-HT increased by 107.0%, 84.5% and 39.8%, in tE2, oCEE and PL groups, respectively. Platelet 5-HT positively correlated with estrone in the oCEE group and with 17β- estradiol in the tE2 group. Platelet 5-HT showed a positive association with RHI, but not CIMT, in the PL and oCEE groups. Reduction in mood scores for depression-dejection and anger-hostility associated with elevations in platelet 5-HT only in the oCEE group (r = −0.5, p = 0.02). Conclusions Effects of oCEE compared to tE2 on RHI and mood may be related to mechanisms involving platelet, and perhaps neuronal, uptake and release of 5-HT and reflect conversion of estrone to bioavailable 17β- estradiol in platelets and the brain. PMID:26652904

  11. Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium

    PubMed Central

    Niaudet, Colin; Vanlandewijck, Michael; Ekvärn, Elisabet; Salvado, M. Dolores; Mehlem, Annika; Al Sayegh, Sahar; He, Liqun; Lebouvier, Thibaud; Castro-Freire, Marco; Katayama, Kan; Hultenby, Kjell; Moessinger, Christine; Tannenberg, Philip; Cunha, Sara; Pietras, Kristian; Laviña, Bàrbara; Hong, JongWook; Berg, Tove; Betsholtz, Christer

    2015-01-01

    Despite its known expression in both the vascular endothelium and the lung epithelium, until recently the physiological role of the adhesion receptor Gpr116/ADGRF5 has remained elusive. We generated a new mouse model of constitutive Gpr116 inactivation, with a large genetic deletion encompassing exon 4 to exon 21 of the Gpr116 gene. This model allowed us to confirm recent results defining Gpr116 as necessary regulator of surfactant homeostasis. The loss of Gpr116 provokes an early accumulation of surfactant in the lungs, followed by a massive infiltration of macrophages, and eventually progresses into an emphysema-like pathology. Further analysis of this knockout model revealed cerebral vascular leakage, beginning at around 1.5 months of age. Additionally, endothelial-specific deletion of Gpr116 resulted in a significant increase of the brain vascular leakage. Mice devoid of Gpr116 developed an anatomically normal and largely functional vascular network, surprisingly exhibited an attenuated pathological retinal vascular response in a model of oxygen-induced retinopathy. These data suggest that Gpr116 modulates endothelial properties, a previously unappreciated function despite the pan-vascular expression of this receptor. Our results support the key pulmonary function of Gpr116 and describe a new role in the central nervous system vasculature. PMID:26394398

  12. Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium.

    PubMed

    Niaudet, Colin; Hofmann, Jennifer J; Mäe, Maarja A; Jung, Bongnam; Gaengel, Konstantin; Vanlandewijck, Michael; Ekvärn, Elisabet; Salvado, M Dolores; Mehlem, Annika; Al Sayegh, Sahar; He, Liqun; Lebouvier, Thibaud; Castro-Freire, Marco; Katayama, Kan; Hultenby, Kjell; Moessinger, Christine; Tannenberg, Philip; Cunha, Sara; Pietras, Kristian; Laviña, Bàrbara; Hong, JongWook; Berg, Tove; Betsholtz, Christer

    2015-01-01

    Despite its known expression in both the vascular endothelium and the lung epithelium, until recently the physiological role of the adhesion receptor Gpr116/ADGRF5 has remained elusive. We generated a new mouse model of constitutive Gpr116 inactivation, with a large genetic deletion encompassing exon 4 to exon 21 of the Gpr116 gene. This model allowed us to confirm recent results defining Gpr116 as necessary regulator of surfactant homeostasis. The loss of Gpr116 provokes an early accumulation of surfactant in the lungs, followed by a massive infiltration of macrophages, and eventually progresses into an emphysema-like pathology. Further analysis of this knockout model revealed cerebral vascular leakage, beginning at around 1.5 months of age. Additionally, endothelial-specific deletion of Gpr116 resulted in a significant increase of the brain vascular leakage. Mice devoid of Gpr116 developed an anatomically normal and largely functional vascular network, surprisingly exhibited an attenuated pathological retinal vascular response in a model of oxygen-induced retinopathy. These data suggest that Gpr116 modulates endothelial properties, a previously unappreciated function despite the pan-vascular expression of this receptor. Our results support the key pulmonary function of Gpr116 and describe a new role in the central nervous system vasculature. PMID:26394398

  13. The influence of vascularization of transplanted processed allograft nerve on return of motor function in rats.

    PubMed

    Giusti, Guilherme; Lee, Joo-Yup; Kremer, Thomas; Friedrich, Patricia; Bishop, Allen T; Shin, Alexander Y

    2016-02-01

    Processed nerve allografts have become an alternative to repair segmental nerve defects, with results comparable with autografts regarding sensory recovery; however, they have failed to reproduce comparable motor recovery. The purpose of this study was to determine how revascularizaton of processed nerve allograft would affect motor recovery. Eighty-eight rats were divided in four groups of 22 animals each. A unilateral 10-mm sciatic nerve defect was repaired with allograft (group I), allograft wrapped with silicone conduit (group II), allograft augmented with vascular endothelial growth factor (group III), or autograft (group IV). Eight animals from each group were sacrificed at 3 days, and the remaining animals at 16 weeks. Revascularization was evaluated by measuring the graft capillary density at 3 days and 16 weeks. Measurements of ankle contracture, compound muscle action potential, tibialis anterior muscle weight and force, and nerve histomorphometry were performed at 16 weeks. All results were normalized to the contralateral side. The results of capillary density at 3 days were 0.99% ± 1.3% for group I, 0.33% ± 0.6% for group II, 0.05% ± 0.1% for group III, and 75.6% ± 45.7% for group IV. At 16 weeks, the results were 69.9% ± 22.4% for group I, 37.0% ± 16.6% for group II, 84.6% ± 46.6% for group III, and 108.3% ± 46.8% for group IV. The results of muscle force were 47.5% ± 14.4% for group I, 21.7% ± 13.5% for group II, 47.1% ± 7.9% for group III, and 54.4% ± 10.6% for group IV. The use of vascular endothelial growth factor in the fashion used in this study improved neither the nerve allograft short-term revascularization nor the functional motor recovery after 16 weeks. Blocking allograft vascularization from surrounding tissues was detrimental for motor recovery. The processed nerve allografts used in this study showed similar functional motor recovery compared with that of the autograft. PMID

  14. Pre-Analytical Parameters Affecting Vascular Endothelial Growth Factor Measurement in Plasma: Identifying Confounders

    PubMed Central

    Walz, Johanna M.; Boehringer, Daniel; Deissler, Heidrun L.; Faerber, Lothar; Goepfert, Jens C.; Heiduschka, Peter; Kleeberger, Susannah M.; Klettner, Alexa; Krohne, Tim U.; Schneiderhan-Marra, Nicole; Ziemssen, Focke; Stahl, Andreas

    2016-01-01

    Background Vascular endothelial growth factor-A (VEGF-A) is intensively investigated in various medical fields. However, comparing VEGF-A measurements is difficult because sample acquisition and pre-analytic procedures differ between studies. We therefore investigated which variables act as confounders of VEGF-A measurements. Methods Following a standardized protocol, blood was taken at three clinical sites from six healthy participants (one male and one female participant at each center) twice one week apart. The following pre-analytical parameters were varied in order to analyze their impact on VEGF-A measurements: analyzing center, anticoagulant (EDTA vs. PECT / CTAD), cannula (butterfly vs. neonatal), type of centrifuge (swing-out vs. fixed-angle), time before and after centrifugation, filling level (completely filled vs. half-filled tubes) and analyzing method (ELISA vs. multiplex bead array). Additionally, intrapersonal variations over time and sex differences were explored. Statistical analysis was performed using a linear regression model. Results The following parameters were identified as statistically significant independent confounders of VEGF-A measurements: analyzing center, anticoagulant, centrifuge, analyzing method and sex of the proband. The following parameters were no significant confounders in our data set: intrapersonal variation over one week, cannula, time before and after centrifugation and filling level of collection tubes. Conclusion VEGF-A measurement results can be affected significantly by the identified pre-analytical parameters. We recommend the use of CTAD anticoagulant, a standardized type of centrifuge and one central laboratory using the same analyzing method for all samples. PMID:26730574

  15. Hyperinsulinemia adversely affects lung structure and function.

    PubMed

    Singh, Suchita; Bodas, Manish; Bhatraju, Naveen K; Pattnaik, Bijay; Gheware, Atish; Parameswaran, Praveen Kolumam; Thompson, Michael; Freeman, Michelle; Mabalirajan, Ulaganathan; Gosens, Reinoud; Ghosh, Balaram; Pabelick, Christina; Linneberg, Allan; Prakash, Y S; Agrawal, Anurag

    2016-05-01

    There is limited knowledge regarding the consequences of hyperinsulinemia on the lung. Given the increasing prevalence of obesity, insulin resistance, and epidemiological associations with asthma, this is a critical lacuna, more so with inhaled insulin on the horizon. Here, we demonstrate that insulin can adversely affect respiratory health. Insulin treatment (1 μg/ml) significantly (P < 0.05) increased the proliferation of primary human airway smooth muscle (ASM) cells and induced collagen release. Additionally, ASM cells showed a significant increase in calcium response and mitochondrial respiration upon insulin exposure. Mice administered intranasal insulin showed increased collagen deposition in the lungs as well as a significant increase in airway hyperresponsiveness. PI3K/Akt mediated activation of β-catenin, a positive regulator of epithelial-mesenchymal transition and fibrosis, was observed in the lungs of insulin-treated mice and lung cells. Our data suggests that hyperinsulinemia may have adverse effects on airway structure and function. Insulin-induced activation of β-catenin in lung tissue and the contractile effects on ASM cells may be causally related to the development of asthma-like phenotype. PMID:26919895

  16. Effects of cranberry juice consumption on vascular function in patients with coronary artery disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cranberry juice contains polyphenolic compounds that could improve endothelial function and reduce cardiovascular disease risk. The objective was to examine the effects of cranberry juice on vascular function in subjects with coronary artery disease. We completed an acute pilot study with no placebo...

  17. 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.

  18. Impaired Coronary and Renal Vascular Function in Spontaneously Type 2 Diabetic Leptin-Deficient Mice

    PubMed Central

    Westergren, Helena U.; Grönros, Julia; Heinonen, Suvi E.; Miliotis, Tasso; Jennbacken, Karin; Sabirsh, Alan; Ericsson, Anette; Jönsson-Rylander, Ann-Cathrine; Svedlund, Sara; Gan, Li-Ming

    2015-01-01

    Background Type 2 diabetes is associated with macro- and microvascular complications in man. Microvascular dysfunction affects both cardiac and renal function and is now recognized as a main driver of cardiovascular mortality and morbidity. However, progression of microvascular dysfunction in experimental models is often obscured by macrovascular pathology and consequently demanding to study. The obese type 2 diabetic leptin-deficient (ob/ob) mouse lacks macrovascular complications, i.e. occlusive atherosclerotic disease, and may therefore be a potential model for microvascular dysfunction. The present study aimed to test the hypothesis that these mice with an insulin resistant phenotype might display microvascular dysfunction in both coronary and renal vascular beds. Methods and Results In this study we used non-invasive Doppler ultrasound imaging to characterize microvascular dysfunction during the progression of diabetes in ob/ob mice. Impaired coronary flow velocity reserve was observed in the ob/ob mice at 16 and 21 weeks of age compared to lean controls. In addition, renal resistivity index as well as pulsatility index was higher in the ob/ob mice at 21 weeks compared to lean controls. Moreover, plasma L-arginine was lower in ob/ob mice, while asymmetric dimethylarginine was unaltered. Furthermore, a decrease in renal vascular density was observed in the ob/ob mice. Conclusion In parallel to previously described metabolic disturbances, the leptin-deficient ob/ob mice also display cardiac and renal microvascular dysfunction. This model may therefore be suitable for translational, mechanistic and interventional studies to improve the understanding of microvascular complications in type 2 diabetes. PMID:26098416

  19. Effect of soy isoflavone supplementation on vascular endothelial function and oxidative stress in postmenopausal women: a community randomized controlled trial.

    PubMed

    Pusparini; Dharma, Rahayuningsih; Suyatna, Fransiscus D; Mansyur, Muchtaruddin; Hidajat, Adi

    2013-01-01

    A 12-month randomized double blind controlled trial was conducted among 182 Indonesian postmenopausal women aged 47 to 60 years to determine the effect of 100 mg/day soy isoflavone supplementation on vascular endothelial function such as vascular cell adhesion molecule-1 (VCAM-1), nitric oxide (NO) and malondialdehyde (MDA) as oxidative stress marker. The subjects were randomized to the intervention group receiving tablets consisting of 100 mg soy isoflavones and calcium carbonate 500 mg, and to the control group receiving 500 mg calcium carbonate. The concentrations of VCAM-1, NO and MDA were measured at baseline, and postsupplementation at 6 months and 12 months. After supplementation, the MDA concentrations were significantly lower in the soy isoflavone group compared with the control group (p=0.001). The concentrations of VCAM-1 and NO were not affected (p=0.992 and p=0.759, respectively). In all group the MDA concentration increased compared with baseline concentrations but the relative change of MDA concentrations was significantly lower in the soy isoflavone group compared with the control group. This study demonstrates that supplemental intake of soy isoflavones for 6 months and 12 months had an effect on oxidative stress by decreasing MDA concentration, but did not improve vascular endothelial function. PMID:23945405

  20. [Progress in research on function and mechanism of cardiac vascular system of taurine].

    PubMed

    Hua, Hao-ming; Ito, Takashi; Qiu, Zhi-gang; Azuma, Junichi

    2005-05-01

    The function for cardiac vascular system of taurine is extensive, and the mechanism is complicated. Taurine protects the cells from the cell injury caused by ischemia etc. Through repressing apoptosis, prevents endothelial dysfunction caused by hyperglycemia, hypercholesterolemia, smoking and homocysteine; suppresses the proliferation and calcification in vascular smooth muscle cells, promotes metabolization and excretion of cholesterol in the animal models of hyperlipemia, and confers the resistance to an oxidant, hypochlorous acid, produced by neutrophil on cells, and taurine chrolamine to inhibit activation of NF-kappaB, which might be associated with anti-atherosclerotic effect. Taurine mainly acts inside the cell. However, taurine transport system becomes aberrant in pathological myocardial and vascular tissue. In addition, taurine improves cardiovascular function in fructose-induced hypertension and an iron-overload murine animal models. PMID:16075725

  1. 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. PMID:27451096

  2. Generation of a functional liver tissue mimic using adipose stromal vascular fraction cell-derived vasculatures

    PubMed Central

    Nunes, S. S.; Maijub, J. G.; Krishnan, L.; Ramakrishnan, V. M.; Clayton, L. R.; Williams, S. K.; Hoying, J. B.; Boyd, N. L.

    2013-01-01

    One of the major challenges in cell implantation therapies is to promote integration of the microcirculation between the implanted cells and the host. We used adipose-derived stromal vascular fraction (SVF) cells to vascularize a human liver cell (HepG2) implant. We hypothesized that the SVF cells would form a functional microcirculation via vascular assembly and inosculation with the host vasculature. Initially, we assessed the extent and character of neovasculatures formed by freshly isolated and cultured SVF cells and found that freshly isolated cells have a higher vascularization potential. Generation of a 3D implant containing fresh SVF and HepG2 cells formed a tissue in which HepG2 cells were entwined with a network of microvessels. Implanted HepG2 cells sequestered labeled LDL delivered by systemic intravascular injection only in SVF-vascularized implants demonstrating that SVF cell-derived vasculatures can effectively integrate with host vessels and interface with parenchymal cells to form a functional tissue mimic. PMID:23828203

  3. 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

  4. The role of mechanotransduction on vascular smooth muscle myocytes cytoskeleton and contractile function

    PubMed Central

    Ye, George J.C.; Nesmith, Alexander P.; Parker, Kevin Kit

    2016-01-01

    Smooth muscle exhibits a highly organized structural hierarchy that extends over multiple spatial scales to perform a wide range of functions at the cellular, tissue, and organ levels. Early efforts primarily focused on understanding vascular smooth muscle function through biochemical signaling. However, accumulating evidence suggests that mechanotransduction, the process through which cells convert mechanical stimuli into biochemical cues, is requisite for regulating contractility. Cytoskeletal proteins that comprise the extracellular, intercellular, and intracellular domains are mechanosensitive and can remodel their structure and function in response to external mechanical cues. Pathological stimuli such as malignant hypertension can act through the same mechanotransductive pathways to induce maladaptive remodeling, leading to changes in cellular shape and loss of contractile function. In both health and disease, the cytoskeletal architecture integrates the mechanical stimuli and mediates structural and functional remodeling in the vascular smooth muscle. PMID:25125187

  5. Does high-density lipoprotein protect vascular function in healthy pregnancy?

    PubMed

    Sulaiman, Wan N Wan; Caslake, Muriel J; Delles, Christian; Karlsson, Helen; Mulder, Monique T; Graham, Delyth; Freeman, Dilys J

    2016-04-01

    The maternal adaptation to pregnancy includes hyperlipidaemia, oxidative stress and chronic inflammation. In non-pregnant individuals, these processes are usually associated with poor vascular function. However, maternal vascular function is enhanced in pregnancy. It is not understood how this is achieved in the face of the adverse metabolic and inflammatory environment. Research into cardiovascular disease demonstrates that plasma HDL (high-density lipoprotein), by merit of its functionality rather than its plasma concentration, exerts protective effects on the vascular endothelium. HDL has vasodilatory, antioxidant, anti-thrombotic and anti-inflammatory effects, and can protect against endothelial cell damage. In pregnancy, the plasma HDL concentration starts to rise at 10 weeks of gestation, peaking at 20 weeks. The initial rise in plasma HDL occurs around the time of the establishment of the feto-placental circulation, a time when the trophoblast plugs in the maternal spiral arteries are released, generating oxidative stress. Thus there is the intriguing possibility that new HDL of improved function is synthesized around the time of the establishment of the feto-placental circulation. In obese pregnancy and, to a greater extent, in pre-eclampsia, plasma HDL levels are significantly decreased and maternal vascular function is reduced. Wire myography studies have shown an association between the plasma content of apolipoprotein AI, the major protein constituent of HDL, and blood vessel relaxation. These observations lead us to hypothesize that HDL concentration, and function, increases in pregnancy in order to protect the maternal vascular endothelium and that in pre-eclampsia this fails to occur. PMID:26888561

  6. [Primary Study on Noninvasive Detection of Vascular Function Based on Finger Temperature Change].

    PubMed

    Dong, Qing; Li, Xia; Wan, Yungao; Lu, Gaoquan; Wang, Xinxin; Zhang, Kuan

    2016-02-01

    By studying the relationship between fingertip temperature changes and arterial function during vascular reactivity test, we established a new non-invasive method for detecting vascular function, in order to provide an assistance for early diagnosis and prevention of cardiovascular diseases. We customized three modules respectively for blood occlusion, measurement of finger temperature and blood oxygen acquisition, and then we established the hardware of data acquisition system. And the software was programmed with Labview. Healthy subjects [group A, n = 24, (44.6 ± 9.0) years] and subjects with cardiovascular diseases [group B, n = 33, (57.2 ± 9.9) years)] were chosen for the study. Subject's finger temperature, blood oxygen and occlusion pressure of block side during and after unilateral arm brachial artery occlusion were recorded, as well as some other regular physiological indexes. By time-domain analysis, we extracted 12 parameters from fingertip temperature signal, including the initial temperature (Ti), temperature rebound (TR), the time of the temperature recovering to initial status (RIt) and other parameters from the finger temperature signal. We in the experiment also measured other regular physiological body mass index (BMI), systolic blood pressure (SBP), diastiolic blood pressure (DBP) and so on. Results showed that 8 parameters difference between the two group of data were significant. based on the statistical results. A discriminant function of vascular function status was established afterwards. We found in the study that the changes of finger temperature during unilateral arms brachial artery occlusion and open were closely related to vascular function. We hope that the method presented in this article could lay a foundation of early detection of vascular function. PMID:27382755

  7. Nitinol-based Nanotubular and Nanowell Coatings for the Modulation of Human Vascular Cell Functions

    NASA Astrophysics Data System (ADS)

    Lee, Phin Peng

    Current approaches to reducing restenosis do not balance the reduction of vascular smooth muscle cell proliferation with the increase in the healing of the endothelium. Here, I present my study on the synthesis and characterization of a nanotubular coating on Nitinol substrates. I found that the coating demonstrated 'pro-healing' properties by increasing primary human aortic endothelial cell spreading, migration and collagen and elastin production. Certain cellular functions such as collagen and elastin production were also found to be affected by changes in nanotube diameter. The coating also reduced the proliferation and mRNA expression of collagen I and MMP2 for primary human aortic smooth muscle cells. I will also demonstrate the synthesis of a nanowell coating on Nitinol stents as well as an additional poly(lactic-co-glycolic acid) coating on top of the nanowells that has the potential for controlling drug release. These findings demonstrate the potential for the coatings to aid in the prevention of restenosis and sets up future explorations of ex vivo and in vivo studies.

  8. Chemokine (C-X-C Motif) Receptor 4 and Atypical Chemokine Receptor 3 Regulate Vascular α1-Adrenergic Receptor Function

    PubMed Central

    Bach, Harold H; Wong, Yee M; Tripathi, Abhishek; Nevins, Amanda M; Gamelli, Richard L; Volkman, Brian F; Byron, Kenneth L; Majetschak, Matthias

    2014-01-01

    Chemokine (C-X-C motif) receptor (CXCR) 4 and atypical chemokine receptor (ACKR) 3 ligands have been reported to modulate cardiovascular function in various disease models. The underlying mechanisms, however, remain unknown. Thus, it was the aim of the present study to determine how pharmacological modulation of CXCR4 and ACKR3 regulate cardiovascular function. In vivo administration of TC14012, a CXCR4 antagonist and ACKR3 agonist, caused cardiovascular collapse in normal animals. During the cardiovascular stress response to hemorrhagic shock, ubiquitin, a CXCR4 agonist, stabilized blood pressure, whereas coactivation of CXCR4 and ACKR3 with CXC chemokine ligand 12 (CXCL12), or blockade of CXCR4 with AMD3100 showed opposite effects. While CXCR4 and ACKR3 ligands did not affect myocardial function, they selectively altered vascular reactivity upon α1-adrenergic receptor (AR) activation in pressure myography experiments. CXCR4 activation with ubiquitin enhanced α1-AR-mediated vasoconstriction, whereas ACKR3 activation with various natural and synthetic ligands antagonized α1-AR-mediated vasoconstriction. The opposing effects of CXCR4 and ACKR3 activation by CXCL12 could be dissected pharmacologically. CXCR4 and ACKR3 ligands did not affect vasoconstriction upon activation of voltage-operated Ca2+ channels or endothelin receptors. Effects of CXCR4 and ACKR3 agonists on vascular α1-AR responsiveness were independent of the endothelium. These findings suggest that CXCR4 and ACKR3 modulate α1-AR reactivity in vascular smooth muscle and regulate hemodynamics in normal and pathological conditions. Our observations point toward CXCR4 and ACKR3 as new pharmacological targets to control vasoreactivity and blood pressure. PMID:25032954

  9. A novel approach to the assessment of vascular endothelial function

    NASA Astrophysics Data System (ADS)

    Sathasivam, S.; Phababpha, S.; Sengmeuan, P.; Detchaporn, P.; Siddiqui, Z.; Kukongviriyapan, U.; Greenwald, S.

    2011-08-01

    Impaired endothelial function (EF) is associated with atherogenesis, and its quantitative assessment has prognostic value. Currently, methods based on assessing flow-mediated dilation (FMD) are technically difficult and expensive. We tested a novel way of assessing EF by measuring the time difference between pulses arriving at the middle fingers of each hand (f-fΔT), whilst FMD is induced in one arm. We compared f-fΔT with standard methods in healthy and diseased subjects. Our findings suggest that the proposed simple and inexpensive technique gives comparable results and has the potential to qualitatively assess EF in the clinical setting, although further work is required.

  10. Does iron deficiency anemia affect olfactory function?

    PubMed

    Dinc, Mehmet Emre; Dalgic, Abdullah; Ulusoy, Seckin; Dizdar, Denizhan; Develioglu, Omer; Topak, Murat

    2016-07-01

    Conclusion This study found a negative effect of IDA on olfactory function. IDA leads to a reduction in olfactory function, and decreases in hemoglobin levels result in further reduction in olfactory function. Objective This study examined the effects of iron-deficiency anemia (IDA) on olfactory function. Method The study enrolled 50 IDA patients and 50 healthy subjects. Olfactory function was evaluated using the Sniffin' Sticks olfactory test. The diagnosis of IDA was made according to World Health Organization (WHO) criteria. Results Patients with IDA had a significantly lower threshold, discrimination, and identification (TDI) value, and a lower threshold compared with the control group. However, there were no significant differences between the groups in terms of smell selectivity values. PMID:26963317

  11. Enhanced biocompatibility of CD47-functionalized vascular stents.

    PubMed

    Slee, Joshua B; Alferiev, Ivan S; Nagaswami, Chandrasekaran; Weisel, John W; Levy, Robert J; Fishbein, Ilia; Stachelek, Stanley J

    2016-05-01

    The effectiveness of endovascular stents is hindered by in-stent restenosis (ISR), a secondary re-obstruction of treated arteries due to unresolved inflammation and activation of smooth muscle cells in the arterial wall. We previously demonstrated that immobilized CD47, a ubiquitously expressed transmembrane protein with an established role in immune evasion, can confer biocompatibility when appended to polymeric surfaces. In present studies, we test the hypothesis that CD47 immobilized onto metallic surfaces of stents can effectively inhibit the inflammatory response thus mitigating ISR. Recombinant CD47 (recCD47) or a peptide sequence corresponding to the Ig domain of CD47 (pepCD47), were attached to the surfaces of both 316L-grade stainless steel foils and stents using bisphosphonate coordination chemistry and thiol-based conjugation reactions to assess the anti-inflammatory properties of CD47-functionalized surfaces. Initial in vitro and ex vivo analysis demonstrated that both recCD47 and pepCD47 significantly reduced inflammatory cell attachment to steel surfaces without impeding on endothelial cell retention and expansion. Using a rat carotid stent model, we showed that pepCD47-functionalized stents prevented fibrin and platelet thrombus deposition, inhibited inflammatory cell attachment, and reduced restenosis by 30%. It is concluded that CD47-modified stent surfaces mitigate platelet and inflammatory cell attachment, thereby disrupting ISR pathophysiology. PMID:26914699

  12. Left Ventricular Diastolic Dysfunction in Ischemic Stroke: Functional and Vascular Outcomes

    PubMed Central

    Park, Hong-Kyun; Kim, Beom Joon; Yoon, Chang-Hwan; Yang, Mi Hwa; Han, Moon-Ku; Bae, Hee-Joon

    2016-01-01

    Background and Purpose Left ventricular (LV) diastolic dysfunction, developed in relation to myocardial dysfunction and remodeling, is documented in 15%-25% of the population. However, its role in functional recovery and recurrent vascular events after acute ischemic stroke has not been thoroughly investigated. Methods In this retrospective observational study, we identified 2,827 ischemic stroke cases with adequate echocardiographic evaluations to assess LV diastolic dysfunction within 1 month after the index stroke. The peak transmitral filling velocity/mean mitral annular velocity during early diastole (E/e’) was used to estimate LV diastolic dysfunction. We divided patients into 3 groups according to E/e’ as follows: <8, 8-15, and ≥15. Recurrent vascular events and functional recovery were prospectively collected at 3 months and 1 year. Results Among included patients, E/e’ was 10.6±6.4: E/e’ <8 in 993 (35%), 8-15 in 1,444 (51%), and ≥15 in 378 (13%) cases. Functional dependency or death (modified Rankin Scale score ≥2) and composite vascular events were documented in 1,298 (46%) and 187 (7%) patients, respectively, at 3 months. In multivariable analyses, ischemic stroke cases with E/e’ ≥15 had increased odds of functional dependence or death at 3 months (adjusted OR [95% CI]: 1.73 [1.27-2.35]) or 1 year (1.47 [1.06-2.06]) and vascular events within 1 year (1.65 [1.08-2.51]). Subgroups with normal ejection fraction or sinus rhythm exhibited a similar overall pattern and direction. Conclusions LV diastolic dysfunction was associated with poor functional outcomes and composite vascular events up to 1 year. PMID:27283279

  13. Effects of short-term endurance exercise training on vascular function in young males.

    PubMed

    Currie, Katharine D; Thomas, Scott G; Goodman, Jack M

    2009-09-01

    We investigated effects of 6 days of endurance exercise training [cycling at 65% of peak oxygen consumption (VO(2peak)) for 2 h a day on six consecutive days] on vascular function in young males. Measures of VO(2peak), arterial stiffness, calf vascular conductance and heart rate variability were obtained pre- and post-training. Indices of arterial stiffness were obtained by applanation tonometry to determine aortic augmentation index normalized to a heart rate of 75 bpm (AI(x) at 75 bpm), and central and peripheral pulse wave velocity (CPWV, PPWV). Resting and maximal calf vascular conductances were calculated from concurrent measures of blood pressure and calf blood flow using venous occlusion strain-gauge plethysmography. Time and frequency domain measures of heart rate variability were obtained from recording R-R intervals during supine and standing conditions. Both CPWV (5.9 +/- 0.8 vs. 5.4 +/- 0.8 m/s) and PPWV (9.7 +/- 0.8 vs. 8.9 +/- 1.3 m/s) were reduced following the training program. No significant changes were observed in AI(x) at 75 bpm, vascular conductance, heart rate variability or VO(2peak). These data indicate that changes in arterial stiffness independent of changes in heart rate variability or vascular conductance can be achieved in healthy young males following only 6 days of intense endurance exercise. PMID:19554346

  14. Alterations in vascular function in primary aldosteronism: a cardiovascular magnetic resonance imaging study.

    PubMed

    Mark, P B; Boyle, S; Zimmerli, L U; McQuarrie, E P; Delles, C; Freel, E M

    2014-02-01

    Excess aldosterone is associated with increased cardiovascular risk. Aldosterone has a permissive effect on vascular fibrosis. Cardiovascular magnetic resonance imaging (CMR) allows study of vascular function by measuring aortic distensibility. We compared aortic distensibility in primary aldosteronism (PA), essential hypertension (EH) and normal controls and explored the relationship between aortic distensibility and pulse wave velocity (PWV). We studied PA (n=14) and EH (n=33) subjects and age-matched healthy controls (n=17) with CMR, including measurement of aortic distensibility, and measured PWV using applanation tonometry. At recruitment, PA and EH patients had similar blood pressure and left ventricular mass. Subjects with PA had significantly lower aortic distensibility and higher PWV compared with EH and healthy controls. These changes were independent of other factors associated with reduced aortic distensibility, including ageing. There was a significant relationship between increasing aortic stiffness and age in keeping with physical and vascular ageing. As expected, aortic distensibility and PWV were closely correlated. These results demonstrate that PA patients display increased arterial stiffness compared with EH, independent of vascular ageing. The implication is that aldosterone invokes functional impairment of arterial function. The long-term implications of arterial stiffening in aldosterone excess require further study. PMID:23884211

  15. [Complex assessment of vasomotor function of vascular endothelium in patients with hypertension].

    PubMed

    Gel'tser, B I; Savchenko, S V; Kotel'nikov, V N; Plotnikova, I V

    2004-01-01

    Vasomotor function of vascular endothelium was studied in 62 patients with grade 1-2 hypertension with moderate and high added risk. Methods included study of brachial and middle cerebral artery endothelium dependent and independent vasodilation/vasoconstriction, measurement of plasma levels of nitric oxide metabolites (NO(n)-), endothelin-1, and antithrombin, as well as registration of their changes during vasomotor tests with calculation of integral indexes. Most patients with hypertension differed from controls by preponderance of vasoconstrictor over vasodilator reactions both in peripheral and cerebral vascular bed. At the same time patients with hypertension had pronounced dissociation between vasomotor responses of cerebral and peripheral vessels compared with subjects with normal blood pressure (p<0.05). Besides lowered basal level of NO(n)- and high concentration of endothelin-1 patients with hypertension were characterized by hyperreactivity of nitricoxidergic system, augmented lability of endothelin producing system, and impaired athrombogenecity of vascular endothelium. Complex assessment of vasomotor function of vascular endothelium by sequential vasoactive tests characterizes functional and metabolic activity of cerebral and peripheral vessels and can be used for improvement of risk stratification and monitoring of efficacy of treatment of patients with hypertension. PMID:15111971

  16. Clinical Correlates of Hachinski Ischemic Score and Vascular Factors in Cognitive Function of Elderly

    PubMed Central

    Kim, Youn Ho

    2014-01-01

    The aim of this study is to investigate the relationship between Hachinski ischemic score (HIS) and vascular factors as well as between HIS and the cognitive function in elderly community. Demographic characteristics, such as sex, age, education, history of drinking and smoking, family history of dementia and stroke, diabetes mellitus, hypertension, hyperlipidemia, cardiovascular disease, stroke, and dementia, were surveyed. Neurological examination was administered to every subject and HIS was checked by a neurologist. From a total of 392 participants aged 65 and over in a rural community, 348 completed the survey and were finally enrolled. Among the vascular factors, history of hypertension (P = 0.008), history of stroke (P < 0.001), family history of dementia (P = 0.01), and history of cardiac diseases (P = 0.012) showed a significant relationship with HIS. In the cognitive function tests, both Korean version of the Mini-Mental State Examination and the Clinical Dementia Rating (Global and Sum of Boxes) had a significant relationship with HIS. Our study suggested HIS may have an association with some vascular factors and cognitive scales in community dwelling elderly. In this study, the HIS seemed to contribute to the evaluation of the quantity of vascular factors and to the prediction of status of cognitive function. PMID:25247189

  17. A Methodological Approach to Non-invasive Assessments of Vascular Function and Morphology

    PubMed Central

    Sandoo, Aamer; Kitas, George D.

    2015-01-01

    The endothelium is the innermost lining of the vasculature and is involved in the maintenance of vascular homeostasis. Damage to the endothelium may predispose the vessel to atherosclerosis and increase the risk for cardiovascular disease. Assessments of peripheral endothelial function are good indicators of early abnormalities in the vascular wall and correlate well with assessments of coronary endothelial function. The present manuscript details the important methodological steps necessary for the assessment of microvascular endothelial function using laser Doppler imaging with iontophoresis, large vessel endothelial function using flow-mediated dilatation, and carotid atherosclerosis using carotid artery ultrasound. A discussion on the methodological considerations for each of the techniques is also presented, and recommendations are made for future research. PMID:25741637

  18. The effect of ozone inhalation on metabolic functioning of vascular endothelium and on ventilatory function

    SciTech Connect

    Gross, K.B.; White, H.J.; Sargent, N.E. )

    1991-06-15

    The primary purpose of this research was to determine the effect of ozone inhalation on pulmonary vascular endothelium. Male Fischer-344 rats were exposed to 0.5 or 0.7 ppm ozone, 20 hr/day for 7 days. Lungs were excised and perfused with Krebs medium containing (14C)serotonin or (14C)hippurylhistidylleucine (HHL). When compared to controls, the animals exposed to the lower ozone concentration showed no statistically significant changes in serotonin removal. In contrast, the higher ozone concentration resulted in a 32% decrease (p less than 0.0001) in serotonin removal, but had no effect on HHL. Rats similarly exposed to 0.7 ppm ozone but allowed to recover for 14 days in clean air showed no decrease in serotonin removal compared to their controls. Animals exposed sequentially to 0.5 ppm ozone for 7 days and then to 0.7 ppm for 7 days showed no alteration in serotonin metabolism, suggesting the development of tolerance initiated by the lower dose. After 7 days exposure to 0.7 ppm ozone, lung ventilatory function measurements revealed small though significant decreases in several parameters. Electron microscopic evaluation of lung capillary endothelium from animals exposed to the 0.7 ppm ozone showed no changes. Positive control animals exposed to greater than 95% oxygen, 20 hr/day for 2 days showed a 23% decrease in serotonin removal (p less than 0.03) and a 12% decrease in HHL removal (p less than 0.017). These studies indicate that inhalation of ozone can induce functional alterations in the lung endothelium, and that this effect occurs at a dosage of ozone that produces minimal ventilatory changes and no observable endothelial ultrastructural changes.

  19. Impaired renal function impacts negatively on vascular stiffness in patients with coronary artery disease

    PubMed Central

    2013-01-01

    Background Chronic kidney disease (CKD) and coronary artery disease (CAD) are independently associated with increased vascular stiffness. We examined whether renal function contributes to vascular stiffness independently of CAD status. Methods We studied 160 patients with CAD and 169 subjects without CAD. The 4-variable MDRD formula was used to estimate glomerular filtration rate (eGFR); impaired renal function was defined as eGFR <60 mL/min. Carotid-femoral pulse wave velocity (PWV) was measured with the SphygmoCor® device. Circulating biomarkers were assessed in plasma using xMAP® multiplexing technology. Results Patients with CAD and impaired renal function had greater PWV compared to those with CAD and normal renal function (10.2 [9.1;11.2] vs 7.3 [6.9;7.7] m/s; P < 0.001). In all patients, PWV was a function of eGFR (β = −0.293; P < 0.001) even after adjustment for age, sex, systolic blood pressure, body mass index and presence or absence of CAD. Patients with CAD and impaired renal function had higher levels of adhesion and inflammatory molecules including E-selectin and osteopontin (all P < 0.05) compared to those with CAD alone, but had similar levels of markers of oxidative stress. Conclusions Renal function is a determinant of vascular stiffness even in patients with severe atherosclerotic disease. This was paralleled by differences in markers of cell adhesion and inflammation. Increased vascular stiffness may therefore be linked to inflammatory remodeling of the vasculature in people with impaired renal function, irrespective of concomitant atherosclerotic disease. PMID:23937620

  20. Functional genomics indicate that schizophrenia may be an adult vascular-ischemic disorder

    PubMed Central

    Moises, H W; Wollschläger, D; Binder, H

    2015-01-01

    In search for the elusive schizophrenia pathway, candidate genes for the disorder from a discovery sample were localized within the energy-delivering and ischemia protection pathway. To test the adult vascular-ischemic (AVIH) and the competing neurodevelopmental hypothesis (NDH), functional genomic analyses of practically all available schizophrenia-associated genes from candidate gene, genome-wide association and postmortem expression studies were performed. Our results indicate a significant overrepresentation of genes involved in vascular function (P<0.001), vasoregulation (that is, perivascular (P<0.001) and shear stress (P<0.01), cerebral ischemia (P<0.001), neurodevelopment (P<0.001) and postischemic repair (P<0.001) among schizophrenia-associated genes from genetic association studies. These findings support both the NDH and the AVIH. The genes from postmortem studies showed an upregulation of vascular-ischemic genes (P=0.020) combined with downregulated synaptic (P=0.005) genes, and ND/repair (P=0.003) genes. Evidence for the AVIH and the NDH is critically discussed. We conclude that schizophrenia is probably a mild adult vascular-ischemic and postischemic repair disorder. Adult postischemic repair involves ND genes for adult neurogenesis, synaptic plasticity, glutamate and increased long-term potentiation of excitatory neurotransmission (i-LTP). Schizophrenia might be caused by the cerebral analog of microvascular angina. PMID:26261884

  1. Multiple dietary supplements do not affect metabolic and cardio-vascular health.

    PubMed

    Soare, Andreea; Weiss, Edward P; Holloszy, John O; Fontana, Luigi

    2014-02-01

    Dietary supplements are widely used for health purposes. However, little is known about the metabolic and cardiovascular effects of combinations of popular over-the-counter supplements, each of which has been shown to have anti-oxidant, anti-inflammatory and pro-longevity properties in cell culture or animal studies. This study was a 6-month randomized, single-blind controlled trial, in which 56 non-obese (BMI 21.0-29.9 kg/m(2)) men and women, aged 38 to 55 yr, were assigned to a dietary supplement (SUP) group or control (CON) group, with a 6-month follow-up. The SUP group took 10 dietary supplements each day (100 mg of resveratrol, a complex of 800 mg each of green, black, and white tea extract, 250 mg of pomegranate extract, 650 mg of quercetin, 500 mg of acetyl-l-carnitine, 600 mg of lipoic acid, 900 mg of curcumin, 1 g of sesamin, 1.7 g of cinnamon bark extract, and 1.0 g fish oil). Both the SUP and CON groups took a daily multivitamin/mineral supplement. The main outcome measures were arterial stiffness, endothelial function, biomarkers of inflammation and oxidative stress, and cardiometabolic risk factors. Twenty-four weeks of daily supplementation with 10 dietary supplements did not affect arterial stiffness or endothelial function in nonobese individuals. These compounds also did not alter body fat measured by DEXA, blood pressure, plasma lipids, glucose, insulin, IGF-1, and markers of inflammation and oxidative stress. In summary, supplementation with a combination of popular dietary supplements has no cardiovascular or metabolic effects in non-obese relatively healthy individuals. PMID:24659610

  2. Interleukin-17 as a novel predictor of vascular function in rheumatoid arthritis

    PubMed Central

    Marder, Wendy; Khalatbari, Shokoufeh; Myles, James D.; Hench, Rita; Yalavarthi, Srilakshmi; Lustig, Susan; Brook, Robert; Kaplan, Mariana J.

    2011-01-01

    Objectives Rheumatoid arthritis (RA) is associated with enhanced cardiovascular (CV) risk and subclinical vascular disease. The proinflammatory milieu has been linked to premature atherosclerosis and endothelial dysfunction in RA. While IL-17 is considered pathogenic in RA, its role in determining vascular dysfunction in this disease has not been systematically assessed. We analyzed candidate variables that could determine endothelial function in various vascular territories in a cohort of RA patients on biologic therapy, with minimal traditional CV risk factors and low disease activity score. Methods RA patients (n=51) on stable biologic therapy underwent measurement of conduit artery endothelial function by brachial artery flow-mediated dilatation (FMD); arterial compliance by pulse wave velocity (PWV) assessment; and endothelium-dependent microvascular testing with Endo-PAT2000 device to assess reactive hyperemia index (RHI). IL-17 was quantified by ELISA and disease activity was assessed by DAS-28. Results IL-17 and high sensitivity CRP were the main determinants of lower RHI in univariate (p=0.004, <0.001) and multivariate (p=0.004, <0.0001) analysis, respectively. Traditional and non-traditional CV risk variables determined PWV, with a significant positive association with IL-17 in univariate and multivariate analysis (p=0.02, 0.01, respectively). In contrast, conduit endothelial function was mainly determined by rheumatoid factor titers (p=0.003). Anti-CCP titers and disease activity did not determine vascular function. Conclusion In RA patients treated with biologics, IL-17 is a main predictor of microvascular function and arterial compliance. This study suggests IL-17 may play a significant role in development of endothelial dysfunction and CVD in RA. PMID:21727237

  3. Vascular endothelial growth factor signaling affects both angiogenesis and osteogenesis during the development of scleral ossicles.

    PubMed

    Jabalee, James; Franz-Odendaal, Tamara A

    2015-10-01

    Intramembranous ossification is a complex multi-step process which relies on extensive interactions among bone cells and surrounding tissues. The embryonic vasculature is essential in regulating endochondral ossification; however, its role during intramembranous ossification remains poorly understood, and in vivo studies are lacking. Previous research from our lab on the development of the intramembranous scleral ossicles has demonstrated an intriguing pattern of vascular development in which the areas of future osteogenesis remain avascular until after bone induction has occurred. Such avascular zones are located directly beneath each of the conjunctival papillae, epithelial structures which provide osteogenic signals to the underlying mesenchyme. Here we provide a high-resolution map of the developing vasculature from the time of ossicle induction to mineralization using a novel technique. We show that vegfa is expressed by the papillae and nearby mesenchymal tissue throughout HH 34-37, when vascular growth is taking place, and is down-regulated thereafter. Localized inhibition of Vegf results in expansion of the avascular zone surrounding the implanted papilla and mispatterning of the scleral ossicles. These results demonstrate that Vegf signaling could provide important insights into the complex relationship between bone and vasculature during intramembranous bone development. PMID:26210172

  4. ECM-mimetic heparin glycosamioglycan-functionalized surface favors constructing functional vascular smooth muscle tissue in vitro.

    PubMed

    Zhang, Jimin; Wang, Jianing; Wei, Yongzhen; Gao, Cheng; Chen, Xuejiao; Kong, Wei; Kong, Deling; Zhao, Qiang

    2016-10-01

    Contractile vascular smooth muscle accounts for the normal physiological function of artery. Heparin, as a native glycosaminoglycan, has been well known for its important function in promoting or maintaining the contractile phenotype of vascular smooth muscle cells (VSMCs). In this study, heparin-functionalized non-woven poly(ε-caprolactone) (PCL) mat was fabricated by a facile and efficient surface modification protocol, which enables the control of surface heparin density within a broad range. Surface heparization remarkably increased the hydrophilicity of PCL, and reduced platelet adhesion. MTT assay showed that VSMC proliferation was evidently inhibited on the heparin-functionalized PCL surface in a dose-dependent manner. Gene analysis confirmed that surface heparization also promoted the transition of VSMCs from synthetic phenotype to contractile one. Furthermore, with a proper surface density of heparin, it allowed VSMCs to grow in a certain rate, while exhibiting contractile phenotype. Culture of VSMCs on a modified PCL mat with moderate heparin density (PCL-Hep-20) for 2 days resulted in a confluent layer of contractile smooth muscle cells. These data suggest that the heparin-modified PCL scaffolds may be a promising candidate to generate functional vascular tissues in vitro. PMID:27351139

  5. Engineering micropatterned surfaces to modulate the function of vascular stem cells

    SciTech Connect

    Li, Jennifer; Wu, Michelle; Chu, Julia; Sochol, Ryan; Patel, Shyam

    2014-02-21

    Highlights: • We examine vascular stem cell function on microgrooved and micropost patterned polymer substrates. • 10 μm microgrooved surfaces significantly lower VSC proliferation but do not modulate calcified matrix deposition. • Micropost surfaces significantly lower VSC proliferation and decrease calcified matrix deposition. - Abstract: Multipotent vascular stem cells have been implicated in vascular disease and in tissue remodeling post therapeutic intervention. Hyper-proliferation and calcified extracellular matrix deposition of VSC cause blood vessel narrowing and plaque hardening thereby increasing the risk of myocardial infarct. In this study, to optimize the surface design of vascular implants, we determined whether micropatterned polymer surfaces can modulate VSC differentiation and calcified matrix deposition. Undifferentiated rat VSC were cultured on microgrooved surfaces of varied groove widths, and on micropost surfaces. 10 μm microgrooved surfaces elongated VSC and decreased cell proliferation. However, microgrooved surfaces did not attenuate calcified extracellular matrix deposition by VSC cultured in osteogenic media conditions. In contrast, VSC cultured on micropost surfaces assumed a dendritic morphology, were significantly less proliferative, and deposited minimal calcified extracellular matrix. These results have significant implications for optimizing the design of cardiovascular implant surfaces.

  6. Construction of a fucoidan/laminin functional multilayer to direction vascular cell fate and promotion hemocompatibility.

    PubMed

    Ye, Changrong; Wang, Yan; Su, Hong; Yang, Ping; Huang, Nan; F Maitz, Manfred; Zhao, Anshan

    2016-07-01

    Surface biofunctional modification of cardiovascular stents is a versatile approach to reduce the adverse effects after implantation. In this work, a novel multifunctional coating was fabricated by coimmobilization of the sulfated polysaccharide of brown algae fucoidan and laminin to biomimic the vascular intimal conditions in order to support rapid endothelialization, prevent restenosis and improve hemocompatibility. The surface properties of the coating such as hydrophilicity, bonding density of biomolecules and stability were evaluated and optimized. According to the biocompatibility tests, the fucoidan/laminin multilayer coated surface displayed less platelet adhesion with favorable anticoagulant property. In addition, the fucoidan/laminin complex showed function to selectively regulate vascular cells growth behavior. The proliferation of endothelial cells (ECs) on the fucoidan/laminin biofunctional coating was significantly promoted. For the smooth muscle cells (SMCs), inhibitory effects on cell adhesion and proliferation were observed. In conclusion, the fucoidan/laminin biofunctional coating was successfully fabricated with desirable anticoagulant and endothelialization properties which show a promising application in the vascular devices such as vascular stents or grafts surface modification. PMID:27127049

  7. Thrombospondin-1 domain-containing peptide properdistatin improves vascular function in human melanoma xenografts.

    PubMed

    Gaustad, Jon-Vidar; Simonsen, Trude G; Andersen, Lise Mari K; Rofstad, Einar K

    2015-03-01

    Properdistatin is a novel peptide derived from the thrombospondin-1 domain of the plasma protein properdin. The purpose of this study was to investigate the effect of properdistatin treatment on the morphology and function of tumor vasculature. A-07 human melanoma xenografts grown in dorsal window chambers were used as preclinical model. Tumors were treated with 80 mg/kg/day properdistatin or vehicle for 4 days. Morphologic parameters of tumor vascular networks were assessed from high-resolution transillumination images, and tumor blood supply time and plasma velocities were assessed from first-pass imaging movies recorded after a bolus of 155 kDa tetramethylrhodamine isothiocyanate-labeled dextran had been administered intravenously. Properdistatin-treated tumors showed reduced density of small-diameter vessels, reduced blood supply time, and increased plasma velocities. In conclusion, properdistatin treatment inhibited angiogenesis and improved vascular function in A-07 tumors. PMID:24555949

  8. Vascular Function, Inflammation, and Variations in Cardiac Autonomic Responses to Particulate Matter Among Welders

    PubMed Central

    Cavallari, Jennifer M.; Eisen, Ellen A.; Chen, Jiu-Chiuan; Mittleman, Murray A.; Christiani, David C.

    2009-01-01

    Patients with health conditions associated with impaired vascular function and inflammation may be more susceptible to the adverse health effects of fine particulate (particulate matter with a mass median aerodynamic diameter of ≤2.5 μm (PM2.5)) exposure. In 2006, the authors conducted a panel study to investigate directly whether vascular function and inflammation (assessed by C-reactive protein) modify PM2.5-associated reductions in heart rate variability among 23 young male workers (mean age, 40 years) from Massachusetts. Concurrent 24-hour ambulatory electrocardiogram and personal PM2.5 exposure information was collected over a total of 36 person-days, including either or both welding and nonwelding days. Linear mixed models were used to examine the 5-minute standard deviation of normal-to-normal intervals (SDNN) in relation to the moving PM2.5 averages in the preceding 1–4 hours. C-reactive protein levels and 3 measures of vascular function (augmentation index, mean arterial pressure, and pulse pressure) were determined at baseline. The authors observed an inverse association between the 1-hour PM2.5 and 5-minute SDNN. Greater SDNN declines were observed among those with C-reactive protein (Pinteraction < 0.001) and augmentation index (P = 0.06) values at or above the 75th percentile and pulse pressure values below the 75th percentile (P < 0.001). Systemic inflammation and poorer vascular function appear to aggravate particle-related declines in heart rate variability among workers. PMID:19153215

  9. Changes in vascular plant functional types drive carbon cycling in peatlands

    NASA Astrophysics Data System (ADS)

    Zeh, Lilli; Bragazza, Luca; Erhagen, Björn; Limpens, Juul; Kalbitz, Karsten

    2016-04-01

    Northern peatlands store a large organic carbon (C) pool that is highly exposed to future environmental changes with consequent risk of releasing enormous amounts of C. Biotic changes in plant community structure and species abundance might have an even stronger impact on soil organic C dynamics in peatlands than the direct effects of abiotic changes. Therefore, a sound understanding of the impact of vegetation dynamics on C cycling will help to better predict the response of peatlands to environmental changes. Here, we aimed to assess the role of plant functional types (PFTs) in affecting peat decomposition in relation to climate warming. To this aim, we selected two peatlands at different altitude (i.e. 1300 and 1700 m asl) on the south-eastern Alps of Italy. The two sites represent a contrast in temperature, overall vascular plant biomass and relative ericoids abundance, with the highest biomass and ericoids occurrence at the low latitude. Within the sites we selected 20 plots of similar microtopographical position and general vegetation type (hummocks). All plots contained both graminoids and ericoids and had a 100% cover of Sphagnum mosses. The plots were subjected to four treatments (control, and three clipping treatments) in which we selectively removed aboveground biomass of ericoids, graminoids or both to explore the contribution of the different PFTs for soil respiration (n=5) and peat chemistry. Peat chemical composition was determined by the analysis of C and N and their stable isotopes in association with pyrolysis GC/MS. Soil respiration was measured after clipping with a Licor system. Preliminary findings suggest that peat decomposition pathway and rate depend on plant species composition and particularly on differences in root activity between PFTs. Finally, this study underlines the importance of biotic drivers to predict the effects of future environmental changes on peatland C cycling.

  10. Identification of chemical components of combustion emissions that affect pro-atherosclerotic vascular responses in mice

    PubMed Central

    Seilkop, Steven K.; Campen, Matthew J.; Lund, Amie K.; McDonald, Jacob D.; Mauderly, Joe L.

    2012-01-01

    Combustion emissions cause pro-atherosclerotic responses in apolipoprotein E-deficient (ApoE/−) mice, but the causal components of these complex mixtures are unresolved. In studies previously reported, ApoE−/− mice were exposed by inhalation 6 h/day for 50 consecutive days to multiple dilutions of diesel or gasoline exhaust, wood smoke, or simulated “downwind” coal emissions. In this study, the analysis of the combined four-study database using the Multiple Additive Regression Trees (MART) data mining approach to determine putative causal exposure components regardless of combustion source is reported. Over 700 physical–chemical components were grouped into 45 predictor variables. Response variables measured in aorta included endothelin-1, vascular endothelin growth factor, three matrix metalloproteinases (3, 7, 9), metalloproteinase inhibitor 2, heme-oxygenase-1, and thiobarbituric acid reactive substances. Two or three predictors typically explained most of the variation in response among the experimental groups. Overall, sulfur dioxide, ammonia, nitrogen oxides, and carbon monoxide were most highly predictive of responses, although their rankings differed among the responses. Consistent with the earlier finding that filtration of particles had little effect on responses, particulate components ranked third to seventh in predictive importance for the eight response variables. MART proved useful for identifying putative causal components, although the small number of pollution mixtures (4) can provide only suggestive evidence of causality. The potential independent causal contributions of these gases to the vascular responses, as well as possible interactions among them and other components of complex pollutant mixtures, warrant further evaluation. PMID:22486345

  11. CONSUMING A BALANCED HIGH FAT DIET FOR 16 WEEKS IMPROVES BODY COMPOSITION, INFLAMMATION AND VASCULAR FUNCTION PARAMETERS IN OBESE PREMENOPAUSAL WOMEN

    PubMed Central

    Silver, Heidi J.; Kang, Hakmook; Keil, Charles D.; Muldowney, James A.; Kocalis, Heidi; Fazio, Sergio; Vaughan, Douglas E.; Niswender, Kevin D.

    2014-01-01

    Objective Inflammation, insulin resistance and vascular dysfunction characterize obesity and predict development of cardiovascular disease (CVD). Although women experience CVD events at an older age, vascular dysfunction is evident 10 years prior to coronary artery disease. Questions remain whether replacing SFA entirely with MUFA or PUFA is the optimal approach for cardiometabolic benefits. This study tested the hypotheses that: a) body composition, inflammation and vascular function would improve with a high fat diet (HFD) when type of fat is balanced as 1/3 SFA, 1/3 MUFA and 1/3 PUFA; and b) body composition, inflammation and vascular function would improve more when balanced HFD is supplemented with 18C fatty acids, in proportion to the degree of 18C unsaturation. Methods Obese premenopausal women were stabilized on balanced HFD and randomized to consume 9 g/d of encapsulated stearate (18:0), oleate (18:1), linoleate (18:2) or placebo. Results Significant improvements occurred in fat oxidation rate (↑6%), body composition (%fat: ↓2.5 ± 2.1%; %lean: ↑2.5 ± 2.1%), inflammation (↓ IL-1α, IL-1β, 1L-12, Il-17, IFNγ, TNFα, TNFβ) and vascular function (↓BP, ↓PAI-1, ↑tPA activity). When compared to HFD+placebo, HFD+stearate had the greatest effect on reducing IFNγ (↓74%) and HFD+linoleate had the greatest effect on reducing PAI-1 (↓31%). Conclusions Balancing the type of dietary fat consumed (SFA/MUFA/PUFA) is a feasible strategy to positively affect markers of CVD risk. Moreover, reductions in inflammatory molecules involved in vascular function might be enhanced when intake of certain 18C fatty acids is supplemented. Long term effects need to be determined for this approach. PMID:24559846

  12. Circulating Adipokines and Vascular Function: Cross-Sectional Associations in a Community-Based Cohort.

    PubMed

    Zachariah, Justin P; Hwang, Susan; Hamburg, Naomi M; Benjamin, Emelia J; Larson, Martin G; Levy, Daniel; Vita, Joseph A; Sullivan, Lisa M; Mitchell, Gary F; Vasan, Ramachandran S

    2016-02-01

    Adipokines may be potential mediators of the association between excess adiposity and vascular dysfunction. We assessed the cross-sectional associations of circulating adipokines with vascular stiffness in a community-based cohort of younger adults. We related circulating concentrations of leptin and leptin receptor, adiponectin, retinol-binding protein 4, and fatty acid-binding protein 4 to vascular stiffness measured by arterial tonometry in 3505 Framingham Third Generation cohort participants free of cardiovascular disease (mean age 40 years, 53% women). Separate regression models estimated the relations of each adipokine to mean arterial pressure and aortic stiffness, as carotid femoral pulse wave velocity, adjusting for age, sex, smoking, heart rate, height, antihypertensive treatment, total and high-density lipoprotein cholesterol, diabetes mellitus, alcohol consumption, estimated glomerular filtration rate, glucose, and C-reactive protein. Models evaluating aortic stiffness also were adjusted for mean arterial pressure. Mean arterial pressure was positively associated with blood retinol-binding protein 4, fatty acid-binding protein 4, and leptin concentrations (all P<0.001) and inversely with adiponectin (P=0.002). In fully adjusted models, mean arterial pressure was positively associated with retinol-binding protein 4 and leptin receptor levels (P<0.002 both). In fully adjusted models, aortic stiffness was positively associated with fatty acid-binding protein 4 concentrations (P=0.02), but inversely with leptin and leptin receptor levels (P≤0.03 both). In our large community-based sample, circulating concentrations of select adipokines were associated with vascular stiffness measures, consistent with the hypothesis that adipokines may influence vascular function and may contribute to the relation between obesity and hypertension. PMID:26628673

  13. Assessment of vascular function in Mexican women exposed to polycyclic aromatic hydrocarbons from wood smoke.

    PubMed

    Ruiz-Vera, Tania; Pruneda-Álvarez, Lucia G; Ochoa-Martínez, Ángeles C; Ramírez-GarcíaLuna, José L; Pierdant-Pérez, Mauricio; Gordillo-Moscoso, Antonio A; Pérez-Vázquez, Francisco J; Pérez-Maldonado, Iván N

    2015-09-01

    The use of solid fuels for cooking and heating is likely to be the largest source of indoor air pollution on a global scale; these fuels emit substantial amounts of toxic pollutants such as polycyclic aromatic hydrocarbons (PAHs) when used in simple cooking stoves (such as open "three-stone" fires). Moreover, indoor air pollution from biomass fuels is considered an important risk factor for human health. The aim of this study was to evaluate the relationship between exposure to PAHs from wood smoke and vascular dysfunction; in a group of Mexican women that use biomass combustion as their main energy source inside their homes. We used 1-hydroxypyrene (1-OHP) as an exposure biomarker to PAHs and it was assessed using high performance liquid chromatography. The endothelium-dependent vasodilation was assessed through a vascular reactivity compression test performed with a pneumatic cuff under visualization of the brachial artery using high resolution ultrasonography (HRU). Assessment of the carotid intima-media thickness (CIMT) was used as an atherosclerosis biomarker (also assessed using HRU); and clinical parameters such as anthropometry, blood pressure, glucose, triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol, among others were also evaluated. The mean concentration of urinary 1-OHP found in exposed women was 0.46±0.32μmol/mol Cr (range: 0.086-1.23μmol/mol Cr). Moreover, vascular dysfunction (diminished endothelium dependent vasodilation) was found in 45% of the women participating in the study. Association between vascular function and 1-OHP levels was found to be significant through a logistic regression analysis (p=0.034; r(2)=0.1329). Furthermore, no association between CIMT and clinical parameters, urinary 1-OHP levels or vascular dysfunction was found. Therefore, with the information obtained in this study, we advocate for the need to implement programs to reduce the risk of exposure to PAHs in communities that use biomass fuels as a main

  14. Effects of real and simulated weightlessness on the cardiac and peripheral vascular functions of humans: A review.

    PubMed

    Zhu, Hui; Wang, Hanqing; Liu, Zhiqiang

    2015-01-01

    Weightlessness is an extreme environment that can cause a series of adaptive changes in the human body. Findings from real and simulated weightlessness indicate altered cardiovascular functions, such as reduction in left ventricular (LV) mass, cardiac arrhythmia, reduced vascular tone and so on. These alterations induced by weightlessness are detrimental to the health, safety and working performance of the astronauts, therefore it is important to study the effects of weightlessness on the cardiovascular functions of humans. The cardiovascular functional alterations caused by weightlessness (including long-term spaceflight and simulated weightlessness) are briefly reviewed in terms of the cardiac and peripheral vascular functions. The alterations include: changes of shape and mass of the heart; cardiac function alterations; the cardiac arrhythmia; lower body vascular regulation and upper body vascular regulation. A series of conclusions are reported, some of which are analyzed, and a few potential directions are presented. PMID:26224491

  15. Thyroid hormone affects both endothelial and vascular smooth muscle cells in rat arteries.

    PubMed

    Cai, Yin; Manio, Michael M; Leung, George P H; Xu, Aimin; Tang, Eva H C; Vanhoutte, Paul M

    2015-01-15

    Hypothyroidism impairs endothelium-dependent dilatations, while hyperthyroidism augments the production of endothelial nitric oxide. Thus, experiments were designed to determine if thyroid hormone causes endothelium-dependent responses, or alleviates diabetic endothelial dysfunction. Isometric tension was measured in rings with or without endothelium of arteries from normal and diabetic Sprague-Dawley rats. Release of 6-keto prostaglandin F1α and thromboxane B2 were measured by enzyme linked immunosorbent assay and protein levels [endothelial nitric oxide synthase (eNOS), cyclooxygenases (COX)] by immunoblotting. Triiodothyronine (T3) caused concentration-dependent (3×10(-6)-3×10(-5)M) relaxations in mesenteric (pEC50, 4.96±0.19) and femoral (pEC50, 4.57±0.35) arteries without endothelium. In femoral arteries of rats with diabetes, 5-methylamino-2-[[(2S,3R,5R,8S,9S)-3,5,9-trimethyl-2-(1-oxo-(1H-pyrrol-2- -yl)propan-2-yl)-1,7-dioxaspiro-(5,5)undecan-8-yl]methyl]benzooxazole-4-carboxylic acid (A23187, 3×10(-7) to 10(-6)M) caused partly endothelium-dependent contractions. After chronic T3-treatment with (10μg/kg/day; four weeks), the contractions to A23187 of preparations with and without endothelium were comparable, the thromboxane B2-release was reduced (by 38.1±9.2%). The pEC50 of 9, 11-dideoxy-11α, 9α-epoxymethanoprostaglandin F2α (U46619, TP-receptor agonist) was increased in T3-treated diabetic rats compared with controls (8.53±0.06 vs 7.94±0.09). The protein expression of eNOS increased (by 228%) but that of COX-1 decreased (by 35%) after chronic T3 treatment. In human umbilical vein endothelial cells incubated for one week with T3 (10(-10)-10(-7)M) in the presence but not in the absence of interleukin-1β (1ng/ml), the expression of eNOS was increased compared to control. In conclusion, thyroid hormone acutely relaxes mesenteric and femoral vascular smooth muscle, but given chronically reduces the release of endothelium-derived vasoconstrictor

  16. The effect of age on the relationship between cardiac and vascular function

    PubMed Central

    Houghton, David; Jones, Thomas W.; Cassidy, Sophie; Siervo, Mario; MacGowan, Guy A.; Trenell, Michael I.; Jakovljevic, Djordje G.

    2016-01-01

    Age-related changes in cardiac and vascular function are associated with increased risk of cardiovascular mortality and morbidity. The aim of the present study was to define the effect of age on the relationship between cardiac and vascular function. Haemodynamic and gas exchange measurements were performed at rest and peak exercise in healthy individuals. Augmentation index was measured at rest. Cardiac power output, a measure of overall cardiac function, was calculated as the product of cardiac output and mean arterial blood pressure. Augmentation index was significantly higher in older than younger participants (27.7 ± 10.1 vs. 2.5 ± 10.1%, P < 0.01). Older people demonstrated significantly higher stroke volume and mean arterial blood pressure (P < 0.05), but lower heart rate (145 ± 13 vs. 172 ± 10 beats/min, P < 0.01) and peak oxygen consumption (22.5 ± 5.2 vs. 41.2 ± 8.4 ml/kg/min, P < 0.01). There was a significant negative relationship between augmentation index and peak exercise cardiac power output (r = −0.73, P = 0.02) and cardiac output (r = −0.69, P = 0.03) in older participants. Older people maintain maximal cardiac function due to increased stroke volume. Vascular function is a strong predictor of overall cardiac function in older but in not younger people. PMID:26590322

  17. Antioxidative effect of aspirin on vascular function of aged ovariectomized rats.

    PubMed

    Demirci, Buket; Demir, Omer; Dost, Turhan; Birincioglu, Mustafa

    2014-02-01

    This study investigated the vascular effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in the very late stage of postmenopausal vascular aging and looked for a better choice of anti-inflammatory drug for women in reducing the cardiovascular risk by decreasing the oxidant status in this term. The rat aorta isolated from young and old rats that were treated with either aspirin (10 mg/kg/day) or indomethacin (INDO, 1 mg/kg/day) within last 10 weeks after 16-month overiectomy (OVX) follow-up. Endothelium-dependant acetylcholine (Ach, 0.001-30 μM) and independent sodium nitroprusside (SNP, 0.0001-3 μM) relaxant; α-receptor phenylephrine (PE, 0.001-30 μM) and voltage-dependant high potassium (KCl; 40 mM) contractile responses were assessed. Total oxidant and antioxidant status were measured from the serum samples. Aged OVX rat's both aortic endothelium and smooth muscle relaxation were significantly less than of younger ones, whereas their contractile functions tended to decrease. INDO did not treat the Ach, SNP responses, whereas it increased the PE and KCl contractility. Aspirin improved the relaxation function and antioxidant capacity and decreased the oxidant status. These data demonstrate that even if they are in the very late stage of life and menopause, the analgesic choices could restore the well established endothelial dysfunction, vascular stiffness, and oxidant status. PMID:23872923

  18. 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

  19. [Cerebral hemodynamics and statokinetic functions in patients with vertebral basilar vascular insufficiency].

    PubMed

    Butko, D Iu

    2004-01-01

    One hundred and forty-eight patients, aged 29-59 years, with vertebral basilar vascular insufficiency were studied before, during and after betaserc treatment in a dose 48 mg/day during 3 weeks. Along with neurological examination, cerebral dopplerography and computer stabilography methods were used. The main clinical appearances of cerebrovascular pathology of vertebrobasilar system were as follows: vertigo (93.2%), asthenia syndrome (91.2%), autonomic vascular disorders (63.5%) and stato-coordinative disturbances, the latter were represented primarily by disturbances of equilibrium system functions (83.8%). Cerebral dopplerography and computer stabilography were found to be reliable methods for patients with chronic insufficiency of cerebral blood circulation in vertebral basilar area. Drug betaserc (betahystine hydrochloride) effectively stops statokinetic disturbances in patients with discirculatory encelopathy in vertebral basilar area. PMID:15847325

  20. The peptide semax affects the expression of genes related to the immune and vascular systems in rat brain focal ischemia: genome-wide transcriptional analysis

    PubMed Central

    2014-01-01

    Background The nootropic neuroprotective peptide Semax (Met-Glu-His-Phe-Pro-Gly-Pro) has proved efficient in the therapy of brain stroke; however, the molecular mechanisms underlying its action remain obscure. Our genome-wide study was designed to investigate the response of the transcriptome of ischemized rat brain cortex tissues to the action of Semax in vivo. Results The gene-expression alteration caused by the action of the peptide Semax was compared with the gene expression of the “ischemia” group animals at 3 and 24 h after permanent middle cerebral artery occlusion (pMCAO). The peptide predominantly enhanced the expression of genes related to the immune system. Three hours after pMCAO, Semax influenced the expression of some genes that affect the activity of immune cells, and, 24 h after pMCAO, the action of Semax on the immune response increased considerably. The genes implicated in this response represented over 50% of the total number of genes that exhibited Semax-induced altered expression. Among the immune-response genes, the expression of which was modulated by Semax, genes that encode immunoglobulins and chemokines formed the most notable groups. In response to Semax administration, 24 genes related to the vascular system exhibited altered expression 3 h after pMCAO, whereas 12 genes were changed 24 h after pMCAO. These genes are associated with such processes as the development and migration of endothelial tissue, the migration of smooth muscle cells, hematopoiesis, and vasculogenesis. Conclusions Semax affects several biological processes involved in the function of various systems. The immune response is the process most markedly affected by the drug. Semax altered the expression of genes that modulate the amount and mobility of immune cells and enhanced the expression of genes that encode chemokines and immunoglobulins. In conditions of rat brain focal ischemia, Semax influenced the expression of genes that promote the formation and

  1. Composition of PM Affects Acute Vascular Inflammatory and Coagulative Markers - The RAPTES Project

    PubMed Central

    Strak, Maciej; Hoek, Gerard; Godri, Krystal J.; Gosens, Ilse; Mudway, Ian S.; van Oerle, René; Spronk, Henri M. H.; Cassee, Flemming R.; Lebret, Erik; Kelly, Frank J.; Harrison, Roy M.; Brunekreef, Bert; Steenhof, Maaike; Janssen, Nicole A. H.

    2013-01-01

    Background Exposure to ambient particulate matter (PM) has been associated with adverse cardiovascular effects in epidemiological studies. Current knowledge of independent effects of individual PM characteristics remains limited. Methods Using a semi-experimental design we investigated which PM characteristics were consistently associated with blood biomarkers believed to be predictive of the risk of cardiovascular events. We exposed healthy adult volunteers at 5 different locations chosen to provide PM exposure contrasts with reduced correlations among PM characteristics. Each of the 31 volunteers was exposed for 5 h, exercising intermittently, 3–7 times at different sites from March to October 2009. Extensive on-site exposure characterization included measurements of PM mass and number concentration, elemental- (EC) and organic carbon (OC), trace metals, sulfate, nitrate, and PM oxidative potential (OP). Before and 2 h and 18 h after exposure we measured acute vascular blood biomarkers - C-reactive protein, fibrinogen, platelet counts, von Willebrand Factor, and tissue plasminogen activator/plasminogen activator inhibitor-1 complex. We used two-pollutant models to assess which PM characteristics were most consistently associated with the measured biomarkers. Results and Conclusion We found OC, nitrate and sulfate to be most consistently associated with different biomarkers of acute cardiovascular risk. Associations with PM mass concentrations and OP were less consistent, whereas other measured components of the air pollution mixture, including PNC, EC, trace metals and NO2, were not associated with the biomarkers after adjusting for other pollutants. PMID:23516583

  2. Extracellular functional noncoding nucleic acid bioaptamers and angiotropin RNP ribokines in vascularization and self-tolerance.

    PubMed

    Wissler, Josef H; Wissler, Joerg E; Logemann, Enno

    2008-08-01

    Endogenous extracellular and circulating functional small noncoding nucleic acids (ncNAs; <200 nucleotides) and complexes with proteins (ribonucleoproteins; RNPs) make up varying biolibraries of molecular imprints of cellular histories. They are nascently formed upon cellular activation by extrinsic (environmental) factors, including mitogens, cell-mediated immune memory reactions (Landsteiner-Chase-Lawrence transfer factors), and metabolic (hypoxia) and (physical) shear stress forces. Those factors are conventional models for epigenetic (non-Mendelian) vascular remodeling variations directed rather to proteinaceous gene expression and regulation than genomic DNA sequence changes. Structurally defined ncNAs are described as small hairpin nc-shRNA bioaptamers in interaction with proteins forming functional (Cu,Ca,Na,K)-metalloregulated complexes (CuRNP; angiotropins). As nonmitogenic angiomorphogen cytokines (ribokines), they may reprogram confluent quiescent (contact-inhibited) endothelial cell types to migratory, phagokinetically active phenotypes in the morphogenesis of tolerated neovascular patterns. Their functions in organized and mess-chaotic vascular patterns were investigated with regard to master gene, information, epigenetic, vascular, and tumor factors. Some ncNAs feature three-dimensional codes (3D episcripts) for distinct protein conformer phases. They are suggested as being specific recognition types, the estimated repertoires of which are superior in diversity and specificity to conventional immune (glyco-)proteins. For episcription of phenotype variations, they may address and integrate information flow on molecular shapes to protein-mediated nucleic acid processing and [post-]translational modification mechanisms in ncNA-, redox, and metalloregulated conformation phase pathway-locked loops (CPLL). Several vascular and cancer epigenetic regulator proteins are shown to be entangled by sharing helix-nucleating structural (proteomic) domains for

  3. 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

  4. Functional spectroscopy approach to the assessment of nitric oxide storage in vascular tissues

    NASA Astrophysics Data System (ADS)

    Rodriguez, Juan; Feelisch, Martin

    2003-10-01

    Much attention has been devoted to the enzymatic production of nitric oxide (NO) by the endothelial layer lining blood vessel walls, which regulates among other things local vasodilatation and platelet adhesion. Considerably less attention, however, has been paid to the accumulation of NO-related products in the vascular wall itself. Such local storage of NO products could conceivably contribute to the local regulation of blood flow and provide additional anti-adhesive protection, if biochemically activated to regenerate NO. Since little is known about their chemical nature, concentrations, and possible role in vascular biology we sought to characterize those species basally resent in rat aorta. To this end we developed a functional form of optical spectroscopy that allows us not only to identify NO-stores in intact tissues but also to monitor their production and disappearance in real-time. The method is based on the ability of NO stores to reversibly release NO when illuminated with light of particular wavelengths, which can be detected as a robust relaxation of vascular smooth muscle (photorelaxation). Characterization of NO-stores is achieved through a careful assessment of photorelaxation action spectra, taking into account the light scattering properties of the tissue, and of depletion of the NO-stores induced by exposure to controlled levels of light. This functional form of optical spectroscopy is applied to rat aortic tissue where the results suggest that the NO photolytically released from tissue stores originated from a low-molecular-weight RSNO as well as from nitrite. The significance of these findings to vascular physiology and pathophysiology is discussed.

  5. Mevalonate availability affects human and rat resistance vessel function.

    PubMed Central

    Roullet, J B; Xue, H; Roullet, C M; Fletcher, W S; Cipolla, M J; Harker, C T; McCarron, D A

    1995-01-01

    Previous data in rat conductance vessels indicated that cellular mevalonate contributes to vascular tone and systemic blood pressure control. Using exogenous mevalonate (M) or lovastatin, a 3-hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitor (L), we characterized the role of mevalonate availability in resistance artery function, both in experimental animals and humans. Rat mesenteric artery resistance vessels (MARV, n = 9) were incubated for 48 h with either L, M, L + M, or vehicle (V) and tested for reactivity to NE, serotonin, acetylcholine, atrial natriuretic peptide, and sodium nitroprusside (SNP). Lovastatin increased sensitivity to NE (P < 0.03) and serotonin (P < 0.003), and significantly impaired the response to all three vasodilators. These effects were reversed by co-incubation with mevalonate. Mevalonate alone had no effect. In separate experiments, intravascular free Ca2+ concentration (ivfCa2+) was determined in fura-2AM loaded MARV. Basal ivfCa2+ was increased after a 48-h exposure to L (52.7 +/- 4.6 nM, L, vs. 29.7 +/- 2.4 nM, V, n = 12, P < 0.003), as were ivfCa2+ levels following stimulation with low (100 nM) NE concentrations. Similar ivfCa2+ concentrations were achieved during maximum contraction with NE (10 mM) in both groups. Human resistance arteries of human adipose tissue were also studied. Lovastatin increased the sensitivity to NE (ED50 = 372 +/- 56 nM, V, and 99 +/- 33 nM, L, P < 0.001) and significantly decreased the relaxation to acetylcholine and SNP of human vessels. We conclude that mevalonate availability directly contribute to resistance vessel function and vascular signal transduction systems in both experimental animals and humans. The study calls for the identification of non-sterol, mevalonate-derived vasoactive metabolites, and suggests that disorders of the mevalonate pathway can alter vascular tone and cause hypertension. PMID:7615793

  6. Mechanics and Function of the Pulmonary Vasculature: Implications for Pulmonary Vascular Disease and Right Ventricular Function

    PubMed Central

    Lammers, Steven; Scott, Devon; Hunter, Kendall; Tan, Wei; Shandas, Robin; Stenmark, Kurt R.

    2012-01-01

    The relationship between cardiac function and the afterload against which the heart muscle must work to circulate blood throughout the pulmonary circulation is defined by a complex interaction between many coupled system parameters. These parameters range broadly and incorporate system effects originating primarily from three distinct locations: input power from the heart, hydraulic impedance from the large conduit pulmonary arteries, and hydraulic resistance from the more distal microcirculation. These organ systems are not independent, but rather, form a coupled system in which a change to any individual parameter affects all other system parameters. The result is a highly nonlinear system which requires not only detailed study of each specific component and the effect of disease on their specific function, but also requires study of the interconnected relationship between the microcirculation, the conduit arteries, and the heart in response to age and disease. Here, we investigate systems-level changes associated with pulmonary hypertensive disease progression in an effort to better understand this coupled relationship. PMID:23487595

  7. The role of mechanotransduction on vascular smooth muscle myocytes' [corrected] cytoskeleton and contractile function.

    PubMed

    Ye, George J C; Nesmith, Alexander P; Parker, Kevin Kit

    2014-09-01

    Smooth muscle (SM) exhibits a highly organized structural hierarchy that extends over multiple spatial scales to perform a wide range of functions at the cellular, tissue, and organ levels. Early efforts primarily focused on understanding vascular SM (VSM) function through biochemical signaling. However, accumulating evidence suggests that mechanotransduction, the process through which cells convert mechanical stimuli into biochemical cues, is requisite for regulating contractility. Cytoskeletal proteins that comprise the extracellular, intercellular, and intracellular domains are mechanosensitive and can remodel their structure and function in response to external mechanical cues. Pathological stimuli such as malignant hypertension can act through the same mechanotransductive pathways to induce maladaptive remodeling, leading to changes in cellular shape and loss of contractile function. In both health and disease, the cytoskeletal architecture integrates the mechanical stimuli and mediates structural and functional remodeling in the VSM. PMID:25125187

  8. Acute Effect of High-Intensity Eccentric Exercise on Vascular Endothelial Function in Young Men.

    PubMed

    Choi, Youngju; Akazawa, Nobuhiko; Zempo-Miyaki, Asako; Ra, Song-Gyu; Shiraki, Hitoshi; Ajisaka, Ryuichi; Maeda, Seiji

    2016-08-01

    Choi, Y, Akazawa, N, Zempo-Miyaki, A, Ra, S-G, Shiraki, H, Ajisaka, R, and Maeda, S. Acute effect of high-intensity eccentric exercise on vascular endothelial function in young men. J Strength Cond Res 30(8): 2279-2285, 2016-Increased central arterial stiffness is as an independent risk factor for cardiovascular disease. Evidence regarding the effects of high-intensity resistance exercise on vascular endothelial function and central arterial stiffness is conflicting. The purpose of this study was to examine the effects of acute high-intensity eccentric exercise on vascular endothelial function and central arterial stiffness. We evaluated the acute changes in endothelium-dependent flow-mediated dilation (FMD), low-flow-mediated constriction (L-FMC), and arterial stiffness after high-intensity eccentric exercise. Seven healthy, sedentary men (age, 24 ± 1 year) performed maximal eccentric elbow flexor exercise using their nondominant arm. Before and 45 minutes after eccentric exercise, carotid arterial compliance and brachial artery FMD and L-FMC in the nonexercised arm were measured. Carotid arterial compliance was significantly decreased, and β-stiffness index significantly increased after eccentric exercise. Brachial FMD was significantly reduced after eccentric exercise, whereas there was no significant difference in brachial L-FMC before and after eccentric exercise. A positive correlation was detected between change in arterial compliance and change in FMD (r = 0.779; p ≤ 0.05), and a negative correlation was detected between change in β-stiffness index and change in FMD (r = -0.891; p < 0.01) with eccentric exercise. In this study, acute high-intensity eccentric exercise increased central arterial stiffness; this increase was accompanied by a decrease in endothelial function caused by reduced endothelium-dependent vasodilation but not by a change in endothelium-dependent vasoconstriction. PMID:24832967

  9. Experimental studies of mitochondrial function in CADASIL vascular smooth muscle cells

    SciTech Connect

    Viitanen, Matti; Sundström, Erik; Baumann, Marc; Tikka, Saara

    2013-02-01

    Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a familiar fatal progressive degenerative disorder characterized by cognitive decline, and recurrent stroke in young adults. Pathological features include a dramatic reduction of brain vascular smooth muscle cells and severe arteriopathy with the presence of granular osmophilic material in the arterial walls. Here we have investigated the cellular and mitochondrial function in vascular smooth muscle cell lines (VSMCs) established from CADASIL mutation carriers (R133C) and healthy controls. We found significantly lower proliferation rates in CADASIL VSMC as compared to VSMC from controls. Cultured CADASIL VSMCs were not more vulnerable than control cells to a number of toxic substances. Morphological studies showed reduced mitochondrial connectivity and increased number of mitochondria in CADASIL VSMCs. Transmission electron microscopy analysis demonstrated increased irregular and abnormal mitochondria in CADASIL VSMCs. Measurements of mitochondrial membrane potential (Δψ{sub m}) showed a lower percentage of fully functional mitochondria in CADASIL VSMCs. For a number of genes previously reported to be changed in CADASIL VSMCs, immunoblotting analysis demonstrated a significantly reduced SOD1 expression. These findings suggest that alteration of proliferation and mitochondrial function in CADASIL VSMCs might have an effect on vital cellular functions important for CADASIL pathology. -- Highlights: ► CADASIL is an inherited disease of cerebral vascular cells. ► Mitochondrial dysfunction has been implicated in the pathogenesis of CADASIL. ► Lower proliferation rates in CADASIL VSMC. ► Increased irregular and abnormal mitochondria and lower mitochondrial membrane potential in CADASIL VSMCs. ► Reduced mitochondrial connectivity and increased number of mitochondria in CADASIL VSMCs.

  10. Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess.

    PubMed

    Wyrwoll, Caitlin S; Noble, June; Thomson, Adrian; Tesic, Dijana; Miller, Mark R; Rog-Zielinska, Eva A; Moran, Carmel M; Seckl, Jonathan R; Chapman, Karen E; Holmes, Megan C

    2016-05-31

    Fetoplacental glucocorticoid overexposure is a significant mechanism underlying fetal growth restriction and the programming of adverse health outcomes in the adult. Placental glucocorticoid inactivation by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) plays a key role. We previously discovered that Hsd11b2(-/-) mice, lacking 11β-HSD2, show marked underdevelopment of the placental vasculature. We now explore the consequences for fetal cardiovascular development and whether this is reversible. We studied Hsd11b2(+/+), Hsd11b2(+/-), and Hsd11b2(-/-) littermates from heterozygous (Hsd11b(+/-)) matings at embryonic day (E)14.5 and E17.5, where all three genotypes were present to control for maternal effects. Using high-resolution ultrasound, we found that umbilical vein blood velocity in Hsd11b2(-/-) fetuses did not undergo the normal gestational increase seen in Hsd11b2(+/+) littermates. Similarly, the resistance index in the umbilical artery did not show the normal gestational decline. Surprisingly, given that 11β-HSD2 absence is predicted to initiate early maturation, the E/A wave ratio was reduced at E17.5 in Hsd11b2(-/-) fetuses, suggesting impaired cardiac function. Pravastatin administration from E6.5, which increases placental vascular endothelial growth factor A and, thus, vascularization, increased placental fetal capillary volume, ameliorated the aberrant umbilical cord velocity, normalized fetal weight, and improved the cardiac function of Hsd11b2(-/-) fetuses. This improved cardiac function occurred despite persisting indications of increased glucocorticoid exposure in the Hsd11b2(-/-) fetal heart. Thus, the pravastatin-induced enhancement of fetal capillaries within the placenta and the resultant hemodynamic changes correspond with restored fetal cardiac function. Statins may represent a useful therapeutic approach to intrauterine growth retardation due to placental vascular hypofunction. PMID:27185937

  11. Functional role of connexins and pannexins in the interaction between vascular and nervous system.

    PubMed

    Gaete, Pablo S; Lillo, Mauricio A; Figueroa, Xavier F

    2014-10-01

    The microvascular network of the microcirculation works in tight communication with surrounding tissues to control blood supply and exchange of solutes. In cerebral circulation, microvascular endothelial cells constitute a selective permeability barrier that controls the environment of parenchymal brain tissue, which is known as the blood-brain barrier (BBB). Connexin- and pannexin-formed channels (gap junctions and hemichannels) play a central role in the coordination of endothelial and smooth muscle cell function and connexin-mediated signaling in endothelial cells is essential in the regulation of BBB permeability. Likewise, gap junction communication between astrocyte end-feet also contributes to maintain the BBB integrity, but the participation of hemichannels in this process cannot be discarded. Sympathetic and sensory perivascular nerves are also involved in the control and coordination of vascular function through the release of vasoconstrictor or vasodilator signals and by the regulation of gap junction communication in the vessel wall. Conversely, ATP release through pannexin-1-formed channels mediates the α1-adrenergic signaling. Furthermore, here we show that capsaicin-induced CGRP release from mesenteric perivascular sensory nerves induces pannexin-1-formed channel opening, which in turn leads to reduction of pannexin-1 and endothelial nitric oxide synthase (eNOS) expression along the time. Interestingly, blockade of CGRP receptors with CGRP8-37 increased eNOS expression by ∼5-fold, suggesting that capsaicin-sensitive sensory nerves are involved in the control of key signaling proteins for vascular function. In this review, we discuss the importance of connexin-based channels in the control of BBB integrity and the functional interaction of vascular connexins and pannexins with the peripheral nervous system. PMID:24446239

  12. Social functioning and age across affective and non-affective psychoses

    PubMed Central

    Martin, Elizabeth A.; Öngür, Dost; Cohen, Bruce M.; Lewandowski, Kathryn E.

    2014-01-01

    Both non-affective and affective psychoses are associated with deficits in social functioning across the course of the illness. However, it is not clear how social functioning varies among diagnostic groups as a function of age. The current study examined the relationship between social functioning and age in schizophrenia (SZ), schizoaffective disorder (SZA), and psychotic bipolar disorder (PBD). We found that individuals with PBD had the highest functioning while individuals with SZ had the poorest. The functioning of individuals with SZA fell in between the other groups. We also found that older ages were associated with poorer functioning. Although there was not a significant diagnostic group by age interaction, visual inspection of our data suggests a subtly steeper trajectory of decline in PBD. These results indicate that a decline in social functioning with may be an important area of unmet need in treatment across psychotic disorders. PMID:25503785

  13. Endothelial Cords Promote Tumor Initial Growth prior to Vascular Function through a Paracrine Mechanism

    PubMed Central

    Zhao, Chengjian; Zhang, Wei; Zhao, Yuwei; Yang, Yun; Luo, Hui; Ji, Gaili; Dong, E; Deng, Hongxing; Lin, Shuo; Wei, Yuquan; Yang, Hanshuo

    2016-01-01

    The angiogenic switch is an important oncogenic step that determines whether microtumors remain dormant or progresses further. It has been generally perceived that the primary function of this tumorgenic event is to supply oxygen and nutrients through blood circulation. Using in vivo imaging of zebrafish and mouse tumor models, we showed that endothelial cords aggressively penetrated into microtumors and remained non-circulatory for several days before undergoing vascular blood perfusion. Unexpectedly, we found that initial tumor growth in both models was significantly reduced if endothelial cords were removed by blocking VEGF-VEGFR2 signaling or using a vascular deficient zebrafish mutant. It was further shown that soluble factors including IL-8, secreted by endothelial cells (ECs) were responsible for stimulating tumor cells proliferation. These findings establish that tumor angiogenesis play a much earlier and broader role in promoting tumor growth, which is independent of vascular circulation. Understanding this novel mechanism of angiogenic tumor progression offers new entry points for cancer therapeutics. PMID:26762853

  14. External Volume Expansion Modulates Vascular Growth and Functional Maturation in a Swine Model

    PubMed Central

    Kao, Huang-Kai; Hsu, Hsiang-Hao; Chuang, Wen-Yu; Chen, Sheng-Chih; Chen, Bin; Wu, Shinn-Chih; Guo, Lifei

    2016-01-01

    Despite increasing application of the pre-grafting expansion during autologous fat transplantation in breast reconstruction, little is known about its mechanism of action. To address that, ventral skins of miniature pigs were treated over a 10-day or 21-day period, with continuous suction at −50 mm Hg via a 7-cm diameter rubber-lined suction-cup device. Soft tissue thickness increased immediately after this external volume expansion (EVE) treatment, such increase completely disappeared by the next day. In the dermis and subcutaneous fat, the EVE treated groups showed significant increases in blood vessel density evident by CD31 staining as well as in vascular networks layered with smooth muscle cells when compared with the control group. This finding was corroborated by the increased percentage of endothelial cells present in the treatment groups. There was no significant difference in the percentages of proliferating basal keratinocytes or adipocytes, nor in epidermal thickness. Moreover, the EVE had no effect on proliferation or differentiation potential of adipose stem cells. Taken together, the major effects of EVE appeared to be vascular remodeling and maturation of functional blood vessels. This understanding may help clinicians optimize the vascularity of the recipient bed to further improve fat graft survival. PMID:27174509

  15. External Volume Expansion Modulates Vascular Growth and Functional Maturation in a Swine Model.

    PubMed

    Kao, Huang-Kai; Hsu, Hsiang-Hao; Chuang, Wen-Yu; Chen, Sheng-Chih; Chen, Bin; Wu, Shinn-Chih; Guo, Lifei

    2016-01-01

    Despite increasing application of the pre-grafting expansion during autologous fat transplantation in breast reconstruction, little is known about its mechanism of action. To address that, ventral skins of miniature pigs were treated over a 10-day or 21-day period, with continuous suction at -50 mm Hg via a 7-cm diameter rubber-lined suction-cup device. Soft tissue thickness increased immediately after this external volume expansion (EVE) treatment, such increase completely disappeared by the next day. In the dermis and subcutaneous fat, the EVE treated groups showed significant increases in blood vessel density evident by CD31 staining as well as in vascular networks layered with smooth muscle cells when compared with the control group. This finding was corroborated by the increased percentage of endothelial cells present in the treatment groups. There was no significant difference in the percentages of proliferating basal keratinocytes or adipocytes, nor in epidermal thickness. Moreover, the EVE had no effect on proliferation or differentiation potential of adipose stem cells. Taken together, the major effects of EVE appeared to be vascular remodeling and maturation of functional blood vessels. This understanding may help clinicians optimize the vascularity of the recipient bed to further improve fat graft survival. PMID:27174509

  16. Receptor for Advanced Glycation End-Products Signaling Interferes with the Vascular Smooth Muscle Cell Contractile Phenotype and Function.

    PubMed

    Simard, Elie; Söllradl, Thomas; Maltais, Jean-Sébastien; Boucher, Julie; D'Orléans-Juste, Pédro; Grandbois, Michel

    2015-01-01

    Increased blood glucose concentrations promote reactions between glucose and proteins to form advanced glycation end-products (AGE). Circulating AGE in the blood plasma can activate the receptor for advanced end-products (RAGE), which is present on both endothelial and vascular smooth muscle cells (VSMC). RAGE exhibits a complex signaling that involves small G-proteins and mitogen activated protein kinases (MAPK), which lead to increased nuclear factor kappa B (NF-κB) activity. While RAGE signaling has been previously addressed in endothelial cells, little is known regarding its impact on the function of VSMC. Therefore, we hypothesized that RAGE signaling leads to alterations in the mechanical and functional properties of VSMC, which could contribute to complications associated with diabetes. We demonstrated that RAGE is expressed and functional in the A7r5 VSMC model, and its activation by AGE significantly increased NF-κB activity, which is known to interfere with the contractile phenotype of VSMC. The protein levels of the contraction-related transcription factor myocardin were also decreased by RAGE activation with a concomitant decrease in the mRNA and protein levels of transgelin (SM-22α), a regulator of VSMC contraction. Interestingly, we demonstrated that RAGE activation increased the overall cell rigidity, an effect that can be related to an increase in myosin activity. Finally, although RAGE stimulation amplified calcium signaling and slightly myosin activity in VSMC challenged with vasopressin, their contractile capacity was negatively affected. Overall, RAGE activation in VSMC could represent a keystone in the development of vascular diseases associated with diabetes by interfering with the contractile phenotype of VSMC through the modification of their mechanical and functional properties. PMID:26248341

  17. Receptor for Advanced Glycation End-Products Signaling Interferes with the Vascular Smooth Muscle Cell Contractile Phenotype and Function

    PubMed Central

    Simard, Elie; Söllradl, Thomas; Maltais, Jean-Sébastien; Boucher, Julie; D’Orléans-Juste, Pédro; Grandbois, Michel

    2015-01-01

    Increased blood glucose concentrations promote reactions between glucose and proteins to form advanced glycation end-products (AGE). Circulating AGE in the blood plasma can activate the receptor for advanced end-products (RAGE), which is present on both endothelial and vascular smooth muscle cells (VSMC). RAGE exhibits a complex signaling that involves small G-proteins and mitogen activated protein kinases (MAPK), which lead to increased nuclear factor kappa B (NF-κB) activity. While RAGE signaling has been previously addressed in endothelial cells, little is known regarding its impact on the function of VSMC. Therefore, we hypothesized that RAGE signaling leads to alterations in the mechanical and functional properties of VSMC, which could contribute to complications associated with diabetes. We demonstrated that RAGE is expressed and functional in the A7r5 VSMC model, and its activation by AGE significantly increased NF-κB activity, which is known to interfere with the contractile phenotype of VSMC. The protein levels of the contraction-related transcription factor myocardin were also decreased by RAGE activation with a concomitant decrease in the mRNA and protein levels of transgelin (SM-22α), a regulator of VSMC contraction. Interestingly, we demonstrated that RAGE activation increased the overall cell rigidity, an effect that can be related to an increase in myosin activity. Finally, although RAGE stimulation amplified calcium signaling and slightly myosin activity in VSMC challenged with vasopressin, their contractile capacity was negatively affected. Overall, RAGE activation in VSMC could represent a keystone in the development of vascular diseases associated with diabetes by interfering with the contractile phenotype of VSMC through the modification of their mechanical and functional properties. PMID:26248341

  18. Short-term exercise training improves vascular function in hypercholesterolemic rabbit femoral artery.

    PubMed

    Jen, Chauying J; Liu, Yu-Fan; Chen, Hsiun-Ing

    2005-06-30

    Chronic exercise in healthy or hypercholesteremic animals for at least two months improves their vascular functions. This study is to examine whether short-term exercise training protocols can correct early-stage vascular dysfunction induced by high-cholesterol diet feeding. Male New Zealand White rabbits were fed for 2, 4 or 6 weeks with rabbit chow with or without the addition of 2% (w/w) cholesterol. They were further divided into control and exercise groups. Animals in exercise groups ran on a leveled treadmill for the same time periods as diet intervention. At the end of experiments, femoral arteries were dissected, loaded with fura 2-AM, and mounted in a tissue flow chamber. Phenylephrine-precontracted vessel specimens were exposed to acetylcholine. The endothelial intracellular calcium elevation and vasorelaxation were determined simultaneously under an epifluorescence microscope with ratio imaging capability. En face oil red O staining was used to evaluate fatty streak formation. Our results showed that 1) high-cholesterol diet feeding for > or = 4 weeks caused lipid deposition, reduced the acetylcholine-evoked endothelial calcium signaling, and impaired both endothelium-dependent and endothelium-independent vascular responses in a time-dependent manner; 2) vasorelaxation at given levels of endothelial intracellular calcium elevation decreased in hypercholesterolemia; 3) concomitant exercise program had reverse effects. We conclude that high-cholesterol diet intervention for as short as 4 weeks induces vascular structural changes, impairs endothelial intracellular calcium signaling and vasodilatation in rabbit femoral arteries. Short-term exercise training in parallel completely eliminates these adverse effects so long as the diet intervention is no more than 6 weeks. PMID:16201452

  19. Dissociation between neural and vascular responses to sympathetic stimulation : contribution of local adrenergic receptor function

    NASA Technical Reports Server (NTRS)

    Jacob, G.; Costa, F.; Shannon, J.; Robertson, D.; Biaggioni, I.

    2000-01-01

    Sympathetic activation produced by various stimuli, eg, mental stress or handgrip, evokes regional vascular responses that are often nonhomogeneous. This phenomenon is believed to be the consequence of the recruitment of differential central neural pathways or of a sympathetically mediated vasodilation. The purpose of this study was to determine whether a similar heterogeneous response occurs with cold pressor stimulation and to test the hypothesis that local differences in adrenergic receptor function could be in part responsible for this diversity. In 8 healthy subjects, local norepinephrine spillover and blood flow were measured in arms and legs at baseline and during sympathetic stimulation induced by baroreflex mechanisms (nitroprusside infusion) or cold pressor stimulation. At baseline, legs had higher vascular resistance (27+/-5 versus 17+/-2 U, P=0.05) despite lower norepinephrine spillover (0.28+/-0.04 versus 0.4+/-0.05 mg. min(-1). dL(-1), P=0.03). Norepinephrine spillover increased similarly in both arms and legs during nitroprusside infusion and cold pressor stimulation. On the other hand, during cold stimulation, vascular resistance increased in arms but not in legs (20+/-9% versus -7+/-4%, P=0.03). Increasing doses of isoproterenol and phenylephrine were infused intra-arterially in arms and legs to estimate beta-mediated vasodilation and alpha-induced vasoconstriction, respectively. beta-Mediated vasodilation was significantly lower in legs compared with arms. Thus, we report a dissociation between norepinephrine spillover and vascular responses to cold stress in lower limbs characterized by a paradoxical decrease in local resistance despite increases in sympathetic activity. The differences observed in adrenergic receptor responses cannot explain this phenomenon.

  20. Vascular endothelial growth factor antagonism restores epithelial barrier dysfunction via affecting zonula occludens proteins

    PubMed Central

    YUKSEL, HASAN; YILMAZ, OZGE; KARAMAN, MERAL; FIRINCI, FATIH; TURKELI, AHMET; KANIK, ESRA TOPRAK; INAN, SEVINC

    2015-01-01

    Epithelial barrier dysfunction is important in the pathogenesis of asthma and allergic responses, and is therefore a therapeutic target. The aim of the present study was to investigate the effects of dexamethasone, a classic therapeutic agent, an anti-tumor necrosis factor agent (etanercept), which is used to treat difficult cases of asthma, and an anti-vascular endothelial growth factor (VEGF) agent (bevacizumab), which is an angiogenesis inhibitor, on zonula occludens (ZO) proteins in an experimental asthma model. The experimental model of asthma was developed using intraperitoneal (IP) and inhaled administration of ovalbumin in 38 BALB/c mice, which were divided into four groups. The control group (n=6) did not receive any treatment, while the four remaining groups (n=8 per group) received an IP injection of saline, etanercept, bevacizumab or dexamethasone, respectively. Occludin, claudin and junctional adhesion molecule (JAM) were immunohistochemically stained in the left middle lobe samples using an indirect avidin-peroxidase method, after which the staining was semiquantified with H-scores. Statistically significant differences were observed in the occludin, claudin and JAM H-scores among the four groups (P<0.001). In the untreated asthma, etanercept, bevacizumab and dexamethasone groups, the median H-scores for occludin were 93, 177, 280 and 198, respectively, while the H-scores for claudin were 82, 193.5, 274 and 202.5, respectively, and the median H-scores for JAM were 130, 210, 288 and 210, respectively. Pairwise comparisons revealed that all three ZO protein H-scores were significantly lower in the saline group when compared with each treatment group. However, the H-scores of the ZO proteins were not significantly different between the etanercept and dexamethasone groups. Furthermore, the bevacizumab group exhibited higher H-scores for all the proteins compared with the dexamethasone group. Therefore, antagonism of VEGF with bevacizumab restores the

  1. 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

  2. Proton pump inhibitors and vascular function: A prospective cross-over pilot study

    PubMed Central

    Ghebremariam, Yohannes T.; Cooke, John P.; Khan, Fouzia; Thakker, Rahul N.; Chang, Peter; Shah, Nigam H.; Nead, Kevin T.; Leeper, Nicholas J.

    2015-01-01

    Background Proton pump inhibitors (PPIs) are commonly used drugs for the treatment of gastric reflux. Recent retrospective cohorts and large database studies have raised concern that the use of PPIs is associated with increased cardiovascular (CV) risk. However, there is no prospective clinical study evaluating whether the use of PPIs directly causes CV harm. Methods We conducted a controlled open-label cross-over pilot study among 21 adults aged 18 and older who are healthy (n = 11) or have established clinical cardiovascular disease (n = 10). Study subjects were assigned to receive a PPI (Prevacid; 30 mg) or a placebo pill once daily for 4 weeks. After a 2 week washout period, participants were crossed-over to receive the alternate treatment for the ensuing 4 weeks. Subjects underwent evaluation of vascular function (by the EndoPAT technique) and had plasma levels of asymmetric dimethylarginine (ADMA, an endogenous inhibitor of endothelial function previously implicated in PPI-mediated risk) measured prior to and after each treatment interval. Results We observed a marginal inverse correlation between the EndoPAT score and plasma levels of ADMA (r = −0.364). Subjects experienced a greater worsening in plasma ADMA levels while on PPI than on placebo, and this trend was more pronounced amongst those subjects with a history of vascular disease. However, these trends did not reach statistical significance, and PPI use was also not associated with an impairment in flow mediated vasodilation during the course of this study. Conclusions In this open-label, cross-over pilot study conducted among healthy subjects and coronary disease patients, PPI use did not significantly influence vascular endothelial function. Larger, long-term and blinded trials are needed to mechanistically explain the correlation between PPI use and adverse clinical outcomes, which has recently been reported in retrospective cohort studies. PMID:25835348

  3. Impaired vascular function after exposure to diesel exhaust generated at urban transient running conditions

    PubMed Central

    2010-01-01

    Background Traffic emissions including diesel engine exhaust are associated with increased respiratory and cardiovascular morbidity and mortality. Controlled human exposure studies have demonstrated impaired vascular function after inhalation of exhaust generated by a diesel engine under idling conditions. Objectives To assess the vascular and fibrinolytic effects of exposure to diesel exhaust generated during urban-cycle running conditions that mimic ambient 'real-world' exposures. Methods In a randomised double-blind crossover study, eighteen healthy male volunteers were exposed to diesel exhaust (approximately 250 μg/m3) or filtered air for one hour during intermittent exercise. Diesel exhaust was generated during the urban part of the standardized European Transient Cycle. Six hours post-exposure, vascular vasomotor and fibrinolytic function was assessed during venous occlusion plethysmography with intra-arterial agonist infusions. Measurements and Main Results Forearm blood flow increased in a dose-dependent manner with both endothelial-dependent (acetylcholine and bradykinin) and endothelial-independent (sodium nitroprusside and verapamil) vasodilators. Diesel exhaust exposure attenuated the vasodilatation to acetylcholine (P < 0.001), bradykinin (P < 0.05), sodium nitroprusside (P < 0.05) and verapamil (P < 0.001). In addition, the net release of tissue plasminogen activator during bradykinin infusion was impaired following diesel exhaust exposure (P < 0.05). Conclusion Exposure to diesel exhaust generated under transient running conditions, as a relevant model of urban air pollution, impairs vasomotor function and endogenous fibrinolysis in a similar way as exposure to diesel exhaust generated at idling. This indicates that adverse vascular effects of diesel exhaust inhalation occur over different running conditions with varying exhaust composition and concentrations as well as physicochemical particle properties. Importantly, exposure to diesel exhaust

  4. 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

  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. How Does Maternal Employment Affect Children's Socioemotional Functioning?

    ERIC Educational Resources Information Center

    Lam, Gigi

    2015-01-01

    The maternal employment becomes an irreversible trend across the globe. The effect of maternal employment on children's socioemotional functioning is so pervasive that it warrants special attention to investigate into the issue. A trajectory of analytical framework of how maternal employment affects children's socioemotional functioning originates…

  7. Regulator of G Protein Signaling 2: A Versatile Regulator of Vascular Function

    PubMed Central

    Osei-Owusu, Patrick; Blumer, Kendall J.

    2016-01-01

    Regulators of G protein signaling (RGS) proteins of the B/R4 family are widely expressed in the cardiovascular system where their role in fine tuning G protein signaling is critical to maintaining homeostasis. Among members of this family, RGS2 and RGS5 have been shown to play key roles in cardiac and smooth muscle function by tightly regulating signaling pathways that are activated through Gq/11 and Gi/o classes of heterotrimeric G proteins. This chapter reviews accumulating evidence supporting a key role for RGS2 in vascular function and the implication of changes in RGS2 function and/or expression in the pathogenesis of blood pressure disorders, particularly hypertension. With such understanding, RGS2 and the signaling pathways it controls may emerge as novel targets for developing next-generation anti-hypertensive drugs/agents. PMID:26123303

  8. Enzyme-functionalized vascular grafts catalyze in-situ release of nitric oxide from exogenous NO prodrug.

    PubMed

    Wang, Zhihong; Lu, Yaxin; Qin, Kang; Wu, Yifan; Tian, Yingping; Wang, Jianing; Zhang, Jimin; Hou, Jingli; Cui, Yun; Wang, Kai; Shen, Jie; Xu, Qingbo; Kong, Deling; Zhao, Qiang

    2015-07-28

    Nitric oxide (NO) is an important signaling molecule in cardiovascular system, and the sustained release of NO by endothelial cells plays a vital role in maintaining patency and homeostasis. In contrast, lack of endogenous NO in artificial blood vessel is believed to be the main cause of thrombus formation. In this study, enzyme prodrug therapy (EPT) technique was employed to construct a functional vascular graft by immobilization of galactosidase on the graft surface. The enzyme-functionalized grafts exhibited excellent catalytic property in decomposition of the exogenously administrated NO prodrug. Localized and on-demand release of NO was demonstrated by in vitro release assay and fluorescent probe tracing in an ex vivo model. The immobilized enzyme retained catalytic property even after subcutaneous implantation of the grafts for one month. The functional vascular grafts were implanted into the rat abdominal aorta with a 1-month monitoring period. Results showed effective inhibition of thrombus formation in vivo and enhancement of vascular tissue regeneration and remodeling on the grafts. Thus, we create an enzyme-functionalized vascular graft that can catalyze prodrug to release NO locally and sustainably, indicating that this approach may be useful to develop new cell-free vascular grafts for treatment of vascular diseases. PMID:26004323

  9. Arterial structure and function in vascular ageing: are you as old as your arteries?

    PubMed

    Thijssen, Dick H J; Carter, Sophie E; Green, Daniel J

    2016-04-15

    Advancing age may be the most potent independent predictor of future cardiovascular events, a relationship that is not fully explained by time-related changes in traditional cardiovascular risk factors. Since some arteries exhibit differential susceptibility to atherosclerosis, generalisations regarding the impact of ageing in humans may be overly simplistic, whereas in vivo assessment of arterial function and health provide direct insight. Coronary and peripheral (conduit, resistance and skin) arteries demonstrate a gradual, age-related impairment in vascular function that is likely to be related to a reduction in endothelium-derived nitric oxide bioavailability and/or increased production of vasoconstrictors (e.g. endothelin-1). Increased exposure and impaired ability for defence mechanisms to resist oxidative stress and inflammation, but also cellular senescence processes, may contribute to age-related changes in vascular function and health. Arteries also undergo structural changes as they age. Gradual thickening of the arterial wall, changes in wall content (i.e. less elastin, advanced glycation end-products) and increase in conduit artery diameter are observed with older age and occur similarly in central and peripheral arteries. These changes in structure have important interactive effects on artery function, with increases in small and large arterial stiffness representing a characteristic change with older age. Importantly, direct measures of arterial function and structure predict future cardiovascular events, independent of age or other cardiovascular risk factors. Taken together, and given the differential susceptibility of arteries to atherosclerosis in humans, direct measurement of arterial function and health may help to distinguish between biological and chronological age-related change in arterial health in humans. PMID:26140618

  10. Aberrant Functional Connectivity and Structural Atrophy in Subcortical Vascular Cognitive Impairment: Relationship with Cognitive Impairments

    PubMed Central

    Zhou, Xia; Hu, Xiaopeng; Zhang, Chao; Wang, Haibao; Zhu, Xiaoqun; Xu, Liyan; Sun, Zhongwu; Yu, Yongqiang

    2016-01-01

    Abnormal structures in the cortical and subcortical regions have been identified in subcortical vascular cognition impairment (SVCI). However, little is known about the functional alterations in SVCI, and no study refers to the functional connectivity in the prefrontal and subcortical regions in this context. The medial prefrontal cortex (MPFC) is an important region of the executive network and default mode network, and the subcortical thalamus plays vital roles in mediating or modulating these two networks. To investigate both thalamus- and MPFC-related functional connectivity as well as its relationship with cognition in SVCI, 32 SVCI patients and 23 control individuals were administered neuropsychological assessments. They also underwent structural and functional magnetic resonance imaging scans. Voxel-based morphometry and functional connectivity analysis were performed to detect gray matter (GM) atrophy and to characterize the functional alterations in the thalamus and the MPFC. For structural data, we observed that GM atrophy was distributed in both cortical regions and subcortical areas. For functional data, we observed that the thalamus functional connectivity in SVCI was significantly decreased in several cortical regions [i.e., the orbitofrontal lobe (OFL)], which are mainly involved in executive function and memory function. However, connectivity was increased in several frontal regions (i.e., the inferior frontal gyrus), which may be induced by the compensatory recruitment of the decreased functional connectivity. The MPFC functional connectivity was also decreased in executive- and memory-related regions (i.e., the anterior cingulate cortex) along with a motor region (i.e., the supplementary motor area). In addition, the cognitive performance was closely correlated with functional connectivity between the left thalamus and the left OFL in SVCI. The present study, thus, provides evidence for an association between structural and functional alterations

  11. Pressor response to intravenous tyramine is a marker of cardiac, but not vascular, adrenergic function

    NASA Technical Reports Server (NTRS)

    Meck, Janice V.; Martin, David S.; D'Aunno, Dominick S.; Waters, Wendy W.

    2003-01-01

    Intravenous injections of the indirect sympathetic amine, tyramine, are used as a test of peripheral adrenergic function. The authors measured the time course of increases in ejection fraction, heart rate, systolic and diastolic pressure, popliteal artery flow, and greater saphenous vein diameter before and after an injection of 4.0 mg/m(2) body surface area of tyramine in normal human subjects. The tyramine caused moderate, significant increases in systolic pressure and significant decreases in total peripheral resistance. The earliest changes were a 30% increase in ejection fraction and a 16% increase in systolic pressure, followed by a 60% increase in popliteal artery flow and a later 11% increase in greater saphenous vein diameter. There were no changes in diastolic pressure or heart rate. These results suggest that pressor responses during tyramine injections are primarily due to an inotropic response that increases cardiac output and pressure and causes a reflex decrease in vascular resistance. Thus, tyramine pressor tests are a measure of cardiac, but not vascular, sympathetic function.

  12. 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

  13. Exercise training improves vascular function in adolescents with type 2 diabetes.

    PubMed

    Naylor, Louise H; Davis, Elizabeth A; Kalic, Rachelle J; Paramalingam, Niru; Abraham, Mary B; Jones, Timothy W; Green, Daniel J

    2016-02-01

    The impact of exercise training on vascular health in adolescents with type 2 diabetes has not been previously studied. We hypothesized that exercise training would improve micro- and macrovascular health in adolescents with type 2 diabetes. Thirteen adolescents (13-21 years, 10F) with type 2 diabetes were recruited from Princess Margaret Hospital. Participants were randomized to receive either an exercise program along with standard clinical care (n = 8) or standard care alone (n = 5). Those in the intervention group received 12 weeks of gym-based, personalized, and supervised exercise training. Those in the control group were instructed to maintain usual activity levels. Assessments were conducted at baseline and following week 12. The exercise group was also studied 12 weeks following the conclusion of their program. Assessments consisted of conduit artery endothelial function (flow-mediated dilation, FMD) and microvascular function (cutaneous laser Doppler). Secondary outcomes included body composition (dual-energy X-ray absorptiometry, DXA), glycemic control (whole body insulin sensitivity, M) assessed using the euglycemic-hyperinsulinemic clamp protocol, cardiorespiratory fitness (V˙O2peak), and muscular strength (1RM). Exercise training increased FMD (P < 0.05), microvascular function (P < 0.05), total lean mass (P < 0.05), and muscle strength (P < 0.001). There were no changes in cardiorespiratory fitness, body weight, BMI, or M. In the control group, body weight (P < 0.01), BMI (P < 0.01), and total fat mass (P < 0.05) increased. At week 24, improvements in vascular function were reversed. This study indicates that exercise training can improve both conduit and microvascular endothelial function and health, independent of changes in insulin sensitivity in adolescents with type 2 diabetes. PMID:26887327

  14. Bilayered vascular graft derived from human induced pluripotent stem cells with biomimetic structure and function

    PubMed Central

    Nakayama, Karina H; Joshi, Prajakta A; Lai, Edwina S; Gujar, Prachi; Joubert, Lydia-M; Chen, Bertha; Huang, Ngan F

    2015-01-01

    Background: We developed an aligned bi-layered vascular graft derived from human induced pluripotent stem cells (iPSCs) that recapitulates the cellular composition, orientation, and anti-inflammatory function of blood vessels. Materials & methods: The luminal layer consisted of longitudinal-aligned nanofibrillar collagen containing primary endothelial cells (ECs) or iPSC-derived ECs (iPSC-ECs). The outer layer contained circumferentially oriented nanofibrillar collagen with primary smooth muscle cells (SMCs) or iPSC-derived SMCs(iPSC-SMCs). Results: On the aligned scaffolds, cells organized F-actin assembly within 8º from the direction of nanofibrils. When compared to randomly-oriented scaffolds, EC-seeded aligned scaffolds had significant reduced inflammatory response, based on adhesivity to monocytes. Conclusion: This study highlights the importance of anisotropic scaffolds in directing cell form and function, and has therapeutic significance as physiologically relevant blood vessels. PMID:26440211

  15. Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation.

    PubMed

    Xue, Mingzhan; Weickert, Martin O; Qureshi, Sheharyar; Kandala, Ngianga-Bakwin; Anwar, Attia; Waldron, Molly; Shafie, Alaa; Messenger, David; Fowler, Mark; Jenkins, Gail; Rabbani, Naila; Thornalley, Paul J

    2016-08-01

    Risk of insulin resistance, impaired glycemic control, and cardiovascular disease is excessive in overweight and obese populations. We hypothesized that increasing expression of glyoxalase 1 (Glo1)-an enzyme that catalyzes the metabolism of reactive metabolite and glycating agent methylglyoxal-may improve metabolic and vascular health. Dietary bioactive compounds were screened for Glo1 inducer activity in a functional reporter assay, hits were confirmed in cell culture, and an optimized Glo1 inducer formulation was evaluated in a randomized, placebo-controlled crossover clinical trial in 29 overweight and obese subjects. We found trans-resveratrol (tRES) and hesperetin (HESP), at concentrations achieved clinically, synergized to increase Glo1 expression. In highly overweight subjects (BMI >27.5 kg/m(2)), tRES-HESP coformulation increased expression and activity of Glo1 (27%, P < 0.05) and decreased plasma methylglyoxal (-37%, P < 0.05) and total body methylglyoxal-protein glycation (-14%, P < 0.01). It decreased fasting and postprandial plasma glucose (-5%, P < 0.01, and -8%, P < 0.03, respectively), increased oral glucose insulin sensitivity index (42 mL ⋅ min(-1) ⋅ m(-2), P < 0.02), and improved arterial dilatation Δbrachial artery flow-mediated dilatation/Δdilation response to glyceryl nitrate (95% CI 0.13-2.11). In all subjects, it decreased vascular inflammation marker soluble intercellular adhesion molecule-1 (-10%, P < 0.01). In previous clinical evaluations, tRES and HESP individually were ineffective. tRES-HESP coformulation could be a suitable treatment for improved metabolic and vascular health in overweight and obese populations. PMID:27207552

  16. Serotonin and Dopamine: Unifying Affective, Activational, and Decision Functions

    PubMed Central

    Cools, Roshan; Nakamura, Kae; Daw, Nathaniel D

    2011-01-01

    Serotonin, like dopamine (DA), has long been implicated in adaptive behavior, including decision making and reinforcement learning. However, although the two neuromodulators are tightly related and have a similar degree of functional importance, compared with DA, we have a much less specific understanding about the mechanisms by which serotonin affects behavior. Here, we draw on recent work on computational models of dopaminergic function to suggest a framework by which many of the seemingly diverse functions associated with both DA and serotonin—comprising both affective and activational ones, as well as a number of other functions not overtly related to either—can be seen as consequences of a single root mechanism. PMID:20736991

  17. Short-Term Exposure to Air Pollution and Digital Vascular Function

    PubMed Central

    Ljungman, Petter L.; Wilker, Elissa H.; Rice, Mary B.; Schwartz, Joel; Gold, Diane R.; Koutrakis, Petros; Vita, Joseph A.; Mitchell, Gary F.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Mittleman, Murray A.; Hamburg, Naomi M.

    2014-01-01

    We investigated associations between ambient air pollution and microvessel function measured by peripheral arterial tonometry between 2003 and 2008 in the Framingham Heart Study Offspring and Third Generation Cohorts. We measured particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5), black carbon, sulfates, particle number, nitrogen oxides, and ozone by using fixed monitors, and we determined moving averages for 1–7 days preceding vascular testing. We examined associations between these exposures and hyperemic response to ischemia and baseline pulse amplitude, a measure of arterial tone (n = 2,369). Higher short-term exposure to air pollutants, including PM2.5, black carbon, and particle number was associated with higher baseline pulse amplitude. For example, higher 3-day average PM2.5 exposure was associated with 6.3% higher baseline pulse amplitude (95% confidence interval: 2.0, 10.9). However, there were no consistent associations between the air pollution exposures assessed and hyperemic response. Our findings in a community-based sample exposed to relatively low pollution levels suggest that short-term exposure to ambient particulate pollution is not associated with vasodilator response, but that particulate air pollution is associated with baseline pulse amplitude, suggesting potentially adverse alterations in baseline vascular tone or compliance. PMID:25100647

  18. Measurements of vascular function using strain-gauge plethysmography: technical considerations, standardization, and physiological findings.

    PubMed

    Alomari, Mahmoud A; Solomito, Angela; Reyes, Rafael; Khalil, Syed Muaz; Wood, Robert H; Welsch, Michael A

    2004-01-01

    The main purpose of the present study was to examine the relationships between measures of fitness [estimated peak oxygen consumption (V(O2) peak) and handgrip strength] and forearm vascular function in 55 young (22.6 +/- 3.5 yr) adults. In addition, the present study considered methodological and technical aspects regarding the examination of the venous system using mercury in-Silastic strain-gauge plethysmography (MSGP). Forearm venous capacitance and outflow were examined using five different [7, 14, 21, 28, and 35 mmHg < diastolic blood pressure (DBP)] venous occlusion pressures and after a 5- and 10-min period of venous occlusion. A pressure of 7 mmHg < DBP and a period of 10 min venous occlusion produced the greatest (P < 0.05) venous capacitance and outflow, without altering arterial indexes. Reproducibility of forearm arterial and venous indexes were evaluated at rest and after 5 min of upper arm arterial occlusion at 240 mmHg on three different occasions within 10 days with the interclass correlation coefficient ranging from 0.70 and 0.94. Estimated V(O2) peak correlated with postocclusion arterial inflow (r = 0.54, P = 0.012) and resting venous outflow (r = 0.56, P = 0.016). Finally, handgrip strength was associated with venous capacitance (r = 0.57, P = 0.007) and outflow (r = 0.67, P = 0.001). These results indicate that the examination of forearm vascular function using MSGP is reproducible. Moreover, the data show the importance of careful consideration of the selection of venous occlusion pressure and period when implementing these measures in longitudinal trials. Finally, the associations between fitness and venous measures suggest a link between venous function and exercise performance. PMID:14512279

  19. Biomechanical activation of vascular endothelium as a determinant of its functional phenotype

    PubMed Central

    García-Cardeña, Guillermo; Comander, Jason; Anderson, Keith R.; Blackman, Brett R.; Gimbrone, Michael A.

    2001-01-01

    One of the striking features of vascular endothelium, the single-cell-thick lining of the cardiovascular system, is its phenotypic plasticity. Various pathophysiologic factors, such as cytokines, growth factors, hormones, and metabolic products, can modulate its functional phenotype in health and disease. In addition to these humoral stimuli, endothelial cells respond to their biomechanical environment, although the functional implications of this biomechanical paradigm of activation have not been fully explored. Here we describe a high-throughput genomic analysis of modulation of gene expression observed in cultured human endothelial cells exposed to two well defined biomechanical stimuli—a steady laminar shear stress and a turbulent shear stress of equivalent spatial and temporal average intensity. Comparison of the transcriptional activity of 11,397 unique genes revealed distinctive patterns of up- and down-regulation associated with each type of stimulus. Cluster analyses of transcriptional profiling data were coupled with other molecular and cell biological techniques to examine whether these global patterns of biomechanical activation are translated into distinct functional phenotypes. Confocal immunofluorescence microscopy of structural and contractile proteins revealed the formation of a complex apical cytoskeleton in response to laminar shear stress. Cell cycle analysis documented different effects of laminar and turbulent shear stresses on cell proliferation. Thus, endothelial cells have the capacity to discriminate among specific biomechanical forces and to translate these input stimuli into distinctive phenotypes. The demonstration that hemodynamically derived stimuli can be strong modulators of endothelial gene expression has important implications for our understanding of the mechanisms of vascular homeostasis and atherogenesis. PMID:11296290

  20. Diabetes and Retinal Vascular Dysfunction

    PubMed Central

    Shin, Eui Seok; Sorenson, Christine M.; Sheibani, Nader

    2014-01-01

    Diabetes predominantly affects the microvascular circulation of the retina resulting in a range of structural changes unique to this tissue. These changes ultimately lead to altered permeability, hyperproliferation of endothelial cells and edema, and abnormal vascularization of the retina with resulting loss of vision. Enhanced production of inflammatory mediators and oxidative stress are primary insults with significant contribution to the pathogenesis of diabetic retinopathy (DR). We have determined the identity of the retinal vascular cells affected by hyperglycemia, and have delineated the cell autonomous impact of high glucose on function of these cells. We discuss some of the high glucose specific changes in retinal vascular cells and their contribution to retinal vascular dysfunction. This knowledge provides novel insight into the molecular and cellular defects contributing to the development and progression of diabetic retinopathy, and will aid in the development of innovative, as well as target specific therapeutic approaches for prevention and treatment of DR. PMID:25667739

  1. Functional role of stromal interaction molecule 1 (STIM1) in vascular smooth muscle cells

    SciTech Connect

    Takahashi, Yoichiro; Watanabe, Hiroyuki; Murakami, Manabu; Ono, Kyoichi; Munehisa, Yoshiko; Koyama, Takashi; Nobori, Kiyoshi; Iijima, Toshihiko; Ito, Hiroshi

    2007-10-05

    We investigated the functional role of STIM1, a Ca{sup 2+} sensor in the endoplasmic reticulum (ER) that regulates store-operated Ca{sup 2+} entry (SOCE), in vascular smooth muscle cells (VSMCs). STIM1 was mainly localized at the ER and plasma membrane. The knockdown of STIM1 expression by small interfering (si) RNA drastically decreased SOCE. In contrast, an EF-hand mutant of STIM1, STIM1{sup E87A}, produced a marked increase in SOCE, which was abolished by co-transfection with siRNA to transient receptor potential canonical 1 (TRPC1). In addition, transfection with siRNA against STIM1 suppressed phosphorylation of cAMP-responsive element binding protein (CREB) and cell growth. These results suggest that STIM1 is an essential component of SOCE and that it is involved in VSMC proliferation.

  2. 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

  3. Vascular Endothelial Function and Blood Pressure Regulation in Afferent Autonomic Failure

    PubMed Central

    Jelani, Qurat-ul-ain; Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio

    2015-01-01

    BACKGROUND Familial dysautonomia (FD) is a rare hereditary disease characterized by loss of afferent autonomic neural fiber signaling and consequent profound impairment of arterial baroreflex function and blood pressure regulation. Whether vascular endothelial dysfunction contributes to defective vasomotor control in this form of afferent autonomic failure is not known. METHODS We assessed blood pressure response to orthostatic stress and vascular endothelial function with brachial artery reactivity testing in 34 FD subjects with afferent autonomic failure and 34 healthy control subjects. RESULTS Forty-four percent of the afferent autonomic failure subjects had uncontrolled hypertension at supine rest (median systolic blood pressure = 148mm Hg, interquartile range (IQR) = 144–155mm Hg; median diastolic blood pressure = 83mm Hg, IQR = 78–105mm Hg), and 88% had abnormal response to orthostatic stress (median decrease in systolic blood pressure after upright tilt = 48mm Hg, IQR = 29–61mm Hg). Flow-mediated brachial artery reactivity did not differ in subjects with afferent autonomic failure vs. healthy control subjects (median = 6.00%, IQR = 1.86–11.77%; vs. median = 6.27%, IQR = 4.65–9.34%; P = 0.75). In afferent autonomic failure subjects, brachial artery reactivity was not associated with resting blood pressure or the magnitude of orthostatic hypotension but was decreased in association with reduced glomerular filtration rate (r = 0.62; P < 0.001). CONCLUSIONS Brachial artery reactivity was preserved in subjects with afferent autonomic failure despite the presence of marked blood pressure dysregulation. Comorbid renal dysfunction was associated with reduced brachial artery reactivity. PMID:25128693

  4. Increasing Muscle Mass Improves Vascular Function in Obese (db/db) Mice

    PubMed Central

    Qiu, Shuiqing; Mintz, James D.; Salet, Christina D.; Han, Weihong; Giannis, Athanassios; Chen, Feng; Yu, Yanfang; Su, Yunchao; Fulton, David J.; Stepp, David W.

    2014-01-01

    Background A sedentary lifestyle is an independent risk factor for cardiovascular disease and exercise has been shown to ameliorate this risk. Inactivity is associated with a loss of muscle mass, which is also reversed with isometric exercise training. The relationship between muscle mass and vascular function is poorly defined. The aims of the current study were to determine whether increasing muscle mass by genetic deletion of myostatin, a negative regulator of muscle growth, can influence vascular function in mesenteric arteries from obese db/db mice. Methods and Results Myostatin expression was elevated in skeletal muscle of obese mice and associated with reduced muscle mass (30% to 50%). Myostatin deletion increased muscle mass in lean (40% to 60%) and obese (80% to 115%) mice through increased muscle fiber size (P<0.05). Myostatin deletion decreased adipose tissue in lean mice, but not obese mice. Markers of insulin resistance and glucose tolerance were improved in obese myostatin knockout mice. Obese mice demonstrated an impaired endothelial vasodilation, compared to lean mice. This impairment was improved by superoxide dismutase mimic Tempol. Deletion of myostatin improved endothelial vasodilation in mesenteric arteries in obese, but not in lean, mice. This improvement was blunted by nitric oxide (NO) synthase inhibitor l‐NG‐nitroarginine methyl ester (l‐NAME). Prostacyclin (PGI2)‐ and endothelium‐derived hyperpolarizing factor (EDHF)‐mediated vasodilation were preserved in obese mice and unaffected by myostatin deletion. Reactive oxygen species) was elevated in the mesenteric endothelium of obese mice and down‐regulated by deletion of myostatin in obese mice. Impaired vasodilation in obese mice was improved by NADPH oxidase inhibitor (GKT136901). Treatment with sepiapterin, which increases levels of tetrahydrobiopterin, improved vasodilation in obese mice, an improvement blocked by l‐NAME. Conclusions Increasing muscle mass by genetic

  5. 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. PMID:26337017

  6. Muscle-derived follistatin-like 1 functions to reduce neointimal formation after vascular injury

    PubMed Central

    Miyabe, Megumi; Ohashi, Koji; Shibata, Rei; Uemura, Yusuke; Ogura, Yasuhiro; Yuasa, Daisuke; Kambara, Takahiro; Kataoka, Yoshiyuki; Yamamoto, Takashi; Matsuo, Kazuhiro; Joki, Yusuke; Enomoto, Takashi; Hayakawa, Satoko; Hiramatsu-Ito, Mizuho; Ito, Masanori; Van Den Hoff, Maurice J.B.; Walsh, Kenneth; Murohara, Toyoaki; Ouchi, Noriyuki

    2014-01-01

    Aims It is well-established that exercise diminishes cardiovascular risk, but whether humoral factors secreted by muscle confer these benefits has not been conclusively shown. We have shown that the secreted protein follistatin-like 1 (Fstl1) has beneficial actions on cardiac and endothelial function. However, the role of muscle-derived Fstl1 in proliferative vascular disease remains largely unknown. Here, we investigated whether muscle-derived Fstl1 modulates vascular remodelling in response to injury. Methods and results The targeted ablation of Fstl1 in muscle led to an increase in neointimal formation following wire-induced arterial injury compared with control mice. Conversely, muscle-specific Fstl1 transgenic (TG) mice displayed a decrease in the neointimal thickening following arterial injury. Muscle-specific Fstl1 ablation and overexpression increased and decreased, respectively, the frequency of BrdU-positive proliferating cells in injured vessels. In cultured human aortic smooth muscle cells (HASMCs), treatment with human FSTL1 protein decreased proliferation and migration induced by stimulation with PDGF-BB. Treatment with FSTL1 enhanced AMPK phosphorylation, and inhibition of AMPK abrogated the inhibitory actions of FSTL1 on HASMC responses to PDGF-BB. The injured arteries of Fstl1-TG mice exhibited an increase in AMPK phosphorylation, and administration of AMPK inhibitor reversed the anti-proliferative actions of Fstl1 on the vessel wall. Conclusion Our findings indicate that muscle-derived Fstl1 attenuates neointimal formation in response to arterial injury by suppressing SMC proliferation through an AMPK-dependent mechanism. Thus, the release of protein factors from muscle, such as Fstl1, may partly explain why the maintenance of muscle function can have a therapeutic effect on the cardiovascular system. PMID:24743592

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

    PubMed Central

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

    2013-01-01

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

  8. Genetic Variation in Vascular Endothelial Growth Factor-A and Lung Function

    PubMed Central

    Custovic, Adnan; Tepper, Robert; Graves, Penelope; Stern, Debra A.; Jones, Marcus; Hankinson, Jenny; Curtin, John A.; Wu, Jiakai; Blekic, Mario; Bukvic, Blazenka Kljaic; Aberle, Neda; Marinho, Susana; Belgrave, Danielle; Morgan, Wayne J.; Martinez, Fernando D.

    2012-01-01

    Rationale: Given the role of vascular endothelial growth factor (VEGF) in lung development, we hypothesized that polymorphisms in VEGF-A may be associated with lung function. Objectives: The current study was designed to assess the role of genetic variants in VEGF-A as determinants of airway function from infancy through early adulthood. Methods: Association between five single-nucleotide polymorphisms (SNPs) in VEGF-A and lung function were assessed longitudinally in two unselected birth cohorts and cross-sectionally among infants. Replication with two SNPs was conducted in adults and children with asthma. We investigated the functionality of the SNP most consistently associated with lung function (rs3025028) using Western blotting to measure the ratio of plasma VEGF-A165b/panVEGF-A165 among homozygotes. Measurements and Main Results: In two populations in infancy, C-allele homozygotes of rs3025028 had significantly higher VmaxFRC, forced expiratory flow50, and forced expiratory flow25–75 compared with other genotype groups. Among preschool children (age 3 yr), C allele of rs3025028 was associated with significantly higher specific airway conductance, with similar findings observed for lung function in school-age children. For FEV1/FVC ratio similar findings were observed among adolescents and young adults (birth cohort), and then replicated in adults and schoolchildren with asthma (cross-sectional studies). For rs3025038, plasma VEGF-A165b/panVEGF-A165 was significantly higher among CC versus GG homozygotes (P ≤ 0.02) at birth, in school-age children, and in adults. Conclusions: We report significant associations between VEGF-A SNP rs3025028 and parameters of airway function measured throughout childhood, with the effect persisting into adulthood. We propose that the mechanism may be mediated through the ratios of active and inhibitory isoforms of VEGF-A165, which may be determined by alternative splicing. PMID:22461367

  9. S-glutathionylation uncouples eNOS and regulates its cellular and vascular function

    PubMed Central

    Chen, Chun-An; Wang, Tse-Yao; Varadharaj, Saradhadevi; Reyes, Levy A.; Hemann, Craig; Hassan Talukder, M. A.; Chen, Yeong-Renn; Druhan, Lawrence J.; Zweier, Jay L.

    2012-01-01

    Endothelial nitric oxide synthase (eNOS) is critical in the regulation of vascular function, and can generate both nitric oxide (NO) and superoxide (O2•−), which are key mediators of cellular signalling. In the presence of Ca2+/calmodulin, eNOS produces NO, endothelial-derived relaxing factor, from L-arginine (L-Arg) by means of electron transfer from NADPH through a flavin containing reductase domain to oxygen bound at the haem of an oxygenase domain, which also contains binding sites for tetrahydrobiopterin (BH4) and L-Arg1–3. In the absence of BH4, NO synthesis is abrogated and instead O2•− is generated4–7. While NOS dysfunction occurs in diseases with redox stress, BH4 repletion only partly restores NOS activity and NOS-dependent vasodilation7. This suggests that there is an as yet unidentified redox-regulated mechanism controlling NOS function. Protein thiols can undergo S-glutathionylation, a reversible protein modification involved in cellular signalling and adaptation8,9. Under oxidative stress, S-glutathionylation occurs through thiol–disulphide exchange with oxidized glutathione or reaction of oxidant-induced protein thiyl radicals with reduced glutathione10,11. Cysteine residues are critical for the maintenance of eNOS function12,13; we therefore speculated that oxidative stress could alter eNOS activity through S-glutathionylation. Here we show that S-glutathionylation of eNOS reversibly decreases NOS activity with an increase in O2•− generation primarily from the reductase, in which two highly conserved cysteine residues are identified as sites of S-glutathionylation and found to be critical for redox-regulation of eNOS function. We show that eNOS S-glutathionylation in endothelial cells, with loss of NO and gain of O2•− generation, is associated with impaired endothelium-dependent vasodilation. In hypertensive vessels, eNOS S-glutathionylation is increased with impaired endothelium-dependent vasodilation that is restored by thiol

  10. Lifetime affect and midlife cognitive function: prospective birth cohort study

    PubMed Central

    Richards, M.; Barnett, J. H.; Xu, M. K.; Croudace, T. J.; Gaysina, D.; Kuh, D.; Jones, P. B.

    2014-01-01

    Background Recurrent affective problems are predictive of cognitive impairment, but the timing and directionality, and the nature of the cognitive impairment, are unclear. Aims To test prospective associations between life-course affective symptoms and cognitive function in late middle age. Method A total of 1668 men and women were drawn from the Medical Research Council National Survey of Health and Development (the British 1946 birth cohort). Longitudinal affective symptoms spanning age 13-53 years served as predictors; outcomes consisted of self-reported memory problems at 60-64 years and decline in memory and information processing from age 53 to 60-64 years. Results Regression analyses revealed no clear pattern of association between longitudinal affective symptoms and decline in cognitive test scores, after adjusting for gender, childhood cognitive ability, education and midlife socioeconomic status. In contrast, affective symptoms were strongly, diffusely and independently associated with self-reported memory problems. Conclusions Affective symptoms are more clearly associated with self-reported memory problems in late midlife than with objectively measured cognitive performance. PMID:24357571

  11. Does Subacromial Osteolysis Affect Shoulder Function after Clavicle Hook Plating?

    PubMed Central

    Sun, Siwei; Gan, Minfeng; Sun, Han; Wu, Guizhong; Yang, Huilin; Zhou, Feng

    2016-01-01

    Purpose. To evaluate whether subacromial osteolysis, one of the major complications of the clavicle hook plate procedure, affects shoulder function. Methods. We had performed a retrospective study of 72 patients diagnosed with a Neer II lateral clavicle fracture or Degree-III acromioclavicular joint dislocation in our hospital from July 2012 to December 2013. All these patients had undergone surgery with clavicle hook plate and were divided into two groups based on the occurrence of subacromial osteolysis. By using the Constant-Murley at the first follow-up visit after plates removal, we evaluated patients' shoulder function to judge if it has been affected by subacromial osteolysis. Results. We have analyzed clinical data for these 72 patients, which shows that there is no significant difference between group A (39 patients) and group B (33 patients) in age, gender, injury types or side, and shoulder function (the Constant-Murley scores are 93.38 ± 3.56 versus 94.24 ± 3.60, P > 0.05). Conclusion. The occurrence of subacromial osteolysis is not rare, and also it does not significantly affect shoulder function. PMID:27034937

  12. Treated effect of silymarin on vascular function of aged rats: Dependant on nitric oxide pathway.

    PubMed

    Demirci, Buket; Demir, Omer; Dost, Turhan; Birincioglu, Mustafa

    2013-11-01

    Abstract Context: Aging leads to endothelial dysfunction and vascular stiffness which are the main causes of many cardiovascular diseases. Previous reports have shown that the cell protective effect of silymarin (SM) is dependent on its antioxidant properties. Objectives: We investigated the effect of SM on vascular functions of aged rats and the involvement of nitric oxide or cyclooxygenase (COX) activity in this effect. Materials and methods: Isolated rat aortas were obtained from 22-month old rats. Each ring was incubated with SM (50 mg/L), SM/l-nitro-arginine methyl ester (100 μM, l-NAME) or SM/indomethacin (10 μM, INDO) in tissue bath. Three- to four-month-old rats were used as young controls. Endothelium-intact rings were precontracted with α-receptor agonist phenylephrine (0.001-30 µM) or voltage-dependent high potassium (40 mM), endothelium dependent/independent relaxant responses were obtained using acetylcholine (0.001-30 µM) and sodium nitroprusside (0.0001-3 µM), respectively. Results: Aging increased phenylephrine sensitivity (6.45 ± 0.08; 6.88 ± 0.09) and decreased KCl contraction (882 ± 118.4; 499 ± 80.4). SM treatment decreased the Emax of both agents (548 ± 109; 223 ± 48.9). Aging deteriorated acetylcholine relaxation (93.9 ± 2.09; 72.0 ± 2.56) and SM improved the response (86.3 ± 1.90). l-NAME prevented the SM effect whereas INDO was ineffective. Discussion and Conclusion: Immediate SM treatment partially restored endothelial dysfunction and vascular tone in aging. The possible mechanism might not be mediated by prostacyclin or the COX pathway in acute administration; the nitric oxide pathway and calcium antagonistic features of SM relate to its action on the vessel. PMID:24188646

  13. Heat acclimation improves cutaneous vascular function and sweating in trained cyclists

    PubMed Central

    Lorenzo, Santiago

    2010-01-01

    The aim of this study was to explore heat acclimation effects on cutaneous vascular responses and sweating to local ACh infusions and local heating. We also sought to examine whether heat acclimation altered maximal skin blood flow. ACh (1, 10, and 100 mM) was infused in 20 highly trained cyclists via microdialysis before and after a 10-day heat acclimation program [two 45-min exercise bouts at 50% maximal O2 uptake (V̇o2max) in 40°C (n = 12)] or control conditions [two 45-min exercise bouts at 50% V̇o2max in 13°C (n = 8)]. Skin blood flow was monitored via laser-Doppler flowmetry (LDF), and cutaneous vascular conductance (CVC) was calculated as LDF ÷ mean arterial pressure. Sweat rate was measured by resistance hygrometry. Maximal brachial artery blood flow (forearm blood flow) was obtained by heating the contralateral forearm in a water spray device and measured by Doppler ultrasound. Heat acclimation increased %CVCmax responses to 1, 10, and 100 mM ACh (43.5 ± 3.4 vs. 52.6 ± 2.6% CVCmax, 67.7 ± 3.4 vs. 78.0 ± 3.0% CVCmax, and 81.0 ± 3.8 vs. 88.5 ± 1.1% CVCmax, respectively, all P < 0.05). Maximal forearm blood flow remained unchanged after heat acclimation (290.9 ± 12.7 vs. 269.9 ± 23.6 ml/min). The experimental group showed significant increases in sweating responses to 10 and 100 mM ACh (0.21 ± 0.03 vs. 0.31 ± 0.03 mg·cm−2·min−1 and 0.45 ± 0.05 vs. 0.67 ± 0.06 mg·cm−2·min−1, respectively, all P < 0.05), but not to 1 mM ACh (0.13 ± 0.02 vs. 0.18 ± 0.02 mg·cm−2·min−1, P = 0.147). No differences in any of the variables were found in the control group. Heat acclimation in highly trained subjects induced local adaptations within the skin microcirculation and sweat gland apparatus. Furthermore, maximal skin blood flow was not altered by heat acclimation, demonstrating that the observed changes were attributable to improvement in cutaneous vascular function and not to structural changes that limit maximal vasodilator capacity

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

    PubMed

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

    2008-06-01

    Metabolic and vascular abnormalities have been found in individuals with type 2 diabetes mellitus (T2D). Family history is often associated with increased risk of the development of T2D. We sought to determine if young, sedentary, insulin-sensitive individuals with a family history of T2D (FH+) have a reduced resting energy expenditure (REE) and vascular endothelial function compared with individuals who have no family history of T2D (FH-). The REE was determined in 18 FH+ individuals and 15 FH- individuals using indirect open-circuit calorimetry. Vascular endothelial function was measured via flow-mediated dilation (FMD) of the brachial artery. C-reactive protein and interleukin-6 were also measured to look at vascular inflammation. Body composition was measured via bioelectrical impedance analysis to determine fat-free mass and fat mass for each individual. Insulin resistance was calculated using the homeostasis model assessment equation and fasting insulin and glucose concentrations. Subjects (n = 42) were approximately 26 years old and had normal fasting serum insulin or glucose concentrations. The REE normalized for body weight (kilocalories per day per kilogram body weight) was significantly reduced in the FH+ women compared with FH- women (P < .001) but not in the men. The FMD was significantly reduced (34.3%) in the FH+ group compared with the FH- in women (P = .002). However, no between-group difference in FMD was present in male subjects (P = .376). Young, healthy, insulin-sensitive women with a family history of T2D have reduced whole-body metabolic rate and vascular endothelial function compared with those with no family history of disease. These differences in whole-body metabolic rate and vascular endothelial function were not present in male subjects. PMID:18502267

  15. Construction of Large-Volume Tissue Mimics with 3D Functional Vascular Networks.

    PubMed

    Kang, Tae-Yun; Hong, Jung Min; Jung, Jin Woo; Kang, Hyun-Wook; Cho, Dong-Woo

    2016-01-01

    We used indirect stereolithography (SL) to form inner-layered fluidic networks in a porous scaffold by introducing a hydrogel barrier on the luminal surface, then seeded the networks separately with human umbilical vein endothelial cells and human lung fibroblasts to form a tissue mimic containing vascular networks. The artificial vascular networks provided channels for oxygen transport, thus reducing the hypoxic volume and preventing cell death. The endothelium of the vascular networks significantly retarded the occlusion of channels during whole-blood circulation. The tissue mimics have the potential to be used as an in vitro platform to examine the physiologic and pathologic phenomena through vascular architecture. PMID:27228079

  16. Construction of Large-Volume Tissue Mimics with 3D Functional Vascular Networks

    PubMed Central

    Kang, Tae-Yun; Hong, Jung Min; Jung, Jin Woo; Kang, Hyun-Wook; Cho, Dong-Woo

    2016-01-01

    We used indirect stereolithography (SL) to form inner-layered fluidic networks in a porous scaffold by introducing a hydrogel barrier on the luminal surface, then seeded the networks separately with human umbilical vein endothelial cells and human lung fibroblasts to form a tissue mimic containing vascular networks. The artificial vascular networks provided channels for oxygen transport, thus reducing the hypoxic volume and preventing cell death. The endothelium of the vascular networks significantly retarded the occlusion of channels during whole-blood circulation. The tissue mimics have the potential to be used as an in vitro platform to examine the physiologic and pathologic phenomena through vascular architecture. PMID:27228079

  17. Hydrogen sulfide replacement therapy protects the vascular endothelium in hyperglycemia by preserving mitochondrial function.

    PubMed

    Suzuki, Kunihiro; Olah, Gabor; Modis, Katalin; Coletta, Ciro; Kulp, Gabriella; Gerö, Domokos; Szoleczky, Petra; Chang, Tuanjie; Zhou, Zongmin; Wu, Lingyun; Wang, Rui; Papapetropoulos, Andreas; Szabo, Csaba

    2011-08-16

    The goal of the present studies was to investigate the role of changes in hydrogen sulfide (H(2)S) homeostasis in the pathogenesis of hyperglycemic endothelial dysfunction. Exposure of bEnd3 microvascular endothelial cells to elevated extracellular glucose (in vitro "hyperglycemia") induced the mitochondrial formation of reactive oxygen species (ROS), which resulted in an increased consumption of endogenous and exogenous H(2)S. Replacement of H(2)S or overexpression of the H(2)S-producing enzyme cystathionine-γ-lyase (CSE) attenuated the hyperglycemia-induced enhancement of ROS formation, attenuated nuclear DNA injury, reduced the activation of the nuclear enzyme poly(ADP-ribose) polymerase, and improved cellular viability. In vitro hyperglycemia resulted in a switch from oxidative phosphorylation to glycolysis, an effect that was partially corrected by H(2)S supplementation. Exposure of isolated vascular rings to high glucose in vitro induced an impairment of endothelium-dependent relaxations, which was prevented by CSE overexpression or H(2)S supplementation. siRNA silencing of CSE exacerbated ROS production in hyperglycemic endothelial cells. Vascular rings from CSE(-/-) mice exhibited an accelerated impairment of endothelium-dependent relaxations in response to in vitro hyperglycemia, compared with wild-type controls. Streptozotocin-induced diabetes in rats resulted in a decrease in the circulating level of H(2)S; replacement of H(2)S protected from the development of endothelial dysfunction ex vivo. In conclusion, endogenously produced H(2)S protects against the development of hyperglycemia-induced endothelial dysfunction. We hypothesize that, in hyperglycemic endothelial cells, mitochondrial ROS production and increased H(2)S catabolism form a positive feed-forward cycle. H(2)S replacement protects against these alterations, resulting in reduced ROS formation, improved endothelial metabolic state, and maintenance of normal endothelial function. PMID:21808008

  18. Effects of resistance training combined with vascular occlusion or hypoxia on neuromuscular function in athletes.

    PubMed

    Manimmanakorn, Apiwan; Manimmanakorn, Nuttaset; Taylor, Robert; Draper, Nick; Billaut, Francois; Shearman, Jeremy P; Hamlin, Michael J

    2013-07-01

    The aim was to investigate the effects of low-load resistant training combined with vascular occlusion or normobaric hypoxic exposure, on neuromuscular function. In a randomised controlled trial, well-trained athletes took part in a 5-week training of knee flexor/extensor muscles in which low-load resistant exercise (20% of one repetition maximum, 1-RM) was combined with either (1) an occlusion pressure of approximately 230 mmHg (KT, n = 10), (2) hypoxic air to generate an arterial blood oxygen saturation of ~80% (HT, n = 10), or (3) with no additional stimulus (CT, n = 10). Before and after training, participants completed the following tests: 3-s maximal voluntary contraction (MVC₃), 30-s MVC, and an endurance test (maximal number of repetitions at 20% 1-RM, Reps₂₀). Electromyographic activity (root mean square, RMS) was measured during tests and the cross-sectional area (CSA) of the quadriceps and hamstrings was measured pre- and post-training. Relative to CT, KT, and HT showed likely increases in MVC₃ (11.0 ± 11.9 and 15.0 ± 13.1%, mean ± 90% confidence interval), MVC₃₀ (10.2 ± 9.0 and 18.3 ± 17.4%), and Reps₂₀ (28.9 ± 23.7 and 23.3 ± 24.0%). Compared to the CT group, CSA increased in the KT (7.6 ± 5.8) and HT groups (5.3 ± 3.0). KT had a large effect on RMS during MVC₃, compared to CT (effect size 0.8) and HT (effect size 0.8). We suspect hypoxic conditions created within the muscles during vascular occlusion and hypoxic training may play a key role in these performance enhancements. PMID:23412543

  19. Structural and Functional Vascular Alterations and Incident Hypertension in Normotensive Adults

    PubMed Central

    Peralta, Carmen A.; Adeney, Kathryn L.; Shlipak, Michael G.; Jacobs, David; Duprez, Daniel; Bluemke, David; Polak, Joseph; Psaty, Bruce; Kestenbaum, Bryan R.

    2010-01-01

    Vascular abnormalities may exist before clinical hypertension. Using Poisson regression, the authors studied the association of coronary artery calcium (CAC), common carotid intima-media thickness (CIMT), aortic distensibility, and large and small arterial elasticity with incident hypertension among 2,512 normotensive US adults free of cardiovascular disease. Incidence rate ratios for incident hypertension (blood pressure ≥140/90 mm Hg or new antihypertensive medication) were calculated. Increased CAC was associated with incident hypertension in demographics-adjusted models (incidence rate ratio (IRR) = 1.35, 95% confidence interval (CI): 1.04, 1.75; IRR = 1.35, 95% CI: 1.02, 1.78; and IRR = 1.59, 95% CI: 1.12, 2.25 for CAC scores of 30–99, 100–399, and ≥400, respectively) but was attenuated after further adjustment. Increased common CIMT was associated with incident hypertension (IRR = 1.77, 95% CI: 1.28, 2.46 for quintile 4; IRR = 1.80, 95% CI: 1.28, 2.53 for quintile 5). Participants with the lowest, compared with the highest, aortic distensibility had an increased risk of hypertension (IRR = 1.75, 95% CI: 1.10, 2.79), as did those with the lowest large arterial elasticity (IRR = 1.49, 95% CI: 1.11, 1.99). Lower small arterial elasticity was incrementally associated with incident hypertension starting at quintile 2 (IRR = 2.01, 95% CI: 1.39, 2.91; IRR = 2.47, 95% CI: 1.71, 3.57; IRR = 2.73, 95% CI: 1.88, 3.95; and IRR = 2.85, 95% CI: 1.95, 4.16). Structural and functional vascular abnormalities are independent predictors of incident hypertension. These findings are important for understanding the pathogenesis of hypertension. PMID:19951938

  20. Nitroso-Redox Status and Vascular Function in Marginal and Severe Ascorbate Deficiency

    PubMed Central

    Garcia-Saura, Maria-Francisca; Saijo, Fumito; Bryan, Nathan S.; Bauer, Selena; Rodriguez, Juan

    2012-01-01

    Abstract Marginal vitamin C (ascorbic acid) deficiency is a prevalent yet underappreciated risk factor for cardiovascular disease. Along with glutathione, ascorbate plays important roles in antioxidant defense and redox signaling. Production of nitric oxide (NO) and reactive oxygen species and their interaction, giving rise to nitroso and nitrosyl product formation, are key components of the redox regulation/signaling network. Numerous in vitro studies have demonstrated that these systems are interconnected via multiple chemical transformation reactions, but little is known about their dynamics and significance in vivo. Aims: We sought to investigate the time-course of changes in NO/redox status and vascular function during ascorbate depletion in rats unable to synthesize vitamin C. Results: We here show that both redox and protein nitros(yl)ation status in blood and vital organs vary dynamically during development of ascorbate deficiency. Prolonged marginal ascorbate deficiency is associated with cell/tissue-specific perturbations in ascorbate and glutathione redox and NO status. Scurvy develops earlier in marginally deficient compared to adequately supplemented animals, with blunted compensatory NO production and a dissociation of biochemistry from clinical symptomology in the former. Paradoxically, aortic endothelial reactivity is enhanced rather than impaired, irrespective of ascorbate status. Innovation/Conclusion: Enhanced NO production and protein nitros(yl)ation are integral responses to the redox stress of acute ascorbate deprivation. The elevated cardiovascular risk in marginal ascorbate deficiency is likely to be associated with perturbations of NO/redox-sensitive signaling nodes unrelated to the regulation of vascular tone. This new model may have merit for the future study of redox-sensitive events in marginal ascorbate deficiency. Antioxid. Redox Signal. 17, 937–950. PMID:22304648

  1. 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

  2. Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-γ Disrupts Vascular Wall Structure and Function

    PubMed Central

    Kleinhenz, Jennifer M.; Murphy, Tamara C.; Pokutta-Paskaleva, Anastassia P.; Gleason, Rudolph L.; Lyle, Alicia N.; Taylor, W. Robert; Blount, Mitsi A.; Cheng, Juan; Yang, Qinglin; Sutliff, Roy L.; Hart, C. Michael

    2015-01-01

    Activation of the nuclear hormone receptor, PPARγ, with pharmacological agonists promotes a contractile vascular smooth muscle cell phenotype and reduces oxidative stress and cell proliferation, particularly under pathological conditions including vascular injury, restenosis, and atherosclerosis. However, pharmacological agonists activate both PPARγ-dependent and -independent mechanisms in multiple cell types confounding efforts to clarify the precise role of PPARγ in smooth muscle cell structure and function in vivo. We, therefore, designed and characterized a mouse model with smooth muscle cell-targeted PPARγ overexpression (smPPARγOE). Our results demonstrate that smPPARγOE attenuated contractile responses in aortic rings, increased aortic compliance, caused aortic dilatation, and reduced mean arterial pressure. Molecular characterization revealed that compared to littermate control mice, aortas from smPPARγOE mice expressed lower levels of contractile proteins and increased levels of adipocyte-specific transcripts. Morphological analysis demonstrated increased lipid deposition in the vascular media and in smooth muscle of extravascular tissues. In vitro adenoviral-mediated PPARγ overexpression in human aortic smooth muscle cells similarly increased adipocyte markers and lipid uptake. The findings demonstrate that smooth muscle PPARγ overexpression disrupts vascular wall structure and function, emphasizing that balanced PPARγ activity is essential for vascular smooth muscle homeostasis. PMID:26451838

  3. Vascular expression, activity and function of indoleamine 2,3-dioxygenase-1 following cerebral ischaemia-reperfusion in mice.

    PubMed

    Jackman, Katherine A; Brait, Vanessa H; Wang, Yutang; Maghzal, Ghassan J; Ball, Helen J; McKenzie, Gavin; De Silva, T Michael; Stocker, Roland; Sobey, Christopher G

    2011-05-01

    Indoleamine 2,3-dioxygenases-1 (Ido1) and -2 initiate the kynurenine pathway of tryptophan metabolism. In addition to the established immune regulatory effects of Ido1 and the ability of nitric oxide to regulate Ido1 activity, it is now also known that Ido1-mediated metabolism of tryptophan to kynurenine can modulate vascular tone. Ido activity is reportedly elevated in stroke patients and correlates with increased risk of death. Thus, the present goals were to test whether, following cerebral ischaemia, Ido activity and cerebrovascular Ido1 expression are altered and whether expression of Ido1 contributes to stroke outcome. Transient cerebral ischaemia was induced in wild-type and Ido1 gene-deficient (Ido1 (-/-)) mice. Mice were pre-treated with vehicle, the Ido1 inhibitor, 1-methyl-D-tryptophan (1-MT; 50 mg/kg i.p.) or the inducible nitric oxide synthase (Nos2) inhibitor, aminoguanidine (AG, 100 mg/kg i.p.). At 24 h, neurological function, brain infarct size and swelling were assessed. In addition, Ido activity was estimated by plasma kynurenine and tryptophan, and Ido1 expression was examined in cerebral arterioles. Cerebral ischaemia-reperfusion in wild-type mice increased Ido activity and its expression in cerebral arterioles. Ido1 (-/-) and 1-MT-treated wild-type mice had lower Ido activity but similar post-stroke neurological function and similar total brain infarct volume and swelling, relative to control mice. Inhibition of Nos2 with AG also did not affect Ido activity or outcome following stroke. This study provides molecular and pharmacological evidence that the expression and the activity of Ido1 increase following stroke. However, such Ido1 expression does not appear to affect overall outcome following acute ischaemic stroke, and furthermore, a regulatory role of Nos2-derived nitric oxide on Ido activity following cerebral ischaemia-reperfusion appears unlikely. PMID:21359968

  4. A single portion of blueberry (Vaccinium corymbosum L) improves protection against DNA damage but not vascular function in healthy male volunteers.

    PubMed

    Del Bó, Cristian; Riso, Patrizia; Campolo, Jonica; Møller, Peter; Loft, Steffen; Klimis-Zacas, Dorothy; Brambilla, Ada; Rizzolo, Anna; Porrini, Marisa

    2013-03-01

    It has been suggested that anthocyanin-rich foods may exert antioxidant effects and improve vascular function as demonstrated mainly in vitro and in the animal model. Blueberries are rich sources of anthocyanins and we hypothesized that their intake could improve cell protection against oxidative stress and affect endothelial function in humans. The aim of the study was to investigate the effect of one portion (300 g) of blueberries on selected markers of oxidative stress and antioxidant protection (endogenous and oxidatively induced DNA damage) and of vascular function (changes in peripheral arterial tone and plasma nitric oxide levels) in male subjects. In a randomized cross-over design, separated by a wash out period ten young volunteers received one portion of blueberries ground by blender or one portion of a control jelly. Before and after consumption (at 1, 2, and 24 hours), blood samples were collected and used to evaluate anthocyanin absorption (through mass spectrometry), endogenous and H(2)O(2)-induced DNA damage in blood mononuclear cells (through the comet assay), and plasma nitric oxide concentrations (through a fluorometric assay). Peripheral arterial function was assessed by means of Endo-PAT 2000. Blueberries significantly reduced (P < .01) H(2)O(2)-induced DNA damage (-18%) 1 hour after blueberry consumption compared to control. No significant differences were observed for endogenous DNA damage, peripheral arterial function and nitric oxide levels after blueberry intake. In conclusion, one portion of blueberries seems sufficient to improve cell antioxidant defense against DNA damage, but further studies are necessary to understand their role on vascular function. PMID:23507228

  5. Exploration of the Rapid Effects of Personal Fine Particulate Matter Exposure on Hemodynamics and Vascular Function during the Same Day

    EPA Science Inventory

    Background: Levels of fine particulate matter [≤ 2.5 μm in aerodynamic diameter (PM2.5)] are associated with alterations in arterial hemodynamics and vascular function. However, the characteristics of the same-day exposure–response relationships remain unclear. Object...

  6. Integrin-specific hydrogels functionalized with VEGF for vascularization and bone regeneration of critical-size bone defects.

    PubMed

    García, José R; Clark, Amy Y; García, Andrés J

    2016-04-01

    Vascularization of bone defects is considered a crucial component to the successful regeneration of large bone defects. Although vascular endothelial growth factor (VEGF) has been delivered to critical-size bone defect models to augment blood vessel infiltration into the defect area, its potential to increase bone repair remains ambiguous. In this study, we investigated whether integrin-specific biomaterials modulate the effects of VEGF on bone regeneration. We engineered protease-degradable, VEGF-loaded poly(ethylene glycol) (PEG) hydrogels functionalized with either a triple-helical, α2 β1 integrin-specific peptide GGYGGGP(GPP)5 GFOGER(GPP)5 GPC (GFOGER) or an αv β3 integrin-targeting peptide GRGDSPC (RGD). Covalent incorporation of VEGF into the PEG hydrogel allowed for protease degradation-dependent release of the protein while maintaining VEGF bioactivity. When applied to critical-size segmental defects in the murine radius, GFOGER-functionalized VEGF-free hydrogels exhibited significantly increased vascular volume and density and resulted in a larger number of thicker blood vessels compared to RGD-functionalized VEGF-free hydrogels. VEGF-loaded RGD hydrogels increased vascularization compared to VEGF-free RGD hydrogels, but the levels of vascularization for these VEGF-containing RGD hydrogels were similar to those of VEGF-free GFOGER hydrogels. VEGF transiently increased bone regeneration in RGD hydrogels but had no effect at later time points. In GFOGER hydrogels, VEGF did not show an effect on bone regeneration. However, VEGF-free GFOGER hydrogels resulted in increased bone regeneration compared to VEGF-free RGD hydrogels. These findings demonstrate the importance of integrin-specificity in engineering constructs for vascularization and associated bone regeneration. PMID:26662727

  7. Vascular functioning and the water balance of ripening kiwifruit (Actinidia chinensis) berries

    PubMed Central

    Clearwater, Michael J.; Luo, Zhiwei; Ong, Sam Eng Chye; Blattmann, Peter; Thorp, T. Grant

    2012-01-01

    Indirect evidence suggests that water supply to fleshy fruits during the final stages of development occurs through the phloem, with the xylem providing little water, or acting as a pathway for water loss back to the plant. This inference was tested by examining the water balance and vascular functioning of ripening kiwifruit berries (Actinidia chinensis var. chinensis ‘Hort16A’) exhibiting a pre-harvest ‘shrivel’ disorder in California, and normal development in New Zealand. Dye labelling and mass balance experiments indicated that the xylem and phloem were both functional and contributed approximately equally to the fruit water supply during this stage of development. The modelled fruit water balance was dominated by transpiration, with net water loss under high vapour pressure deficit (Da) conditions in California, but a net gain under cooler New Zealand conditions. Direct measurement of pedicel sap flow under controlled conditions confirmed inward flows in both the phloem and xylem under conditions of both low and high Da. Phloem flows were required for growth, with gradual recovery after a step increase in Da. Xylem flows alone were unable to support growth, but did supply transpiration and were responsive to Da-induced pressure fluctuations. The results suggest that the shrivel disorder was a consequence of a high fruit transpiration rate, and that the perception of complete loss or reversal of inward xylem flows in ripening fruits should be re-examined. PMID:22155631

  8. Investigating surface topology and cyclic-RGD peptide functionalization on vascular endothelialization.

    PubMed

    McNichols, Colton; Wilkins, Justin; Kubota, Atsutoshi; Shiu, Yan T; Aouadi, Samir M; Kohli, Punit

    2014-02-01

    The advantages of endothelialization of a stent surface in comparison with the bare metal and drug-eluting stents used today include reduced late-stent restenosis and in-stent thrombosis. In this article, we study the effect of surface topology and functionalization of tantalum (Ta) with cyclic-(arginine-glycine-aspartic acid-d-phenylalanine-lysine) (cRGDfK) on the attachment, spreading, and growth of vascular endothelial cells. Self-assembled nanodimpling on Ta surfaces was performed using a one-step electropolishing technique. Next, cRGDfK was covalently bonded onto the surface using silane chemistry. Our results suggest that nanotexturing alone was sufficient to enhance cell spreading, but the combination of a nanodimpled surfaces along with the cRGDfK peptide may produce a better endothelialization coating on the surface in terms of higher cell density, better cell spreading, and more cell-cell interactions, when compared to using cRGDfK peptide functionalization alone or nanotexturing alone. We believe that future research should look into how to implement both modifications (topographic and chemical modifications) to optimize the stent surface for endothelialization. PMID:23505215

  9. Localization and function of KLF4 in cytoplasm of vascular smooth muscle cell

    SciTech Connect

    Liu, Yan; Zheng, Bin; Zhang, Xin-hua; Nie, Chan-juan; Li, Yong-hui; Wen, Jin-kun

    2013-06-28

    Highlights: •PDGF-BB prompts the translocation of KLF4 to the cytoplasm. •PDGF-BB promotes interaction between KLF4 and actin in the cytoplasm. •Phosphorylation and SUMOylation of KLF4 participates in regulation of cytoskeletal organization. •KLF4 regulates cytoskeleton by promoting the expression of contraction-associated genes. -- Abstract: The Krüppel-like factor 4 is a DNA-binding transcriptional regulator that regulates a diverse array of cellular processes, including development, differentiation, proliferation, and apoptosis. The previous studies about KLF4 functions mainly focused on its role as a transcription factor, its functions in the cytoplasm are still unknown. In this study, we found that PDGF-BB could prompt the translocation of KLF4 to the cytoplasm through CRM1-mediated nuclear export pathway in vascular smooth muscle cells (VSMCs) and increased the interaction of KLF4 with actin in the cytoplasm. Further study showed that both KLF4 phosphorylation and SUMOylation induced by PDGF-BB participates in regulation of cytoskeletal organization by stabilizing the actin cytoskeleton in VSMCs. In conclusion, these results identify that KLF4 participates in the cytoskeletal organization by stabilizing cytoskeleton in the cytoplasm of VSMCs.

  10. Differentiation and functional connection of vascular elements in compatible and incompatible pear/quince internode micrografts.

    PubMed

    Espen, Luca; Cocucci, Maurizio; Sacchi, Gian Attilio

    2005-11-01

    Micrografts of internodes excised from in vitro grown pear plants (Pyrus communis L. cv. 'Bosc' (B) and cv. 'Butirra Hardy' (BH)) and quince (Cydonia oblonga Mill. East Malling clone C (EMC)), were cultured aseptically to test the effectiveness of their functional vascular reconnection in relation to incompatibility-compatibility relationships that these genotypes exhibit in the field. The incompatible heterograft (B/EMC) showed a marked delay in internode cohesion compared with the autografts (both B/B and BH/BH) and the compatible heterograft (BH/EMC). Even when fused, the translocation of [14C]-sorbitol from upper to lower internode was lower in B/EMC micrografts than in the other combinations. Epifluorescence studies performed with carboxyfluorescin, a specific phloem probe, indicated that the limited translocation was caused by a delay in the establishment of functional phloem continuity between the two internodes. In the B/EMC combination, new differentiated tracheary elements (TE) in the parenchyma tissue at the graft interface between the two internodes were not detected until 30 days after grafting, whereas in the BH/EMC heterograft and both autografts, new xylem connections appeared to cross the interface 20 days after grafting. Immunohistochemical detection (terminal nick-end labeling assay) of the number of cells undergoing nuclear DNA fragmentation at the graft interface confirmed that the limited and delayed TE differentiation in B/EMC heterografts was associated with a decrease in the activity of programmed cell death processes involved in the differentiation of TE. PMID:16105809

  11. Investigating Surface Topology and Cyclic-RGD Peptide functionalization on Vascular Endothelialization

    PubMed Central

    McNichols, Colton; Wilkins, Justin; Kubota, Atsu; Shiu, Yan T.; Aouadi, Samir M.; Kohli, Punit

    2013-01-01

    The advantages of endothelialization of a stent surface in comparison with the bare metal and drug eluting stents used today include reduced late-stent restenosis and in-stent thrombosis. In this paper, we study the effect of surface topology and functionalization of tantalum (Ta) with cyclic-(arginine-glycine-aspartic acid-D-phenylalanine-lysine (cRGDfK)) on the attachment, spreading, and growth of vascular endothelial cells. Self-assembled nano-dimpling on Ta surfaces was performed using a one-step electropolishing technique. Next, cRGDfK was covalently bonded onto the surface using silane chemistry. Our results suggest that nano-texturing alone was sufficient to enhance cell spreading, but the combination of a nano-dimpled surfaces along with the cRGDfK peptide may produce a better endothelialization coating on the surface in terms of higher cell density, better cell spreading, and more cell-cell interactions, when compared to using cRGDfK peptide functionalization alone or nano-texturing alone. We believe that future research should look into how to implement both modifications (topographic and chemical modifications) to optimize the stent surface for endothelialization. PMID:23505215

  12. Graded effects of unregulated smooth muscle myosin on intestinal architecture, intestinal motility and vascular function in zebrafish.

    PubMed

    Abrams, Joshua; Einhorn, Zev; Seiler, Christoph; Zong, Alan B; Sweeney, H Lee; Pack, Michael

    2016-05-01

    Smooth muscle contraction is controlled by the regulated activity of the myosin heavy chain ATPase (Myh11). Myh11 mutations have diverse effects in the cardiovascular, digestive and genitourinary systems in humans and animal models. We previously reported a recessive missense mutation, meltdown (mlt), which converts a highly conserved tryptophan to arginine (W512R) in the rigid relay loop of zebrafish Myh11. The mlt mutation disrupts myosin regulation and non-autonomously induces invasive expansion of the intestinal epithelium. Here, we report two newly identified missense mutations in the switch-1 (S237Y) and coil-coiled (L1287M) domains of Myh11 that fail to complement mlt Cell invasion was not detected in either homozygous mutant but could be induced by oxidative stress and activation of oncogenic signaling pathways. The smooth muscle defect imparted by the mlt and S237Y mutations also delayed intestinal transit, and altered vascular function, as measured by blood flow in the dorsal aorta. The cell-invasion phenotype induced by the three myh11 mutants correlated with the degree of myosin deregulation. These findings suggest that the vertebrate intestinal epithelium is tuned to the physical state of the surrounding stroma, which, in turn, governs its response to physiologic and pathologic stimuli. Genetic variants that alter the regulation of smooth muscle myosin might be risk factors for diseases affecting the intestine, vasculature, and other tissues that contain smooth muscle or contractile cells that express smooth muscle proteins, particularly in the setting of redox stress. PMID:26893369

  13. Influence of Vascular Variant of the Posterior Cerebral Artery (PCA) on Cerebral Blood Flow, Vascular Response to CO2 and Static Functional Connectivity

    PubMed Central

    Emmert, Kirsten; Zöller, Daniela; Preti, Maria Giulia; Van De Ville, Dimitri; Giannakopoulos, Panteleimon; Haller, Sven

    2016-01-01

    Introduction The fetal origin of the posterior cerebral artery (fPCA) is a frequent vascular variant in 11–29% of the population. For the fPCA, blood flow in the PCA originates from the anterior instead of the posterior circulation. We tested whether this blood supply variant impacts the cerebral blood flow assessed by arterial spin labeling (ASL), cerebrovascular reserve as well as resting-state static functional connectivity (sFC) in the sense of a systematic confound. Methods The study included 385 healthy, elderly subjects (mean age: 74.18 years [range: 68.9–90.4]; 243 female). Participants were classified into normal vascular supply (n = 296, 76.88%), right fetal origin (n = 23, 5.97%), left fetal origin (n = 16, 4.16%), bilateral fetal origin (n = 4, 1.04%), and intermediate (n = 46, 11.95%, excluded from further analysis) groups. ASL-derived relative cerebral blood flow (relCBF) maps and cerebrovascular reserve (CVR) maps derived from a CO2 challenge with blocks of 7% CO2 were compared. Additionally, sFC between 90 regions of interest (ROIs) was compared between the groups. Results CVR was significantly reduced in subjects with ipsilateral fPCA, most prominently in the temporal lobe. ASL yielded a non-significant trend towards reduced relCBF in bilateral posterior watershed areas. In contrast, conventional atlas-based sFC did not differ between groups. Conclusions In conclusion, fPCA presence may bias the assessment of cerebrovascular reserve by reducing the response to CO2. In contrast, its effect on ASL-assessed baseline perfusion was marginal. Moreover, fPCA presence did not systematically impact resting-state sFC. Taken together, this data implies that perfusion variables should take into account the vascularization patterns. PMID:27532633

  14. Peripheral artery disease is associated with severe impairment of vascular function.

    PubMed

    Kiani, Soroosh; Aasen, Jonathan G; Holbrook, Monika; Khemka, Abhishek; Sharmeen, Farhana; LeLeiko, Rebecca M; Tabit, Corey E; Farber, Alik; Eberhardt, Robert T; Gokce, Noyan; Vita, Joseph A; Hamburg, Naomi M

    2013-04-01

    Patients with peripheral artery disease (PAD) have higher cardiovascular event rates than patients with established coronary artery disease (CAD) and abnormal endothelial function predicts cardiovascular risk in PAD and CAD. We investigated the hypothesis that PAD is associated with a greater degree of impairment in vascular function than CAD. We used several non-invasive tests to evaluate endothelial function in 1320 men and women with combined PAD and CAD (n = 198), PAD alone (n = 179), CAD alone (n = 466), or controls aged > 45 years without CAD or PAD (n = 477). Patients with PAD had lower brachial artery flow-mediated dilation (5.1 ± 3.9% PAD and CAD, 5.9 ± 4.4% PAD alone) compared to patients with CAD alone (7.0 ± 4.5%) and no PAD or CAD (8.1 ± 5.1%, p < 0.0001). In multivariable models adjusting for clinical covariates and the presence of CAD, PAD remained associated with lower flow-mediated dilation (p < 0.0001). PAD was associated also with lower nitroglycerin-mediated dilation and reactive hyperemia. Patients with both PAD and CAD had a lower digital pulse amplitude tonometry (PAT) ratio in unadjusted models but not in adjusted models. Flow-mediated dilation was modestly associated with PAT ratio in patients with atherosclerotic disease (r = 0.23, p < 0.0001) but not among control participants (r = 0.008, p = 0.93). Our findings indicate that patients with PAD have greater impairment of vasodilator function and are consistent with the possibility that endothelial dysfunction may contribute to adverse cardiovascular prognosis in PAD. PMID:23509089

  15. Peripheral artery disease is associated with severe impairment of vascular function

    PubMed Central

    Kiani, Soroosh; Aasen, Jonathan G; Holbrook, Monika; Khemka, Abhishek; Sharmeen, Farhana; LeLeiko, Rebecca M; Tabit, Corey E; Farber, Alik; Eberhardt, Robert T; Gokce, Noyan; Vita, Joseph A; Hamburg, Naomi M

    2013-01-01

    Patients with peripheral artery disease (PAD) have higher cardiovascular event rates than patients with established coronary artery disease (CAD) and abnormal endothelial function predicts cardiovascular risk in PAD and CAD. We investigated the hypothesis that PAD is associated with a greater degree of impairment in vascular function than CAD. We used several non-invasive tests to evaluate endothelial function in 1320 men and women with combined PAD and CAD (n = 198), PAD alone (n = 179), CAD alone (n = 466), or controls aged > 45 years without CAD or PAD (n = 477). Patients with PAD had lower brachial artery flow-mediated dilation (5.1 ± 3.9% PAD and CAD, 5.9 ± 4.4% PAD alone) compared to patients with CAD alone (7.0 ± 4.5%) and no PAD or CAD (8.1 ± 5.1%, p < 0.0001). In multivariable models adjusting for clinical covariates and the presence of CAD, PAD remained associated with lower flow-mediated dilation (p < 0.0001). PAD was associated also with lower nitroglycerin-mediated dilation and reactive hyperemia. Patients with both PAD and CAD had a lower digital pulse amplitude tonometry (PAT) ratio in unadjusted models but not in adjusted models. Flow-mediated dilation was modestly associated with PAT ratio in patients with atherosclerotic disease (r = 0.23, p < 0.0001) but not among control participants (r = 0.008, p = 0.93). Our findings indicate that patients with PAD have greater impairment of vasodilator function and are consistent with the possibility that endothelial dysfunction may contribute to adverse cardiovascular prognosis in PAD. PMID:23509089

  16. Regional MRI Diffusion, White-Matter Hyperintensities, and Cognitive Function in Alzheimer's Disease and Vascular Dementia

    PubMed Central

    Scrascia, Federica; Quattrocchi, Carlo Cosimo; Errante, Yuri; Gangemi, Emma; Curcio, Giuseppe; Ursini, Francesca; Silvestrini, Mauro; Maggio, Paola; Beomonte Zobel, Bruno; Rossini, Paolo Maria; Pasqualetti, Patrizio; Falsetti, Lorenzo; Vernieri, Fabrizio

    2016-01-01

    Background and Purpose An increase in brain water diffusivity as measured using magnetic resonance imaging (MRI) has been recently reported in normal-appearing white matter (NAWM) in patients affected by cognitive impairment. However, it remains to be clarified if this reflects an overt neuronal tissue disruption that leads to degenerative or microvascular lesions. This question was addressed by comparing the regional MRI apparent diffusion coefficients (ADCs) of NAWM in patients affected by Alzheimer's disease (AD) or vascular dementia (VaD). The relationships of ADCs with the white-matter hyperintensity (WMH) burden, carotid atherosclerosis, and cognitive performance were also investigated. Methods Forty-nine AD and 31 VaD patients underwent brain MRI to assess the WMH volume and regional NAWM ADCs, neuropsychological evaluations, and carotid ultrasound to assess the plaque severity and intima-media thickness (IMT). Results Regional ADCs in NAWM did not differ between VaD and AD patients, while the WMH volume was greater in VaD than in AD patients. The ADC in the anterior corpus callosum was related to the WMH volume, while a greater carotid IMT was positively correlated with the temporal ADC and WMH volume. The memory performance was worse in patients with higher temporal ADCs. Constructional praxis scores were related to ADCs in the frontal, and occipital lobes, in the anterior and posterior corpus callosum as well as to the WMH volume. Abstract reasoning was related to frontal, parietal, and temporal ADCs. Conclusions Our data show that higher regional ADCs in NAWM are associated with microcirculatory impairment, as depicted by the WMH volume. Moreover, regional ADCs in NAWM are differently associated with the neuropsychological performances in memory, constructional praxia, and abstract reasoning domains. PMID:27074295

  17. Functional significance of preserved affect recognition in schizophrenia

    PubMed Central

    Fiszdon, Joanna M.; Johannesen, Jason K.

    2009-01-01

    Affect recognition (AR) is a core component of social information processing, thus may be critical to understanding social behavior and functioning in broader aspects of daily living. Deficits in AR are well documented in schizophrenia, however, there is also evidence that many individuals with schizophrenia perform AR tasks at near-normal levels. In the current study, we sought to evaluate the functional significance of AR deficits in schizophrenia by comparing subgroups with normal-range and impaired AR performance on proxy and interviewer-rated measures of real-world functioning. Schizophrenia outpatients were classified as normal-range (N=17) and impaired (N=31) based on a logistic cut point in the sample distribution of BLERT scores, referenced to a normative sample of healthy control subjects (N=56). The derived schizophrenia subgroups were then compared on proxy (UCSD, UPSA, SSPA, MMAA) and interviewer-rated (QLS, ILSS) measures of functioning, as well as battery of neurocognitive tests. Initial analyses indicated superior MMAA and QLS performance in the near-normal AR subgroup. Covariate analyses indicated that group differences in neurocognition fully mediated the observed associations between AR and MMAA and attenuated the observed relationships between AR classification and QLS. These results support three main conclusions. First, AR, like many other domains of psychopathology studied in schizophrenia, is preserved in select subgroups. Second, there is a positive relationship between AR performance and functional outcome measures. Third, neurocognition appears to mediate the relationship between AR and measures of functioning. PMID:20202689

  18. 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

  19. Effects of exercise training on tumor hypoxia and vascular function in the rodent preclinical orthotopic prostate cancer model.

    PubMed

    McCullough, Danielle J; Nguyen, Linda M-D; Siemann, Dietmar W; Behnke, Bradley J

    2013-12-01

    Regular physical exercise is considered to be an integral component of cancer care strategies. However, the effect of exercise training on tumor microvascular oxygenation, hypoxia, and vascular function, all of which can affect the tumor microenvironment, remains unknown. Using an orthotopic preclinical model of prostate cancer, we tested the hypotheses that, after exercise training, in the tumor, there would be an enhanced microvascular Po2, increased number of patent vessels, and reduced hypoxia. We also investigated tumor resistance artery contractile properties. Dunning R-3327 AT-1 tumor cells (10(4)) were injected into the ventral prostate of 4-5-mo-old male Copenhagen or Nude rats, which were randomly assigned to tumor-bearing exercise trained (TB-Ex trained; n = 15; treadmill exercise for 5-7 wk) or sedentary groups (TB-Sedentary; n = 12). Phosphorescence quenching was used to measure tumor microvascular Po2, and Hoechst-33342 and EF-5 were used to measure patent vessels and tumor hypoxia, respectively. Tumor resistance artery function was assessed in vitro using the isolated microvessel technique. Compared with sedentary counterparts, tumor microvascular Po2 increased ∼100% after exercise training (TB-Sedentary, 6.0 ± 0.3 vs. TB-Ex Trained, 12.2 ± 1.0 mmHg, P < 0.05). Exercise training did not affect the number of patent vessels but did significantly reduce tumor hypoxia in the conscious, resting condition from 39 ± 12% of the tumor area in TB-Sedentary to 4 ± 1% in TB-Ex Trained. Exercise training did not affect vessel contractile function. These results demonstrate that after exercise training, there is a large increase in the driving force of O2 from the tumor microcirculation, which likely contributes to the considerable reduction in tumor hypoxia. These results suggest that exercise training can modulate the microenvironment of the tumor, such that a sustained reduction in tumor hypoxia occurs, which may lead to a less aggressive phenotype and

  20. DNA Damage and Repair in Vascular Disease.

    PubMed

    Uryga, Anna; Gray, Kelly; Bennett, Martin

    2016-01-01

    DNA damage affecting both genomic and mitochondrial DNA is present in a variety of both inherited and acquired vascular diseases. Multiple cell types show persistent DNA damage and a range of lesions. In turn, DNA damage activates a variety of DNA repair mechanisms, many of which are activated in vascular disease. Such DNA repair mechanisms either stall the cell cycle to allow repair to occur or trigger apoptosis or cell senescence to prevent propagation of damaged DNA. Recent evidence has indicated that DNA damage occurs early, is progressive, and is sufficient to impair function of cells composing the vascular wall. The consequences of persistent genomic and mitochondrial DNA damage, including inflammation, cell senescence, and apoptosis, are present in vascular disease. DNA damage can thus directly cause vascular disease, opening up new possibilities for both prevention and treatment. We review the evidence for and the causes, types, and consequences of DNA damage in vascular disease. PMID:26442438

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

    PubMed Central

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

    2012-01-01

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

  2. Vascular Effects of Endothelin Receptor Antagonists Depends on Their Selectivity for ETA Versus ETB Receptors and on the Functionality of Endothelial ETB Receptors

    PubMed Central

    Steiner, Pauline; Wanner, Daniel; Rey, Markus; Hess, Patrick; Clozel, Martine

    2015-01-01

    Introduction: The goal of this study was to characterize the role of Endothelin (ET) type B receptors (ETB) on vascular function in healthy and diseased conditions and demonstrate how it affects the pharmacological activity of ET receptor antagonists (ERAs). Methods: The contribution of the ETB receptor to vascular relaxation or constriction was characterized in isolated arteries from healthy and diseased rats with systemic (Dahl-S) or pulmonary hypertension (monocrotaline). Because the role of ETB receptors is different in pathological vis-à-vis normal conditions, we compared the efficacy of ETA-selective and dual ETA/ETB ERAs on blood pressure in hypertensive rats equipped with telemetry. Results: In healthy vessels, ETB receptors stimulation with sarafotoxin S6c induced vasorelaxation and no vasoconstriction. In contrast, in arteries of rats with systemic or pulmonary hypertension, endothelial ETB-mediated relaxation was lost while vasoconstriction on stimulation by sarafotoxin S6c was observed. In hypertensive rats, administration of the dual ETA/ETB ERA macitentan on top of a maximal effective dose of the ETA-selective ERA ambrisentan further reduced blood pressure, indicating that ETB receptors blockade provides additional benefit. Conclusions: Taken together, these data suggest that in pathology, dual ETA/ETB receptor antagonism can provide superior vascular effects compared with ETA-selective receptor blockade. PMID:25992919

  3. Factors affecting sexual function in menopause: A review article.

    PubMed

    Nazarpour, Soheila; Simbar, Masoumeh; Tehrani, Fahimeh Ramezani

    2016-08-01

    This study aimed to systematically review the articles on factors affecting sexual function during menopause. Searching articles indexed in Pubmed, Science Direct, Iranmedex, EMBASE, Scopus, and Scientific Information Database databases, a total number of 42 studies published between 2003 and 2013 were selected. Age, estrogen deficiency, type of menopause, chronic medical problems, partner's sex problems, severity of menopause symptoms, dystocia history, and health status were the physical factors influencing sexual function of menopausal women. There were conflicting results regarding the amount of androgens, hormonal therapy, exercise/physical activity, and obstetric history. In the mental-emotional area, all studies confirmed the impact of depression and anxiety. Social factors, including smoking, alcohol consumption, the quality of relationship with husband, partner's loyalty, sexual knowledge, access to health care, a history of divorce or the death of a husband, living apart from a spouse, and a negative understanding of women's health were found to affect sexual function; however, there were conflicting results regarding the effects of education, occupation, socioeconomic status, marital duration, and frequency of sexual intercourse. PMID:27590367

  4. Microbial composition affects the functioning of estuarine sediments

    PubMed Central

    Reed, Heather E; Martiny, Jennifer BH

    2013-01-01

    Although microorganisms largely drive many ecosystem processes, the relationship between microbial composition and their functioning remains unclear. To tease apart the effects of composition and the environment directly, microbial composition must be manipulated and maintained, ideally in a natural ecosystem. In this study, we aimed to test whether variability in microbial composition affects functional processes in a field setting, by reciprocally transplanting riverbed sediments between low- and high-salinity locations along the Nonesuch River (Maine, USA). We placed the sediments into microbial ‘cages' to prevent the migration of microorganisms, while allowing the sediments to experience the abiotic conditions of the surroundings. We performed two experiments, short- (1 week) and long-term (7 weeks) reciprocal transplants, after which we assayed a variety of functional processes in the cages. In both experiments, we examined the composition of bacteria generally (targeting the 16S rDNA gene) and sulfate-reducing bacteria (SRB) specifically (targeting the dsrAB gene) using terminal restriction fragment length polymorphism (T-RFLP). In the short-term experiment, sediment processes (CO2 production, CH4 flux, nitrification and enzyme activities) depended on both the sediment's origin (reflecting differences in microbial composition between salt and freshwater sediments) and the surrounding environment. In the long-term experiment, general bacterial composition (but not SRB composition) shifted in response to their new environment, and this composition was significantly correlated with sediment functioning. Further, sediment origin had a diminished effect, relative to the short-term experiment, on sediment processes. Overall, this study provides direct evidence that microbial composition directly affects functional processes in these sediments. PMID:23235294

  5. Vascular Endothelial Growth Factor Prevents Apoptosis and Preserves Contractile Function in Hypertrophied Infant Heart

    PubMed Central

    Friehs, Ingeborg; Barillas, Rodrigo; Vasilyev, Nikolay V.; Roy, Nathalie; McGowan, Francis X.; del Nido, Pedro J.

    2012-01-01

    Background Cardiac hypertrophy is an adaptive response to increased workload that, if unrelieved, leads to heart failure. It has been reported that cardiomyocyte apoptosis contributes to failure, and that vascular endothelial growth factor (VEGF) treatment of hypertrophied myocardium increases capillary density and improves myocardial perfusion. In this study we hypothesized that VEGF treatment reduces cardiomyocyte apoptosis and thereby preserves myocardial contractile function. Methods and Results Newborn rabbits underwent aortic banding. At 4 and 6 weeks of age, hypertrophied animals were treated with intrapericardial administration of recombinant VEGF protein. Three groups of animals were investigated: age-matched controls (C), untreated hypertrophied (H), and VEGF-treated hypertrophied hearts (T). Cardiomyocyte apoptosis was determined by TUNEL staining and PARP cleavage (immunoblotting of nuclear extracts) and cardiac function by transthoracic echocardiography. Death attributable to severe heart failure occurred in 14 of 43 untreated and 2 of 29 VEGF-treated animals (P<0.01). TUNEL-positive cardiomyocyte nuclei (n/1000 nuclei) were significantly increased in untreated hearts at 5 weeks (H: 10±1.8 versus T: 3±0.7) and at 7 weeks (H: 13±3.6 versus T: 5±1.5; P<0.05). Increased apoptosis in untreated hypertrophy was also confirmed by the presence of PARP cleavage (H: 74±7 versus T: 41±4 arbitrary densitometry units; P<0.05). VEGF treatment preserved left ventricular mass, prevented dilation (T: 1.01±0.06 versus H: 0.77±0.07; P<0.05), and preserved contractility indices compared with untreated hearts. Conclusions Lack of adaptive capillary growth impairs myocardial perfusion and substrate delivery in hypertrophying myocardium. VEGF treatment reduces myocardial apoptosis and prolongs survival in a model of severe progressive left ventricular hypertrophy. Promoting capillary growth with VEGF reduces apoptosis, preserves myocardial contractile function, and

  6. Agonist-mediated changes in intracellular pH: role in vascular smooth muscle cell function

    SciTech Connect

    Berk, B.C.; Canessa, M.; Vallega, G.; Alexander, R.W.

    1988-01-01

    Changes in intracellular pH (pHi) are likely to play an important role in regulation of vascular smooth muscle cell (VSMC) function. In most blood vessels, acidification is associated with decreased contractile tone and alkalinization with increased tone. However, the nature of agonist-mediated alterations in pHi and the role of pHi in other VSMC responses has been little studied. We have used the pH sensitive dye, BCECF, to study pHi in cultured rat aortic VSMC. Basal pHi at 37 degrees C in physiologic saline buffer (pH 7.3) was 7.08 in suspended VSMC and 7.26 in substrate-attached VSMC. An amiloride-sensitive Na+/H+ exchanger mediated pHi recovery following an acid load. Angiotensin II- and platelet-derived growth factor typified one class of VSMC agonists, causing an initial transient (less than 5 min) acidification followed by a sustained (greater than 20 min) alkalinization. The acidification phase was associated with increased Ca2+ mobilization as demonstrated by increases in intracellular Ca2+ and 45Ca2+ efflux. The alkalinization was associated with Na+ influx and H+ efflux consistent with Na+/H+ exchange. Epidermal growth factor and phorbol esters typified another class of agonists which stimulated only a sustained alkalinization. Alterations in regulation of VSMC pHi may play an important role in VSMC hypertrophy and/or proliferation as suggested by the finding of increased cell growth and Na+/H+ exchange in spontaneously hypertensive rat VSMC compared to Wistar-Kyoto VSMC. Although no functional correlate for initial acidification has been identified, cytoplasmic alkalinization appears to be required for the sustained formation of diacylglycerol following angiotensin II stimulation. These findings suggest that alterations in pHi may regulate several VSMC functions such as agonist-mediated signal transduction, excitation-response coupling, and growth.

  7. Chloride ion currents contribute functionally to norepinephrine-induced vascular contraction.

    PubMed

    Lamb, F S; Barna, T J

    1998-07-01

    Norepinephrine (NE) increases Cl- efflux from vascular smooth muscle (VSM) cells. An increase in Cl- conductance produces membrane depolarization. We hypothesized that if Cl- currents are important for agonist-induced depolarization, then interfering with cellular Cl- handling should alter contractility. Isometric contraction of rat aortic rings was studied in a bicarbonate buffer. Substitution of extracellular Cl- with 130 mM methanesulfonate (MS; 8 mM Cl-) did not cause contraction. NE- and serotonin-induced contractions were potentiated in this low-Cl- buffer, whereas responses to K+, BAY K 8644, or NE in the absence of Ca2+ were unaltered. Substitution of Cl- with I- or Br- suppressed responses to NE. Inhibition of Cl- transport with bumetanide (10(-5) M) or bicarbonate-free conditions (10 mM HEPES) inhibited NE- but not KCl-induced contraction. The Cl--channel blockers DIDS (10(-3) M), anthracene-9-carboxylic acid (10(-3) M), and niflumic acid (10(-5) M) all inhibited NE-induced contraction, whereas tamoxifen (10(-5) M) did not. Finally, disruption of sarcoplasmic reticular function with cyclopiazonic acid (10(-7) M) or ryanodine (10(-5) M) prevented the increase in the peak response to NE produced by low-Cl- buffer. We conclude that a Cl- current with a permeability sequence of I- > Br- > Cl- > MS is critical to agonist-induced contraction of VSM. PMID:9688908

  8. Non-invasive functional imaging of Cerebral Blood Volume with Vascular-Space-Occupancy (VASO) MRI

    PubMed Central

    Lu, Hanzhang; Hua, Jun; van Zijl, Peter C.M.

    2013-01-01

    Functional MRI (fMRI) based on changes in cerebral blood volume (CBV) can directly probe vasodilatation and vasoconstriction during brain activation or physiologic challenges, and can provide important insights into the mechanism of Blood-Oxygenation-Level-Dependent (BOLD) signal changes. At present, the most widely used CBV fMRI technique in humans is called Vascular-Space-Occupancy (VASO) MRI and this article provides a technical review of this method. VASO MRI utilizes T1 differences between blood and tissue to distinguish these two compartments within a voxel and uses blood-nulling inversion recovery sequence to yield an MR signal proportional to 1-CBV. As such, vasodilatation will result in a VASO signal decrease and vasoconstriction will have the reverse effect. The VASO technique can be performed dynamically with a temporal resolution comparable to several other fMRI methods such as BOLD or Arterial-Spin-Labeling (ASL), and is particularly powerful when conducted in conjunction with these complementary techniques. The pulse sequence and imaging parameters of VASO can be optimized such that the signal change is predominantly of CBV origin, but careful considerations should be taken to minimize other contributions, such as those from the BOLD effect, CBF, and CSF. Sensitivity of the VASO technique remains to be the primary disadvantage when compared to BOLD, but this technique is increasingly demonstrating utility in neuroscientific and clinical applications. PMID:23355392

  9. The effect of an advanced glycation end-product crosslink breaker and exercise training on vascular function in older individuals: a randomized factorial design trial.

    PubMed

    Oudegeest-Sander, Madelijn H; Olde Rikkert, Marcel G M; Smits, Paul; Thijssen, Dick H J; van Dijk, Arie P J; Levine, Benjamin D; Hopman, Maria T E

    2013-12-01

    Aging leads to accumulation of irreversible advanced glycation end-products (AGEs), contributing to vascular stiffening and endothelial dysfunction. When combined with the AGE-crosslink breaker Alagebrium, exercise training reverses cardiovascular aging in experimental animals. This study is the first to examine the effect of Alagebrium, with and without exercise training, on endothelial function, arterial stiffness and cardiovascular risk in older individuals. Forty-eight non-exercising individuals (mean age 70 ± 4 years) without manifest diseases or use of medication were allocated into 4 groups for a 1-year intervention: Exercise training & Alagebrium (200 mg/day); exercise training & placebo; no exercise training & Alagebrium (200 mg/day); and no exercise training & placebo. We performed a maximal exercise test (VO2max) and measured endothelial function using venous occlusion plethysmography and intra-arterial infusion of acetylcholine, sodium nitroprusside and NG-monomethyl-l-arginine. Arterial stiffness was measured using pulse wave velocity. Cardiovascular risk was calculated using the Lifetime Risk Score (LRS). In the exercise training groups, LRS and VO2max improved significantly (23.9 ± 4.5 to 27.2 ± 4.6mLO2/min/kg, p < 0.001). Endothelial response to the vasoactive substances did not change, nor did arterial stiffness in any of the four groups. In conclusion, one year of exercise training significantly improved physical fitness and lifetime risk for cardiovascular disease without affecting endothelial function or arterial stiffness. The use of the AGE-crosslink breaker Alagebrium had no independent effect on vascular function, nor did it potentiate the effect of exercise training. Despite the clinical benefits of exercise training for older individuals, neither exercise training nor Alagebrium (alone or in combination) was able to reverse the vascular effects of decades of sedentary aging. PMID:24400341

  10. Deletion of thioredoxin-interacting protein preserves retinal neuronal function by preventing inflammation and vascular injury

    PubMed Central

    El-Azab, M F; Baldowski, B R B; Mysona, B A; Shanab, A Y; Mohamed, I N; Abdelsaid, M A; Matragoon, S; Bollinger, K E; Saul, A; El-Remessy, A B

    2014-01-01

    BACKGROUND AND PURPOSE Retinal neurodegeneration is an early and critical event in several diseases associated with blindness. Clinically, therapies that target neurodegeneration fail. We aimed to elucidate the multiple roles by which thioredoxin-interacting protein (TXNIP) contributes to initial and sustained retinal neurodegeneration. EXPERIMENTAL APPROACH Neurotoxicity was induced by intravitreal injection of NMDA into wild-type (WT) and TXNIP-knockout (TKO) mice. The expression of apoptotic and inflammatory markers was assessed by immunohistochemistry, elisa and Western blot. Microvascular degeneration was assessed by periodic acid-Schiff and haematoxylin staining and retinal function by electroretinogram. KEY RESULTS NMDA induced early (1 day) and significant retinal PARP activation, a threefold increase in TUNEL-positive nuclei and 40% neuronal loss in ganglion cell layer (GCL); and vascular permeability in WT but not TKO mice. NMDA induced glial activation, expression of TNF-α and IL-1β that co-localized with Müller cells in WT but not TKO mice. In parallel, NMDA triggered the expression of NOD-like receptor protein (NLRP3), activation of caspase-1, and release of IL-1β and TNF-α in primary WT but not TKO Müller cultures. After 14 days, NMDA induced 1.9-fold microvascular degeneration, 60% neuronal loss in GCL and increased TUNEL-labelled cells in the GCL and inner nuclear layer in WT but not TKO mice. Electroretinogram analysis showed more significant reductions in b-wave amplitudes in WT than in TKO mice. CONCLUSION AND IMPLICATIONS Targeting TXNIP expression prevented early retinal ganglion cell death, glial activation, retinal inflammation and secondary neuro/microvascular degeneration and preserved retinal function. TXNIP is a promising new therapeutic target for retinal neurodegenerative diseases. PMID:24283717

  11. How does temperature affect the function of tissue macrophages?

    NASA Astrophysics Data System (ADS)

    Lee, Chen-Ting; Repasky, Elizabeth A.

    2011-03-01

    Macrophages create a major danger signal following injury or infection and upon activation release pro-inflammatory cytokines, which in turn help to generate febrile conditions. Thus, like other cells of the body, tissue macrophages are often exposed to naturally occurring elevations in tissue temperature during inflammation and fever. However, whether macrophages sense and respond to temperature changes in a specific manner which modulates their function is still not clear. In this brief review, we highlight recent studies which have analyzed the effects of temperatures on macrophage function, and summarize the possible underlying molecular mechanisms which have been identified. Mild, physiological range hyperthermia has been shown to have both pro- and anti-inflammatory roles in regulating macrophage inflammatory cytokine production and at the meeting presentation, we will show new data demonstrating that hyperthermia can indeed exert both positive and negative signals to macrophages. While some thermal effects are correlated with the induction of heat shock factors/heat shock proteins, overall it is not clear how mild hyperthermia can exert both pro- and anti-inflammatory functions. We also summarize data which shows that hyperthermia can affect other macrophage effector functions, including the anti-tumor cytotoxicity. Overall, these studies may help us to better understand the immunological role of tissue temperature and may provide important information needed to maximize the application of heat in the treatment of various diseases including cancer.

  12. Can the hydrophilicity of functional monomers affect chemical interaction?

    PubMed

    Feitosa, V P; Ogliari, F A; Van Meerbeek, B; Watson, T F; Yoshihara, K; Ogliari, A O; Sinhoreti, M A; Correr, A B; Cama, G; Sauro, S

    2014-02-01

    The number of carbon atoms and/or ester/polyether groups in spacer chains may influence the interaction of functional monomers with calcium and dentin. The present study assessed the chemical interaction and bond strength of 5 standard-synthesized phosphoric-acid ester functional monomers with different spacer chain characteristics, by atomic absorption spectroscopy (AAS), ATR-FTIR, thin-film x-ray diffraction (TF-XRD), scanning electron microscopy (SEM), and microtensile bond strength (μTBS). The tested functional monomers were 2-MEP (two-carbon spacer chain), 10-MDP (10-carbon), 12-MDDP (12-carbon), MTEP (more hydrophilic polyether spacer chain), and CAP-P (intermediate hydrophilicity ester spacer). The intensity of monomer-calcium salt formation measured by AAS differed in the order of 12-MDDP=10-MDP>CAP-P>MTEP>2-MEP. FTIR and SEM analyses of monomer-treated dentin surfaces showed resistance to rinsing for all monomer-dentin bonds, except with 2-MEP. TF-XRD confirmed the weaker interaction of 2-MEP. Highest µTBS was observed for 12-MDDP and 10-MDP. A shorter spacer chain (2-MEP) of phosphate functional monomers induced formation of unstable monomer-calcium salts, and lower chemical interaction and dentin bond strength. The presence of ester or ether groups within longer spacer carbon chains (CAP-P and MTEP) may affect the hydrophilicity, μTBS, and also the formation of monomer-calcium salts. PMID:24284259

  13. Monocyte/macrophage cytokine activity regulates vascular smooth muscle cell function within a degradable polyurethane scaffold.

    PubMed

    Battiston, K G; Ouyang, B; Labow, R S; Simmons, C A; Santerre, J P

    2014-03-01

    Tissue engineering strategies rely on the ability to promote cell proliferation and migration into porous biomaterial constructs, as well as to support specific phenotypic states of the cells in vitro. The present study investigated the use of released factors from monocytes and their derived macrophages (MDM) and the mechanism by which they regulate vascular smooth muscle cell (VSMC) response in a VSMC-monocyte co-culture system within a porous degradable polyurethane (D-PHI) scaffold. VSMCs cultured in monocyte/MDM-conditioned medium (MCM), generated from the culture of monocytes/MDM on D-PHI scaffolds for up to 28 days, similarly affected VSMC contractile marker expression, growth and three-dimensional migration when compared to direct VSMC-monocyte co-culture. Monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6) were identified as two cytokines present in MCM, at concentrations that have previously been shown to influence VSMC phenotype. VSMCs cultured alone on D-PHI scaffolds and exposed to MCP-1 (5 ng ml(-1)) or IL-6 (1 ng ml(-1)) for 7 days experienced a suppression in contractile marker expression (with MCP-1 or IL-6) and increased growth (with MCP-1) compared to no cytokine medium supplementation. These effects were also observed in VSMC-monocyte co-culture on D-PHI. Neutralization of IL-6, but not MCP-1, was subsequently shown to decrease VSMC growth and enhance calponin expression for VSMC-monocyte co-cultures on D-PHI scaffolds for 7 days, implying that IL-6 mediates VSMC response in monocyte-VSMC co-cultures. This study highlights the use of monocytes and their derived macrophages in conjunction with immunomodulatory biomaterials, such as D-PHI, as agents for regulating VSMC response, and demonstrates the importance of monocyte/MDM-released factors, such as IL-6 in particular, in this process. PMID:24361424

  14. Quercetin Affects Erythropoiesis and Heart Mitochondrial Function in Mice.

    PubMed

    Ruiz, Lina M; Salazar, Celia; Jensen, Erik; Ruiz, Paula A; Tiznado, William; Quintanilla, Rodrigo A; Barreto, Marlen; Elorza, Alvaro A

    2015-01-01

    Quercetin, a dietary flavonoid used as a food supplement, showed powerful antioxidant effects in different cellular models. However, recent in vitro and in vivo studies in mammals have suggested a prooxidant effect of quercetin and described an interaction with mitochondria causing an increase in O2 (∙-) production, a decrease in ATP levels, and impairment of respiratory chain in liver tissue. Therefore, because of its dual actions, we studied the effect of quercetin in vivo to analyze heart mitochondrial function and erythropoiesis. Mice were injected with 50 mg/kg of quercetin for 15 days. Treatment with quercetin decreased body weight, serum insulin, and ceruloplasmin levels as compared with untreated mice. Along with an impaired antioxidant capacity in plasma, quercetin-treated mice showed a significant delay on erythropoiesis progression. Heart mitochondrial function was also impaired displaying more protein oxidation and less activity for IV, respectively, than no-treated mice. In addition, a significant reduction in the protein expression levels of Mitofusin 2 and Voltage-Dependent Anion Carrier was observed. All these results suggest that quercetin affects erythropoiesis and mitochondrial function and then its potential use as a dietary supplement should be reexamined. PMID:26106459

  15. Bisphenol A affects androgen receptor function via multiple mechanisms

    PubMed Central

    Teng, Christina; Goodwin, Bonnie; Shockley, Keith; Xia, Menghang; Huang, Ruili; Norris, John; Merrick, B. Alex; Jetten, Anton M.; Austin, Christopher, P.; Tice, Raymond R.

    2013-01-01

    Bisphenol A (BPA), is a well-known endocrine disruptor compound (EDC) that affects the normal development and function of the female and male reproductive system, however the mechanisms of action remain unclear. To investigate the molecular mechanisms of how BPA may affect ten different nuclear receptors, stable cell lines containing individual nuclear receptor ligand binding domain (LBD)-linked to the β-Gal reporter were examined by a quantitative high throughput screening (qHTS) format in the Tox21 Screening Program of the NIH. The results showed that two receptors, estrogen receptor alpha (ERα) and androgen receptor (AR), are affected by BPA in opposite direction. To confirm the observed effects of BPA on ERα and AR, we performed transient transfection experiments with full-length receptors and their corresponding response elements linked to luciferase reporters. We also included in this study two BPA analogs, bisphenol AF (BPAF) and bisphenol S (BPS). As seen in African green monkey kidney CV1 cells, the present study confirmed that BPA and BPAF act as ERα agonists (half maximal effective concentration EC50 of 10-100 nM) and as AR antagonists (half maximal inhibitory concentration IC50 of 1-2 μM). Both BPA and BPAF antagonized AR function via competitive inhibition of the action of synthetic androgen R1881. BPS with lower estrogenic activity (EC50 of 2.2 μM), did not compete with R1881 for AR binding, when tested at 30 μM. Finally, the effects of BPA were also evaluated in a nuclear translocation assays using EGPF-tagged receptors. Similar to 17β-estradiol (E2) which was used as control, BPA was able to enhance ERα nuclear foci formation but at a 100-fold higher concentration. Although BPA was able to bind AR, the nuclear translocation was reduced. Furthermore, BPA was unable to induce functional foci in the nuclei and is consistent with the transient transfection study that BPA is unable to activate AR. PMID:23562765

  16. Bisphenol A affects androgen receptor function via multiple mechanisms.

    PubMed

    Teng, Christina; Goodwin, Bonnie; Shockley, Keith; Xia, Menghang; Huang, Ruili; Norris, John; Merrick, B Alex; Jetten, Anton M; Austin, Christopher P; Tice, Raymond R

    2013-05-25

    Bisphenol A (BPA), is a well-known endocrine disruptor compound (EDC) that affects the normal development and function of the female and male reproductive system, however the mechanisms of action remain unclear. To investigate the molecular mechanisms of how BPA may affect ten different nuclear receptors, stable cell lines containing individual nuclear receptor ligand binding domain (LBD)-linked to the β-Gal reporter were examined by a quantitative high throughput screening (qHTS) format in the Tox21 Screening Program of the NIH. The results showed that two receptors, estrogen receptor alpha (ERα) and androgen receptor (AR), are affected by BPA in opposite direction. To confirm the observed effects of BPA on ERα and AR, we performed transient transfection experiments with full-length receptors and their corresponding response elements linked to luciferase reporters. We also included in this study two BPA analogs, bisphenol AF (BPAF) and bisphenol S (BPS). As seen in African green monkey kidney CV1 cells, the present study confirmed that BPA and BPAF act as ERα agonists (half maximal effective concentration EC50 of 10-100 nM) and as AR antagonists (half maximal inhibitory concentration IC50 of 1-2 μM). Both BPA and BPAF antagonized AR function via competitive inhibition of the action of synthetic androgen R1881. BPS with lower estrogenic activity (EC50 of 2.2 μM), did not compete with R1881 for AR binding, when tested at 30 μM. Finally, the effects of BPA were also evaluated in a nuclear translocation assays using EGPF-tagged receptors. Similar to 17β-estradiol (E2) which was used as control, BPA was able to enhance ERα nuclear foci formation but at a 100-fold higher concentration. Although BPA was able to bind AR, the nuclear translocation was reduced. Furthermore, BPA was unable to induce functional foci in the nuclei and is consistent with the transient transfection study that BPA is unable to activate AR. PMID:23562765

  17. Prevention of Hippocampal Neuronal Damage and Cognitive Function Deficits in Vascular Dementia by Dextromethorphan.

    PubMed

    Xu, Xiaofeng; Zhang, Bin; Lu, Kaili; Deng, Jiangshan; Zhao, Fei; Zhao, Bing-Qiao; Zhao, Yuwu

    2016-07-01

    Dextromethorphan (DM) is a non-competitive antagonist of NMDA receptors and a widely used component of cough medicine. Recently, its indication has been extended experimentally to a wide range of disorders including inflammation-mediated central nervous system disorders such as Parkinson disease (PD) and multiple sclerosis (MS). In this study, we investigate whether DM treatment has protective effects on the hippocampal neuron damage induced by bilateral occlusion of the common carotid arteries (two-vessel occlusion [2VO]), an animal model of vascular dementia (VaD). Sprague-Dawley (SD) (10 weeks of age) rats were subjected to the 2VO, and DM was injected intraperitoneally once per day for 37 days. Neuron death, glial activation, and cognitive function were assessed at 37 days after 2VO (0.2 mg/kg, i.p., "DM-0.2" and 2 mg/kg, i.p., "DM-2"). DM-2 treatment provided protection against neuronal death and glial activation in the hippocampal CA1 subfield and reduced cognitive impairment induced by 2VO in rats. The study also demonstrates that activation of the Nrf2-HO-1 pathway and upregulation of superoxide dismutase (SOD) play important roles in these effects. These results suggest that DM is effective in treating VaD and protecting against oxidative stress, which is strongly implicated in the pathogenesis of VaD. Therefore, the present study suggests that DM treatment may represent a new and promising protective strategy for treating VaD. PMID:26887382

  18. IL-33 and IL-4 impair barrier functions of human vascular endothelium via different mechanisms.

    PubMed

    Chalubinski, Maciej; Wojdan, Katarzyna; Luczak, Emilia; Gorzelak, Paulina; Borowiec, Maciej; Gajewski, Adrian; Rudnicka, Karolina; Chmiela, Magdalena; Broncel, Marlena

    2015-10-01

    The vascular endothelium forms a barrier that controls flow of solutes and proteins and the entry of leukocytes into tissue. Injured tissue releases IL-33, which then alarms the immune system and attracts Th2 cells, thus increasing local concentration of IL-4. The aim of the study was to assess the influence of IL-33 and IL-4 on barrier functions of the human endothelium, expression of tight and adherent junction proteins, apoptosis and adhesive molecule surface expression in human endothelium in order to describe the mechanism of this effect. IL-33 and IL-4 decreased endothelial integrity and increased permeability. When added together, both cytokines lowered the endothelial integrity twice as much as used alone. This effect was accompanied by the down-regulation of occludin and VE-cadherin mRNA expression. Additionally, IL-4, but not IL-33, induced cell apoptosis. Both IL-33 and IL-4 showed the additive potency to down-regulate VE-cadherin mRNA expression. IL-33, unlike IL-4, increased the surface expression of ICAM-1, but not PECAM-1 in endothelial cells. Our results indicate that IL-33 may reversibly destabilize the endothelial barrier, thus accelerating the supply with immunomodulators and assisting leukocytes to reach wounded tissue. However, extended and less-controlled down-regulation of endothelial barrier, which may be a consequence of IL-33-initiated, but in fact IL-4-induced apoptosis of endothelial cells, may be deleterious and may eventually lead to the aggravation of inflammatory processes and the prolongation of tissue dysfunction. PMID:26231284

  19. TLR4-Activated MAPK-IL-6 Axis Regulates Vascular Smooth Muscle Cell Function.

    PubMed

    Lee, Guan-Lin; Wu, Jing-Yiing; Tsai, Chien-Sung; Lin, Chih-Yuan; Tsai, Yi-Ting; Lin, Chin-Sheng; Wang, Yi-Fu; Yet, Shaw-Fang; Hsu, Yu-Juei; Kuo, Cheng-Chin

    2016-01-01

    Migration of vascular smooth muscle cells (VSMCs) into the intima is considered to be a vital event in the pathophysiology of atherosclerosis. Despite substantial evidence supporting the pathogenic role of Toll-like receptor 4 (TLR4) in the progression of atherogenesis, its function in the regulation of VSMC migration remains unclear. The goal of the present study was to elucidate the mechanism by which TLR4 regulates VSMC migration. Inhibitor experiments revealed that TLR4-induced IL-6 secretion and VSMC migration were mediated via the concerted actions of MyD88 and TRIF on the activation of p38 MAPK and ERK1/2 signaling. Neutralizing anti-IL-6 antibodies abrogated TLR4-driven VSMC migration and F-actin polymerization. Blockade of p38 MAPK or ERK1/2 signaling cascade inhibited TLR4 agonist-mediated activation of cAMP response element binding protein (CREB). Moreover, siRNA-mediated suppression of CREB production repressed TLR4-induced IL-6 production and VSMC migration. Rac-1 inhibitor suppressed TLR4-driven VSMC migration but not IL-6 production. Importantly, the serum level of IL-6 and TLR4 endogenous ligand HMGB1 was significantly higher in patients with coronary artery diseases (CAD) than in healthy subjects. Serum HMGB1 level was positively correlated with serum IL-6 level in CAD patients. The expression of both HMGB1 and IL-6 was clearly detected in the atherosclerotic tissue of the CAD patients. Additionally, there was a positive association between p-CREB and HMGB1 in mouse atherosclerotic tissue. Based on our findings, we concluded that, upon ligand binding, TLR4 activates p38 MAPK and ERK1/2 signaling through MyD88 and TRIF in VSMCs. These signaling pathways subsequently coordinate an additive augmentation of CREB-driven IL-6 production, which in turn triggers Rac-1-mediated actin cytoskeleton to promote VSMC migration. PMID:27563891

  20. Tertiary structure and function of an RNA motif required for plant vascular entry to initiate systemic trafficking.

    PubMed

    Zhong, Xuehua; Tao, Xiaorong; Stombaugh, Jesse; Leontis, Neocles; Ding, Biao

    2007-08-22

    Vascular entry is a decisive step for the initiation of long-distance movement of infectious and endogenous RNAs, silencing signals and developmental/defense signals in plants. However, the mechanisms remain poorly understood. We used Potato spindle tuber viroid (PSTVd) as a model to investigate the direct role of the RNA itself in vascular entry. We report here the identification of an RNA motif that is required for PSTVd to traffic from nonvascular into the vascular tissue phloem to initiate systemic infection. This motif consists of nucleotides U/C that form a water-inserted cis Watson-Crick/Watson-Crick base pair flanked by short helices that comprise canonical Watson-Crick/Watson-Crick base pairs. This tertiary structural model was inferred by comparison with X-ray crystal structures of similar motifs in rRNAs and is supported by combined mutagenesis and covariation analyses. Hydration pattern analysis suggests that water insertion induces a widened minor groove conducive to protein and/or RNA interactions. Our model and approaches have broad implications to investigate the RNA structural motifs in other RNAs for vascular entry and to study the basic principles of RNA structure-function relationships. PMID:17660743

  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. PMID:26965898

  2. Role of Vascular Networks in Extending Glucose Sensor Function: Impact of Angiogenesis and Lymphangiogenesis on Continuous Glucose Monitoring in vivo

    PubMed Central

    Klueh, Ulrike; Antar, Omar; Qiao, Yi; Kreutzer, Donald L.

    2014-01-01

    The concept of increased blood vessel (BV) density proximal to glucose sensors implanted in the interstitial tissue increases the accuracy and lifespan of sensors is accepted, despite limited existing experimental data. Interestingly, there is no previous data or even conjecture in the literature on the role of lymphatic vessels (LV) alone, or in combination with BV, in enhancing continuous glucose monitoring (CGM) in vivo. To investigate the impact of inducing vascular networks (BV and LV) at sites of glucose sensor implantation, we utilized adenovirus based local gene therapy of vascular endothelial cell growth factor-A (VEGF-A) to induce vessels at sensor implantation sites. The results of these studies demonstrated that 1) VEGF-A based local gene therapy increases vascular networks (blood vessels and lymphatic vessels) at sites of glucose sensor implantation; and 2) this local increase of vascular networks enhances glucose sensor function in vivo from 7 days to greater than 28 days post sensor implantation. This data provides “proof of concept” for the effective usage of local angiogenic factor (AF) gene therapy in mammalian models in an effort to extend CGM in vivo. It also supports the practice of a variety of viral and non-viral vectors as well as gene products (e.g. anti-inflammatory and anti-fibrosis genes) to engineer “implant friendly tissues” for the usage with implantable glucose sensors as well as other implantable devices. PMID:24243850

  3. Regulation of Microvascular Function by Adipose Tissue in Obesity and Type 2 Diabetes: Evidence of an Adipose-Vascular Loop

    PubMed Central

    Zhang, Hanrui; Zhang, Cuihua

    2009-01-01

    In recent years, the general concept has emerged that chronic low-grade inflammation is the condition linking excessive development of adipose tissue and obesity-associated pathologies such as type 2 diabetes and cardiovascular diseases. Obesity and type 2 diabetes are characterized by a diminished production of protective factors such as adiponectin and increased detrimental adipocytokines such as leptin, resistin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), and monocyte chemoattractant protein-1 (MCP-1) by adipose tissue. Moreover, the evidence that the growth of the fat mass is associated with an accumulation of adipose tissue macrophages and T-lymphocytes has raised the hypothesis that the development of an inflammatory process within the growing fat mass is a primary event involved in the genesis of systemic metabolic and vascular alterations. This crosstalk of adipocyte, macrophage, lymphocyte, endothelial cells, and vascular smooth muscle cells contribute to the production of various cytokines, chemokines, and hormone-like factors, which actively participate in the regulation of vascular function by an endocrine and/or paracrine pattern. Thus, the signaling from perivascular adipose to the blood vessels is emerging as a potential therapeutic target for obesity and diabetes-associated vascular dysfunction. PMID:20098632

  4. Can lifestyle modification affect men’s erectile function?

    PubMed Central

    Hehemann, Marah C.

    2016-01-01

    Erectile dysfunction (ED) is a common condition affecting millions of men worldwide. The pathophysiology and epidemiologic links between ED and risk factors for cardiovascular disease (CVD) are well-established. Lifestyle modifications such as smoking cessation, weight reduction, dietary modification, physical activity, and psychological stress reduction have been increasingly recognized as foundational to the prevention and treatment of ED. The aim of this review is to outline behavioral choices which may increase ones risk of developing ED, to present relevant studies addressing lifestyle factors correlated with ED, and to highlight proposed mechanisms for intervention aimed at improving erectile function in men with ED. These recommendations can provide a framework for counseling patients with ED about lifestyle modification. PMID:27141445

  5. Scorpion venom components that affect ion-channels function

    PubMed Central

    Quintero-Hernández, V.; Jiménez-Vargas, J.M.; Gurrola, G.B.; Valdivia, H.H.F.; Possani, L.D.

    2014-01-01

    SUMMARY The number and types of venom components that affect ion-channel function are reviewed. These are the most important venom components responsible for human intoxication, deserving medical attention, often requiring the use of specific anti-venoms. Special emphasis is given to peptides that recognize Na+-, K+- and Ca++-channels of excitable cells. Knowledge generated by direct isolation of peptides from venom and components deduced from cloned genes, whose amino acid sequences are deposited into databanks are now adays in the order of 1.5 thousands, out of an estimate biodiversity closed to 300,000. Here the diversity of components is briefly reviewed with mention to specific references. Structural characteristic are discussed with examples taken from published work. The principal mechanisms of action of the three different types of peptides are also reviewed. Na+-channel specific venom components usually are modifier of the open and closing kinetic mechanisms of the ion-channels, whereas peptides affecting K+-channels are normally pore blocking agents. The Ryanodine Ca++-channel specific peptides are known for causing sub-conducting stages of the channels conductance and some were shown to be able to internalize penetrating inside the muscle cells. PMID:23891887

  6. 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

  7. Integrating Negative Affect Measures in a Measurement Model: Assessing the Function of Negative Affect as Interference to Self-Regulation

    ERIC Educational Resources Information Center

    Magno, Carlo

    2010-01-01

    The present study investigated the composition of negative affect and its function as inhibitory to thought processes such as self-regulation. Negative affect in the present study were composed of anxiety, worry, thought suppression, and fear of negative evaluation. These four factors were selected based on the criteria of negative affect by…

  8. To what extent does urbanisation affect fragmented grassland functioning?

    PubMed

    van der Walt, L; Cilliers, S S; Kellner, K; Du Toit, M J; Tongway, D

    2015-03-15

    Urbanisation creates altered environments characterised by increased human habitation, impermeable surfaces, artificial structures, landscape fragmentation, habitat loss, resulting in different resource loss pathways. The vulnerable Rand Highveld Grassland vegetation unit in the Tlokwe Municipal area, South Africa, has been extensively affected and transformed by urbanisation, agriculture, and mining. Grassland fragments in urban areas are often considered to be less species rich and less functional than in the more untransformed or "natural" exurban environments, and are therefore seldom a priority for conservation. Furthermore, urban grassland fragments are often being more intensely managed than exurban areas, such as consistent mowing in open urban areas. Four urbanisation measures acting as indicators for patterns and processes associated with urban areas were calculated for matrix areas surrounding each selected grassland fragment to quantify the position of each grassland remnant along an urbanisation gradient. The grassland fragments were objectively classified into two classes of urbanisation, namely "exurban" and "urban" based on the urbanisation measure values. Grazing was recorded in some exurban grasslands and mowing in some urban grassland fragments. Unmanaged grassland fragments were present in both urban and exurban areas. Fine-scale biophysical landscape function was determined by executing the Landscape Function Analysis (LFA) method. LFA assesses fine-scale landscape patchiness (entailing resource conserving potential and erosion resistance) and 11 soil surface indicators to produce three main LFA parameters (stability, infiltration, and nutrient cycling), which indicates how well a system is functioning in terms of fine-scale biophysical soil processes and characteristics. The aim of this study was to determine the effects of urbanisation and associated management practices on fine-scale biophysical landscape function of urban and exurban

  9. Graded effects of unregulated smooth muscle myosin on intestinal architecture, intestinal motility and vascular function in zebrafish

    PubMed Central

    Abrams, Joshua; Einhorn, Zev; Seiler, Christoph; Zong, Alan B.; Sweeney, H. Lee; Pack, Michael

    2016-01-01

    ABSTRACT Smooth muscle contraction is controlled by the regulated activity of the myosin heavy chain ATPase (Myh11). Myh11 mutations have diverse effects in the cardiovascular, digestive and genitourinary systems in humans and animal models. We previously reported a recessive missense mutation, meltdown (mlt), which converts a highly conserved tryptophan to arginine (W512R) in the rigid relay loop of zebrafish Myh11. The mlt mutation disrupts myosin regulation and non-autonomously induces invasive expansion of the intestinal epithelium. Here, we report two newly identified missense mutations in the switch-1 (S237Y) and coil-coiled (L1287M) domains of Myh11 that fail to complement mlt. Cell invasion was not detected in either homozygous mutant but could be induced by oxidative stress and activation of oncogenic signaling pathways. The smooth muscle defect imparted by the mlt and S237Y mutations also delayed intestinal transit, and altered vascular function, as measured by blood flow in the dorsal aorta. The cell-invasion phenotype induced by the three myh11 mutants correlated with the degree of myosin deregulation. These findings suggest that the vertebrate intestinal epithelium is tuned to the physical state of the surrounding stroma, which, in turn, governs its response to physiologic and pathologic stimuli. Genetic variants that alter the regulation of smooth muscle myosin might be risk factors for diseases affecting the intestine, vasculature, and other tissues that contain smooth muscle or contractile cells that express smooth muscle proteins, particularly in the setting of redox stress. PMID:26893369

  10. The Peroxisome Proliferator Activated Receptor‐γ Pioglitazone Improves Vascular Function and Decreases Disease Activity in Patients With Rheumatoid Arthritis

    PubMed Central

    Marder, Wendy; Khalatbari, Shokoufeh; Myles, James D.; Hench, Rita; Lustig, Susan; Yalavarthi, Srilakshmi; Parameswaran, Aishwarya; Brook, Robert D.; Kaplan, Mariana J.

    2013-01-01

    Background Rheumatoid arthritis (RA) is associated with heightened mortality due to atherosclerotic cardiovascular disease (CVD). Inflammatory pathways in RA negatively affect vascular physiology and promote metabolic disturbances that contribute to CVD. We hypothesized that the peroxisome proliferator activated receptor‐γ (PPAR‐γ) pioglitazone could promote potent vasculoprotective and anti‐inflammatory effects in RA. Methods and Results One hundred forty‐three non‐diabetic adult RA patients (76.2% female, age 55.2±12.1 [mean±SD]) on stable RA standard of care treatment were enrolled in a randomized, double‐blind placebo controlled crossover trial of 45 mg daily pioglitazone versus placebo, with a 3‐month duration/arm and a 2‐month washout period. Pulse wave velocity of the aorta (PWV), brachial artery flow mediated dilatation (FMD), nitroglycerin mediated dilatation (NMD), microvascular endothelial function (reactive hyperemia index [RHI]), and circulating biomarkers of inflammation, insulin resistance, and atherosclerosis risk all were quantified. RA disease activity was assessed with the 28‐Joint Count Disease Activity Score (DAS‐28) C‐reactive protein (CRP) and the Short Form (36) Health Survey quality of life questionnaire. When added to standard of care RA treatment, pioglitazone significantly decreased pulse wave velocity (ie, aortic stiffness) (P=0.01), while FMD and RHI remained unchanged when compared to treatment with placebo. Further, pioglitazone significantly reduced RA disease activity (P=0.02) and CRP levels (P=0.001), while improving lipid profiles. The drug was well tolerated. Conclusions Addition of pioglitazone to RA standard of care significantly improves aortic elasticity and decreases inflammation and disease activity with minimal safety issues. The clinical implications of these findings remain to be established. Clinical Trial Registration URL: ClinicalTrials.gov Unique Identifier: NCT00554853. PMID:24252844

  11. Vascular function and nitric oxide production in chronic social-stress-exposed rats with various family history of hypertension.

    PubMed

    Bernatowa, I; Csizmadiova, Z; Kopincova, J; Puzserova, A

    2007-09-01

    The study investigated the effect of chronic crowding stress on vascular function and nitric oxide (NO) production in rats with various family history of hypertension. Wistar (W), wBHR (offspring of W dams and spontaneously hypertensive sires), sBHR (offspring of spontaneously hypertensive dams and W sires) and spontaneously hypertensive rats (SHR) were used. Twelve-week-old males were divided into the control or crowded group for eight weeks. Basal blood pressure (BP, determined by tail-cuff plethysmography) of W, wBHR, sBHR and SHR rats was 112 +/- 3, 129 +/- 2, 135 +/- 2 and 187 +/- 3 mmHg, respectively. Crowding increased BP and reduced aortic NO synthase activity only in sBHR and SHR rats, without alterations in hypothalamic NO production. Acetylcholine-induced vasorelaxation of the femoral artery of stress-exposed rats was improved in W, unaltered in wBHR and sBHR and reduced in SHR. Crowding reduced serotonin-induced vasoconstriction in W and wBHR rats but had no effect in sBHR and SHR rats. In conclusion, the results suggest that crowded offspring of normotensive mothers were able to modify their vascular function in order to maintain BP at normal levels. On the other hand, offspring of hypertensive mothers were unable of effective adaptation of vascular function in stressful conditions resulting in gradual development of hypertension. PMID:17928645

  12. Does Ramadan Fasting Adversely Affect Cognitive Function in Young Females?

    PubMed Central

    Ghayour Najafabadi, Mahboubeh; Rahbar Nikoukar, Laya; Memari, Amir; Ekhtiari, Hamed; Beygi, Sara

    2015-01-01

    We examined the effects of Ramadan fasting on cognitive function in 17 female athletes. Data were obtained from participants of two fasting (n = 9) and nonfasting (n = 8) groups at three periods of the study (before Ramadan, at the third week in Ramadan, and after Ramadan). Digit span test (DST) and Stroop color test were employed to assess short-term memory and inhibition/cognitive flexibility at each time point. There were no significant changes for DST and Stroop task 1 in both groups, whereas Stroop task 2 and task 3 showed significant improvements in Ramadan condition (p < 0.05). Interference indices did not change significantly across the study except in post-Ramadan period of fasting group (p < 0.05). Group × week interaction was significant only for error numbers (p < 0.05). Athletes in nonfasting showed a significant decrease in number of errors in Ramadan compared to baseline (p < 0.05). The results suggest that Ramadan fasting may not adversely affect cognitive function in female athletes. PMID:26697263

  13. Does Bowel Preparation for Colonoscopy Affect Cognitive Function?

    PubMed Central

    Wadsworth, P.; Blackburne, H.; Dixon, L.; Dobbs, B.; Eglinton, T.; Ing, A.; Mulder, R.; Porter, R.J.; Wakeman, C.; Frizelle, F.A.

    2015-01-01

    Abstract Colonoscopy is a common procedure used in the diagnosis and treatment of a range of bowel disorders. Prior preparation involving potent laxatives is a necessary stage to ensure adequate visualization of the bowel wall. It is known that the sedatives given to most patients during the colonoscopy cause a temporary impairment in cognitive function; however, the potential for bowel preparation to affect cognitive function has not previously been investigated. To assess the effect of bowel preparation for colonoscopy on cognitive function. This was a prospective, nonrandomized controlled study of cognitive function in patients who had bowel preparation for colonoscopy compared with those having gastroscopy and therefore no bowel preparation. Cognitive function was assessed using the Modified Mini Mental State Examination (MMMSE) and selected tests from the Cambridge Neuropsychological Test Automated Battery. Individual test scores and changes between initial and subsequent tests were compared between the groups. Age, gender, and weight were also compared. Forty-three colonoscopy and 25 gastroscopy patients were recruited. The 2 groups were similar for age and gender; however, patients having gastroscopy were heavier. MMMSE scores for colonoscopy and gastroscopy groups, respectively, were 28.6 and 29.5 (P = 0.24) at baseline, 28.7 and 29.8 (P = 0.32) at test 2, 28.1 and 28.5 (P = 0.76) at test 3. Motor screening scores for colonoscopy and gastroscopy groups, respectively, were 349.3 and 354.1 (P = 0.97) at baseline, 307.5 and 199.7 (P = 0.06) at test 2, 212.0 and 183.2 (P = 0.33) at test 3. Spatial working memory scores for colonoscopy and gastroscopy groups, respectively, were 14.4 and 6.7 (P = 0.29) at baseline, 9.7 and 4.3 (P = 0.27) at test 2, 10 and 4.5 (P = 0.33) at test 3. Digit Symbol Substitution Test scores for colonoscopy and gastroscopy groups, respectively, were 36.3 and 37.8 (P = 0.84) at baseline, 36.4 and

  14. Does Bowel Preparation for Colonoscopy Affect Cognitive Function?

    PubMed

    Wadsworth, P; Blackburne, H; Dixon, L; Dobbs, B; Eglinton, T; Ing, A; Mulder, R; Porter, R J; Wakeman, C; Frizelle, F A

    2015-11-01

    Colonoscopy is a common procedure used in the diagnosis and treatment of a range of bowel disorders. Prior preparation involving potent laxatives is a necessary stage to ensure adequate visualization of the bowel wall. It is known that the sedatives given to most patients during the colonoscopy cause a temporary impairment in cognitive function; however, the potential for bowel preparation to affect cognitive function has not previously been investigated. To assess the effect of bowel preparation for colonoscopy on cognitive function. This was a prospective, nonrandomized controlled study of cognitive function in patients who had bowel preparation for colonoscopy compared with those having gastroscopy and therefore no bowel preparation. Cognitive function was assessed using the Modified Mini Mental State Examination (MMMSE) and selected tests from the Cambridge Neuropsychological Test Automated Battery. Individual test scores and changes between initial and subsequent tests were compared between the groups. Age, gender, and weight were also compared. Forty-three colonoscopy and 25 gastroscopy patients were recruited. The 2 groups were similar for age and gender; however, patients having gastroscopy were heavier. MMMSE scores for colonoscopy and gastroscopy groups, respectively, were 28.6 and 29.5 (P = 0.24) at baseline, 28.7 and 29.8 (P = 0.32) at test 2, 28.1 and 28.5 (P = 0.76) at test 3. Motor screening scores for colonoscopy and gastroscopy groups, respectively, were 349.3 and 354.1 (P = 0.97) at baseline, 307.5 and 199.7 (P = 0.06) at test 2, 212.0 and 183.2 (P = 0.33) at test 3. Spatial working memory scores for colonoscopy and gastroscopy groups, respectively, were 14.4 and 6.7 (P = 0.29) at baseline, 9.7 and 4.3 (P = 0.27) at test 2, 10 and 4.5 (P = 0.33) at test 3. Digit Symbol Substitution Test scores for colonoscopy and gastroscopy groups, respectively, were 36.3 and 37.8 (P = 0.84) at baseline, 36.4 and 40.0 (P

  15. Classical cardiovascular disease risk factors associate with vascular function and morphology in rheumatoid arthritis: a six-year prospective study

    PubMed Central

    2013-01-01

    Introduction Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD). An early manifestation of CVD is endothelial dysfunction which can lead to functional and morphological vascular abnormalities. Classical CVD risk factors and inflammation are both implicated in causing endothelial dysfunction in RA. The objective of the present study was to examine the effect of baseline inflammation, cumulative inflammation, and classical CVD risk factors on the vasculature following a six-year follow-up period. Methods A total of 201 RA patients (155 females, median age (25th to 75th percentile): 61 years (53 to 67)) were examined at baseline (2006) for presence of classical CVD risk factors and determination of inflammation using C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). At follow-up (2012) patients underwent assessments of microvascular and macrovascular endothelium-dependent and endothelium-independent function, along with assessment of carotid atherosclerosis. The CRP and ESR were recorded from the baseline study visit to the follow-up visit for each patient to calculate cumulative inflammatory burden. Results Classical CVD risk factors, but not RA disease-related inflammation, predicted microvascular endothelium-dependent and endothelium-independent function, macrovascular endothelium-independent function and carotid atherosclerosis. These findings were similar in a sub-group of patients free from CVD, and not receiving non-steroidal anti-inflammatory drugs, cyclooxygenase 2 inhibitors or biologics. Cumulative inflammation was not associated with microvascular and macrovascular endothelial function, but a weak association was apparent between area under the curve for CRP and carotid atherosclerosis. Conclusions Classical CVD risk factors may be better long-term predictors of vascular function and morphology than systemic disease-related inflammation in patients with RA. Further studies are needed to

  16. Postprandial hyperglycemia impairs vascular endothelial function in healthy men by inducing lipid peroxidation and increasing asymmetric dimethylarginine:arginine.

    PubMed

    Mah, Eunice; Noh, Sang K; Ballard, Kevin D; Matos, Manuel E; Volek, Jeff S; Bruno, Richard S

    2011-11-01

    Postprandial hyperglycemia induces vascular endothelial dysfunction (VED) and increases future cardiovascular disease risk. We hypothesized that postprandial hyperglycemia would decrease vascular function in healthy men by inducing oxidative stress and proinflammatory responses and increasing asymmetric dimethylarginine:arginine (ADMA:arginine), a biomarker that is predictive of reduced NO biosynthesis. In a randomized, cross-over design, healthy men (n = 16; 21.6 ± 0.8 y) ingested glucose or fructose (75 g) after an overnight fast. Brachial artery flow-mediated dilation (FMD), plasma glucose and insulin, antioxidants, malondialdehyde (MDA), inflammatory proteins, arginine, and ADMA were measured at regular intervals during the 3-h postprandial period. Baseline FMD did not differ between trials (P > 0.05). Postprandial FMD was reduced following the ingestion of glucose only. Postprandial MDA concentrations increased to a greater extent following the ingestion of glucose compared to fructose. Plasma arginine decreased and the ratio of ADMA:arginine increased to a greater extent following the ingestion of glucose. Inflammatory cytokines and cellular adhesion molecules were unaffected by the ingestion of either sugar. Postprandial AUC(0-3 h) for FMD and MDA were inversely related (r = -0.80; P < 0.05), suggesting that hyperglycemia-induced lipid peroxidation suppresses postprandial vascular function. Collectively, these findings suggest that postprandial hyperglycemia in healthy men reduces endothelium-dependent vasodilation by increasing lipid peroxidation independent of inflammation. Postprandial alterations in arginine and ADMA:arginine also suggest that acute hyperglycemia may induce VED by decreasing NO bioavailability through an oxidative stress-dependent mechanism. Additional work is warranted to define whether inhibiting lipid peroxidation and restoring arginine metabolism would mitigate hyperglycemia-mediated decreases in vascular function. PMID:21940510

  17. Mimicking Form and Function of Native Small Diameter Vascular Conduits Using Mulberry and Non-mulberry Patterned Silk Films.

    PubMed

    Gupta, Prerak; Kumar, Manishekhar; Bhardwaj, Nandana; Kumar, Jadi Praveen; Krishnamurthy, C S; Nandi, Samit Kumar; Mandal, Biman B

    2016-06-29

    Autologous graft replacement as a strategy to treat diseased peripheral small diameter (≤6 mm) blood vessel is often challenged by prior vein harvesting. To address this issue, we fabricated native-tissue mimicking multilayered small diameter vascular graft (SDVG) using mulberry (Bombyx mori) and Indian endemic non-mulberry (Antheraea assama and Philosamia ricini) silk. Patterned silk films were fabricated on microgrooved PDMS mold, casted by soft lithography. The biodegradable patterned film templates with aligned cell sheets were rolled onto an inert mandrel to mimic vascular conduit. The hemocompatible and mechanically strong non-mulberry films with RGD motif supported ∼1.2 folds greater proliferation of vascular cells with aligned anchorage. Elicitation of minimal immune response on subcutaneous implantation of the films in mice was complemented by ∼45% lower TNF α secretion by in vitro macrophage culture post 7 days. Pattern-induced alignment favored the functional contractile phenotype of smooth muscle cells (SMCs), expressing the signature markers-calponin, α-smooth muscle actin (α-SMA), and smooth muscle myosin heavy chain (SM-MHC). Endothelial cells (ECs) exhibited a typical punctuated pattern of von Willebrand factor (vWF). Deposition of collagen and elastin by the SMCs substantiated the aptness of the graft with desired biomechanical attributes. Furthermore, the burst strength of the fabricated conduit was in the range of ∼915-1260 mmHg, a prerequisite to withstand physiological pressure. This novel fabrication approach may eliminate the need of maturation in a pulsatile bioreactor for obtaining functional cellular phenotype. This work is thereby an attestation to the immense prospects of exploring non-mulberry silk for bioengineering a multilayered vascular conduit similar to a native vessel in "form and function", befitting for in vivo transplantation. PMID:27269821

  18. Tie-dyed2 Encodes a Callose Synthase That Functions in Vein Development and Affects Symplastic Trafficking within the Phloem of Maize Leaves12[C][W][OA

    PubMed Central

    Slewinski, Thomas L.; Baker, R. Frank; Stubert, Adam; Braun, David M.

    2012-01-01

    The tie-dyed2 (tdy2) mutant of maize (Zea mays) displays variegated green and yellow leaves. Intriguingly, the yellow leaf tissues hyperaccumulate starch and sucrose, the soluble sugar transported long distance through the phloem of veins. To determine the molecular basis for Tdy2 function, we cloned the gene and found that Tdy2 encodes a callose synthase. RNA in situ hybridizations revealed that in developing leaves, Tdy2 was most highly expressed in the vascular tissue. Comparative expression analysis with the vascular marker maize PINFORMED1a-yellow fluorescent protein confirmed that Tdy2 was expressed in developing vein tissues. To ascertain whether the defect in tdy2 leaves affected the movement of sucrose into the phloem or its long-distance transport, we performed radiolabeled and fluorescent dye tracer assays. The results showed that tdy2 yellow leaf regions were defective in phloem export but competent in long-distance transport. Furthermore, transmission electron microscopy of tdy2 yellow leaf regions showed incomplete vascular differentiation and implicated a defect in cell-to-cell solute movement between phloem companion cells and sieve elements. The disruption of sucrose movement in the phloem in tdy2 mutants provides evidence that the Tdy2 callose synthase functions in vascular maturation and that the vascular defects result in impaired symplastic trafficking into the phloem translocation stream. PMID:22932757

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

    PubMed

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

    2016-05-01

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

  20. In vitro effects of waterpipe smoke condensate on endothelial cell function: A potential risk factor for vascular disease

    PubMed Central

    Rammah, Mayyasa; Dandachi, Farah; Salman, Rola; Shihadeh, Alan; El-Sabban, Marwan

    2013-01-01

    Aim Despite its increasing popularity, little is known about the health effects of waterpipe smoking (WPS), particularly on the cardiovascular system. To investigate the role of WPS as a risk factor for vascular disease, we evaluated its effect on endothelial cell function, which is an early event in vascular disease pathogenesis. We assessed the changes in cell viability, ROS generation, inflammatory and vasodilatory markers and in vitro angiogenesis of human aortic endothelial cells in response to waterpipe smoke condensate exposure. Methods and results Mainstream waterpipe smoke condensate (WSC) was generated using a standard laboratory machine protocol. Compared to control, WSC induced cell cycle arrest, apoptosis, and oxidative stress in human primary endothelial cells. In addition, we assayed for impaired endothelium-dependent vasodilation and induced inflammation by studying the effect of WPS on the content and activity of AMPK, eNOS proteins and NF-κB p65 ser536 phosphorylation, respectively. WSC inhibited AMPK/eNOS phosphorylation and induced phosphorylation of p65. Moreover, we evaluated endothelial cells repair mechanism related properties that include migration/invasion and in vitro tube formation upon treatment with WSC. WSC reduced the motility and inhibited angiogenic potential of HAEC cells. Conclusions WPS induced endothelial cell dysfunction as evident by exerting oxidative stress, inflammation, and impaired endothelial vasodilatory function and repair mechanisms. All together these data provide evidence for the potential contribution of WPS to endothelial dysfunction and thus to vascular disease. PMID:23454654

  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. Association of digital vascular function with cardiovascular risk factors: a population study

    PubMed Central

    Kuznetsova, Tatiana; Van Vlierberghe, Eline; Knez, Judita; Szczesny, Gregory; Thijs, Lutgarde; Jozeau, Dominique; Balestra, Costantino; D'hooge, Jan; Staessen, Jan A

    2014-01-01

    Objectives Vasodilation of the peripheral arteries during reactive hyperaemia depends in part on release of nitric oxide from endothelial cells. Previous studies mainly employed a fingertip tonometric device to derive pulse wave amplitude (PWA) and PWA hyperaemic changes. An alternative approach is based on photoplethysmography (PPG). We sought to evaluate the correlates of digital PPG PWA hyperaemic responses as a measure of peripheral vascular function. Design The Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO) is a population-based cohort study. Setting Respondents were examined at one centre in northern Belgium. Participants For this analysis, our sample consisted of 311 former participants (53.5% women; mean age 52.6 years; 43.1% hypertensive), who were examined from January 2010 until March 2012 (response rate 85.1%). Primary outcome measures Using a fingertip PPG device, we measured digital PWA at baseline and at 30 s intervals for 4 min during reactive hyperaemia induced by a 5 min forearm cuff occlusion. We performed stepwise regression to identify correlates of the hyperaemic response ratio for each 30 s interval after cuff deflation. Results The maximal hyperaemic response was detected in the 30–60 s interval. The explained variance for the PPG PWA ratio ranged from 9.7% at 0–30 s interval to 22.5% at 60–90 s time interval. The hyperaemic response at each 30 s interval was significantly higher in women compared with men (p≤0.001). The PPG PWA changes at 0–90 s intervals decreased with current smoking (p≤0.0007) and at 0–240 s intervals decreased with higher body mass index (p≤0.035). These associations with sex, current smoking and body mass index were mutually independent. Conclusions Our study is the first to implement the new PPG technique to measure digital PWA hyperaemic changes in a general population. Hyperaemic response, as measured by PPG, is inversely associated with traditional

  3. Inflammation in the Vascular Bed

    PubMed Central

    Aguirre, Rene; May, James M.

    2008-01-01

    Despite decreases in atherosclerotic coronary vascular disease over the last several decades, atherosclerosis remains a major cause of mortality in developed nations. One possible contributor to this residual risk is oxidant stress, which is generated by the inflammatory response of atherosclerosis. Although there is a wealth of in vitro, cellular, and animal data supporting a protective role for antioxidant vitamins and nutrients in the atherosclerotic process, the best clinical trials have been negative. This may be due to the fact that antioxidant therapies are applied “too little and too late.” This review considers the role of vitamin C, or ascorbic acid in preventing the earliest inflammatory changes in atherosclerosis. It focuses on the three major vascular cell types involved in atherosclerosis: endothelial cells, vascular smooth muscle cells, and macrophages. Ascorbate chemistry, recycling, and function are described for these cell types, with emphasis on whether and how the vitamin might affect the inflammatory process. For endothelial cells, ascorbate helps to prevent endothelial dysfunction, stimulates type IV collagen synthesis, and enhances cell proliferation. For vascular smooth muscle cells, ascorbate inhibits dedifferentiation, recruitment, and proliferation in areas of vascular damage. For macrophages, ascorbate decreases oxidant stress related to their activation, decreases uptake and degradation of oxidized LDL in some studies, and enhances several aspects of their function. Although further studies of ascorbate function in these cell types and in novel animal models are needed, available evidence generally supports a salutary role for this vitamin in ameliorating the earliest stages of atherosclerosis. PMID:18582947

  4. Leukocyte Subtype Counts and Its Association with Vascular Structure and Function in Adults with Intermediate Cardiovascular Risk. MARK Study

    PubMed Central

    Gomez-Sanchez, Leticia; García-Ortiz, Luis; Recio-Rodríguez, José I.; Patino-Alonso, Maria C.; Agudo-Conde, Cristina; Rigo, Fernando; Ramos, Rafel; Martí, Ruth; Gomez-Marcos, Manuel A.

    2015-01-01

    Objectives We investigated the relationship between leukocyte subtype counts and vascular structure and function based on carotid intima-media thickness, pulse wave velocity, central augmentation index and cardio-ankle vascular index by gender in intermediate cardiovascular risk patients. Methods This study analyzed 500 subjects who were included in the MARK study, aged 35 to 74 years (mean: 60.3±8.4), 45.6% women. Measurement: Brachial ankle Pulse Wave Velocity (ba-PWV) estimate by equation, Cardio-AnkleVascular Index (CAVI) using the VaSera device and Carotid ultrasound was used to measure carotid Intima Media Thickness (IMT). The Mobil-O-Graph was used to measure the Central Augmentation Index (CAIx). Results Total leukocyte, neutrophil and monocyte counts were positively correlated with IMT (p < 0.01) in men. Monocyte count was positively correlated with CAIx in women (p < 0.01). In a multiple linear regression analysis, the IMT mean maintained a positive association with the neutrophil count (β = 1.500, p = 0.007) in men. CAIx maintained a positive association with the monocyte count (β = 2.445, p = 0.022) in women. Conclusion The results of this study suggest that the relationship between subtype circulating leukocyte counts and vascular structure and function, although small, may be different by gender. In men, the neutrophil count was positively correlated with IMT and in women, the monocyte count with CAIx, in a large sample of intermediate-risk patients. These association were maintained after adjusting for age and other confounders. Trial Registration ClinicalTrials.gov NCT01428934 PMID:25885665

  5. Perivascular adipose tissue in vascular function and disease: a review of current research and animal models

    PubMed Central

    Brown, Nicholas K.; Zhou, Zhou; Zhang, Jifeng; Zeng, Rong; Wu, Jiarui; Eitzman, Daniel T.; Chen, Y. Eugene; Chang, Lin

    2014-01-01

    Perivascular adipose tissue (PVAT), long assumed to be nothing more than vessel-supporting connective tissue, is now understood to be an important, active component of the vasculature, with integral roles in vascular health and disease. PVAT is an adipose tissue with similarities to both brown and white adipose tissue, although recent evidence suggests that PVAT develops from its own precursors. Like other adipose tissue depots, PVAT secretes numerous biologically active substances that can act in both autocrine and paracrine fashion. PVAT has also proven to be involved in vascular inflammation. While PVAT can support inflammation during atherosclerosis via macrophage accumulation, emerging evidence suggests that PVAT also has anti-atherosclerotic properties related to its abilities to induce non-shivering thermogenesis and metabolize fatty acids. We here discuss the accumulated knowledge of PVAT biology, and related research on models of hypertension and atherosclerosis. PMID:24833795

  6. The factors affecting outcome after non-vascular bone grafting and internal fixation for nonunion of the scaphoid.

    PubMed

    Ramamurthy, C; Cutler, L; Nuttall, D; Simison, A J M; Trail, I A; Stanley, J K

    2007-05-01

    This study identified variables which influence the outcome of surgical management on 126 ununited scaphoid fractures managed by internal fixation and non-vascular bone grafting. The site of fracture was defined by a new method: the ratio of the length of the proximal fragment to the sum of the lengths of both fragments, calculated using specific views in the plain radiographs. Bone healing occurred in 71% (89) of cases. Only the site of nonunion (p = 1 x 10(-6)) and the delay to surgery (p = 0.001) remained significant on multivariate analysis. The effect of surgical delay on the probability of union increased as the fracture site moved proximally. A prediction model was produced by stepwise logistic regression analysis, enabling the surgeon to predict the success of surgery where the site of the nonunion and delay to surgery is known. PMID:17540748

  7. TGF-β Is Required for Vascular Barrier Function, Endothelial Survival and Homeostasis of the Adult Microvasculature

    PubMed Central

    Maharaj, Arindel S. R.; Sekiyama, Eiichi; Maldonado, Angel E.; D'Amore, Patricia A.

    2009-01-01

    Pericyte-endothelial cell (EC) interactions are critical to both vascular development and vessel stability. We have previously shown that TGF-β signaling between EC and mural cells participates in vessel stabilization in vitro. We therefore investigated the role of TGF-β signaling in maintaining microvessel structure and function in the adult mouse retinal microvasculature. TGF-β signaling was inhibited by systemic expression of soluble endoglin (sEng) and inhibition was demonstrated by reduced phospho-smad2 in the adult retina. Blockade of TGF-β signaling led to increased vascular and neural cell apoptosis in the retina, which was associated with decreased retinal function, as measured by electroretinogram (ERG). Perfusion of the inner retinal vasculature was impaired and was accompanied by defective autoregulation and loss of capillary integrity. Fundus angiography and Evans blue permeability assay revealed a breakdown of the blood-retinal-barrier that was characterized by decreased association between the tight junction proteins zo-1 and occludin. Inhibition of TGF-β signaling in cocultures of EC and 10T1/2 cells corroborated the in vivo findings, with impaired EC barrier function, dissociation of EC from 10T1/2 cells, and endothelial cell death, supporting the role of EC-mesenchymal interactions in TGF-β signaling. These results implicate constitutive TGF-β signaling in maintaining the integrity and function of the adult microvasculature and shed light on the potential role of TGF-β signaling in vasoproliferative and vascular degenerative retinal diseases. PMID:19340291

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

    PubMed

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

    2016-06-01

    We examined independent and cumulative effects of 2 Alzheimer's-related genetic polymorphisms, Apolipoprotein E (APOE) and Clusterin (CLU), in relation to the deleterious effects of poor vascular health (pulse pressure [PP]) on executive function (EF) performance and change in nondemented older adults. Using a sample (n = 593; age range = 53-95 years) from the Victoria Longitudinal Study, we applied latent growth modeling to test the effect of PP, as moderated by APOE and CLU, on an EF latent variable. EF was affected by higher levels of PP but differentially less so for carriers of low-risk alleles (APOE ɛ2+; CLU TT) than for moderate- or high-risk alleles (APOE ɛ2-; CLU C+). The cumulative genetic risk of APOE plus CLU provided similar moderation of PP level effects on EF. Future research may focus on how APOE and CLU might provide different but complementary contributions to predicting EF level and change. Vascular health risk in synergistic association with risk-related polymorphisms can elucidate the neurobiological underpinnings of cognitive trajectories in nondemented aging. PMID:27143425

  9. Evaluation of the Effect of Hypercapnia on Vascular Function in Normal Tension Glaucoma

    PubMed Central

    Quill, B.; Henry, E.; Simon, E.; O'Brien, C. J.

    2015-01-01

    Introduction. Altered ocular perfusion and vascular dysregulation have been reported in glaucoma. The aim of this paper was to evaluate the vascular response to a hypercapnic stimulus. Methods. Twenty normal tension glaucoma (NTG) patients and eighteen age- and gender-matched controls had pulsatile ocular blood flow (POBF) measurements, systemic cardiovascular assessment, and laser Doppler digital blood flow (DBF) assessed. Measurements were taken at baseline, after 10-minutes rest, in the stable sitting and supine positions and following induction and stabilization of hypercapnia, which induced a 15% increase in end-tidal pCO2. The POBF response to hypercapnia was divided into high (>20%) and low responders (<20%). Results. 65% of NTG patients had a greater than 41% increase in POBF following CO2 rebreathing (high responders). These high responders had a lower baseline POBF, lower baseline DBF, and a greater DBF response to thermal stimulus. Conclusion. NTG patients that have a greater than 20% increase in POBF after a hypercapnic stimulus have lower baseline POBF and DBF values. This suggests that there is impaired regulation of blood flow in a significant subgroup of NTG patients. This observation may reflect a generalised dysfunction of the vascular endothelium. PMID:26557667

  10. Obesity-induced adipokine imbalance impairs mouse pulmonary vascular endothelial function and primes the lung for injury

    PubMed Central

    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

  11. 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

  12. The tyrosine phosphatase SHP-2 controls urokinase-dependent signaling and functions in human vascular smooth muscle cells

    SciTech Connect

    Kiyan, Julia Haller, Hermann; Dumler, Inna

    2009-04-01

    The urokinase (uPA)/urokinase receptor (uPAR) multifunctional system is an important mediator of functional behaviour of human vascular smooth muscle cells (VSMC). uPAR associates with platelet-derived growth factor receptor {beta} (PDGFR-{beta}), which serves as a transmembrane adaptor for uPAR in VSMC, to transduce intracellular signaling and initiate functional changes. The precise and rapid propagation of these signaling cascades demands both strict and flexible regulatory mechanisms that remain unexplored. We provide evidence that the tyrosine phosphatase SHP-2 mediates these processes. uPA regulated SHP-2 phosphorylation, catalytic activity, and its co-localization and association with the PDGFR-{beta}. Active PDGFR-{beta} was required for the uPA-induced SHP-2 phosphorylation. uPAR-directed STAT1 pathway was disturbed in cells expressing SHP-2 inactive mutant. Both, cell proliferation and migration were impaired in VSMC with downregulated SHP-2. Elucidating the underlying mechanisms, we found that uPA induced SHP-2 recruitment to lipid rafts. Disruption of rafts abolished uPA-related control of SHP-2 phosphorylation, its association with PDGFR-{beta} and finally the VSMC functional responses. Our results demonstrate that SHP-2 plays an important role in uPA-directed signaling and functional control of human VSMC and suggest that this phosphatase might contribute to the pathogenesis of the uPA-related vascular remodeling.

  13. Dual Delivery of Hepatocyte and Vascular Endothelial Growth Factors via a Protease-Degradable Hydrogel Improves Cardiac Function in Rats

    PubMed Central

    Boopathy, Archana V.; Che, Pao-lin; Brown, Milton; García, Andrés J.; Davis, Michael E.

    2012-01-01

    Acute myocardial infarction (MI) caused by ischemia and reperfusion (IR) is the most common cause of cardiac dysfunction due to local cell death and a temporally regulated inflammatory response. Current therapeutics are limited by delivery vehicles that do not address spatial and temporal aspects of healing. The aim of this study was to engineer biotherapeutic delivery materials to harness endogenous cell repair to enhance myocardial repair and function. We have previously engineered poly(ethylene glycol) (PEG)-based hydrogels to present cell adhesive motifs and deliver VEGF to promote vascularization in vivo. In the current study, bioactive hydrogels with a protease-degradable crosslinker were loaded with hepatocyte and vascular endothelial growth factors (HGF and VEGF, respectively) and delivered to the infarcted myocardium of rats. Release of both growth factors was accelerated in the presence of collagenase due to hydrogel degradation. When delivered to the border zones following ischemia-reperfusion injury, there was no acute effect on cardiac function as measured by echocardiography. Over time there was a significant increase in angiogenesis, stem cell recruitment, and a decrease in fibrosis in the dual growth factor delivery group that was significant compared with single growth factor therapy. This led to an improvement in chronic function as measured by both invasive hemodynamics and echocardiography. These data demonstrate that dual growth factor release of HGF and VEGF from a bioactive hydrogel has the capacity to significantly improve cardiac remodeling and function following IR injury. PMID:23226440

  14. Vascular Lesions.

    PubMed

    Jahnke, Marla N

    2016-08-01

    Vascular lesions in childhood are comprised of vascular tumors and vascular malformations. Vascular tumors encompass neoplasms of the vascular system, of which infantile hemangiomas (IHs) are the most common. Vascular malformations, on the other hand, consist of lesions due to anomalous development of the vascular system, including the capillary, venous, arterial, and lymphatic systems. Capillary malformations represent the most frequent type of vascular malformation. IHs and vascular malformations tend to follow relatively predictable growth patterns in that IHs grow then involute during early childhood, whereas vascular malformations tend to exhibit little change. Both vascular tumors and vascular malformations can demonstrate a wide range of severity and potential associated complications necessitating specialist intervention when appropriate. Evaluation and treatment of the most common types of vascular lesions are discussed in this article. [Pediatr Ann. 2016;45(8):e299-e305.]. PMID:27517358

  15. Functional vascular smooth muscle cells derived from human induced pluripotent stem cells via mesenchymal stem cell intermediates

    PubMed Central

    Bajpai, Vivek K.; Mistriotis, Panagiotis; Loh, Yuin-Han; Daley, George Q.; Andreadis, Stelios T.

    2012-01-01

    Aims Smooth muscle cells (SMC) play an important role in vascular homeostasis and disease. Although adult mesenchymal stem cells (MSC) have been used as a source of contractile SMC, they suffer from limited proliferation potential and culture senescence, particularly when originating from older donors. By comparison, human induced pluripotent stem cells (hiPSC) can provide an unlimited source of functional SMC for autologous cell-based therapies and for creating models of vascular disease. Our goal was to develop an efficient strategy to derive functional, contractile SMC from hiPSC. Methods and results We developed a robust, stage-wise, feeder-free strategy for hiPSC differentiation into functional SMC through an intermediate stage of multipotent MSC, which could be coaxed to differentiate into fat, bone, cartilage, and muscle. At this stage, the cells were highly proliferative and displayed higher clonogenic potential and reduced senescence when compared with parental hair follicle mesenchymal stem cells. In addition, when exposed to differentiation medium, the myogenic proteins such as α-smooth muscle actin, calponin, and myosin heavy chain were significantly upregulated and displayed robust fibrillar organization, suggesting the development of a contractile phenotype. Indeed, tissue constructs prepared from these cells exhibited high levels of contractility in response to receptor- and non-receptor-mediated agonists. Conclusion We developed an efficient stage-wise strategy that enabled hiPSC differentiation into contractile SMC through an intermediate population of clonogenic and multipotent MSC. The high yield of MSC and SMC derivation suggests that our strategy may facilitate an acquisition of the large numbers of cells required for regenerative medicine or for studying vascular disease pathophysiology. PMID:22941255

  16. Engineering vascular tissue with functional smooth muscle cells derived from human iPS cells and nanofibrous scaffolds.

    PubMed

    Wang, Yongyu; Hu, Jiang; Jiao, Jiao; Liu, Zhongning; Zhou, Zhou; Zhao, Chao; Chang, Lung-Ji; Chen, Y Eugene; Ma, Peter X; Yang, Bo

    2014-10-01

    Tissue-engineered blood vessels (TEBVs) are promising in the replacement of diseased vascular tissues. However, it remains a great challenge to obtain a sufficient number of functional smooth muscle cells (SMCs) in a clinical setting to construct patient-specific TEBVs. In addition, it is critical to develop a scaffold to accommodate these cells and retain their functional phenotype for the regeneration of TEBVs. In this study, human induced pluripotent stem cells (iPSCs) were established from primary human aortic fibroblasts, and characterized with the pluripotency markers expression and cells' capabilities to differentiate into all three germ layer cells. A highly efficient method was then developed to induce these human iPSCs into proliferative SMCs. After multiple times of expansion, the expanded SMCs retained the potential to be induced into the functional contractile phenotype of mature SMCs, which was characterized by the contractile response to carbachol treatment, up-regulation of specific collagen genes under transforming growth factor β1 treatment, and up-regulation of specific matrix metalloproteinase genes under cytokine stimulation. We also developed an advanced macroporous and nanofibrous (NF) poly(l-lactic acid) (PLLA) scaffold with suitable pore size and interpore connectivity to seed these human iPSC-derived SMCs and maintain their differentiated phenotype. Subcutaneous implantation of the SMC-scaffold construct in nude mice demonstrated vascular tissue formation, with robust collagenous matrix deposition inside the scaffold and the maintenance of differentiated SMC phenotype. Taken together, this study established an exciting approach towards the construction of patient-specific TEBVs. We established patient-specific human iPSCs, derived proliferative SMCs for expansion, turned on their mature contractile SMC phenotype, and developed an advanced scaffold for these cells to regenerate vascular tissue in vivo. PMID:25085858

  17. Markers of T Cell Infiltration and Function Associate with Favorable Outcome in Vascularized High-Grade Serous Ovarian Carcinoma

    PubMed Central

    Townsend, Katelin N.; Spowart, Jaeline E.; Huwait, Hassan; Eshragh, Sima; West, Nathan R.; Elrick, Mary A.; Kalloger, Steve E.; Anglesio, Michael; Watson, Peter H.; Huntsman, David G.; Lum, Julian J.

    2013-01-01

    Background When T cells infiltrate the tumor environment they encounter a myriad of metabolic stressors including hypoxia. Overcoming the limitations imposed by an inadequate tumor vasculature that contributes to these stressors may be a crucial step to immune cells mounting an effective anti-tumor response. We sought to determine whether the functional capacity of tumor infiltrating lymphocytes (TIL) could be influenced by the tumor vasculature and correlated this with survival in patients with ovarian cancer. Methodology and Principal Findings In 196 high-grade serous ovarian tumors, we confirmed that the tumor vascularity as measured by the marker CD31 was associated with improved patient disease-specific survival. We also found that tumors positive for markers of TIL (CD8, CD4 and forkhead box P3 (FoxP3)) and T cell function (granzyme B and T-cell restricted intracellular antigen-1 (TIA-1)) correlated significantly with elevated vascularity. In vitro, hypoxic CD8 T cells showed reduced cytolytic activity, secreted less effector cytokines and upregulated autophagy. Survival analysis revealed that patients had a significant improvement in disease-specific survival when FoxP3 expressing cells were present in CD31-high tumors compared to patients with FoxP3 expressing cells in CD31-low tumors [HR: 2.314 (95% CI 1.049–5.106); p = 0.0377]. Patients with high vascular endothelial growth factor (VEGF) expressing tumors containing granzyme B positive cells had improved survival compared to patients with granzyme B positive cells in VEGF-low tumors [HR: 2.522 (95% CI 1.097–5.799); p = 0.0294]. Significance Overall, this data provides a rationale for developing strategies aimed at improving the adaptability and function of TIL to hypoxic tumor conditions. PMID:24376535

  18. Vascular Precursor Cells

    PubMed Central

    Chaudhury, Hera; Goldie, Lauren C.

    2011-01-01

    Understanding the mechanisms that regulate the proliferation and differentiation of human stem and progenitor cells is critically important for the development and optimization of regenerative medicine strategies. For vascular regeneration studies, specifically, a true “vascular stem cell” population has not yet been identified. However, a number of cell types that exist endogenously, or can be generated or propagated ex vivo, function as vascular precursor cells and can participate in and/or promote vascular regeneration. Herein, we provide an overview of what is known about the regulation of their differentiation specifically toward a vascular endothelial cell phenotype. PMID:22866199

  19. MicroRNA-26a is a novel regulator of vascular smooth muscle cell function.

    PubMed

    Leeper, Nicholas J; Raiesdana, Azad; Kojima, Yoko; Chun, Hyung J; Azuma, Junya; Maegdefessel, Lars; Kundu, Ramendra K; Quertermous, Thomas; Tsao, Philip S; Spin, Joshua M

    2011-04-01

    Aberrant smooth muscle cell (SMC) plasticity has been implicated in a variety of vascular disorders including atherosclerosis, restenosis, and abdominal aortic aneurysm (AAA) formation. While the pathways governing this process remain unclear, epigenetic regulation by specific microRNAs (miRNAs) has been demonstrated in SMCs. We hypothesized that additional miRNAs might play an important role in determining vascular SMC phenotype. Microarray analysis of miRNAs was performed on human aortic SMCs undergoing phenotypic switching in response to serum withdrawal, and identified 31 significantly regulated entities. We chose the highly conserved candidate miRNA-26a for additional studies. Inhibition of miRNA-26a accelerated SMC differentiation, and also promoted apoptosis, while inhibiting proliferation and migration. Overexpression of miRNA-26a blunted differentiation. As a potential mechanism, we investigated whether miRNA-26a influences TGF-β-pathway signaling. Dual-luciferase reporter assays demonstrated enhanced SMAD signaling with miRNA-26a inhibition, and the opposite effect with miRNA-26a overexpression in transfected human cells. Furthermore, inhibition of miRNA-26a increased gene expression of SMAD-1 and SMAD-4, while overexpression inhibited SMAD-1. MicroRNA-26a was also found to be downregulated in two mouse models of AAA formation (2.5- to 3.8-fold decrease, P < 0.02) in which enhanced switching from contractile to synthetic phenotype occurs. In summary, miRNA-26a promotes vascular SMC proliferation while inhibiting cellular differentiation and apoptosis, and alters TGF-β pathway signaling. MicroRNA-26a represents an important new regulator of SMC biology and a potential therapeutic target in AAA disease. PMID:20857419

  20. Effect of computerized cognitive training with virtual spatial navigation task during bed rest immobilization and recovery on vascular function: A pilot study

    PubMed Central

    Goswami, Nandu; Kavcic, Voyko; Marusic, Uros; Simunic, Bostjan; Rössler, Andreas; Hinghofer-Szalkay, Helmut; Pisot, Rado

    2015-01-01

    We investigated the effects of bed rest (BR) immobilization, with and without computerized cognitive training with virtual spatial navigation task (CCT), on vascular endothelium on older subjects. The effects of 14-day BR immobilization in healthy older males (n=16) of ages 53–65 years on endothelial function were studied using EndoPAT®, a noninvasive and user-independent method. From the group of 16 older men, 8 randomly received CCT during the BR, using virtual navigation tasks in a virtual environment with joystick device. In all the cases, EndoPAT assessments were done at pre- and post-BR immobilization as well as following 28 days of ambulatory recovery. The EndoPAT index increased from 1.53±0.09 (mean ± standard error of the mean) at baseline to 1.61±0.16 following immobilization (P=0.62) in the group with CCT. The EndoPAT index decreased from 2.06±0.13 (mean ± standard error of the mean) at baseline to 1.70±0.09 at the last day of BR study, day 14 (BR14) (P=0.09) in the control group. Additionally, there were no statistically significant differences between BR14 and at 28 days of follow-up (rehabilitation program) (R28). Our results show a trend of immobilization in older persons affecting the vasoconstrictory endothelial response. As the control subjects had a greater increase in EndoPAT index after R28 (+0.018) compared to subjects who had cognitive training (+0.11) (calculated from the first day of BR study), it is possible that cognitive training during BR does not improve endothelial function but rather contributes to slowing down the impairment of endothelial function. Finally, our results also show that EndoPAT may be a useful noninvasive tool to assess the vascular reactivity. PMID:25709419

  1. Cytoskeletal mechanisms regulating vascular endothelial barrier function in response to acute lung injury.

    PubMed

    Kása, Anita; Csortos, Csilla; Verin, Alexander D

    2015-01-01

    Endothelial cells (EC) form a semi-permeable barrier between the interior space of blood vessels and the underlying tissues. In acute lung injury (ALI) the EC barrier is weakened leading to increased vascular permeability. It is widely accepted that EC barrier integrity is critically dependent upon intact cytoskeletal structure and cell junctions. Edemagenic agonists, like thrombin or endotoxin lipopolysaccharide (LPS), induced cytoskeletal rearrangement, and EC contractile responses leading to disruption of intercellular contacts and EC permeability increase. The highly clinically-relevant cytoskeletal mechanisms of EC barrier dysfunction are currently under intense investigation and will be described and discussed in the current review. PMID:25838980

  2. Cytoskeletal mechanisms regulating vascular endothelial barrier function in response to acute lung injury

    PubMed Central

    Kása, Anita; Csortos, Csilla; Verin, Alexander D

    2014-01-01

    Endothelial cells (EC) form a semi-permeable barrier between the interior space of blood vessels and the underlying tissues. In acute lung injury (ALI) the EC barrier is weakened leading to increased vascular permeability. It is widely accepted that EC barrier integrity is critically dependent upon intact cytoskeletal structure and cell junctions. Edemagenic agonists, like thrombin or endotoxin lipopolysaccharide (LPS), induced cytoskeletal rearrangement, and EC contractile responses leading to disruption of intercellular contacts and EC permeability increase. The highly clinically-relevant cytoskeletal mechanisms of EC barrier dysfunction are currently under intense investigation and will be described and discussed in the current review. PMID:25838980

  3. Penile vascular evaluation and sexual function before and after radical retropubic prostatectomy: 5-year follow-up.

    PubMed

    Dubbelman, Yvette D; Wildhagen, Mark F; Dohle, Gert R

    2008-09-01

    Sexual dysfunction is common after surgery for prostate cancer. The aetiology of changes in sexual potency after radical prostatectomy is probably multifactorial, including neurogenic, vascular and psychosexual factors. A prospective study was designed to investigate haemodynamic and psychosexual changes before and after radical retropubic prostatectomy (RRP) for organ-confined prostate cancer. Penile haemodynamic evaluation and an assessment of sexual excitement were performed preoperatively and 3 months after RRP by colour Doppler ultrasonography (CDU) with visual erotic stimulation combined with a single intracavernous injection of a mixture of papaverine/phentolamine. Questionnaires on sexual function [International Index of Erectile Function (IIEF)], general health and quality of life were sent to the patients preoperative, 3 months and 5 years after operation. Forty-eight men participated in the study. Mean age was 62.6 years (range 55-69). CDU did not show any significant reduction in mean peak systolic flow velocity and mean resistance index. From the men who preoperatively had normal arterial inflow 18% developed arteriogenic insufficiency. Some form of veno-occlusive insufficiency and low resistance indices were already present in the majority of normal potent men preoperatively. Surgical technique did not influence penile arterial blood flow after the operation. Three months and 5 years postoperatively, there was a highly significant reduction in erectile function, intercourse satisfaction, overall satisfaction, orgasmic function and sexual desire. However, with respect to the outcome at 3 months there was a significant improvement of orgasmic function 5 years after operation, especially after a bilateral nerve sparing procedure. Erections sufficient for vaginal penetration (questions 3 and 4 of the IIEF, score >or=8) improved from 2% to 11% 3 months and 5 years after RRP respectively. Total IIEF score was significantly better after a bilateral nerve

  4. Taurine Supplementation Lowers Blood Pressure and Improves Vascular Function in Prehypertension: Randomized, Double-Blind, Placebo-Controlled Study.

    PubMed

    Sun, Qianqian; Wang, Bin; Li, Yingsha; Sun, Fang; Li, Peng; Xia, Weijie; Zhou, Xunmei; Li, Qiang; Wang, Xiaojing; Chen, Jing; Zeng, Xiangru; Zhao, Zhigang; He, Hongbo; Liu, Daoyan; Zhu, Zhiming

    2016-03-01

    Taurine, the most abundant, semiessential, sulfur-containing amino acid, is well known to lower blood pressure (BP) in hypertensive animal models. However, no rigorous clinical trial has validated whether this beneficial effect of taurine occurs in human hypertension or prehypertension, a key stage in the development of hypertension. In this randomized, double-blind, placebo-controlled study, we assessed the effects of taurine intervention on BP and vascular function in prehypertension. We randomly assigned 120 eligible prehypertensive individuals to receive either taurine supplementation (1.6 g per day) or a placebo for 12 weeks. Taurine supplementation significantly decreased the clinic and 24-hour ambulatory BPs, especially in those with high-normal BP. Mean clinic systolic BP reduction for taurine/placebo was 7.2/2.6 mm Hg, and diastolic BP was 4.7/1.3 mm Hg. Mean ambulatory systolic BP reduction for taurine/placebo was 3.8/0.3 mm Hg, and diastolic BP was 3.5/0.6 mm Hg. In addition, taurine supplementation significantly improved endothelium-dependent and endothelium-independent vasodilation and increased plasma H2S and taurine concentrations. Furthermore, changes in BP were negatively correlated with both the plasma H2S and taurine levels in taurine-treated prehypertensive individuals. To further elucidate the hypotensive mechanism, experimental studies were performed both in vivo and in vitro. The results showed that taurine treatment upregulated the expression of hydrogen sulfide-synthesizing enzymes and reduced agonist-induced vascular reactivity through the inhibition of transient receptor potential channel subtype 3-mediated calcium influx in human and mouse mesenteric arteries. In conclusion, the antihypertensive effect of chronic taurine supplementation shows promise in the treatment of prehypertension through improvement of vascular function. PMID:26781281

  5. Sertoli Cells Modulate Testicular Vascular Network Development, Structure, and Function to Influence Circulating Testosterone Concentrations in Adult Male Mice

    PubMed Central

    Rebourcet, Diane; Wu, Junxi; Cruickshanks, Lyndsey; Smith, Sarah E.; Milne, Laura; Fernando, Anuruddika; Wallace, Robert J.; Gray, Calum D.; Hadoke, Patrick W. F.; Mitchell, Rod T.; O'Shaughnessy, Peter J.

    2016-01-01

    The testicular vasculature forms a complex network, providing oxygenation, micronutrients, and waste clearance from the testis. The vasculature is also instrumental to testis function because it is both the route by which gonadotropins are delivered to the testis and by which T is transported away to target organs. Whether Sertoli cells play a role in regulating the testicular vasculature in postnatal life has never been unequivocally demonstrated. In this study we used models of acute Sertoli cell ablation and acute germ cell ablation to address whether Sertoli cells actively influence vascular structure and function in the adult testis. Our findings suggest that Sertoli cells play a key role in supporting the structure of the testicular vasculature. Ablating Sertoli cells (and germ cells) or germ cells alone results in a similar reduction in testis size, yet only the specific loss of Sertoli cells leads to a reduction in total intratesticular vascular volume, the number of vascular branches, and the numbers of small microvessels; loss of germ cells alone has no effect on the testicular vasculature. These perturbations to the testicular vasculature leads to a reduction in fluid exchange between the vasculature and testicular interstitium, which reduces gonadotropin-stimulated circulating T concentrations, indicative of reduced Leydig cell stimulation and/or reduced secretion of T into the vasculature. These findings describe a new paradigm by which the transport of hormones and other factors into and out of the testis may be influenced by Sertoli cells and highlights these cells as potential targets for enhancing this endocrine relationship. PMID:27145015

  6. Sertoli Cells Modulate Testicular Vascular Network Development, Structure, and Function to Influence Circulating Testosterone Concentrations in Adult Male Mice.

    PubMed

    Rebourcet, Diane; Wu, Junxi; Cruickshanks, Lyndsey; Smith, Sarah E; Milne, Laura; Fernando, Anuruddika; Wallace, Robert J; Gray, Calum D; Hadoke, Patrick W F; Mitchell, Rod T; O'Shaughnessy, Peter J; Smith, Lee B

    2016-06-01

    The testicular vasculature forms a complex network, providing oxygenation, micronutrients, and waste clearance from the testis. The vasculature is also instrumental to testis function because it is both the route by which gonadotropins are delivered to the testis and by which T is transported away to target organs. Whether Sertoli cells play a role in regulating the testicular vasculature in postnatal life has never been unequivocally demonstrated. In this study we used models of acute Sertoli cell ablation and acute germ cell ablation to address whether Sertoli cells actively influence vascular structure and function in the adult testis. Our findings suggest that Sertoli cells play a key role in supporting the structure of the testicular vasculature. Ablating Sertoli cells (and germ cells) or germ cells alone results in a similar reduction in testis size, yet only the specific loss of Sertoli cells leads to a reduction in total intratesticular vascular volume, the number of vascular branches, and the numbers of small microvessels; loss of germ cells alone has no effect on the testicular vasculature. These perturbations to the testicular vasculature leads to a reduction in fluid exchange between the vasculature and testicular interstitium, which reduces gonadotropin-stimulated circulating T concentrations, indicative of reduced Leydig cell stimulation and/or reduced secretion of T into the vasculature. These findings describe a new paradigm by which the transport of hormones and other factors into and out of the testis may be influenced by Sertoli cells and highlights these cells as potential targets for enhancing this endocrine relationship. PMID:27145015

  7. 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

  8. Calcium entry blocking drugs, 'calcium antagonists' and vascular smooth muscle function.

    PubMed

    Bou, J; Llenas, J; Massingham, R

    1983-09-01

    The group of drugs known as "calcium antagonists' is under extensive investigation in experimental animals and man and a re-evaluation of their pharmacological properties is overdue. Recent proposals to adopt the more specific nomenclature of calcium entry blockers for some of these compounds (Vanhoutte & Bohr, 1981) should be supported since there is much confusion in the literature with this class of compound. In this review, which concentrates on vascular smooth muscle, only nifedipine, verapamil, their close chemical analogues and diltiazem are recognised as being relatively selective calcium entry blocking drugs. Whilst definitive evidence for calcium entry blockade must include the demonstration of a selective inhibition of Ca2+-influx into a tissue over a range of concentrations also inhibiting contraction, it is nevertheless possible to define several simple pharmacological criteria which may aid in the identification of such activity. These criteria include the selective antagonism of K+ and Ca2+-induced contractions, relative to those of noradrenaline in suitable vascular smooth muscle preparations and a selective inhibition of alpha 2- as opposed to alpha 1-adrenoreceptor mediated pressor responses in, for example, pithed rat preparations. Recent pharmacological and biochemical studies have identified 3 major subgroups of "calcium antagonist' drugs but the compounds within each subgroup varies with the technique adopted. It is therefore suggested that a combination of both pharmacological and ligand-binding studies be used for purposes of classification. Which mechanism, if any, of inhibiting calcium entry is therapeutically most desirable remains an important question for future research. PMID:6315739

  9. Transient functional expression of alphaVbeta 3 on vascular cells during wound repair.

    PubMed Central

    Clark, R. A.; Tonnesen, M. G.; Gailit, J.; Cheresh, D. A.

    1996-01-01

    During early granulation tissue formation of wound repair, new capillaries invade the fibrin clot, a process that undoubtedly requires an interaction of vascular cells with the wound provisional matrix composed mainly of fibrin, fibronectin, and vitronectin. Integrin alphaVbeta3 is the vascular cell receptor for these wound-associated adhesive proteins. Therefore, we investigated the expression of this receptor on new capillaries of healing full-thickness cutaneous porcine wounds. During granulation tissue formation, alphaVbeta3 was expressed specifically on capillary sprouts invading the central fibrin clot whereas the closely related integrin alphaVbeta5 failed to localize to these cells. Cyclic peptides or antibody antagonists of alphaVbeta3 specifically inhibited granulation tissue formation in a transient manner during the period of invasive angiogenesis. Immunolocalization studies revealed that alphaVbeta3 became aggregated and lost from sprouting vessels after treatment with a peptide antagonist. In contrast, beta 1 integrins were not modulated by this treatment. Once granulation tissue filled the wound and invasive angiogenesis terminated, the alphaVbeta3 showed little or no expression in the granulation tissue microvasculature. These data demonstrate that integrin alphaVbeta3 plays a fundamental, but transient, role during invasive angiogenesis and granulation tissue formation in a healing wound. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 8 Figure 9 Figure 10 PMID:8623913

  10. Association between smoking status and the parameters of vascular structure and function in adults: results from the EVIDENT study

    PubMed Central

    2013-01-01

    Background The present study analyses the relation between smoking status and the parameters used to assess vascular structure and function. Methods This cross-sectional, multi-centre study involved a random sample of 1553 participants from the EVIDENT study. Measurements: The smoking status, peripheral augmentation index and ankle-brachial index were measured in all participants. In a small subset of the main population (265 participants), the carotid intima-media thickness and pulse wave velocity were also measured. Results After controlling for the effect of age, sex and other risk factors, present smokers have higher values of carotid intima-media thickness (p = 0.011). Along the same lines, current smokers have higher values of pulse wave velocity and lower mean values of ankle-brachial index but without statistical significance in both cases. Conclusions Among the parameters of vascular structure and function analysed, only the IMT shows association with the smoking status, after adjusting for confounders. PMID:24289208

  11. Interaction of Panax quinquefolius Saponin and Dual Antiplatelets on Vascular Endothelial Function in Rats with Acute Myocardial Infarction

    PubMed Central

    Wang, Baojun; Liu, Yue; Shang, Qinghua; Zhang, Qingxiang; Zhang, Lei; Liu, Jiangang; Shi, Dazhuo

    2015-01-01

    The objective of this study is to investigate the interaction of Panax quinquefolius saponin (PQS) and dual antiplatelets (aspirin and clopidogrel) on antiplatelet activity and vascular endothelial function in rats with acute myocardial infarction (AMI). Forty-eight male SD rats were randomly designed into sham group, model group, dual antiplatelet group, and PQS plus dual antiplatelet group. AMI rats were induced by ligation of left anterior descending coronary artery (LAD) and dual antiplatelet agents and additional PQS to dual antiplatelets were intragastrically administered for 28 days, respectively. The ventricular cavity area and cardiac transverse area ratio in PQS + dual antiplatelet group showed a decreased tendency. PAgT(%) decreased significantly in both dual antiplatelet group and PQS + dual antiplatelet group. TXB2 concentration significantly decreased in dual antiplatelet and PQS + dual antiplatelet groups, whereas 6-keto-PGF1α concentration significantly increased in PQS + dual antiplatelet group. Rats in PQS + dual antiplatelet group demonstrated a significant decrease in plasma ET-1 concentration and an increase in serum NO concentration compared with dual antiplatelet group. The combination therapy of PQS and dual antiplatelets showed some beneficial effects on vascular endothelial function and ventricular remodeling in rats with AMI. PMID:26090462

  12. Vascular function and tissue injury in murine skin following hyperthermia and photodynamic therapy, alone and in combination.

    PubMed Central

    Moore, J. V.; West, C. M.; Haylett, A. K.

    1992-01-01

    The murine tail has been used as a model for injury to skin when hyperthermia (HT) and photodynamic therapy (PDT) using haematoporphyrin derivative, are used in combination. Skin injury by either agent alone was quantitated by the probability of tail necrosis as a function of dose of agent. 'Tolerance' doses of each modality were given and changes in skin vascular function were measured by the rate of clearance of 133Xenon. This was promptly inhibited but restored to normal by 7 days. The absolute numbers of hypodermal vessels of different sizes were measured in tail cross-sections and capillary numbers were found to be greatly reduced between 1 and 7 days, and restored to normal by 21-28 days. When a tolerance dose of PDT was followed at 1, 7, 21 and 28 days by test doses of HT, or vice versa, marked enhancements in probability of necrosis were observed when the interval was 1 or 7 days (Enhancement ratio (ER)PDT-HT = 1.5 and ERHT-PDT = 1.8). Prolonging the interval between modalities to 21-28 days spared the tissue (ERHT-PDT/21 DAYS = 1.1; ERPDT-HT/28 DAYS = 1.0). Close temporal apposition of PDT and HT, such as has been advocated to improve tumour control, may also increase injury to normal tissue through vascular effects common to both. PMID:1457342

  13. Spectral imaging of microvascular function in a renal cell carcinoma after treatment with a vascular disrupting agent

    NASA Astrophysics Data System (ADS)

    Wankhede, Mamta; deDeugd, Casey; Siemann, Dietmar W.; Sorg, Brian S.

    2009-02-01

    Tumors are highly metabolically active and thus require ample oxygen and nutrients to proliferate. Neovasculature generated by angiogenesis is required for tumors to grow beyond a size of about 1-2mm. Functional tumor vasculature also provides an access point for development of distant metastases. Due to the importance of the microvasculature for tumor growth, proliferation, and metastasis, the microvasculature has emerged as a therapeutic target for treatment of solid tumors. We employed spectral imaging in a rodent window chamber model to observe and measure the oxygen transport function of tumor microvasculature in a human renal cell carcinoma after treatment with a fast acting vascular disrupting agent. Human Caki-1 cells were grown in a dorsal skin-fold window chamber in athymic nude mice. Spectral imaging was used to measure hemoglobin saturation immediately before, immediately after and also at 2, 4, 6, 8, 24 and 48 hours after administration of the tubulin binding agent OXi4503. Up to 4 hours after treatment, tumor microvasculature was disrupted from the tumor core towards the periphery as seen in deoxygenation as well as structural changes of the vasculature. Reoxygenation and neovascularization commenced from the periphery towards the core from 6 - 48 hours after treatment. The timing of the effects of vascular disrupting agents can influence scheduling of repeat treatments and combinatorial treatments such as chemotherapy and radiation therapy. Spectral imaging can potentially provide this information in certain laboratory models from endogenous signals with microvessel resolution.

  14. Breast cancer drugs dampen vascular functions by interfering with nitric oxide signaling in endothelium

    SciTech Connect

    Gajalakshmi, Palanivel; Priya, Mani Krishna; Pradeep, Thangaraj; Behera, Jyotirmaya; Muthumani, Kandasamy; Madhuwanti, Srinivasan; Saran, Uttara; Chatterjee, Suvro

    2013-06-01

    Widely used chemotherapeutic breast cancer drugs such as Tamoxifen citrate (TC), Capecitabine (CP) and Epirubicin (EP) are known to cause various cardiovascular side-effects among long term cancer survivors. Vascular modulation warrants nitric oxide (NO) signal transduction, which targets the vascular endothelium. We hypothesize that TC, CP and EP interference with the nitric oxide downstream signaling specifically, could lead to cardiovascular dysfunctions. The results demonstrate that while all three drugs attenuate NO and cyclic guanosine mono-phosphate (cGMP) production in endothelial cells, they caused elevated levels of NO in the plasma and RBC. However, PBMC and platelets did not show any significant changes under treatment. This implies that the drug effects are specific to the endothelium. Altered eNOS and phosphorylated eNOS (Ser-1177) localization patterns in endothelial cells were observed following drug treatments. Similarly, the expression of phosphorylated eNOS (Ser-1177) protein was decreased under the treatment of drugs. Altered actin polymerization was also observed following drug treatment, while addition of SpNO and 8Br-cGMP reversed this effect. Incubation with the drugs decreased endothelial cell migration whereas addition of YC-1, SC and 8Br-cGMP recovered the effect. Additionally molecular docking studies showed that all three drugs exhibited a strong binding affinity with the catalytic domain of human sGC. In conclusion, results indicate that TC, CP and EP cause endothelial dysfunctions via the NO–sGC–cGMP pathway and these effects could be recovered using pharmaceutical agonists of NO signaling pathway. Further, the study proposes a combination therapy of chemotherapeutic drugs and cGMP analogs, which would confer protection against chemotherapy mediated vascular dysfunctions in cancer patients. - Highlights: • NO production is reduced in endothelial cells under breast cancer drug treatment. • Cellular cGMP level is decreased under

  15. Concomitant gastroparesis negatively affects children with functional gallbladder disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The aim of the present study was to determine whether concomitant gastroparesis and biliary dyskinesia (BD) occur in children, and if so, to determine whether concomitant gastroparesis affects clinical outcome in children with BD. We conducted a retrospective chart review of children with BD (ejecti...

  16. Gene expression profiling during intensive cardiovascular lifestyle modification: Relationships with vascular function and weight loss

    PubMed Central

    Blackburn, Heather L.; McErlean, Seóna; Jellema, Gera L.; van Laar, Ryan; Vernalis, Marina N.; Ellsworth, Darrell L.

    2015-01-01

    Heart disease and related sequelae are a leading cause of death and healthcare expenditure throughout the world. Although many patients opt for surgical interventions, lifestyle modification programs focusing on nutrition and exercise have shown substantial health benefits and are becoming increasing popular. We conducted a year-long lifestyle modification program to mediate cardiovascular risk through traditional risk factors and to investigate how molecular changes, if present, may contribute to long-term risk reduction. Here we describe the lifestyle intervention, including clinical and molecular data collected, and provide details of the experimental methods and quality control parameters for the gene expression data generated from participants and non-intervention controls. Our findings suggest successful and sustained modulation of gene expression through healthy lifestyle changes may have beneficial effects on vascular health that cannot be discerned from traditional risk factor profiles. The data are deposited in the Gene Expression Omnibus, series GSE46097 and GSE66175. PMID:26484175

  17. ASSOCIATION BETWEEN WHITE MATTER MICROSTRUCTURE, EXECUTIVE FUNCTIONS AND PROCESSING SPEED IN OLDER ADULTS: THE IMPACT OF VASCULAR HEALTH

    PubMed Central

    Jacobs, Heidi I.L.; Leritz, Elizabeth C.; Williams, Victoria J.; Van Boxtel, Martin P.J.; van der Elst, Wim; Jolles, Jelle; Verhey, Frans R. J.; McGlinchey, Regina E.; Milberg, William P.; Salat, David H.

    2013-01-01

    Cerebral white matter damage is a commonly reported consequence of healthy aging, but is also associated with cognitive decline and dementia. The aetiology of this damage is unclear, however, individuals with hypertension have a greater burden of white matter signal abnormalities (WMSA) on MR imaging than those without hypertension. It is therefore possible that elevated blood pressure (BP) impacts white matter tissue structure which in turn has a negative impact on cognition. However, little information exists about whether vascular health indexed by BP mediates the relationship between cognition and white matter tissue structure. We used diffusion tensor imaging to examine the impact of vascular health on regional associations between white matter integrity and cognition in healthy older adults spanning the normotensive to moderate-severe hypertensive BP range (43–87 years; N=128). We examined how white matter structure was associated with performance on tests of two cognitive domains, executive functioning (EF) and processing speed (PS), and how patterns of regional associations were modified by BP and WMSA. Multiple linear regression and structural equation models demonstrated associations between tissue structure, EF and PS in frontal, temporal, parietal and occipital white matter regions. Radial diffusivity was more prominently associated with performance than axial diffusivity. BP only minimally influenced the relationship between white matter integrity, EF and PS. However, WMSA volume had a major impact on neurocognitive associations. This suggests that, although BP and WMSA are causally related, these differential metrics of vascular health may act via independent pathways to influence brain structure, EF and PS. PMID:21954054

  18. Association between white matter microstructure, executive functions, and processing speed in older adults: the impact of vascular health.

    PubMed

    Jacobs, Heidi I L; Leritz, Elizabeth C; Williams, Victoria J; Van Boxtel, Martin P J; van der Elst, Wim; Jolles, Jelle; Verhey, Frans R J; McGlinchey, Regina E; Milberg, William P; Salat, David H

    2013-01-01

    Cerebral white matter damage is not only a commonly reported consequence of healthy aging, but is also associated with cognitive decline and dementia. The aetiology of this damage is unclear; however, individuals with hypertension have a greater burden of white matter signal abnormalities (WMSA) on MR imaging than those without hypertension. It is therefore possible that elevated blood pressure (BP) impacts white matter tissue structure which in turn has a negative impact on cognition. However, little information exists about whether vascular health indexed by BP mediates the relationship between cognition and white matter tissue structure. We used diffusion tensor imaging to examine the impact of vascular health on regional associations between white matter integrity and cognition in healthy older adults spanning the normotensive to moderate-severe hypertensive BP range (43-87 years; N = 128). We examined how white matter structure was associated with performance on tests of two cognitive domains, executive functioning (EF) and processing speed (PS), and how patterns of regional associations were modified by BP and WMSA. Multiple linear regression and structural equation models demonstrated associations between tissue structure, EF and PS in frontal, temporal, parietal, and occipital white matter regions. Radial diffusivity was more prominently associated with performance than axial diffusivity. BP only minimally influenced the relationship between white matter integrity, EF and PS. However, WMSA volume had a major impact on neurocognitive associations. This suggests that, although BP and WMSA are causally related, these differential metrics of vascular health may act via independent pathways to influence brain structure, EF and PS. PMID:21954054

  19. In vivo vascularization of MSC-loaded porous hydroxyapatite constructs coated with VEGF-functionalized collagen/heparin multilayers

    PubMed Central

    Jin, Kai; Li, Bo; Lou, Lixia; Xu, Yufeng; Ye, Xin; Yao, Ke; Ye, Juan; Gao, Changyou

    2016-01-01

    Rapid and adequate vascularization is vital to the long-term success of porous orbital enucleation implants. In this study, porous hydroxyapatite (HA) scaffolds coated with vascular endothelial growth factor (VEGF)-functionalized collagen (COL)/heparin (HEP) multilayers (porosity 75%, pore size 316.8 ± 77.1 μm, VEGF dose 3.39 ng/mm3) were fabricated to enhance vascularization by inducing the differentiation of mesenchymal stem cells (MSCs) to endothelial cells. The in vitro immunofluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting results demonstrated that the expression of the endothelial differentiation markers CD31, Flk-1, and von Willebrand factor (vWF) was significantly increased in the HA/(COL/HEP)5/VEGF/MSCs group compared with the HA/VEGF/MSCs group. Moreover, the HA/(COL/HEP)5 scaffolds showed a better entrapment of the MSCs and accelerated cell proliferation. The in vivo assays showed that the number of newly formed vessels within the constructs after 28 d was significantly higher in the HA/(COL/HEP)5/VEGF/MSCs group (51.9 ± 6.3/mm2) than in the HA (26.7 ± 2.3/mm2) and HA/VEGF/MSCs (38.2 ± 2.4/mm2) groups. The qRT-PCR and western blotting results demonstrated that the HA/(COL/HEP)5/VEGF/MSCs group also had the highest expression of CD31, Flk-1, and vWF at both the mRNA and protein levels. PMID:26794266

  20. Palmitic acid increases pro-oxidant adaptor protein p66Shc expression and affects vascularization factors in angiogenic mononuclear cells: Action of resveratrol.

    PubMed

    Favre, Julie; Yildirim, Cansu; Leyen, Thomas A; Chen, Weena J Y; van Genugten, Renate E; van Golen, Larissa W; Garcia-Vallejo, Juan-Jesus; Musters, Rene; Baggen, Josefien; Fontijn, Ruud; van der Pouw Kraan, Tineke; Serné, Erik; Koolwijk, Pieter; Diamant, Michaela; Horrevoets, Anton J G

    2015-12-01

    A defect in neo-vascularization process involving circulating angiogenic mononuclear cells (CACs) dysfunction is associated with diabetes. We showed that oxidative stress was elevated in CACs cultured from blood of individuals with metabolic syndrome (MetS) and diabetes. We then assessed the action of palmitic acid (PA), a deregulated and increased NEFA in metabolic disorders, focusing on its oxidant potential. We observed that the phyto-polyphenol resveratrol normalized oxidative stress both in CACs isolated from MetS patients or treated with PA. Resveratrol further decreased the deleterious action of PA on gene expression of vascularization factors (TNFα, VEGF-A, SDF1α, PECAM-1, VEGFR2, Tie2 and CXCR4) and improved CAC motility. Particularly, resveratrol abolished the PA-induced over-expression of the pro-oxidant protein p66Shc. Neither KLF2 nor SIRT1, previously shown in resveratrol and p66Shc action, was directly involved. Silencing p66Shc normalized PA action on VEGF-A and TNFα specifically, without abolishing the PA-induced oxidative stress, which suggests a deleterious role of p66Shc independently of any major modulation of the cellular oxidative status in a high NEFA levels context. Besides showing that resveratrol reverses PA-induced harmful effects on human CAC function, certainly through profound cellular modifications, we establish p66Shc as a major therapeutic target in metabolic disorders, independent from glycemic control. PMID:26254104

  1. SUMO1 Affects Synaptic Function, Spine Density and Memory

    PubMed Central

    Matsuzaki, Shinsuke; Lee, Linda; Knock, Erin; Srikumar, Tharan; Sakurai, Mikako; Hazrati, Lili-Naz; Katayama, Taiichi; Staniszewski, Agnieszka; Raught, Brian; Arancio, Ottavio; Fraser, Paul E.

    2015-01-01

    Small ubiquitin-like modifier-1 (SUMO1) plays a number of roles in cellular events and recent evidence has given momentum for its contributions to neuronal development and function. Here, we have generated a SUMO1 transgenic mouse model with exclusive overexpression in neurons in an effort to identify in vivo conjugation targets and the functional consequences of their SUMOylation. A high-expressing line was examined which displayed elevated levels of mono-SUMO1 and increased high molecular weight conjugates in all brain regions. Immunoprecipitation of SUMOylated proteins from total brain extract and proteomic analysis revealed ~95 candidate proteins from a variety of functional classes, including a number of synaptic and cytoskeletal proteins. SUMO1 modification of synaptotagmin-1 was found to be elevated as compared to non-transgenic mice. This observation was associated with an age-dependent reduction in basal synaptic transmission and impaired presynaptic function as shown by altered paired pulse facilitation, as well as a decrease in spine density. The changes in neuronal function and morphology were also associated with a specific impairment in learning and memory while other behavioral features remained unchanged. These findings point to a significant contribution of SUMO1 modification on neuronal function which may have implications for mechanisms involved in mental retardation and neurodegeneration. PMID:26022678

  2. Mammalian cadherins DCHS1-FAT4 affect functional cerebral architecture.

    PubMed

    Beste, Christian; Ocklenburg, Sebastian; von der Hagen, Maja; Di Donato, Nataliya

    2016-06-01

    Cortical development is a complex process where a multitude of factors, including cadherins, plays an important role and where disruptions are known to have far reaching effects in neural development and cortical patterning. Cadherins play a central role in structural left-right differentiation during brain and body development, but their effect on a functional level remains elusive. We addressed this question by examining functional cerebral asymmetries in a patient with Van Maldergem Syndrome (VMS) (MIM#601390), which is caused by mutations in DCHS1-FAT4 cadherins, using a dichotic listening task. Using neurophysiological (EEG) data, we show that when key regulators during mammalian cerebral cortical development are disrupted due to DCHS1-FAT4 mutations, functional cerebral asymmetries are stronger. Basic perceptual processing of biaurally presented auditory stimuli was unaffected. This suggests that the strength and emergence of functional cerebral asymmetries is a direct function of proliferation and differentiation of neuronal stem cells. Moreover, these results support the recent assumption that the molecular mechanisms establishing early left-right differentiation are an important factor in the ontogenesis of functional lateralization. PMID:25930014

  3. SUMO1 Affects Synaptic Function, Spine Density and Memory.

    PubMed

    Matsuzaki, Shinsuke; Lee, Linda; Knock, Erin; Srikumar, Tharan; Sakurai, Mikako; Hazrati, Lili-Naz; Katayama, Taiichi; Staniszewski, Agnieszka; Raught, Brian; Arancio, Ottavio; Fraser, Paul E

    2015-01-01

    Small ubiquitin-like modifier-1 (SUMO1) plays a number of roles in cellular events and recent evidence has given momentum for its contributions to neuronal development and function. Here, we have generated a SUMO1 transgenic mouse model with exclusive overexpression in neurons in an effort to identify in vivo conjugation targets and the functional consequences of their SUMOylation. A high-expressing line was examined which displayed elevated levels of mono-SUMO1 and increased high molecular weight conjugates in all brain regions. Immunoprecipitation of SUMOylated proteins from total brain extract and proteomic analysis revealed ~95 candidate proteins from a variety of functional classes, including a number of synaptic and cytoskeletal proteins. SUMO1 modification of synaptotagmin-1 was found to be elevated as compared to non-transgenic mice. This observation was associated with an age-dependent reduction in basal synaptic transmission and impaired presynaptic function as shown by altered paired pulse facilitation, as well as a decrease in spine density. The changes in neuronal function and morphology were also associated with a specific impairment in learning and memory while other behavioral features remained unchanged. These findings point to a significant contribution of SUMO1 modification on neuronal function which may have implications for mechanisms involved in mental retardation and neurodegeneration. PMID:26022678

  4. Temperament Affects Sympathetic Nervous Function in a Normal Population

    PubMed Central

    Kim, Bora; Lee, Jae-Hon; Kang, Eun-Ho

    2012-01-01

    Objective Although specific temperaments have been known to be related to autonomic nervous function in some psychiatric disorders, there are few studies that have examined the relationship between temperaments and autonomic nervous function in a normal population. In this study, we examined the effect of temperament on the sympathetic nervous function in a normal population. Methods Sixty eight healthy subjects participated in the present study. Temperament was assessed using the Korean version of the Cloninger Temperament and Character Inventory (TCI). Autonomic nervous function was determined by measuring skin temperature in a resting state, which was recorded for 5 minutes from the palmar surface of the left 5th digit using a thermistor secured with a Velcro® band. Pearson's correlation analysis and multiple linear regression were used to examine the relationship between temperament and skin temperature. Results A higher harm avoidance score was correlated with a lower skin temperature (i.e. an increased sympathetic tone; r=-0.343, p=0.004) whereas a higher persistence score was correlated with a higher skin temperature (r=0.433, p=0.001). Hierarchical linear regression analysis revealed that harm avoidance was able to predict the variance of skin temperature independently, with a variance of 7.1% after controlling for sex, blood pressure and state anxiety and persistence was the factor predicting the variance of skin temperature with a variance of 5.0%. Conclusion These results suggest that high harm avoidance is related to an increased sympathetic nervous function whereas high persistence is related to decreased sympathetic nervous function in a normal population. PMID:22993530

  5. Fetal urinoma and prenatal hydronephrosis: how is renal function affected?

    PubMed Central

    Oktar, Tayfun; Salabaş, Emre; Kalelioğlu, İbrahim; Atar, Arda; Ander, Haluk; Ziylan, Orhan; Has, Recep; Yüksel, Atıl

    2013-01-01

    Objective: In our study, the functional prognosis of kidneys with prenatal urinomas were investigated. Material and methods: Between 2006 and 2010, fetal urinomas were detected in 19 fetuses using prenatal ultrasonography (US), and the medical records were reviewed retrospectively. Of the 19 cases, the follow-up data were available for 10 fetuses. The gestational age at diagnosis, prognosis of urinomas, clinical course and renal functions were recorded. Postnatal renal functions were assessed with renal scintigraphy. Results: Unilateral urinomas and increased parenchyma echogenicity in the ipsilateral kidney were detected in all of the fetuses. Of the 10 fetuses with follow-up data, the option of termination was offered in 6 cases of anhydramnios, including 3 cases with signs of infravesical obstruction (a possible posterior urethral valve (PUV) and poor prognostic factors and 3 cases with unilateral hydronephrosis and increased echogenicity in the contralateral kidney. Only one family agreed the termination. The other 5 fetuses died during the early postnatal period. The average postnatal follow-up period in the 4 surviving fetuses was 22.5 months (8–38 months). One patient with a PUV underwent ablation surgery during the early postnatal period. In the postnatal period, none of the 4 kidneys that were ipsilateral to the urinoma were functional on scintigraphic evaluation. The urinomas disappeared in 3 cases. Nephrectomy was performed in one case due to recurrent urinary tract infections. Conclusion: In our study, no function was detected in the ipsilateral kidney of surviving patients with urinomas. Upper urinary tract dilatation accompanied by a urinoma is a poor prognostic factor for renal function. PMID:26328088

  6. The Effects of Tumstatin on Vascularity, Airway Inflammation and Lung Function in an Experimental Sheep Model of Chronic Asthma.

    PubMed

    Van der Velden, Joanne; Harkness, Louise M; Barker, Donna M; Barcham, Garry J; Ugalde, Cathryn L; Koumoundouros, Emmanuel; Bao, Heidi; Organ, Louise A; Tokanovic, Ana; Burgess, Janette K; Snibson, Kenneth J

    2016-01-01

    Tumstatin, a protein fragment of the alpha-3 chain of Collagen IV, is known to be significantly reduced in the airways of asthmatics. Further, there is evidence that suggests a link between the relatively low level of tumstatin and the induction of angiogenesis and inflammation in allergic airway disease. Here, we show that the intra-segmental administration of tumstatin can impede the development of vascular remodelling and allergic inflammatory responses that are induced in a segmental challenge model of experimental asthma in sheep. In particular, the administration of tumstatin to lung segments chronically exposed to house dust mite (HDM) resulted in a significant reduction of airway small blood vessels in the diameter range 10(+)-20 μm compared to controls. In tumstatin treated lung segments after HDM challenge, the number of eosinophils was significantly reduced in parenchymal and airway wall tissues, as well as in the bronchoalveolar lavage fluid. The expression of VEGF in airway smooth muscle was also significantly reduced in tumstatin-treated segments compared to control saline-treated segments. Allergic lung function responses were not attenuated by tumstatin administration in this model. The data are consistent with the concept that tumstatin can act to suppress vascular remodelling and inflammation in allergic airway disease. PMID:27199164

  7. The Effects of Tumstatin on Vascularity, Airway Inflammation and Lung Function in an Experimental Sheep Model of Chronic Asthma

    PubMed Central

    Van der Velden, Joanne; Harkness, Louise M.; Barker, Donna M.; Barcham, Garry J.; Ugalde, Cathryn L.; Koumoundouros, Emmanuel; Bao, Heidi; Organ, Louise A.; Tokanovic, Ana; Burgess, Janette K.; Snibson, Kenneth J.

    2016-01-01

    Tumstatin, a protein fragment of the alpha-3 chain of Collagen IV, is known to be significantly reduced in the airways of asthmatics. Further, there is evidence that suggests a link between the relatively low level of tumstatin and the induction of angiogenesis and inflammation in allergic airway disease. Here, we show that the intra-segmental administration of tumstatin can impede the development of vascular remodelling and allergic inflammatory responses that are induced in a segmental challenge model of experimental asthma in sheep. In particular, the administration of tumstatin to lung segments chronically exposed to house dust mite (HDM) resulted in a significant reduction of airway small blood vessels in the diameter range 10+–20 μm compared to controls. In tumstatin treated lung segments after HDM challenge, the number of eosinophils was significantly reduced in parenchymal and airway wall tissues, as well as in the bronchoalveolar lavage fluid. The expression of VEGF in airway smooth muscle was also significantly reduced in tumstatin-treated segments compared to control saline-treated segments. Allergic lung function responses were not attenuated by tumstatin administration in this model. The data are consistent with the concept that tumstatin can act to suppress vascular remodelling and inflammation in allergic airway disease. PMID:27199164

  8. Vascularized Thoracodorsal to Suprascapular Nerve Transfer, a Novel Technique to Restore Shoulder Function in Partial Brachial Plexopathy

    PubMed Central

    Potter, Shirley M.; Ferris, Scott I.

    2016-01-01

    We describe the clinical outcome of a novel nerve transfer to restore active shoulder motion in upper brachial plexus injury. The thoracodorsal nerve (TDN) was successfully used as a vascularized donor nerve to neurotize to the suprascapular nerve (SSN) in a patient with limited donor nerve availability. At 4 years follow-up, he had regained useful external rotation of the injured limb, with no significant donor site morbidity. Shoulder abduction return was less impressive, however, and reasons for this are discussed. We provide a comprehensive review of the literature on this topic and a subsequent discussion on the details of this novel technique. This is the first reported case of TDN to SSN transfer, and also the first reported case of a vascularized TDN transfer in the English language literature. We advocate direct thoracodorsal to SSN transfer as a valid surgical option for the restoration of shoulder function in patients with partial brachial plexus avulsion, when conventional nerve donors are unavailable. PMID:27014699

  9. Can Particulate Pollution Affect Lung Function in Healthy Adults?

    EPA Science Inventory

    Accompanying editorial to paper from Harvard by Rice et al. entitled "Long-Term Exposure to Traffic Emissions and Fine Particulate Matter and Lung Function Decline in the Framingham Heart StudyBy almost any measure the Clean Air Act and its amendments has to be considered as one...

  10. Drying process strongly affects probiotics viability and functionalities.

    PubMed

    Iaconelli, Cyril; Lemetais, Guillaume; Kechaou, Noura; Chain, Florian; Bermúdez-Humarán, Luis G; Langella, Philippe; Gervais, Patrick; Beney, Laurent

    2015-11-20

    Probiotic formulations are widely used and are proposed to have a variety of beneficial effects, depending on the probiotic strains present in the product. The impact of drying processes on the viability of probiotics is well documented. However, the impact of these processes on probiotics functionality remains unclear. In this work, we investigated variations in seven different bacterial markers after various desiccation processes. Markers were composed of four different viability evaluation (combining two growth abilities and two cytometric measurements) and in three in vitro functionalities: stimulation of IL-10 and IL-12 production by PBMCs (immunomodulation) and bacterial adhesion to hexadecane. We measured the impact of three drying processes (air-drying, freeze-drying and spray-drying), without the use of protective agents, on three types of probiotic bacteria: Bifidobacterium bifidum, Lactobacillus plantarum and Lactobacillus zeae. Our results show that the bacteria respond differently to the three different drying processes, in terms of viability and functionality. Drying methods produce important variations in bacterial immunomodulation and hydrophobicity, which are correlated. We also show that adherence can be stimulated (air-drying) or inhibited (spray-drying) by drying processes. Results of a multivariate analysis show no direct correlation between bacterial survival and functionality, but do show a correlation between probiotic responses to desiccation-rewetting and the process used to dry the bacteria. PMID:26325197

  11. Chemical Modifications that Affect Nutritional and Functional Properties of Proteins.

    ERIC Educational Resources Information Center

    Richardson, T.; Kester, J. J.

    1984-01-01

    Discusses chemical alterations of selected amino acids resulting from environmental effects (photooxidations, pH extremes, thermally induced effects). Also dicusses use of intentional chemical derivatizations of various functional groups in amino acid residue side chains and how recombinant DNA techniques might be useful in structure/function…

  12. Dietary nitrate improves vascular function in patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled study123

    PubMed Central

    Velmurugan, Shanti; Gan, Jasmine Ming; Rathod, Krishnaraj S; Khambata, Rayomand S; Ghosh, Suborno M; Hartley, Amy; Van Eijl, Sven; Sagi-Kiss, Virag; Chowdhury, Tahseen A; Curtis, Mike; Kuhnle, Gunter GC; Wade, William G; Ahluwalia, Amrita

    2016-01-01

    Background: The beneficial cardiovascular effects of vegetables may be underpinned by their high inorganic nitrate content. Objective: We sought to examine the effects of a 6-wk once-daily intake of dietary nitrate (nitrate-rich beetroot juice) compared with placebo intake (nitrate-depleted beetroot juice) on vascular and platelet function in untreated hypercholesterolemics. Design: A total of 69 subjects were recruited in this randomized, double-blind, placebo-controlled parallel study. The primary endpoint was the change in vascular function determined with the use of ultrasound flow-mediated dilatation (FMD). Results: Baseline characteristics were similar between the groups, with primary outcome data available for 67 patients. Dietary nitrate resulted in an absolute increase in the FMD response of 1.1% (an ∼24% improvement from baseline) with a worsening of 0.3% in the placebo group (P < 0.001). A small improvement in the aortic pulse wave velocity (i.e., a decrease of 0.22 m/s; 95% CI: −0.4, −0.3 m/s) was evident in the nitrate group, showing a trend (P = 0.06) to improvement in comparison with the placebo group. Dietary nitrate also caused a small but significant reduction (7.6%) in platelet-monocyte aggregates compared with an increase of 10.1% in the placebo group (P = 0.004), with statistically significant reductions in stimulated (ex vivo) P-selectin expression compared with the placebo group (P < 0.05) but no significant changes in unstimulated expression. No adverse effects of dietary nitrate were detected. The composition of the salivary microbiome was altered after the nitrate treatment but not after the placebo treatment (P < 0.01). The proportions of 78 bacterial taxa were different after the nitrate treatment; of those taxa present, 2 taxa were responsible for >1% of this change, with the proportions of Rothia mucilaginosa trending to increase and Neisseria flavescens (P < 0.01) increased after nitrate treatment relative to after placebo

  13. 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

  14. Structure and vascular function of MEKK3–cerebral cavernous malformations 2 complex

    SciTech Connect

    Fisher, Oriana S.; Deng, Hanqiang; Liu, Dou; Zhang, Ya; Wei, Rong; Deng, Yong; Zhang, Fan; Louvi, Angeliki; Turk, Benjamin E.; Boggon, Titus J.; Su, Bing

    2015-08-03

    Cerebral cavernous malformations 2 (CCM2) loss is associated with the familial form of CCM disease. The protein kinase MEKK3 (MAP3K3) is essential for embryonic angiogenesis in mice and interacts physically with CCM2, but how this interaction is mediated and its relevance to cerebral vasculature are unknown. Here we report that Mekk3 plays an intrinsic role in embryonic vascular development. Inducible endothelial Mekk3 knockout in neonatal mice is lethal due to multiple intracranial haemorrhages and brain blood vessels leakage. We discover direct interaction between CCM2 harmonin homology domain (HHD) and the N terminus of MEKK3, and determine a 2.35 Å cocrystal structure. We find Mekk3 deficiency impairs neurovascular integrity, which is partially dependent on Rho–ROCK signalling, and that disruption of MEKK3:CCM2 interaction leads to similar neurovascular leakage. We conclude that CCM2:MEKK3-mediated regulation of Rho signalling is required for maintenance of neurovascular integrity, unravelling a mechanism by which CCM2 loss leads to disease.

  15. 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

  16. Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex.

    PubMed

    Fisher, Oriana S; Deng, Hanqiang; Liu, Dou; Zhang, Ya; Wei, Rong; Deng, Yong; Zhang, Fan; Louvi, Angeliki; Turk, Benjamin E; Boggon, Titus J; Su, Bing

    2015-01-01

    Cerebral cavernous malformations 2 (CCM2) loss is associated with the familial form of CCM disease. The protein kinase MEKK3 (MAP3K3) is essential for embryonic angiogenesis in mice and interacts physically with CCM2, but how this interaction is mediated and its relevance to cerebral vasculature are unknown. Here we report that Mekk3 plays an intrinsic role in embryonic vascular development. Inducible endothelial Mekk3 knockout in neonatal mice is lethal due to multiple intracranial haemorrhages and brain blood vessels leakage. We discover direct interaction between CCM2 harmonin homology domain (HHD) and the N terminus of MEKK3, and determine a 2.35 Å cocrystal structure. We find Mekk3 deficiency impairs neurovascular integrity, which is partially dependent on Rho-ROCK signalling, and that disruption of MEKK3:CCM2 interaction leads to similar neurovascular leakage. We conclude that CCM2:MEKK3-mediated regulation of Rho signalling is required for maintenance of neurovascular integrity, unravelling a mechanism by which CCM2 loss leads to disease. PMID:26235885

  17. Structure and vascular function of MEKK3–cerebral cavernous malformations 2 complex

    PubMed Central

    Fisher, Oriana S.; Deng, Hanqiang; Liu, Dou; Zhang, Ya; Wei, Rong; Deng, Yong; Zhang, Fan; Louvi, Angeliki; Turk, Benjamin E.; Boggon, Titus J.; Su, Bing

    2015-01-01

    Cerebral cavernous malformations 2 (CCM2) loss is associated with the familial form of CCM disease. The protein kinase MEKK3 (MAP3K3) is essential for embryonic angiogenesis in mice and interacts physically with CCM2, but how this interaction is mediated and its relevance to cerebral vasculature are unknown. Here we report that Mekk3 plays an intrinsic role in embryonic vascular development. Inducible endothelial Mekk3 knockout in neonatal mice is lethal due to multiple intracranial haemorrhages and brain blood vessels leakage. We discover direct interaction between CCM2 harmonin homology domain (HHD) and the N terminus of MEKK3, and determine a 2.35 Å cocrystal structure. We find Mekk3 deficiency impairs neurovascular integrity, which is partially dependent on Rho–ROCK signalling, and that disruption of MEKK3:CCM2 interaction leads to similar neurovascular leakage. We conclude that CCM2:MEKK3-mediated regulation of Rho signalling is required for maintenance of neurovascular integrity, unravelling a mechanism by which CCM2 loss leads to disease. PMID:26235885

  18. SLE-associated risk factors affect DC function

    PubMed Central

    Son, Myoungsun; Kim, Sun Jung; Diamond, Betty

    2016-01-01

    Numerous risk alleles for systemic lupus erythematosus (SLE) have now been identified. Analysis of the expression of genes with risk alleles in cells of hematopoietic origin demonstrates them to be most abundantly expressed in B cells and dendritic cells (DCs), suggesting that these cell types may be the drivers of the inflammatory changes seen in SLE. DCs are of particular interest as they act to connect the innate and the adaptive immune response. Thus, DCs can transform inflammation into autoimmunity, and autoantibodies are the hallmark of SLE. In this review, we focus on mechanisms of tolerance that maintain DCs in a non-activated, non-immunogenic state. We demonstrate, using examples from our own studies, how alterations in DC function stemming from either DC-intrinsic abnormalities or DC-extrinsic regulators of function can predispose to autoimmunity. PMID:26683148

  19. RIGHT HEMISPHERIC FUNCTION IN NORMALS, AFFECTIVE DISORDER AND SCHIZOPHRENIA

    PubMed Central

    Borde, Milind; Roy, Amal; Davis, Elizabeth J.B.; Davis, Rachel

    1996-01-01

    The happy-sad chimeric faces test has been established as a useful test of right hemispheric function. It is known to elicit a left hemifacial bias (LHF bias) in right handed subjects. 41 normals and 19 manic, depressive and schizophrenic patients each were tested. All subjects were strictly right handed. Normals and depressives showed significant LHF bias. Monies and schizophrenics did not show significant LHF Bias. This suggests right hemispheric dysfunction in both mania and schizophrenia. PMID:21584135

  20. Nuclear cyclophilins affect spliceosome assembly and function in vitro

    PubMed Central

    Adams, B.M.; Coates, Miranda N.; Jackson, S. RaElle; Jurica, Melissa S.; Davis, Tara L.

    2015-01-01

    Cyclophilins are ubiquitously expressed proteins that bind to prolines and can catalyse cis/trans isomerization of proline residues. There are 17 annotated members of the cyclophilin family in humans, ubiquitously expressed and localized variously to the cytoplasm, nucleus or mitochondria. Surprisingly, all eight of the nuclear localized cyclophilins are found associated with spliceosomal complexes. However, their particular functions within this context are unknown. We have therefore adapted three established assays for in vitro pre-mRNA splicing to probe the functional roles of nuclear cyclophilins in the context of the human spliceosome. We find that four of the eight spliceosom-associated cyclophilins exert strong effects on splicing in vitro. These effects are dose-dependent and, remarkably, uniquely characteristic of each cyclophilin. Using both qualitative and quantitative means, we show that at least half of the nuclear cyclophilins can act as regulatory factors of spliceosome function in vitro. The present work provides the first quantifiable evidence that nuclear cyclophilins are splicing factors and provides a novel approach for future work into small molecule-based modulation of pre-mRNA splicing. PMID:25967372

  1. Prenatal Drug Exposure Affects Neonatal Brain Functional Connectivity

    PubMed Central

    Salzwedel, Andrew P.; Vachet, Clement; Gerig, Guido; Lin, Weili

    2015-01-01

    Prenatal drug exposure, particularly prenatal cocaine exposure (PCE), incurs great public and scientific interest because of its associated neurodevelopmental consequences. However, the neural underpinnings of PCE remain essentially uncharted, and existing studies in school-aged children and adolescents are confounded greatly by postnatal environmental factors. In this study, leveraging a large neonate sample (N = 152) and non-invasive resting-state functional magnetic resonance imaging, we compared human infants with PCE comorbid with other drugs (such as nicotine, alcohol, marijuana, and antidepressant) with infants with similar non-cocaine poly drug exposure and drug-free controls. We aimed to characterize the neural correlates of PCE based on functional connectivity measurements of the amygdala and insula at the earliest stage of development. Our results revealed common drug exposure-related connectivity disruptions within the amygdala–frontal, insula–frontal, and insula–sensorimotor circuits. Moreover, a cocaine-specific effect was detected within a subregion of the amygdala–frontal network. This pathway is thought to play an important role in arousal regulation, which has been shown to be irregular in PCE infants and adolescents. These novel results provide the earliest human-based functional delineations of the neural-developmental consequences of prenatal drug exposure and thus open a new window for the advancement of effective strategies aimed at early risk identification and intervention. PMID:25855194

  2. Prenatal drug exposure affects neonatal brain functional connectivity.

    PubMed

    Salzwedel, Andrew P; Grewen, Karen M; Vachet, Clement; Gerig, Guido; Lin, Weili; Gao, Wei

    2015-04-01

    Prenatal drug exposure, particularly prenatal cocaine exposure (PCE), incurs great public and scientific interest because of its associated neurodevelopmental consequences. However, the neural underpinnings of PCE remain essentially uncharted, and existing studies in school-aged children and adolescents are confounded greatly by postnatal environmental factors. In this study, leveraging a large neonate sample (N = 152) and non-invasive resting-state functional magnetic resonance imaging, we compared human infants with PCE comorbid with other drugs (such as nicotine, alcohol, marijuana, and antidepressant) with infants with similar non-cocaine poly drug exposure and drug-free controls. We aimed to characterize the neural correlates of PCE based on functional connectivity measurements of the amygdala and insula at the earliest stage of development. Our results revealed common drug exposure-related connectivity disruptions within the amygdala-frontal, insula-frontal, and insula-sensorimotor circuits. Moreover, a cocaine-specific effect was detected within a subregion of the amygdala-frontal network. This pathway is thought to play an important role in arousal regulation, which has been shown to be irregular in PCE infants and adolescents. These novel results provide the earliest human-based functional delineations of the neural-developmental consequences of prenatal drug exposure and thus open a new window for the advancement of effective strategies aimed at early risk identification and intervention. PMID:25855194

  3. The effect of negative affect on cognition: Anxiety, not anger, impairs executive function.

    PubMed

    Shields, Grant S; Moons, Wesley G; Tewell, Carl A; Yonelinas, Andrew P

    2016-09-01

    It is often assumed that negative affect impairs the executive functions that underlie our ability to control and focus our thoughts. However, support for this claim has been mixed. Recent work has suggested that different negative affective states like anxiety and anger may reflect physiologically separable states with distinct effects on cognition. However, the effects of these 2 affective states on executive function have never been assessed. As such, we induced anxiety or anger in participants and examined the effects on executive function. We found that anger did not impair executive function relative to a neutral mood, whereas anxiety did. In addition, self-reports of induced anxiety, but not anger, predicted impairments in executive function. These results support functional models of affect and cognition, and highlight the need to consider differences between anxiety and anger when investigating the influence of negative affect on fundamental cognitive processes such as memory and executive function. (PsycINFO Database Record PMID:27100367

  4. Proepileptic Influence of a Focal Vascular Lesion Affecting Entorhinal Cortex-CA3 Connections After Status Epilepticus

    PubMed Central

    Biagini, Giuseppe; Baldelli, Enrica; Longo, Daniela; Contri, Miranda Baccarani; Guerrini, Uliano; Sironi, Luigi; Gelosa, Paolo; Zini, Isabella; Ragsdale, David S.; Avoli, Massimo

    2016-01-01

    In limbic seizures, neuronal excitation is conveyed from the entorhinal cortex directly to CA1 and subicular regions. This phenomenon is associated with a reduced ability of CA3 to respond to entorhinal cortex inputs. Here, we describe a lesion that destroys the perforant path in CA3 after status epilepticus (SE) induced by pilocarpine injection in 8-week-old rats. Using magnetic resonance imaging, immunohistochemical, and ultrastructural analyses, we determined that this lesion develops after 30 minutes of SE and is characterized by microhemorrhages and ischemia. After a longer period of SE, the lesion invariably involves the upper blade of the dentate gyrus. Adult rats treated with subcutaneous diazepam (20 mg kg−1 for 3 days) did not develop the dentate gyrus lesion and had less frequent spontaneous recurrent seizures (p < 0.01). Young (3-week-old) rats rarely (20%) developed the CA3 lesion, and their spontaneous seizures were delayed (p < 0.01). To investigate the role of the damaged CA3 in seizure activity, we reinduced SE in adult and young epileptic rats. Using FosB/ΔFosB markers, we found induction of FosB/ΔFosB immunopositivity in CA3 neurons of young but not in adult rats. These experiments indicate that SE can produce a focal lesion in the perforant path that may affect the roles of the hippocampus in epileptic rats. PMID:18596544

  5. Yersinia enterocolitica Affects Intestinal Barrier Function in the Colon.

    PubMed

    Hering, Nina A; Fromm, Anja; Kikhney, Judith; Lee, In-Fah M; Moter, Annette; Schulzke, Jörg D; Bücker, Roland

    2016-04-01

    Infection with Yersinia enterocolitica causes acute diarrhea in early childhood. A mouse infection model presents new findings on pathological mechanisms in the colon. Symptoms involve diarrhea with watery feces and weight loss that have their functional correlates in decreased transepithelial electrical resistance and increased fluorescein permeability. Y. enterocolitica was present within the murine mucosa of both ileum and colon. Here, the bacterial insult was of focal nature and led to changes in tight junction protein expression and architecture. These findings are in concordance with observations from former cell culture studies and suggest a leak flux mechanism of diarrhea. PMID:26621910

  6. Myocardial performance index is sensitive to changes in cardiac contractility, but is also affected by vascular load condition.

    PubMed

    Uemura, Kazunori; Kawada, Toru; Zheng, Can; Li, Meihua; Shishido, Toshiaki; Sugimachi, Masaru

    2013-01-01

    Myocardial performance index (MPI), or Tei index, is measured by Doppler echocardiography in clinical practice. MPI has been shown to be useful in evaluating left ventricular (LV) performance and predicting prognosis in cardiac patients. However, the effects of LV load and contractile states on MPI remain to be thoroughly investigated. In 14 anesthetized dogs, we obtained LV pressure-volume relationship with use of sonomicrometry and catheter-tip manometry. MPI was determined from the time derivative of LV volume and pressure. LV end-systolic pressure-volume ratio (Ees'), effective arterial elastance (Ea) and LV end-diastolic volume (Ved) were used as indices of LV contractility, afterload and preload, respectively. Hemodynamic conditions were varied over wide ranges [heart rate (HR), 66-192 bpm; mean arterial pressure, 71-177 mmHg] by infusing cardiovascular agents, by inducing ischemic heart failure and by electrical atrial pacing. Multiple linear regression analysis of pooled data (66 data sets) indicated that MPI (0.6-1.8) significantly correlated with Ees' [1.5-17.5 mmHg · ml(-1), p<0.0001, standard partial regression coefficient (β) =-0.66], Ea (3.6-21.9 mmHg · ml(-1), p<0.001, β = 0.4) and Ved (11-100 ml, p<0.0001, β = -0.69). MPI directly correlated with the time constant of isovolumic relaxation (19-66 ms, p<0.05), but not with HR or LV diastolic-stiffness (all p>0.1). Theoretical analysis also indicated that MPI decreases following the increases in LV contractility and in preload, while it increases in response to an increase in LV afterload. We conclude that MPI sensitively detects changes in LV contractility. However, MPI is also affected by changes in LV afterload and preload. PMID:24109782

  7. Affected functional networks associated with sentence production in classic galactosemia.

    PubMed

    Timmers, Inge; van den Hurk, Job; Hofman, Paul Am; Zimmermann, Luc Ji; Uludağ, Kâmil; Jansma, Bernadette M; Rubio-Gozalbo, M Estela

    2015-08-01

    Patients with the inherited metabolic disorder classic galactosemia have language production impairments in several planning stages. Here, we assessed potential deviations in recruitment and connectivity across brain areas responsible for language production that may explain these deficits. We used functional magnetic resonance imaging (fMRI) to study neural activity and connectivity while participants carried out a language production task. This study included 13 adolescent patients and 13 age- and gender-matched healthy controls. Participants passively watched or actively described an animated visual scene using two conditions, varying in syntactic complexity (single words versus a sentence). Results showed that patients recruited additional and more extensive brain regions during sentence production. Both groups showed modulations with syntactic complexity in left inferior frontal gyrus (IFG), a region associated with syntactic planning, and in right insula. In addition, patients showed a modulation with syntax in left superior temporal gyrus (STG), whereas the controls did not. Further, patients showed increased activity in right STG and right supplementary motor area (SMA). The functional connectivity data showed similar patterns, with more extensive connectivity with frontal and motor regions, and restricted and weaker connectivity with superior temporal regions. Patients also showed higher baseline cerebral blood flow (CBF) in right IFG and trends towards higher CBF in bilateral STG, SMA and the insula. Taken together, the data demonstrate that language abnormalities in classic galactosemia are associated with specific changes within the language network. These changes point towards impairments related to both syntactic planning and speech motor planning in these patients. PMID:25979518

  8. Cardiac and Vascular Function in Bedrested Volunteers: Effects of Artificial Gravity Training

    NASA Technical Reports Server (NTRS)

    Meng, M.; Platts, S.; Stenger, M.; Diedrich, A.; Schlegel, T.; Natapoff, A.; Knapp, C.; Evans, J.

    2007-01-01

    Cardiovascular effects of an artificial gravity (AG) countermeasure on deconditioned male volunteers were studied. In two groups of men we measured cardiovascular parameters at rest and in response to 30 minutes of 80 deg. head up tilt (HUT) before, at the end of, and four days following 21 days of 6 deg. head down bed rest (HDBR). One group (N=7) underwent no countermeasure while the other (N=8) received a daily, one hour, dose (2.5 gz at the foot, decreasing to 1.0 gz at the heart) of AG training on the Johnson Space Center short radius centrifuge. Cardiovascular parameters measured included heart rate, blood pressure, stroke volume, cardiac output, peripheral vascular resistance, plasma volume shifts, and vasoactive hormones. Untrained subjects exhibited shorter tilt survival (on average 8 minutes shorter) compared to trained subjects. By the end of bed rest, mean heart rate (MHR) was elevated in both groups (both supine and during tilt). In addition, treated subjects demonstrated lower, tilt-induced, increases in MHR four days following HDBR, indicating a more rapid return to pre bed rest conditions. Results from an index of autonomic balance (percentage of MHR spectral power in the respiratory frequency range) in control of heart rate are consistent with the interpretation that parasympathetic nervous system withdrawal was responsible for both tilt- and bed rest-induced increases in MHR. Our data support our pre-study hypothesis that AG treatment would lessen cardiovascular effects of deconditioning in bed rested men and suggest that AG should be further pursued as a space flight countermeasure.

  9. Vasoconstrictor-induced endocytic recycling regulates focal adhesion protein localization and function in vascular smooth muscle

    PubMed Central

    Poythress, Ransom H.; Gallant, Cynthia; Vetterkind, Susanne

    2013-01-01

    Turnover of focal adhesions (FAs) is known to be critical for cell migration and adhesion of proliferative vascular smooth muscle (VSM) cells. However, it is often assumed that FAs in nonmigratory, differentiated VSM (dVSM) cells embedded in the wall of healthy blood vessels are stable structures. Recent work has demonstrated agonist-induced actin polymerization and Src-dependent FA phosphorylation in dVSM cells, suggesting that agonist-induced FA remodeling occurs. However, the mechanisms and extent of FA remodeling are largely unknown in dVSM. Here we show, for the first time, that a distinct subpopulation of dVSM FA proteins, but not the entire FA, remodels in response to the α-agonist phenylephrine. Vasodilator-stimulated phosphoprotein and zyxin displayed the largest redistributions, while β-integrin and FA kinase showed undetectable redistribution. Vinculin, metavinculin, Src, Crk-associated substrate, and paxillin displayed intermediate degrees of redistribution. Redistributions into membrane fractions were especially prominent, suggesting endosomal mechanisms. Deconvolution microscopy, quantitative colocalization analysis, and Duolink proximity ligation assays revealed that phenylephrine increases the association of FA proteins with early endosomal markers Rab5 and early endosomal antigen 1. Endosomal disruption with the small-molecule inhibitor primaquine inhibits agonist-induced redistribution of FA proteins, confirming endosomal recycling. FA recycling was also inhibited by cytochalasin D, latrunculin B, and colchicine, indicating that the redistribution is actin- and microtubule-dependent. Furthermore, inhibition of endosomal recycling causes a significant inhibition of the rate of development of agonist-induced dVSM contractions. Thus these studies are consistent with the concept that FAs in dVSM cells, embedded in the wall of the aorta, remodel during the action of a vasoconstrictor. PMID:23703522

  10. Gene Risk Factors for Age-Related Brain Disorders May Affect Immune System Function

    MedlinePlus

    ... for age-related brain disorders may affect immune system function June 17, 2014 Scientists have discovered gene ... factors for age-related neurological disorders to immune system functions, such as inflammation, offers new insights into ...

  11. Does Vitamin C Deficiency Affect Cognitive Development and Function?

    PubMed Central

    Hansen, Stine Normann; Tveden-Nyborg, Pernille; Lykkesfeldt, Jens

    2014-01-01

    Vitamin C is a pivotal antioxidant in the brain and has been reported to have numerous functions, including reactive oxygen species scavenging, neuromodulation, and involvement in angiogenesis. Absence of vitamin C in the brain has been shown to be detrimental to survival in newborn SVCT2(−/−) mice and perinatal deficiency have shown to reduce hippocampal volume and neuron number and cause decreased spatial cognition in guinea pigs, suggesting that maternal vitamin C deficiency could have severe consequences for the offspring. Furthermore, vitamin C deficiency has been proposed to play a role in age-related cognitive decline and in stroke risk and severity. The present review discusses the available literature on effects of vitamin C deficiency on the developing and aging brain with particular focus on in vivo experimentation and clinical studies. PMID:25244370

  12. Consumption of bee pollen affects rat ovarian functions.

    PubMed

    Kolesarova, A; Bakova, Z; Capcarova, M; Galik, B; Juracek, M; Simko, M; Toman, R; Sirotkin, A V

    2013-12-01

    The aim of this study was to examine possible effects of bee pollen added to the feed mixture (FM) on rat ovarian functions (secretion activity and apoptosis). We evaluated the bee pollen effect on the release of insulin-like growth factor I (IGF-I) and steroid hormones (progesterone and estradiol), as well as on the expression of markers of apoptosis (Bcl-2, Bax and caspase-3) in rat ovarian fragments. Female rats (n = 15) were fed during 90 days by FM without or with rape seed bee pollen in dose either 3 kg/1000 kg FM or 5 kg/1000 kg FM. Fragments of ovaries isolated from rats of each group (totally 72 pieces) were incubated for 24 h. Hormonal secretion into the culture medium was detected by RIA. The markers of apoptosis were evaluated by Western blotting. It was observed that IGF-I release by rat ovarian fragments was significantly (p < 0.05) decreased; on the other hand, progesterone and estradiol secretion was increased after bee pollen treatment at dose 5 kg/1000 kg FM but not at 3 kg/1000 FM. Accumulation of Bcl-2 was increased by bee pollen added at 3 kg/1000 kg FM, but not at higher dose. Accumulation of Bax was increased in ovaries of rats fed by bee pollen at doses either 3 or 5 kg/1000 kg FM, whilst accumulation of caspase-3 increased after feeding with bee pollen at dose 5 kg/1000 kg FM, but not at 3 kg/1000 kg FM. Our results contribute to new insights regarding the effect of bee pollen on both secretion activity (release of growth factor IGF-I and steroid hormones progesterone and estradiol) and apoptosis (anti- and pro-apoptotic markers Bcl-2, Bax and caspase-3). Bee pollen is shown to be a potent regulator of rat ovarian functions. PMID:23137268

  13. Early and late-onset effect of chronic stress on vascular function in mice: a possible model of the impact of depression on vascular disease in aging.

    PubMed

    Isingrini, Elsa; Belzung, Catherine; d'Audiffret, Alexandre; Camus, Vincent

    2011-04-01

    Depression is recognized as a predictor of increased cardiac morbidity and mortality. In addition, depressed patients exhibit an increase in the serum markers of endothelial dysfunction and platelet activation involved in the cascade of events leading to atherosclerosis. The purpose of this study was to determine the early and late-onset expression of various vascular markers in a rodent model of depression. Male DBA (an inbred strain of mice)/2J mice were exposed to either 7 weeks of controlled living conditions or unpredictable chronic mild stress (UCMS), and subsequently given daily fluoxetine (10 mg/kg) or NaCl (9%) during the last 5 weeks of the experiment. Depressive-like behavior was evaluated by using motivational and self-care behavior, including the assessment of the animal's coat state and grooming behavior. Enzyme-linked immunoassay was used to quantify matrix metalloproteinase-9 (MMP-9), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and plasminogen activator inhibitor-1 (PAI-1) expression either immediately after the end of the UCMS procedure (short term condition) or 10 months later (long-term condition). Results indicate that 1) UCMS procedure induces a short-term depressive-like behavior in mice, defined as coat state deterioration, an effect that is prevented by fluoxetine treatment; 2) UCMS procedure has no effect on the short-term expression of the studied markers; however, UCMS increases expression of plasminogen activator inhibitor-1 only in the long-term group; 3) fluoxetine treatment is unable to counteract this UCMS-induced change; 4) aging induces behavioral perturbation, defined as a decrease in grooming motivation, and an increase of all the vascular markers in both control and UCMS groups and 5) pretreatment with fluoxetine has no protective effects on aging-induced behavioral and vascular alterations. Thus, in this model of depression-like behavior, UCMS appears to induce late

  14. Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells.

    PubMed

    Ballweg, Korbinian; Mutze, Kathrin; Königshoff, Melanie; Eickelberg, Oliver; Meiners, Silke

    2014-12-01

    Cigarette smoke is the main risk factor for chronic obstructive pulmonary disease (COPD). Exposure of cells to cigarette smoke induces an initial adaptive cellular stress response involving increased oxidative stress and induction of inflammatory signaling pathways. Exposure of mitochondria to cellular stress alters their fusion/fission dynamics. Whereas mild stress induces a prosurvival response termed stress-induced mitochondrial hyperfusion, severe stress results in mitochondrial fragmentation and mitophagy. In the present study, we analyzed the mitochondrial response to mild and nontoxic doses of cigarette smoke extract (CSE) in alveolar epithelial cells. We characterized mitochondrial morphology, expression of mitochondrial fusion and fission genes, markers of mitochondrial proteostasis, as well as mitochondrial functions such as membrane potential and oxygen consumption. Murine lung epithelial (MLE)12 and primary mouse alveolar epithelial cells revealed pronounced mitochondrial hyperfusion upon treatment with CSE, accompanied by increased expression of the mitochondrial fusion protein mitofusin 2 and increased metabolic activity. We did not observe any alterations in mitochondrial proteostasis, i.e., induction of the mitochondrial unfolded protein response or mitophagy. Therefore, our data indicate an adaptive prosurvival response of mitochondria of alveolar epithelial cells to nontoxic concentrations of CSE. A hyperfused mitochondrial network, however, renders the cell more vulnerable to additional stress, such as sustained cigarette smoke exposure. As such, cigarette smoke-induced mitochondrial hyperfusion, although part of a beneficial adaptive stress response in the first place, may contribute to the pathogenesis of COPD. PMID:25326581

  15. Non-invasive imaging of flow and vascular function in disease of the aorta

    PubMed Central

    Whitlock, Matthew C.; Hundley, W. Gregory

    2015-01-01

    With advancements in technology and a better understanding of human cardiovascular physiology, research as well as clinical care can go beyond dimensional anatomy offered by traditional imaging and investigate aortic functional properties and the impact disease has on this function. Linking the knowledge of the histopathological changes with the alterations in aortic function observed on noninvasive imaging results in a better understanding of disease pathophysiology. Translating this to clinical medicine, these noninvasive imaging assessments of aortic function are proving to be able to diagnosis disease, better predict risk, and assess response to therapies. This review is designed to summarize the various hemodynamic measures that can characterize the aorta, the various non-invasive techniques, and applications for various disease states. PMID:26381770

  16. Neurology of Affective Prosody and Its Functional-Anatomic Organization in Right Hemisphere

    ERIC Educational Resources Information Center

    Ross, Elliott D.; Monnot, Marilee

    2008-01-01

    Unlike the aphasic syndromes, the organization of affective prosody in brain has remained controversial because affective-prosodic deficits may occur after left or right brain damage. However, different patterns of deficits are observed following left and right brain damage that suggest affective prosody is a dominant and lateralized function of…

  17. Impact of Aspirin and Clopidogrel Interruption on Platelet Function in Patients Undergoing Major Vascular Surgery

    PubMed Central

    Le Manach, Yannick; Kahn, David; Bachelot-Loza, Christilla; Le Sache, Frederic; Smadja, David M.; Remones, Veronique; Loriot, Marie-Anne; Coriat, Pierre; Gaussem, Pascale

    2014-01-01

    Aims To investigate functional platelet recovery after preoperative withdrawal of aspirin and clopidogrel and platelet function 5 days after treatment resumption. Methods/Results We conducted an observational study, which prospectively included consecutive patients taking aspirin, taking clopidogrel, and untreated controls (15 patients in each group). The antiplatelet drugs were withdrawn five days before surgery (baseline) and were reintroduced two days after surgery. Platelet function was evaluated by optical aggregation in the presence of collagen, arachidonic acid (aspirin) and ADP (clopidogrel) and by VASP assay (clopidogrel). Platelet-leukocyte complex (PLC) level was quantified at each time-point. At baseline, platelet function was efficiently inhibited by aspirin and had recovered fully in most patients 5 days after drug withdrawal. PLC levels five days after aspirin reintroduction were similar to baseline (+4±10%; p = 0.16), in line with an effective platelet inhibition. Chronic clopidogrel treatment was associated with variable platelet inhibition and its withdrawal led to variable functional recovery. PLC levels were significantly increased five days after clopidogrel reintroduction (+10±15%; p = 0.02), compared to baseline. Conclusions Aspirin withdrawal 5 days before high-bleeding-risk procedures was associated with functional platelet recovery, and its reintroduction two days after surgery restored antiplaletet efficacy five days later. This was not the case of clopidogrel, and further work is therefore needed to define its optimal perioperative management. PMID:25141121

  18. Functional TLR5 genetic variants affect human colorectal cancer survival.

    PubMed

    Klimosch, Sascha N; Försti, Asta; Eckert, Jana; Knezevic, Jelena; Bevier, Melanie; von Schönfels, Witigo; Heits, Nils; Walter, Jessica; Hinz, Sebastian; Lascorz, Jesus; Hampe, Jochen; Hartl, Dominik; Frick, Julia-Stefanie; Hemminki, Kari; Schafmayer, Clemens; Weber, Alexander N R

    2013-12-15

    Toll-like receptors (TLR) are overexpressed on many types of cancer cells, including colorectal cancer cells, but little is known about the functional relevance of these immune regulatory molecules in malignant settings. Here, we report frequent single-nucleotide polymorphisms (SNP) in the flagellin receptor TLR5 and the TLR downstream effector molecules MyD88 and TIRAP that are associated with altered survival in a large cohort of Caucasian patients with colorectal cancer (n = 613). MYD88 rs4988453, a SNP that maps to a promoter region shared with the acetyl coenzyme-A acyl-transferase-1 (ACAA1), was associated with decreased survival of patients with colorectal cancer and altered transcriptional activity of the proximal genes. In the TLR5 gene, rs5744174/F616L was associated with increased survival, whereas rs2072493/N592S was associated with decreased survival. Both rs2072493/N592S and rs5744174/F616L modulated TLR5 signaling in response to flagellin or to different commensal and pathogenic intestinal bacteria. Notably, we observed a reduction in flagellin-induced p38 phosphorylation, CD62L shedding, and elevated expression of interleukin (IL)-6 and IL-1β mRNA in human primary immune cells from TLR5 616LL homozygote carriers, as compared with 616FF carriers. This finding suggested that the well-documented effect of cytokines like IL-6 on colorectal cancer progression might be mediated by TLR5 genotype-dependent flagellin sensing. Our results establish an important link between TLR signaling and human colorectal cancer with relevance for biomarker and therapy development. PMID:24154872

  19. Effects of Clopidogrel Therapy on Oxidative Stress, Inflammation, Vascular Function and Progenitor Cells in Stable Coronary Artery Disease

    PubMed Central

    Ramadan, Ronnie; Dhawan, Saurabh S.; Syed, Hamid; Pohlel, F. Khan; Binongo, Jose Nilo G.; Ghazzal, Ziyad B.; Quyyumi, Arshed A.

    2014-01-01

    Background Traditional cardiovascular risk factors lead to endothelial injury and activation of leucocytes and platelets that initiate and propagate atherosclerosis. We proposed that clopidogrel therapy in patients with stable CAD imparts a pleiotropic effect that extends beyond anti-platelet aggregation to other athero-protective processes. Methods Forty-one subjects were randomized in a double-blind, placebo-controlled crossover study to either clopidogrel 75 mg daily or placebo for 6-weeks, and then transitioned immediately to the other treatment for an additional 6 weeks. We assessed 1) endothelial function as flow-mediated dilation of the brachial artery, 2) arterial stiffness and central augmentation index using applanation tonometry, 3) vascular function as fingertip reactive hyperemia index, 4) inflammation by measuring plasma CD40 ligand and serum high-sensitivity c-reactive protein levels, 5) oxidative stress by measuring plasma aminothiols, and 6) circulating progenitor cells, at baseline and at the end of each 6-week treatment period. Results Clopidogrel therapy resulted in a significant reduction in soluble CD40 ligand (p=0.03), a pro-thrombotic and pro-inflammatory molecule derived mainly from activated platelets. However, clopidogrel therapy had no effect on endothelial function, arterial stiffness, inflammatory and oxidative stress markers, or progenitor cells. Conclusions Our findings suggest a solitary anti-platelet effect of clopidogrel therapy in patients with stable CAD, with no effect on other sub-clinical markers of cardiovascular disease risk. PMID:24336012

  20. Familial Clustering of Executive Functioning in Affected Sibling Pair Families with ADHD

    ERIC Educational Resources Information Center

    Slaats-Willemse, Dorine; Swaab-Barneveld, Hanna; De Sonneville, Leo; Buitelaar, Jan

    2005-01-01

    Objective: To investigate familial clustering of executive functioning (i.e., response inhibition, fine visuomotor functioning, and attentional control) in attention-deficit/hyperactivity disorder (ADHD)-affected sibling pairs. Method: Fifty-two affected sibling pairs aged 6 to 18 years and diagnosed with ADHD according to DSM-IV performed the…

  1. Vascular ring

    MedlinePlus

    ... with aberrant subclavian and left ligamentum ateriosus; Congenital heart defect - vascular ring; Birth defect heart - vascular ring ... accounts for less than 1% of all congenital heart problems. The condition occurs as often in males ...

  2. Phosphate Ions Affect the Water Structure at Functionalized Membrane Surfaces.

    PubMed

    Barrett, Aliyah; Imbrogno, Joseph; Belfort, Georges; Petersen, Poul B

    2016-09-01

    Antifouling surfaces improve function, efficiency, and safety in products such as water filtration membranes, marine vehicle coatings, and medical implants by resisting protein and biofilm adhesion. Understanding the role of water structure at these materials in preventing protein adhesion and biofilm formation is critical to designing more effective coatings. Such fouling experiments are typically performed under biological conditions using isotonic aqueous buffers. Previous studies have explored the structure of pure water at a few different antifouling surfaces, but the effect of electrolytes and ionic strength (I) on the water structure at antifouling surfaces is not well studied. Here sum frequency generation (SFG) spectroscopy is used to characterize the interfacial water structure at poly(ether sulfone) (PES) and two surface-modified PES films in contact with 0.01 M phosphate buffer with high and low salt (Ionic strength, I= 0.166 and 0.025 M, respectively). Unmodified PES, commonly used as a filtration membrane, and modified PES with a hydrophobic alkane (C18) and with a poly(ethylene glycol) (PEG) were used. In the low ionic strength phosphate buffer, water was strongly ordered near the surface of the PEG-modified PES film due to exclusion of phosphate ions and the creation of a surface potential resulting from charge separation between phosphate anions and sodium cations. However, in the high ionic strength phosphate buffer, the sodium and potassium chloride (138 and 3 mM, respectively) in the phosphate buffered saline screened this charge and substantially reduced water ordering. A much smaller water ordering and subsequent reduction upon salt addition was observed for the C18-modified PES, and little water structure change was seen for the unmodified PES. The large difference in water structuring with increasing ionic strength between widely used phosphate buffer and phosphate buffered saline at the PEG interface demonstrates the importance of studying

  3. Structural and functional vascular alterations and incident hypertension in normotensive adults: the Multi-Ethnic Study of Atherosclerosis.

    PubMed

    Peralta, Carmen A; Adeney, Kathryn L; Shlipak, Michael G; Jacobs, David; Duprez, Daniel; Bluemke, David; Polak, Joseph; Psaty, Bruce; Kestenbaum, Bryan R

    2010-01-01

    Vascular abnormalities may exist before clinical hypertension. Using Poisson regression, the authors studied the association of coronary artery calcium (CAC), common carotid intima-media thickness (CIMT), aortic distensibility, and large and small arterial elasticity with incident hypertension among 2,512 normotensive US adults free of cardiovascular disease. Incidence rate ratios for incident hypertension (blood pressure > or =140/90 mm Hg or new antihypertensive medication) were calculated. Increased CAC was associated with incident hypertension in demographics-adjusted models (incidence rate ratio (IRR) = 1.35, 95% confidence interval (CI): 1.04, 1.75; IRR = 1.35, 95% CI: 1.02, 1.78; and IRR = 1.59, 95% CI: 1.12, 2.25 for CAC scores of 30-99, 100-399, and > or =400, respectively) but was attenuated after further adjustment. Increased common CIMT was associated with incident hypertension (IRR = 1.77, 95% CI: 1.28, 2.46 for quintile 4; IRR = 1.80, 95% CI: 1.28, 2.53 for quintile 5). Participants with the lowest, compared with the highest, aortic distensibility had an increased risk of hypertension (IRR = 1.75, 95% CI: 1.10, 2.79), as did those with the lowest large arterial elasticity (IRR = 1.49, 95% CI: 1.11, 1.99). Lower small arterial elasticity was incrementally associated with incident hypertension starting at quintile 2 (IRR = 2.01, 95% CI: 1.39, 2.91; IRR = 2.47, 95% CI: 1.71, 3.57; IRR = 2.73, 95% CI: 1.88, 3.95; and IRR = 2.85, 95% CI: 1.95, 4.16). Structural and functional vascular abnormalities are independent predictors of incident hypertension. These findings are important for understanding the pathogenesis of hypertension. PMID:19951938

  4. Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function.

    PubMed

    Yoshioka, Kazuaki; Yoshida, Kotaro; Cui, Hong; Wakayama, Tomohiko; Takuwa, Noriko; Okamoto, Yasuo; Du, Wa; Qi, Xun; Asanuma, Ken; Sugihara, Kazushi; Aki, Sho; Miyazawa, Hidekazu; Biswas, Kuntal; Nagakura, Chisa; Ueno, Masaya; Iseki, Shoichi; Schwartz, Robert J; Okamoto, Hiroshi; Sasaki, Takehiko; Matsui, Osamu; Asano, Masahide; Adams, Ralf H; Takakura, Nobuyuki; Takuwa, Yoh

    2012-10-01

    The class II α-isoform of phosphatidylinositol 3-kinase (PI3K-C2α) is localized in endosomes, the trans-Golgi network and clathrin-coated vesicles; however, its functional role is not well understood. Global or endothelial-cell-specific deficiency of PI3K-C2α resulted in embryonic lethality caused by defects in sprouting angiogenesis and vascular maturation. PI3K-C2α knockdown in endothelial cells resulted in a decrease in the number of PI3-phosphate-enriched endosomes, impaired endosomal trafficking, defective delivery of VE-cadherin to endothelial cell junctions and defective junction assembly. PI3K-C2α knockdown also impaired endothelial cell signaling, including vascular endothelial growth factor receptor internalization and endosomal RhoA activation. Together, the effects of PI3K-C2α knockdown led to defective endothelial cell migration, proliferation, tube formation and barrier integrity. Endothelial PI3K-C2α deficiency in vivo suppressed postischemic and tumor angiogenesis and diminished vascular barrier function with a greatly augmented susceptibility to anaphylaxis and a higher incidence of dissecting aortic aneurysm formation in response to angiotensin II infusion. Thus, PI3K-C2α has a crucial role in vascular formation and barrier integrity and represents a new therapeutic target for vascular disease. PMID:22983395

  5. Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's disease

    PubMed Central

    Lin, Ai-Ling; Zheng, Wei; Halloran, Jonathan J; Burbank, Raquel R; Hussong, Stacy A; Hart, Matthew J; Javors, Martin; Shih, Yen-Yu Ian; Muir, Eric; Solano Fonseca, Rene; Strong, Randy; Richardson, Arlan G; Lechleiter, James D; Fox, Peter T; Galvan, Veronica

    2013-01-01

    Vascular pathology is a major feature of Alzheimer's disease (AD) and other dementias. We recently showed that chronic administration of the target-of-rapamycin (TOR) inhibitor rapamycin, which extends lifespan and delays aging, halts the progression of AD-like disease in transgenic human (h)APP mice modeling AD when administered before disease onset. Here we demonstrate that chronic reduction of TOR activity by rapamycin treatment started after disease onset restored cerebral blood flow (CBF) and brain vascular density, reduced cerebral amyloid angiopathy and microhemorrhages, decreased amyloid burden, and improved cognitive function in symptomatic hAPP (AD) mice. Like acetylcholine (ACh), a potent vasodilator, acute rapamycin treatment induced the phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) and NO release in brain endothelium. Administration of the NOS inhibitor L-NG-Nitroarginine methyl ester reversed vasodilation as well as the protective effects of rapamycin on CBF and vasculature integrity, indicating that rapamycin preserves vascular density and CBF in AD mouse brains through NOS activation. Taken together, our data suggest that chronic reduction of TOR activity by rapamycin blocked the progression of AD-like cognitive and histopathological deficits by preserving brain vascular integrity and function. Drugs that inhibit the TOR pathway may have promise as a therapy for AD and possibly for vascular dementias. PMID:23801246

  6. Novel functional germline variants in the vascular endothelial growth factor receptor 2 gene and their effect on gene expression and microvessel density in lung cancer

    PubMed Central

    Glubb, Dylan M; Cerri, Elisa; Giese, Alexandra; Zhang, Wei; Mirza, Osman; Thompson, Emma E.; Chen, Peixian; Das, Soma; Jassem, Jacek; Rzyman, Witold; Lingen, Mark W.; Salgia, Ravi; Hirsch, Fred R.; Dziadziuszko, Rafal; Ballmer-Hofer, Kurt; Innocenti, Federico

    2011-01-01

    Purpose VEGFR-2 plays a crucial role in mediating angiogenic endothelial cell responses via the VEGF pathway and angiogenesis inhibitors targeting VEGFR-2 are in clinical use. As angiogenesis is a host-driven process, functional heritable variation in KDR, the gene encoding VEGFR-2, may affect VEGFR-2 function, and ultimately, the extent of tumor angiogenesis. Experimental Design We resequenced KDR using 24 DNAs each from healthy Caucasian, African American and Asian groups. Non-synonymous genetic variants were assessed for function using phosphorylation assays. Luciferase reporter gene assays were used to examine effects of variants on gene expression. KDR mRNA and protein expression, and microvessel density (MVD) were measured in non-small cell lung cancer (NSCLC) tumor samples and matching patient DNA samples were genotyped to test for associations with variants of interest. Results KDR resequencing led to the discovery of 120 genetic variants, of which 25 had not been previously reported. Q472H had increased VEGFR-2 protein phosphorylation and associated with increased MVD in NSCLC tumor samples. −2854C and −2455A increased luciferase expression and associated with higher KDR mRNA levels in NSCLC samples. −271A reduced luciferase expression and associated with lower VEGFR-2 levels in NSCLC samples. −906C and 23408G, associated with higher KDR mRNA levels in NSCLC samples. Conclusions This study has defined KDR genetic variation in three populations and identified common variants that impact on tumoral KDR expression and vascularization. These findings may have important implications for understanding the molecular basis of genetic associations between KDR variation and clinical phenotypes related to VEGFR-2 function. PMID:21712447

  7. Regulation and function of an activation-dependent epitope of the beta 1 integrins in vascular cells after balloon injury in baboon arteries and in vitro.

    PubMed Central

    Koyama, N.; Seki, J.; Vergel, S.; Mattsson, E. J.; Yednock, T.; Kovach, N. L.; Harlan, J. M.; Clowes, A. W.

    1996-01-01

    Migration and proliferation of endothelial cells (ECs) and smooth muscle cells (SMCs) contribute to the response to injury in damaged and atherosclerotic vessels. These events might be regulated by cellular interactions with extracellular matrix through the expression and activation of integrins. To study the functions of beta 1 integrins in the vessel wall, we used monoclonal antibody (MAb) 15/7, which recognizes an activation epitope of beta 1 integrin subunits, and MAb 8A2, which induces a high affinity form of beta 1 integrins recognized by MAb 15/7. Immunohistochemical analyses were done on samples of normal baboon saphenous arteries and from arteries subjected to balloon injury. EC and SMC expressed the activation epitope of beta 1 integrin in uninjured arteries. By contrast, in balloon-injured arteries 6 weeks after injury, regenerating EC did not express the activation epitope, and there was no decrease in the expression of total beta 1 integrin, whereas SMC migrating into the intima exhibited decreased expression of the total and activated beta 1 integrin. Flow cytometer analysis of cultured cells indicated that baboon EC and SMC weakly express the activation epitope of beta 1 integrin. Next, we determined by utilizing MAb 8A2 the effects of increased expression of activation epitope of beta 1 integrin on the functions of SMC and EC. The activation of beta 1 integrins on SMC induced by MAb 8A2 enhanced SMC adhesion and suppressed SMC migration in a Boyden chamber assay. SMC proliferation was inhibited by MAb 8A2 dose-dependently. Similarly, MAb 8A2-induced activation of beta 1 integrins on EC suppressed EC migration into a wound. However, MAb 8A2 did not affect the basic fibroblast growth factor-induced proliferation of EC, although it blocked the decrease in EC number caused by the removal of basic fibroblast growth factor. These results suggest that activation of beta 1 integrins in vascular cells is regulated in a cell-type dependent manner and plays an

  8. Correlation of CT cerebral vascular territories with function. 3. Middle cerebral artery

    SciTech Connect

    Berman, S.A.; Hayman, L.A.; Hinck, V.C.

    1984-05-01

    Schematic displays are presented of the cerebral territories supplied by branches of the middle cerebral artery as they would appear on axial and coronal computed tomographic (CT) scan sections. Companion diagrams of regional cortical function and a discussion of the fiber tracts are provided to simplify correlation of clinical deficits with coronal and axial CT abnormalities.

  9. Effect of Vascular Endothelial Growth Factor and Erythropoietin on Functional Activity of Fibroblasts and Multipotent Mesenchymal Stromal Cells.

    PubMed

    Bondarenko, N A; Nikonorova, Yu V; Surovtseva, M A; Lykov, A P; Poveshchenko, O V; Poveshchenko, A F; Pokushalov, E A; Romanov, A B; Konenkov, V I

    2016-02-01

    The study examined the effect of VEGF and erythropoietin on proliferative and migratory activities of skin fibroblasts and multipotent mesenchymal stromal cells of human adipose tissue. VEGF stimulated proliferation and migration of fi broblasts, but produced no significant effect on functional activity of multipotent mesenchymal stem cells. Erythropoietin stimulated proliferation of both cell types, but did not affect their migration. PMID:26899850

  10. EFFECT OF OIL COMBUSTION PARTICLE BIOAVAILABLE CONSTITUENTS ON EX VIVO VASCULAR FUNCTION OF AORTAS RECOVERED FROM NORMAL AND TYPE 2 DIABETIC RATS

    EPA Science Inventory

    Effect of Oil Combustion Particle Bioavailable Constituents on Ex Vivo Vascular Function of Aortae Recovered from Healthy and Early Type 2 Diabetic Rats
    KL Dreher1, SE Kelly2, SD Proctor2, and JC Russell2. 1National Health and Environmental Effects Laboratory, US EPA, RTP, NC;...

  11. Role of leptin signaling in hemato-vascular development and niche function: Leptin receptor-mediated signaling regulates LT-HSC homeostasis in vivo

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Homeostatic functioning of the cardiovascular and hematopoietic systems is known to be interdependent and strongly influenced by the microenvironment in which hemato-vascular cells develop and reside. The role of nutrition and metabolism as regulable and dynamic extracellular cues however, remains a...

  12. Statins in type 2 diabetes mellitus: target on lipids and vascular wall function

    PubMed Central

    van de Ree, M.A.; van Venrooij, F.V.; Meinders, A.E.; Jonkers, I.J.A.M.; Berk-Planken, I.; Huisman, M.V.

    2003-01-01

    The typical dyslipidaemia in type 2 diabetes mellitus shows high levels of triglycerides, low levels of highdensity lipoprotein cholesterol (HDL-c) and small dense low-density lipoprotein (LDL) particles. In these patients low-dose atorvastatin (10 mg) results in a significant and relevant reduction in triglycerides and LDL-c. High-dose atorvastatin (80 mg) results in a better LDL-c reduction. The endothelial dysfunction is likely to be caused by factors related to insulin resistance and not by dyslipidaemia alone. The results from the DALI study (Diabetes Atorvastatin Lipid Intervention) on lipids and endothelial function are discussed, together with two invasive endothelial function studies in diabetics and hypertriglyceridaemic patients. The subgroup of diabetics in the large secondary prevention trials using statins are analysed with respect to total cholesterol lowering and death due to coronary heart disease and nonfatal myocardial infarction. ImagesFigure 2 PMID:25696194

  13. Increasing functional modularity with residence time in the co-distribution of native and introduced vascular plants.

    PubMed

    Hui, Cang; Richardson, David M; Pyšek, Petr; Le Roux, Johannes J; Kučera, Tomáš; Jarošík, Vojtěch

    2013-01-01

    Species gain membership of regional assemblages by passing through multiple ecological and environmental filters. To capture the potential trajectory of structural changes in regional meta-communities driven by biological invasions, one can categorize species pools into assemblages of different residence times. Older assemblages, having passed through more environmental filters, should become more functionally ordered and structured. Here we calculate the level of compartmentalization (modularity) for three different-aged assemblages (neophytes, introduced after 1500 AD; archaeophytes, introduced before 1500 AD, and natives), including 2,054 species of vascular plants in 302 reserves in central Europe. Older assemblages are more compartmentalized than younger ones, with species composition, phylogenetic structure and habitat characteristics of the modules becoming increasingly distinctive. This sheds light on two mechanisms of how alien species are functionally incorporated into regional species pools: the settling-down hypothesis of diminishing stochasticity with residence time, and the niche-mosaic hypothesis of inlaid neutral modules in regional meta-communities. PMID:24045305

  14. Increasing functional modularity with residence time in the co-distribution of native and introduced vascular plants

    PubMed Central

    Hui, Cang; Richardson, David M.; Pyšek, Petr; Le Roux, Johannes J.; Kučera, Tomáš; Jarošík, Vojtěch

    2013-01-01

    Species gain membership of regional assemblages by passing through multiple ecological and environmental filters. To capture the potential trajectory of structural changes in regional meta-communities driven by biological invasions, one can categorize species pools into assemblages of different residence times. Older assemblages, having passed through more environmental filters, should become more functionally ordered and structured. Here we calculate the level of compartmentalization (modularity) for three different-aged assemblages (neophytes, introduced after 1500 AD; archaeophytes, introduced before 1500 AD, and natives), including 2,054 species of vascular plants in 302 reserves in central Europe. Older assemblages are more compartmentalized than younger ones, with species composition, phylogenetic structure and habitat characteristics of the modules becoming increasingly distinctive. This sheds light on two mechanisms of how alien species are functionally incorporated into regional species pools: the settling-down hypothesis of diminishing stochasticity with residence time, and the niche-mosaic hypothesis of inlaid neutral modules in regional meta-communities. PMID:24045305

  15. Nitrosylated Hemoglobin Levels in Human Venous Erythrocytes Correlate with Vascular Endothelial Function Measured by Digital Reactive Hyperemia

    PubMed Central

    Lobysheva, Irina I.; Biller, Pauline; Gallez, Bernard; Beauloye, Christophe; Balligand, Jean-Luc

    2013-01-01

    Impaired nitric oxide (NO)–dependent endothelial function is associated with the development of cardiovascular diseases. We hypothesized that erythrocyte levels of nitrosylated hemoglobin (HbNO-heme) may reflect vascular endothelial function in vivo. We developed a modified subtraction method using Electron Paramagnetic Resonance (EPR) spectroscopy to identify the 5-coordinate α-HbNO (HbNO) concentration in human erythrocytes and examined its correlation with endothelial function assessed by peripheral arterial tonometry (PAT). Changes in digital pulse amplitude were measured by PAT during reactive hyperemia following brachial arterial occlusion in a group of healthy volunteers (50 subjects). Erythrocyte HbNO levels were measured at baseline and at the peak of hyperemia. We digitally subtracted an individual model EPR signal of erythrocyte free radicals from the whole EPR spectrum to unmask and quantitate the HbNO EPR signals. Results Mean erythrocyte HbNO concentration at baseline was 219+/−12 nmol/L (n = 50). HbNO levels and reactive hyperemia (RH) indexes were higher in female (free of contraceptive pills) than male subjects. We observed a dynamic increase of HbNO levels in erythrocytes isolated at 1–2 min of post-occlusion hyperemia (120+/−8% of basal levels); post-occlusion HbNO levels were correlated with basal levels. Both basal and post-occlusion HbNO levels were significantly correlated with reactive hyperemia (RH) indexes (r = 0.58; P<0.0001 for basal HbNO). Conclusion The study demonstrates quantitative measurements of 5-coordinate α-HbNO in human venous erythrocytes, its dynamic physiologic regulation and correlation with endothelial function measured by tonometry during hyperemia. This opens the way to further understanding of in vivo determinants of NO bioavailability in human circulation. PMID:24130774

  16. The Relationship of Ectopic Lipid Accumulation to Cardiac and Vascular Function in Obesity and Metabolic Syndrome

    PubMed Central

    Ruberg, Frederick L.; Chen, Zhongjing; Hua, Ning; Bigornia, Sherman; Guo, Zifang; Hallock, Kevin; Jara, Hernan; LaValley, Michael; Phinikaridou, Alkystis; Qiao, Ye; Viereck, Jason; Apovian, Caroline M.; Hamilton, James A.

    2010-01-01

    Storage of lipid in ectopic depots outside of abdominal visceral and subcutaneous stores, including within the pericardium and liver, has been associated with obesity, insulin resistance, and cardiovascular risk. We sought to determine whether anatomically distinct ectopic depots were physiologically correlated and site-specific effects upon cardiovascular function could be identified. Obese subjects (n = 28) with metabolic syndrome but without known atherosclerotic disease and healthy controls (n = 18) underwent magnetic resonance imaging (MRI) and proton MR spectroscopy (MRS) to quantify pericardial and periaortic lipid volumes, cardiac function, aortic compliance, and intrahepatic lipid content. Fasting plasma lipoproteins, glucose, insulin, and free-fatty acids were measured. Pericardial and intrahepatic (P < 0.01) and periaortic (P < 0.05) lipid volumes were increased in obese subjects vs. controls and were strongly and positively correlated (P ≤ 0.01) but independent of BMI (P = NS) among obese subjects. Intrahepatic lipid was associated with insulin resistance (P < 0.01) and triglycerides (P < 0.05), whereas pericardial and periaortic lipid were not (P = NS). Periaortic and pericardial lipid positively correlated to free-fatty acids (P ≤ 0.01) and negatively correlated to high-density lipoprotein (HDL) cholesterol (P < 0.05). Pericardial lipid negatively correlated to cardiac output (P = 0.03) and stroke volume (P = 0.01) but not to left ventricular ejection fraction (P = 0.46). None of the ectopic depots correlated to aortic compliance. In conclusion, ectopic storage of lipid in anatomically distinct depots appeared tightly correlated but independent of body size. Site-specific functional abnormalities were observed for pericardial but not periaortic lipid. These findings underscore the utility of MRI to assess individual differences in ectopic lipid that are not predictable from BMI. PMID:19875992

  17. Engineering a growth factor embedded nanofiber matrix niche to promote vascularization for functional cardiac regeneration.

    PubMed

    Lakshmanan, Rajesh; Kumaraswamy, Priyadharshini; Krishnan, Uma Maheswari; Sethuraman, Swaminathan

    2016-08-01

    The major loss of tissue extracellular matrix (ECM) after myocardial ischemia is a serious burden that gradually leads to heart failure. Due to lack of available treatment methods to restore the cardiac function, various research strategies have come up to treat the ischemic myocardium. However these have met with limited success due to the complexity of the cardiac tissue, which exhibits a nanofibrous collagenous matrix with spatio-temporal localization of a combination of growth factors. To mimic the topographical and chemical cues of the natural cardiac tissue, we have fabricated a growth factor embedded nanofibrous scaffold through electrospinning. In our previous work, we have reported a nanofibrous matrix made of PLCL and PEOz with an average diameter of 500 nm. The scaffold properties were specifically characterized in vitro for cardio-compatibility. In the present study, we have loaded dual growth factors VEGF and bFGF in the nanofiber matrix and investigated its suitability for cardiac tissue engineering. The encapsulation and release of dual growth factors from the matrix were studied using XPS and ELISA. Bioactivity of the loaded growth factors towards proliferation and migration of endothelial cells (HUVECs) was evaluated through MTS and Boyden chamber assays respectively. The efficiency of growth factors on the nanofibrous matrix to activate signaling molecules was studied in HUVECs through gene expression analysis. Preclinical evaluation of the growth factor embedded nanofibrous patch in a rabbit acute myocardial infarction (AMI) model was studied and cardiac function assessment was made through ECG and echocardiography. The evidence for angiogenesis in the patch secured regions was analyzed through histopathology and immunohistochemistry. Our results confirm the effectiveness of growth factor embedded nanofiber matrix in restoration of cardiac function after ischemia when compared to conventional patch material thereby exhibiting promise as a

  18. From Structure to Function: Mitochondrial Morphology, Motion and Shaping in Vascular Smooth Muscle

    PubMed Central

    McCarron, John G.; Wilson, Calum; Sandison, Mairi E.; Olson, Marnie L.; Girkin, John M.; Saunter, Christopher; Chalmers, Susan

    2013-01-01

    The diversity of mitochondrial arrangements, which arise from the organelle being static or moving, or fusing and dividing in a dynamically reshaping network, is only beginning to be appreciated. While significant progress has been made in understanding the proteins that reorganise mitochondria, the physiological significance of the various arrangements is poorly understood. The lack of understanding may occur partly because mitochondrial morphology is studied most often in cultured cells. The simple anatomy of cultured cells presents an attractive model for visualizing mitochondrial behaviour but contrasts with the complexity of native cells in which elaborate mitochondrial movements and morphologies may not occur. Mitochondrial changes may take place in native cells (in response to stress and proliferation), but over a slow time-course and the cellular function contributed is unclear. To determine the role mitochondrial arrangements play in cell function, a crucial first step is characterisation of the interactions among mitochondrial components. Three aspects of mitochondrial behaviour are described in this review: (1) morphology, (2) motion and (3) rapid shape changes. The proposed physiological roles to which various mitochondrial arrangements contribute and difficulties in interpreting some of the physiological conclusions are also outlined. PMID:23887139

  19. Microcapsules functionalized with neuraminidase can enter vascular endothelial cells in vitro.

    PubMed

    Liu, Weizhi; Wang, Xiaocong; Bai, Ke; Lin, Miao; Sukhorukov, Gleb; Wang, Wen

    2014-12-01

    Microcapsules made of polyelectrolyte multilayers exhibit no or low toxicity, appropriate mechanical stability, variable controllable degradation and can incorporate remote release mechanisms triggered by various stimuli, making them well suited for targeted drug delivery to live cells. This study investigates interactions between microcapsules made of synthetic (i.e. polystyrenesulfonate sodium salt/polyallylamine hydrochloride) or natural (i.e. dextran sulfate/poly-L-arginine) polyelectrolyte and human umbilical vein endothelial cells with particular focus on the effect of the glycocalyx layer on the intake of microcapsules by endothelial cells. Neuraminidase cleaves N-acetyl neuraminic acid residues of glycoproteins and targets the sialic acid component of the glycocalyx on the cell membrane. Three-dimensional confocal images reveal that microcapsules, functionalized with neuraminidase, can be internalized by endothelial cells. Capsules without neuraminidase are blocked by the glycocalyx layer. Uptake of the microcapsules is most significant in the first 2 h. Following their internalization by endothelial cells, biodegradable DS/PArg capsules rupture by day 5; however, there is no obvious change in the shape and integrity of PSS/PAH capsules within the period of observation. Results from the study support our hypothesis that the glycocalyx functions as an endothelial barrier to cross-membrane movement of microcapsules. Neuraminidase-loaded microcapsules can enter endothelial cells by localized cleavage of glycocalyx components with minimum disruption of the glycocalyx layer and therefore have high potential to act as drug delivery vehicles to reach tissues beyond the endothelial barrier of blood vessels. PMID:25339691

  20. Age related vascular endothelial function following lifelong sedentariness: positive impact of cardiovascular conditioning without further improvement following low frequency high intensity interval training

    PubMed Central

    Grace, Fergal M.; Herbert, Peter; Ratcliffe, John W.; New, Karl J.; Baker, Julien S.; Sculthorpe, Nicholas F.

    2015-01-01

    Abstract Aging is associated with diffuse impairments in vascular endothelial function and traditional aerobic exercise is known to ameliorate these changes. High intensity interval training (HIIT) is effective at improving vascular function in aging men with existing disease, but its effectiveness remains to be demonstrated in otherwise healthy sedentary aging. However, the frequency of commonly used HIIT protocols may be poorly tolerated in older cohorts. Therefore, the present study investigated the effectiveness of lower frequency HIIT (LfHIIT) on vascular function in a cohort of lifelong sedentary (SED; n =22, age 62.7 ± 5.2 years) men compared with a positive control group of lifelong exercisers (LEX; n = 17, age 61.1 ± 5.4 years). The study consisted of three assessment phases; enrolment to the study (Phase A), following 6 weeks of conditioning exercise in SED (Phase B) and following 6 weeks of low frequency HIIT in both SED and LEX (LfHIIT; Phase C). Conditioning exercise improved FMD in SED (3.4 ± 1.5% to 4.9 ± 1.1%; P <0.01) such that the difference between groups on enrolment (3.4 ± 1.5% vs. 5.3 ± 1.4%; P <0.01) was abrogated. This was maintained but not further improved following LfHIIT in SED whilst FMD remained unaffected by LfHIIT in LEX. In conclusion, LfHIIT is effective at maintaining improvements in vascular function achieved during conditioning exercise in SED. LfHIIT is a well‐tolerated and effective exercise mode for reducing cardiovascular risk and maintaining but does not improve vascular function beyond that achieved by conditioning exercise in aging men, irrespective of fitness level. PMID:25626864

  1. The impact of milk proteins and peptides on blood pressure and vascular function: a review of evidence from human intervention studies.

    PubMed

    Fekete, Ágnes A; Givens, D Ian; Lovegrove, Julie A

    2013-12-01

    CVD are the leading cause of death worldwide. Hypertension, a major controllable risk factor of CVD, is intimately associated with vascular dysfunction, a defect which is also now recognised to be a major, modifiable risk factor for the development of CVD. The purpose of the present review was to critically evaluate the evidence for the effects of milk proteins and their associated peptides on blood pressure (BP) and vascular dysfunction. After a detailed literature search, the number of human trials evaluating the antihypertensive effects of casein-derived peptides (excluding isoleucine-proline-proline and valine-proline-proline) was found to be limited; the studies were preliminary with substantial methodological limitations. Likewise, the data from human trials that examined the effects of whey protein and peptides were also scarce and inconsistent. To date, only one study has conducted a comparative investigation on the relative effects of the two main intact milk proteins on BP and vascular function. While both milk proteins were shown to reduce BP, only whey protein improved measures of arterial stiffness. In contrast, a growing number of human trials have produced evidence to support beneficial effects of both milk proteins and peptides on vascular health. However, comparison of the relative outcomes from these trials is difficult owing to variation in the forms of assessment and measures of vascular function. In conclusion, there is an accumulating body of evidence to support positive effects of milk proteins in improving and/or maintaining cardiovascular health. However, the variable quality of the studies that produced this evidence, and the lack of robust, randomised controlled intervention trials, undermines the formulation of firm conclusions on the potential benefits of milk proteins and peptides on vascular health. PMID:24135454

  2. Knock-down of pantothenate kinase 2 severely affects the development of the nervous and vascular system in zebrafish, providing new insights into PKAN disease.

    PubMed

    Zizioli, Daniela; Tiso, Natascia; Guglielmi, Adele; Saraceno, Claudia; Busolin, Giorgia; Giuliani, Roberta; Khatri, Deepak; Monti, Eugenio; Borsani, Giuseppe; Argenton, Francesco; Finazzi, Dario

    2016-01-01

    Pantothenate Kinase Associated Neurodegeneration (PKAN) is an autosomal recessive disorder with mutations in the pantothenate kinase 2 gene (PANK2), encoding an essential enzyme for Coenzyme A (CoA) biosynthesis. The molecular connection between defects in this enzyme and the neurodegenerative phenotype observed in PKAN patients is still poorly understood. We exploited the zebrafish model to study the role played by the pank2 gene during embryonic development and get new insight into PKAN pathogenesis. The zebrafish orthologue of hPANK2 lies on chromosome 13, is a maternal gene expressed in all development stages and, in adult animals, is highly abundant in CNS, dorsal aorta and caudal vein. The injection of a splice-inhibiting morpholino induced a clear phenotype with perturbed brain morphology and hydrocephalus; edema was present in the heart region and caudal plexus, where hemorrhages with reduction of blood circulation velocity were detected. We characterized the CNS phenotype by studying the expression pattern of wnt1 and neurog1 neural markers and by use of the Tg(neurod:EGFP/sox10:dsRed) transgenic line. The results evidenced that downregulation of pank2 severely impairs neuronal development, particularly in the anterior part of CNS (telencephalon). Whole-mount in situ hybridization analysis of the endothelial markers cadherin-5 and fli1a, and use of Tg(fli1a:EGFP/gata1a:dsRed) transgenic line, confirmed the essential role of pank2 in the formation of the vascular system. The specificity of the morpholino-induced phenotype was proved by the restoration of a normal development in a high percentage of embryos co-injected with pank2 mRNA. Also, addition of pantethine or CoA, but not of vitamin B5, to pank2 morpholino-injected embryos rescued the phenotype with high efficiency. The zebrafish model indicates the relevance of pank2 activity and CoA homeostasis for normal neuronal development and functioning and provides evidence of an unsuspected role for this

  3. Knock-down of pantothenate kinase 2 severely affects the development of the nervous and vascular system in zebrafish, providing new insights into PKAN disease

    PubMed Central

    Zizioli, Daniela; Tiso, Natascia; Guglielmi, Adele; Saraceno, Claudia; Busolin, Giorgia; Giuliani, Roberta; Khatri, Deepak; Monti, Eugenio; Borsani, Giuseppe; Argenton, Francesco; Finazzi, Dario

    2016-01-01

    Pantothenate Kinase Associated Neurodegeneration (PKAN) is an autosomal recessive disorder with mutations in the pantothenate kinase 2 gene (PANK2), encoding an essential enzyme for Coenzyme A (CoA) biosynthesis. The molecular connection between defects in this enzyme and the neurodegenerative phenotype observed in PKAN patients is still poorly understood. We exploited the zebrafish model to study the role played by the pank2 gene during embryonic development and get new insight into PKAN pathogenesis. The zebrafish orthologue of hPANK2 lies on chromosome 13, is a maternal gene expressed in all development stages and, in adult animals, is highly abundant in CNS, dorsal aorta and caudal vein. The injection of a splice-inhibiting morpholino induced a clear phenotype with perturbed brain morphology and hydrocephalus; edema was present in the heart region and caudal plexus, where hemorrhages with reduction of blood circulation velocity were detected. We characterized the CNS phenotype by studying the expression pattern of wnt1 and neurog1 neural markers and by use of the Tg(neurod:EGFP/sox10:dsRed) transgenic line. The results evidenced that downregulation of pank2 severely impairs neuronal development, particularly in the anterior part of CNS (telencephalon). Whole-mount in situ hybridization analysis of the endothelial markers cadherin-5 and fli1a, and use of Tg(fli1a:EGFP/gata1a:dsRed) transgenic line, confirmed the essential role of pank2 in the formation of the vascular system. The specificity of the morpholino-induced phenotype was proved by the restoration of a normal development in a high percentage of embryos co-injected with pank2 mRNA. Also, addition of pantethine or CoA, but not of vitamin B5, to pank2 morpholino-injected embryos rescued the phenotype with high efficiency. The zebrafish model indicates the relevance of pank2 activity and CoA homeostasis for normal neuronal development and functioning and provides evidence of an unsuspected role for this

  4. Antiedema effects of Siberian ginseng in humans and its molecular mechanism of lymphatic vascular function in vitro.

    PubMed

    Fukada, Kaedeko; Kajiya-Sawane, Mika; Matsumoto, Yuko; Hasegawa, Tatsuya; Fukaya, Yukitaka; Kajiya, Kentaro

    2016-07-01

    The lymphatic system in the skin plays a major role in tissue fluid homeostasis, in the afferent phase of the immune response, and in tumor metastasis. Although lymphangiogenic factors involved in embryonic development and the metastatic spread of tumor cells have been well studied, little is known about small-molecule compounds that activate lymphatic function, especially under physiological conditions. We hypothesized that the identification of a lymphatic-activating compound could provide a method for improving edema. Here, we show that Siberian ginseng (Eleutherococcus senticosus) and its component eleutheroside E induce phosphorylation of the endothelial-specific receptor Tie2 in vitro. The activation of Tie2 on lymphatic endothelial cells (LECs) is known to stabilize lymphatic vessels, so we examined the effects of Siberian ginseng on LECs. We found that Siberian ginseng induces the migration and cord formation of LECs. Permeability assays demonstrated that it stabilizes LECs by promoting the intercellular localization of vascular endothelial cadherin, which is an endothelium-specific cell-cell adhesion molecule involved in endothelial barrier function, and it induces the phosphorylation of endothelial nitric oxide synthase by LECs. These effects appear to be mediated by the activation of Tie2 in LECs. Finally, we investigated whether the consumption of Siberian ginseng powder improves edema in a 2-way, randomized, crossover study in 50 healthy female volunteers. Edema of the lower limbs was significantly attenuated at 2 and 4hours after ingestion as compared with the control group. Thus, we demonstrate that Siberian ginseng exerts its potent antiedema activity mainly by promoting lymphatic function. PMID:27333960

  5. New Insights into Mechanisms and Functions of Chemokine (C-X-C Motif) Receptor 4 Heteromerization in Vascular Smooth Muscle

    PubMed Central

    Evans, Ann E.; Tripathi, Abhishek; LaPorte, Heather M.; Brueggemann, Lioubov I.; Singh, Abhay Kumar; Albee, Lauren J.; Byron, Kenneth L.; Tarasova, Nadya I.; Volkman, Brian F.; Cho, Thomas Yoonsang; Gaponenko, Vadim; Majetschak, Matthias

    2016-01-01

    Recent evidence suggests that C-X-C chemokine receptor type 4 (CXCR4) heteromerizes with α1A/B-adrenoceptors (AR) and atypical chemokine receptor 3 (ACKR3) and that CXCR4:α1A/B-AR heteromers are important for α1-AR function in vascular smooth muscle cells (VSMC). Structural determinants for CXCR4 heteromerization and functional consequences of CXCR4:α1A/B-AR heteromerization in intact arteries, however, remain unknown. Utilizing proximity ligation assays (PLA) to visualize receptor interactions in VSMC, we show that peptide analogs of transmembrane-domain (TM) 2 and TM4 of CXCR4 selectively reduce PLA signals for CXCR4:α1A-AR and CXCR4:ACKR3 interactions, respectively. While both peptides inhibit CXCL12-induced chemotaxis, only the TM2 peptide inhibits phenylephrine-induced Ca2+-fluxes, contraction of VSMC and reduces efficacy of phenylephrine to constrict isolated arteries. In a Cre-loxP mouse model to delete CXCR4 in VSMC, we observed 60% knockdown of CXCR4. PLA signals for CXCR4:α1A/B-AR and CXCR4:ACKR3 interactions in VSMC, however, remained constant. Our observations point towards TM2/4 of CXCR4 as possible contact sites for heteromerization and suggest that TM-derived peptide analogs permit selective targeting of CXCR4 heteromers. A molecular dynamics simulation of a receptor complex in which the CXCR4 homodimer interacts with α1A-AR via TM2 and with ACKR3 via TM4 is presented. Our findings further imply that CXCR4:α1A-AR heteromers are important for intrinsic α1-AR function in intact arteries and provide initial and unexpected insights into the regulation of CXCR4 heteromerization in VSMC. PMID:27331810

  6. New Insights into Mechanisms and Functions of Chemokine (C-X-C Motif) Receptor 4 Heteromerization in Vascular Smooth Muscle.

    PubMed

    Evans, Ann E; Tripathi, Abhishek; LaPorte, Heather M; Brueggemann, Lioubov I; Singh, Abhay Kumar; Albee, Lauren J; Byron, Kenneth L; Tarasova, Nadya I; Volkman, Brian F; Cho, Thomas Yoonsang; Gaponenko, Vadim; Majetschak, Matthias

    2016-01-01

    Recent evidence suggests that C-X-C chemokine receptor type 4 (CXCR4) heteromerizes with α1A/B-adrenoceptors (AR) and atypical chemokine receptor 3 (ACKR3) and that CXCR4:α1A/B-AR heteromers are important for α₁-AR function in vascular smooth muscle cells (VSMC). Structural determinants for CXCR4 heteromerization and functional consequences of CXCR4:α1A/B-AR heteromerization in intact arteries, however, remain unknown. Utilizing proximity ligation assays (PLA) to visualize receptor interactions in VSMC, we show that peptide analogs of transmembrane-domain (TM) 2 and TM4 of CXCR4 selectively reduce PLA signals for CXCR4:α1A-AR and CXCR4:ACKR3 interactions, respectively. While both peptides inhibit CXCL12-induced chemotaxis, only the TM2 peptide inhibits phenylephrine-induced Ca(2+)-fluxes, contraction of VSMC and reduces efficacy of phenylephrine to constrict isolated arteries. In a Cre-loxP mouse model to delete CXCR4 in VSMC, we observed 60% knockdown of CXCR4. PLA signals for CXCR4:α1A/B-AR and CXCR4:ACKR3 interactions in VSMC, however, remained constant. Our observations point towards TM2/4 of CXCR4 as possible contact sites for heteromerization and suggest that TM-derived peptide analogs permit selective targeting of CXCR4 heteromers. A molecular dynamics simulation of a receptor complex in which the CXCR4 homodimer interacts with α1A-AR via TM2 and with ACKR3 via TM4 is presented. Our findings further imply that CXCR4:α1A-AR heteromers are important for intrinsic α₁-AR function in intact arteries and provide initial and unexpected insights into the regulation of CXCR4 heteromerization in VSMC. PMID:27331810

  7. Predicting the accuracy of facial affect recognition: the interaction of child maltreatment and intellectual functioning.

    PubMed

    Shenk, Chad E; Putnam, Frank W; Noll, Jennie G

    2013-02-01

    Previous research demonstrates that both child maltreatment and intellectual performance contribute uniquely to the accurate identification of facial affect by children and adolescents. The purpose of this study was to extend this research by examining whether child maltreatment affects the accuracy of facial recognition differently at varying levels of intellectual functioning. A sample of maltreated (n=50) and nonmaltreated (n=56) adolescent females, 14 to 19 years of age, was recruited to participate in this study. Participants completed demographic and study-related questionnaires and interviews to control for potential psychological and psychiatric confounds such as symptoms of posttraumatic stress disorder, negative affect, and difficulties in emotion regulation. Participants also completed an experimental paradigm that recorded responses to facial affect displays starting in a neutral expression and changing into a full expression of one of six emotions: happiness, sadness, anger, disgust, fear, or surprise. Hierarchical multiple regression assessed the incremental advantage of evaluating the interaction between child maltreatment and intellectual functioning. Results indicated that the interaction term accounted for a significant amount of additional variance in the accurate identification of facial affect after controlling for relevant covariates and main effects. Specifically, maltreated females with lower levels of intellectual functioning were least accurate in identifying facial affect displays, whereas those with higher levels of intellectual functioning performed as well as nonmaltreated females. These results suggest that maltreatment and intellectual functioning interact to predict the recognition of facial affect, with potential long-term consequences for the interpersonal functioning of maltreated females. PMID:23036371

  8. Single Low-Density Lipoprotein Apheresis Does Not Improve Vascular Endothelial Function in Chronically Treated Hypercholesterolemic Patients

    PubMed Central

    Ballard, Kevin D.; Mah, Eunice; Guo, Yi; Bruno, Richard S.; Taylor, Beth A.; Beam, Jo Ellen; Polk, Donna M.; Thompson, Paul D.

    2016-01-01

    Objective. To investigate vascular endothelial function (VEF) responses to a single low-density lipoprotein (LDL) apheresis session in hypercholesterolemic patients undergoing chronic treatment. Methods. We measured brachial artery flow-mediated dilation (FMD), plasma lipids, vitamin E (α- and γ-tocopherol), markers of oxidative/nitrative stress (malondialdehyde (MDA) and nitro-γ-tocopherol (NGT)), and regulators of NO metabolism (arginine (ARG) and asymmetric dimethylarginine (ADMA)) prior to (Pre) and immediately following (Post) LDL apheresis and at 1, 3, 7, and 14 d Post in 5 hypercholesterolemic patients (52 ± 11 y). Results. Relative to Pre, total cholesterol (7.8 ± 1.5 mmol/L) and LDL-cholesterol (6.2 ± 1.2 mmol/L) were 61% and 70% lower (P < 0.01), respectively, at Post and returned to Pre levels at 14 d. Brachial FMD responses (6.9 ± 3.6%) and plasma MDA, ARG, and ADMA concentrations were unaffected by LDL apheresis. Plasma α-tocopherol, γ-tocopherol, and NGT concentrations were 52–69% lower at Post (P < 0.01), and α-tocopherol remained 36% lower at 1 d whereas NGT remained 41% lower at d 3. Conclusions. Acute cholesterol reduction by LDL apheresis does not alter VEF, oxidative stress, or NO homeostasis in patients treated chronically for hypercholesterolemia. PMID:26998360

  9. Differential effects of EPA versus DHA on postprandial vascular function and the plasma oxylipin profile in men[S

    PubMed Central

    McManus, Seán; Tejera, Noemi; Awwad, Khader; Rigby, Neil; Fleming, Ingrid; Cassidy, Aedin; Minihane, Anne Marie

    2016-01-01

    Our objective was to investigate the impact of EPA versus DHA on arterial stiffness and reactivity and underlying mechanisms (with a focus on plasma oxylipins) in the postprandial state. In a three-arm crossover acute test meal trial, men (n = 26, 35–55 years) at increased CVD risk received a high-fat (42.4 g) test meal providing 4.16 g of EPA or DHA or control oil in random order. At 0 h and 4 h, blood samples were collected to quantify plasma fatty acids, long chain n-3 PUFA-derived oxylipins, nitrite and hydrogen sulfide, and serum lipids and glucose. Vascular function was assessed using blood pressure, reactive hyperemia index, pulse wave velocity, and augmentation index (AIx). The DHA-rich oil significantly reduced AIx by 13% (P = 0.047) with the decrease following EPA-rich oil intervention not reaching statistical significance. Both interventions increased EPA- and DHA-derived oxylipins in the acute postprandial state, with an (1.3-fold) increase in 19,20-dihydroxydocosapentaenoic acid evident after DHA intervention (P < 0.001). In conclusion, a single dose of DHA significantly improved postprandial arterial stiffness as assessed by AIx, which if sustained would be associated with a significant decrease in CVD risk. The observed increases in oxylipins provide a mechanistic insight into the AIx effect. PMID:27170732

  10. The Synthetic Tie2 Agonist Peptide Vasculotide Protects Renal Vascular Barrier Function In Experimental Acute Kidney Injury

    PubMed Central

    Rübig, Eva; Stypmann, Jörg; Van Slyke, Paul; Dumont, Daniel J; Spieker, Tilmann; Buscher, Konrad; Reuter, Stefan; Goerge, Tobias; Pavenstädt, Hermann; Kümpers, Philipp

    2016-01-01

    Microvascular barrier dysfunction plays a major role in the pathophysiology of acute kidney injury (AKI). Angiopoietin-1, the natural agonist ligand for the endothelial-specific Tie2 receptor, is a non-redundant endothelial survival and vascular stabilization factor. Here we evaluate the efficacy of a polyethylene glycol-clustered Tie2 agonist peptide, vasculotide (VT), to protect against endothelial-cell activation with subsequent microvascular dysfunction in a murine model of ischemic AKI. Renal ischemia reperfusion injury (IRI) was induced by clamping of the renal arteries for 35 minutes. Mice were treated with VT or PEGylated cysteine before IRI. Sham-operated animals served as time-matched controls. Treatment with VT significantly reduced transcapillary albumin flux and renal tissue edema after IRI. The protective effects of VT were associated with activation of Tie2 and stabilization of its downstream effector, VE-cadherin in renal vasculature. VT abolished the decline in renal tissue blood flow, attenuated the increase of serum creatinine and blood urea nitrogen after IRI, improved recovery of renal function and markedly reduced mortality compared to PEG [HR 0.14 (95% CI 0.05–0.78) P < 0.05]. VT is inexpensive to produce, chemically stable and unrelated to any Tie2 ligands. Thus, VT may represent a novel therapy to prevent AKI in patients. PMID:26911791

  11. Differential effects of EPA versus DHA on postprandial vascular function and the plasma oxylipin profile in men.

    PubMed

    McManus, Seán; Tejera, Noemi; Awwad, Khader; Vauzour, David; Rigby, Neil; Fleming, Ingrid; Cassidy, Aedin; Minihane, Anne Marie

    2016-09-01

    Our objective was to investigate the impact of EPA versus DHA on arterial stiffness and reactivity and underlying mechanisms (with a focus on plasma oxylipins) in the postprandial state. In a three-arm crossover acute test meal trial, men (n = 26, 35-55 years) at increased CVD risk received a high-fat (42.4 g) test meal providing 4.16 g of EPA or DHA or control oil in random order. At 0 h and 4 h, blood samples were collected to quantify plasma fatty acids, long chain n-3 PUFA-derived oxylipins, nitrite and hydrogen sulfide, and serum lipids and glucose. Vascular function was assessed using blood pressure, reactive hyperemia index, pulse wave velocity, and augmentation index (AIx). The DHA-rich oil significantly reduced AIx by 13% (P = 0.047) with the decrease following EPA-rich oil intervention not reaching statistical significance. Both interventions increased EPA- and DHA-derived oxylipins in the acute postprandial state, with an (1.3-fold) increase in 19,20-dihydroxydocosapentaenoic acid evident after DHA intervention (P < 0.001). In conclusion, a single dose of DHA significantly improved postprandial arterial stiffness as assessed by AIx, which if sustained would be associated with a significant decrease in CVD risk. The observed increases in oxylipins provide a mechanistic insight into the AIx effect. PMID:27170732

  12. Improving Functional Outcomes for Vascular Amputees Through Use of Mirror Therapy and Elimination of the Effects of Electromagnetic Fields.

    PubMed

    Houston, Helen; Dickerson, Anne E

    2016-01-01

    The objective of this pilot study was to investigate the effectiveness of combining an amputee limb cover to eliminate the effects of electromagnetic fields (i.e., pain) and a Mirror Therapy exercise program to improve functional outcomes for vascular amputees. A cross-sectional repeated-measures design was used with 14 participants with either acute amputations or surgery at least 8 to 24 months previously. The 4-week intervention included the use of an amputee limb cover and mirror therapy exercises each day. The outcome measures were activities of daily living interference (e.g., self-care, walking, car transfer, low chair transfer, sleep), and well-being (e.g., satisfaction, mood, quality of life) at three times (pre- and posttreatment and maintenance). Participants with acute amputations made significant improvements in the areas of self-care, walking, car transfer, sleep, mood, and quality of life, while the subacute participants improved significantly in sleep and satisfaction. A reduction in the time required before prosthetic fitting decreased from 12 weeks to 8 weeks for acute amputees and an improvement in wearing tolerance from 0-2 to 8-12 hours for the subacute amputees were unexpected results suggesting the combined intervention may improves the extent to which amputees can increase participation in their activities of everyday living. PMID:26295593

  13. Adiponectin, ghrelin, and leptin differentially influence human platelet and human vascular endothelial cell functions: implication in obesity-associated cardiovascular diseases.

    PubMed

    Elbatarny, Hisham S; Netherton, Stuart J; Ovens, Jeffrey D; Ferguson, Alastair V; Maurice, Donald H

    2007-03-01

    A very strong epidemiological link exists between obesity, the metabolic syndrome, diabetes and diabetes-associated cardiovascular pathologies. For this reason the peripheral effects of the centrally-acting satiety adipokines, adiponectin and leptin, and of non-adipose-derived hormones with similar effects, like ghrelin, have received considerable attention. In this report, we have extended our previous studies of the pro-thrombotic effects of leptin and determined the effects of adiponectin or ghrelin on human platelet activation. Thus, while leptin stimulated human platelet aggregation and adhesion, addition of adiponectin or of ghrelin did not affect either aggregation or adhesion of these cells; even at supra-physiological concentrations. In addition, we compared the impact of these three important hormones on microvascular endothelial cell permeability, an important parameter of endothelial function that when impaired contributes to several vascular pathologies. While physiologically relevant concentrations of either leptin or adiponectin increased the integrity of the diffusion barrier formed by a monolayer of human microvascular endothelial cells, only supra-physiological concentrations of ghrelin had this effect. None of these agents reduced microvascular endothelial barrier function. Taken together, our data are consistent with the ideas that leptin activates human platelets and limits transendothelial cell diffusion but that adiponectin only influences endothelial cell permeability. In contrast, ghrelin had neither of these effects. We propose that these data identify important differences in the effects of leptin, adiponectin or ghrelin on microvascular endothelial cells and platelets and may provide a basis on which to pharmacologically manipulate the selective effects of these peptides on these cell types in human cardiovascular or thrombotic diseases associated with obesity. PMID:17207790

  14. Usefulness of visceral obesity (waist/hip ratio) in predicting vascular endothelial function in healthy overweight adults.

    PubMed

    Brook, R D; Bard, R L; Rubenfire, M; Ridker, P M; Rajagopalan, S

    2001-12-01

    Vascular endothelial dysfunction (VED) is associated with obesity; however, its etiology remains controversial. By determining the predictors of fasting and postprandial endothelial function in overweight adults without other cardiovascular risk factors, we were able to investigate novel mechanisms directly linking obesity to VED. Thirty-two healthy adults (body mass index [BMI] > or =27 kg/m(2)) underwent determination of fasting low-density lipoprotein (LDL) particle size, high sensitivity C-reactive protein levels, anthropometric measurements, and endothelial function by flow-mediated dilation (FMD) of the brachial artery. Postprandial lipemia and FMD were measured 4 hours after ingestion of a high-fat meal. Blood pressures and fasting levels of lipoproteins, glucose, insulin, and fatty acids were within normal limits in all subjects. An abdominal fat pattern, as determined by an increased waist/hip ratio (WHR), was the sole significant predictor of FMD (r = -0.58, p = 0.001), despite no significant correlation between whole body obesity (BMI) and FMD. At comparable levels of BMI, obese subjects with a WHR > or =0.85 had a significantly blunted FMD compared with those with a WHR <0.85 (3.93 +/- 2.85% vs 8.34 +/- 5.47%, p = 0.016). Traditional coronary risk factors, C-reactive protein, postprandial lipemia, and LDL particle size did not predict FMD. We found no appreciable alteration in the postprandial state from fasting FMD (6.31 +/- 4.62% vs 6.25 +/- 5.47%, p = 0.95). The same results were found when women were analyzed alone. Increased abdominal adiposity determined by a simple WHR is a strong independent predictor of VED even in healthy overweight adults; this is a finding unexplained by alterations in conventional risk factors, systemic inflammation, or the atherogenic lipoprotein pattern. PMID:11728354

  15. On Cross-Sectional Associations of Leukocyte Telomere Length with Cardiac Systolic, Diastolic and Vascular Function: The Asklepios Study

    PubMed Central

    De Buyzere, Marc L.; Van daele, Caroline M.; Segers, Patrick; De Bacquer, Dirk; Van Criekinge, Wim; Bekaert, Sofie; Gillebert, Thierry C.; De Meyer, Tim

    2014-01-01

    Background Systemic telomere length has been associated with measures of diastolic function, vascular stiffness and left ventricular mass mainly in smaller, patient-specific settings and not in a general population. In this study we describe the applicability of these findings in a large, representative population. Methods and Results Peripheral blood leukocyte telomere length (PBL TL) was measured using telomere restriction fragment analysis in the young to middle-aged (>2500 volunteers, ∼35 to 55 years old) Asklepios study population, free from overt cardiovascular disease. Subjects underwent extensive echocardiographic, hemodynamic and biochemical phenotyping. After adjusting for relevant confounders (age, sex, systolic blood pressure, heart rate, body mass index and use of antihypertensive drugs) we found no associations between PBL TL and left ventricular mass index (P = 0.943), ejection fraction (P = 0.933), peak systolic septal annular motion (P = 0.238), pulse wave velocity (P = 0.971) or pulse pressure (P = 0.999). In contrast, our data showed positive associations between PBL TL and parameters of LV filling: the transmitral flow early (E) to late (A) velocity ratio (E/A-ratio; P<0.001), the ratio of early (e′) to late (a′) mitral annular velocities (e′/a′-ratio; P = 0.012) and isovolumic relaxation time (P = 0.015). Interestingly, these associations were stronger in women than in men and were driven by associations between PBL TL and the late diastolic components (A and a′). Conclusions In a generally healthy, young to middle-aged population, PBL TL is not related to LV mass or systolic function, but might be associated with an altered LV filling pattern, especially in women. PMID:25506937

  16. Effects of Oral Lycopene Supplementation on Vascular Function in Patients with Cardiovascular Disease and Healthy Volunteers: A Randomised Controlled Trial

    PubMed Central

    Gajendragadkar, Parag R.; Hubsch, Annette; Mäki-Petäjä, Kaisa M.; Serg, Martin; Wilkinson, Ian B.; Cheriyan, Joseph

    2014-01-01

    Aims The mechanisms by which a ‘Mediterranean diet’ reduces cardiovascular disease (CVD) burden remain poorly understood. Lycopene is a potent antioxidant found in such diets with evidence suggesting beneficial effects. We wished to investigate the effects of lycopene on the vasculature in CVD patients and separately, in healthy volunteers (HV). Methods and Results We randomised 36 statin treated CVD patients and 36 healthy volunteers in a 2∶1 treatment allocation ratio to either 7 mg lycopene or placebo daily for 2 months in a double-blind trial. Forearm responses to intra-arterial infusions of acetylcholine (endothelium-dependent vasodilatation; EDV), sodium nitroprusside (endothelium-independent vasodilatation; EIDV), and NG-monomethyl-L-arginine (basal nitric oxide (NO) synthase activity) were measured using venous plethysmography. A range of vascular and biochemical secondary endpoints were also explored. EDV in CVD patients post-lycopene improved by 53% (95% CI: +9% to +93%, P = 0.03 vs. placebo) without changes to EIDV, or basal NO responses. HVs did not show changes in EDV after lycopene treatment. Blood pressure, arterial stiffness, lipids and hsCRP levels were unchanged for lycopene vs. placebo treatment groups in the CVD arm as well as the HV arm. At baseline, CVD patients had impaired EDV compared with HV (30% lower; 95% CI: −45% to −10%, P = 0.008), despite lower LDL cholesterol (1.2 mmol/L lower, 95% CI: −1.6 to −0.9 mmol/L, P<0.001). Post-therapy EDV responses for lycopene-treated CVD patients were similar to HVs at baseline (2% lower, 95% CI: −30% to +30%, P = 0.85), also suggesting lycopene improved endothelial function. Conclusions Lycopene supplementation improves endothelial function in CVD patients on optimal secondary prevention, but not in HVs. Trial Registration ClinicalTrials.gov NCT01100385 PMID:24911964

  17. Vascular quality of care pilot study: how admission to a vascular surgery service affects evidence-based pharmacologic risk factor modification in patients with lower extremity peripheral arterial disease

    PubMed Central

    Steenhof, Naomi; Le Piane, Francesca; Leblanc, Kori; Eisenberg, Naomi R; Kwan, Yvonne; Malmberg, Christine; Papadopoulos, Alexandra; Roche-Nagle, Graham

    2014-01-01

    Background Peripheral arterial disease (PAD) guidelines recommend aggressive risk factor modification to improve cardiovascular outcomes. Recommended pharmacologic therapies include antiplatelets, angiotensin converting enzyme (ACE) inhibitors, and HMG-CoA-reductase inhibitors (statins). Purpose We studied the degree to which patient admission to a vascular surgery service increased the use of these therapies. Patients and methods The authors conducted a retrospective chart review of 150 patients with PAD admitted to the vascular surgery service at a large Canadian tertiary care hospital. The use of recommended pharmacologic therapies at the time of admission and discharge were compared. A multidisciplinary clinical team established criteria by which patients were deemed ineligible to receive any of the recommended therapies. Angiotensin receptor blockers (ARBs) were considered an alternative to ACE inhibitors. Results Prior to hospital admission, 64% of patients were on antiplatelet therapy, 67% were on an ACE inhibitor or ARB, and 71% were on a statin. At the time of discharge, 91% of patients were on an antiplatelet (or not, with an acceptable reason), 77% were on an ACE inhibitor or an ARB (or not, with an acceptable reason), and 85% were on a statin (or not, with an acceptable reason). While new prescriptions were largely responsible for improved guideline adherence with antiplatelets and statins, most of the apparent improvement in ACE inhibitor and ARB use was the result of identifying an acceptable reason for not having them prescribed. Conclusion This hypothesis generating pilot study supports the findings of others that there is suboptimal prescription of pharmacologic risk reduction therapies in the PAD population. Admission to a vascular service increases these rates. Nevertheless, some patients are still not receiving evidence-based treatment at discharge even after consideration of acceptable reasons. Strategies are needed to improve PAD guideline

  18. Positive Affect in the Midst of Distress: Implications for Role Functioning

    PubMed Central

    Moskowitz, Judith Tedlie; Shmueli-Blumberg, Dikla; Acree, Michael; Folkman, Susan

    2012-01-01

    Stress has been shown to deplete the self-regulation resources hypothesized to facilitate effective role functioning. However, recent research suggests that positive affect may help to replenish these vital self-regulation resources. Based on revised Stress and Coping theory and the Broaden-and-Build theory of positive emotion, three studies provide evidence of the potential adaptive function of positive affect in the performance of roles for participants experiencing stress. Participants were students (Study 1), caregivers of ill children (Study 2), and individuals recently diagnosed with HIV (Study 3). In cross sectional analyses, using role functioning as an indicator of self-regulation performance, we found that positive affect was significantly correlated with better self regulation performance, independent of the effects of negative affect. The effects were not as strong longitudinally, however, and there was little evidence of a reciprocal association between increases in positive affect and improvements in role functioning over time. The results provide some modest support for hypotheses stemming from the Broaden and Build model of positive emotion and revised Stress and Coping theory, both of which argue for unique adaptive functions of positive affect under stressful conditions. PMID:23175617

  19. The effects of Δ9-Tetrahydrocannabinole treatment on gonadal micro-vascularization and affected fertility examined by SEM and 3D-morphometry

    NASA Astrophysics Data System (ADS)

    Erlbacher, K. M. T.; Minnich, B.

    2015-10-01

    The present study focuses on the effects of Δ9-tetrahydrocannabinol (THC) on the reproductive system in nude rats with special emphasis on how Δ9-THC impacts the vascularization of testes which in turn indirectly influences fertility. Basically, Δ9-tetrahydrocannabinol (THC) causes not only negative (psychoactive) effects in the human body as cannabinole administration in medical use (dose-dependent) offers multiple new treatment opportunities such as pain relief or containment of various cancers. Concerning the reproductive system it strongly influences CB-receptors along the hypothalamic-pituitary-gonadal axis resulting in reduced plasma testosterone levels. There is also altered sperm quality parameters reported such as sperm motility or sperm count. On the other hand Δ9-THC effects endothelial growth factors (VEGF, Ang-1 etc.) respectively acts on their specific receptors which in turn modify angiogenesis and vascularization of tissues and organs (e.g. tumorous tissues). This leads to new therapeutical strategies in the suppression of various cancers by inhibiting (neo-)vascularization and in turn famishment of tumorous tissues (lack of nutrition supply). Here we studied the micro-vascularization of gonads in a long-term THC-treated nude rat model by vascular corrosion casting, SEM and 3D-morphometry.

  20. Improved Endothelial Function of Endothelial Cell Monolayer on the Soft Polyelectrolyte Multilayer Film with Matrix-Bound Vascular Endothelial Growth Factor.

    PubMed

    Chang, Hao; Hu, Mi; Zhang, He; Ren, Ke-Feng; Li, Bo-Chao; Li, Huan; Wang, Li-Mei; Lei, Wen-Xi; Ji, Jian

    2016-06-15

    Endothelialization on the vascular implants is of great importance for prevention of undesired postimplantation symptoms. However, endothelial dysfunction of regenerated endothelial cell (EC) monolayer has been frequently observed, leading to severe complications, such as neointimal hyperplasia, late thrombosis, and neoatherosclerosis. It has significantly impeded long-term success of the therapy. So far, very little attention has been paid on endothelial function of EC monolayer. Bioinspired by the microenvironment of the endothelium in a blood vessel, this study described a soft polyelectrolyte multilayer film (PEM) through layer-by-layer assembly of poly(l-lysine) (PLL) and hyaluronan (HA). The (PLL/HA) PEM was chemically cross-linked and further incorporated with vascular endothelial growth factor. It demonstrated that this approach could promote EC adhesion and proliferation, further inducing formation of EC monolayer. Further, improved endothelial function of the EC monolayer was achieved as shown with the tighter integrity, higher production of nitric oxide, and expression level of endothelial function related genes, compared to EC monolayers on traditional substrates with high stiffness (e.g., glass, tissue culture polystyrene, and stainless steel). Our findings highlighted the influence of substrate stiffness on endothelial function of EC monolayer, giving a new strategy in the surface design of vascular implants. PMID:27223460

  1. Vascular Regeneration in a Basal Chordate Is Due to the Presence of Immobile, Bi-Functional Cells

    PubMed Central

    Braden, Brian P.; Taketa, Daryl A.; Pierce, James D.; Kassmer, Susannah; Lewis, Daniel D.; De Tomaso, Anthony W.

    2014-01-01

    The source of tissue turnover during homeostasis or following injury is usually due to proliferation of a small number of resident, lineage-restricted stem cells that have the ability to amplify and differentiate into mature cell types. We are studying vascular regeneration in a chordate model organism, Botryllus schlosseri, and have previously found that following surgical ablation of the extracorporeal vasculature, new tissue will regenerate in a VEGF-dependent process within 48 hrs. Here we use a novel vascular cell lineage tracing methodology to assess regeneration in parabiosed individuals and demonstrate that the source of regenerated vasculature is due to the proliferation of pre-existing vascular resident cells and not a mobile progenitor. We also show that these cells are bi-potential, and can reversibly adopt two fates, that of the newly forming vessels or the differentiated vascular tissue at the terminus of the vasculature, known as ampullae. In addition, we show that pre-existing vascular resident cells differentially express progenitor and differentiated cell markers including the Botryllus homologs of CD133, VEGFR-2, and Cadherin during the regenerative process. PMID:24736432

  2. Carbohydrates and Endothelial Function: Is a Low-Carbohydrate Diet or a Low-Glycemic Index Diet Favourable for Vascular Health?

    PubMed Central

    Jovanovski, Elena; Zurbau, Andreea

    2015-01-01

    Low-carbohydrate diets have become increasingly popular in both media and clinical research settings. Although they may improve some metabolic markers, their effects on arterial function remain unclear. Endothelial dysfunction is the well-established response to cardiovascular risk factors and a pivotal feature that precedes atherosclerotic diseases. It has been demonstrated that a high carbohydrate-induced hyperglycemia and subsequent oxidative stress acutely worsen the efficacy of the endothelial vasodilatory system. Thus, in theory, a carbohydrate restricted diet may preserve the integrity of the arterial system. This review attempts to provide insight on whether low-carbohydrate diets have a favorable or detrimental impact on vascular function, or it is perhaps the quality of carbohydrate that should direct dietary recommendations. Research to date suggests that diets low in carbohydrate amount may negatively impact vascular endothelial function. Conversely, it appears that maintaining recommended carbohydrate intake with utilization of low glycemic index foods generates a more favorable vascular profile. Understanding these relationships will aid in deciphering the diverging role of modulating quantity and quality of carbohydrates on cardiovascular risk. PMID:25954727

  3. Functional hepatocyte heterogeneity. Vascular 2-oxoglutarate is almost exclusively taken up by perivenous, glutamine-synthetase-containing hepatocytes.

    PubMed

    Stoll, B; Hüssinger, D

    1989-05-15

    about 100% utilization of the [14C]oxoglutarate taken up by the liver for glutamine synthesis. This was again true for both the antegrade and the retrograde perfusion directions. On the other hand, addition of ammonia did not affect 14CO2 production from labeled oxoglutarate, when glutamine synthetase was inhibited by methionine sulfoximine. 4. The data suggest that vascular oxoglutarate is almost exclusively taken up by the small perivenous hepatocyte population containing glutamine synthetase, i.e. a cell population comprising only 6-7% of all hepatocytes. Thus, the findings demonstrate the existence of a, to date, uniquely zonally distributed oxoglutarate transport system which is probably Na+-dependent in the plasma membrane.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2567236

  4. Vascular rings.

    PubMed

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

    2016-06-01

    The term vascular ring refers to congenital vascular anomalies of the aortic arch system that compress the esophagus and trachea, causing symptoms related to those two structures. The most common vascular rings are double aortic arch and right aortic arch with left ligamentum. Pulmonary artery sling is rare and these patients need to be carefully evaluated for frequently associated tracheal stenosis. Another cause of tracheal compression occurring only in infants is the innominate artery compression syndrome. In the current era, the diagnosis of a vascular ring is best established by CT imaging that can accurately delineate the anatomy of the vascular ring and associated tracheal pathology. For patients with a right aortic arch there recently has been an increased recognition of a structure called a Kommerell diverticulum which may require resection and transfer of the left subclavian artery to the left carotid artery. A very rare vascular ring is the circumflex aorta that is now treated with the aortic uncrossing operation. Patients with vascular rings should all have an echocardiogram because of the incidence of associated congenital heart disease. We also recommend bronchoscopy to assess for additional tracheal pathology and provide an assessment of the degree of tracheomalacia and bronchomalacia. The outcomes of surgical intervention are excellent and most patients have complete resolution of symptoms over a period of time. PMID:27301603

  5. Low dietary protein intake during pregnancy differentially affects mitochondrial copy number in stromal vascular cells from subcutaneous versus visceral adipose tissue in the offspring

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The present study examined the influence of protein intake during pregnancy on mitochondrial metabolism in stromal vascular cells from subcutaneous (SVSu) and visceral (SVVi) adipose tissue of offspring fed a high fat diet. Obese-prone Sprague-Dawley rats were fed diets containing either 8% or 20% p...

  6. Cultured human vascular smooth muscle cells with functional thromboxane A2 receptors: measurement of U46619-induced /sup 45/calcium efflux

    SciTech Connect

    Dorn, G.W. II; Sens, D.; Chaikhouni, A.; Mais, D.; Halushka, P.V.

    1987-06-01

    Thromboxane A2 (TXA2)/prostaglandin H2 (PGH2) are potent vasoconstrictors whose contractile effects are mediated by increases in cellular calcium. Stable analogues of these compounds have shown calcium ionophore activity at high concentrations. To determine if effects of TXA2/PGH2 analogues on /sup 45/Ca/sup 2 +/ fluxes are receptor mediated, the effects of the stable TXA2/PGH2 mimetic U46619 and the TXA2/PGH2 receptor antagonist I-PTA-OH on /sup 45/Ca/+ fluxes in cultured human vascular smooth muscle cells were studied. The smooth muscle cells were cultured from human saphenous vein explants, and they retained the morphologic and immunologic characteristics of vascular smooth muscle cells. U46619 stimulated /sup 45/Ca/sup 2 +/ efflux in a dose-dependent manner with an EC50 of 398 +/- 26 nM (n = 4). The maximal /sup 45/Ca/sup 2 +/ efflux in response to U46619 (5 microM) was significantly greater (p = 0.006) than the /sup 45/Ca/sup 2 +/ efflux induced by KCl (40 mM). I-PTA-OH inhibited the U46619-induced /sup 45/Ca/sup 2 +/ efflux but had no effect on KCl-induced /sup 45/Ca/sup 2 +/ efflux. These results suggest that the effects of U46619 in increasing vascular smooth muscle cell calcium efflux are receptor mediated. Furthermore, vascular smooth muscle cells with functional TXA2/PGH2 receptors were cultured from human saphenous veins and provide a potentially useful in vitro system for the further study of TXA2/PGH2 receptor-mediated phenomena in human vascular tissue.

  7. Vascular Complications of Cancer Chemotherapy.

    PubMed

    Cameron, Alan C; Touyz, Rhian M; Lang, Ninian N

    2016-07-01

    Development of new anticancer drugs has resulted in improved mortality rates and 5-year survival rates in patients with cancer. However, many of the modern chemotherapies are associated with cardiovascular toxicities that increase cardiovascular risk in cancer patients, including hypertension, thrombosis, heart failure, cardiomyopathy, and arrhythmias. These limitations restrict treatment options and might negatively affect the management of cancer. The cardiotoxic effects of older chemotherapeutic drugs such as alkylating agents, antimetabolites, and anticancer antibiotics have been known for a while. The newer agents, such as the antiangiogenic drugs that inhibit vascular endothelial growth factor signalling are also associated with cardiovascular pathology, especially hypertension, thromboembolism, myocardial infarction, and proteinuria. Exact mechanisms by which vascular endothelial growth factor inhibitors cause these complications are unclear but impaired endothelial function, vascular and renal damage, oxidative stress, and thrombosis might be important. With increasing use of modern chemotherapies and prolonged survival of cancer patients, the incidence of cardiovascular disease in this patient population will continue to increase. Accordingly, careful assessment and management of cardiovascular risk factors in cancer patients by oncologists and cardiologists working together is essential for optimal care so that prolonged cancer survival is not at the expense of increased cardiovascular events. PMID:26968393

  8. The Vascular Depression Hypothesis: Mechanisms Linking Vascular Disease with Depression

    PubMed Central

    Taylor, Warren D.; Aizenstein, Howard J.; Alexopoulos, George S.

    2013-01-01

    The ‘Vascular Depression’ hypothesis posits that cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes. This hypothesis stimulated much research that has improved our understanding of the complex relationships between late-life depression (LLD), vascular risk factors, and cognition. Succinctly, there are well-established relationships between late-life depression, vascular risk factors, and cerebral hyperintensities, the radiological hallmark of vascular depression. Cognitive dysfunction is common in late-life depression, particularly executive dysfunction, a finding predictive of poor antidepressant response. Over time, progression of hyperintensities and cognitive deficits predicts a poor course of depression and may reflect underlying worsening of vascular disease. This work laid the foundation for examining the mechanisms by which vascular disease influences brain circuits and influences the development and course of depression. We review data testing the vascular depression hypothesis with a focus on identifying potential underlying vascular mechanisms. We propose a disconnection hypothesis, wherein focal vascular damage and white matter lesion location is a crucial factor influencing neural connectivity that contributes to clinical symptomatology. We also propose inflammatory and hypoperfusion hypotheses, concepts that link underlying vascular processes with adverse effects on brain function that influence the development of depression. Testing such hypotheses will not only inform the relationship between vascular disease and depression but also provide guidance on the potential repurposing of pharmacological agents that may improve late-life depression outcomes. PMID:23439482

  9. Conditional deletion of FAK in mice endothelium disrupts lung vascular barrier function due to destabilization of RhoA and Rac1 activities

    PubMed Central

    Schmidt, Tracy Thennes; Tauseef, Mohammad; Yue, Lili; Bonini, Marcelo G.; Gothert, Joachim; Shen, Tang-Long; Guan, Jun-Lin; Predescu, Sanda; Sadikot, Ruxana

    2013-01-01

    Loss of lung-fluid homeostasis is the hallmark of acute lung injury (ALI). Association of catenins and actin cytoskeleton with vascular endothelial (VE)-cadherin is generally considered the main mechanism for stabilizing adherens junctions (AJs), thereby preventing disruption of lung vascular barrier function. The present study identifies endothelial focal adhesion kinase (FAK), a nonreceptor tyrosine kinase that canonically regulates focal adhesion turnover, as a novel AJ-stabilizing mechanism. In wild-type mice, induction of ALI by intraperitoneal administration of lipopolysaccharide or cecal ligation and puncture markedly decreased FAK expression in lungs. Using a mouse model in which FAK was conditionally deleted only in endothelial cells (ECs), we show that loss of EC-FAK mimicked key features of ALI (diffuse lung hemorrhage, increased transvascular albumin influx, edema, and neutrophil accumulation in the lung). EC-FAK deletion disrupted AJs due to impairment of the fine balance between the activities of RhoA and Rac1 GTPases. Deletion of EC-FAK facilitated RhoA's interaction with p115-RhoA guanine exchange factor, leading to activation of RhoA. Activated RhoA antagonized Rac1 activity, destabilizing AJs. Inhibition of Rho kinase, a downstream effector of RhoA, reinstated normal endothelial barrier function in FAK−/− ECs and lung vascular integrity in EC-FAK−/− mice. Our findings demonstrate that EC-FAK plays an essential role in maintaining AJs and thereby lung vascular barrier function by establishing the normal balance between RhoA and Rac1 activities. PMID:23771883

  10. Conditional deletion of FAK in mice endothelium disrupts lung vascular barrier function due to destabilization of RhoA and Rac1 activities.

    PubMed

    Schmidt, Tracy Thennes; Tauseef, Mohammad; Yue, Lili; Bonini, Marcelo G; Gothert, Joachim; Shen, Tang-Long; Guan, Jun-Lin; Predescu, Sanda; Sadikot, Ruxana; Mehta, Dolly

    2013-08-15

    Loss of lung-fluid homeostasis is the hallmark of acute lung injury (ALI). Association of catenins and actin cytoskeleton with vascular endothelial (VE)-cadherin is generally considered the main mechanism for stabilizing adherens junctions (AJs), thereby preventing disruption of lung vascular barrier function. The present study identifies endothelial focal adhesion kinase (FAK), a nonreceptor tyrosine kinase that canonically regulates focal adhesion turnover, as a novel AJ-stabilizing mechanism. In wild-type mice, induction of ALI by intraperitoneal administration of lipopolysaccharide or cecal ligation and puncture markedly decreased FAK expression in lungs. Using a mouse model in which FAK was conditionally deleted only in endothelial cells (ECs), we show that loss of EC-FAK mimicked key features of ALI (diffuse lung hemorrhage, increased transvascular albumin influx, edema, and neutrophil accumulation in the lung). EC-FAK deletion disrupted AJs due to impairment of the fine balance between the activities of RhoA and Rac1 GTPases. Deletion of EC-FAK facilitated RhoA's interaction with p115-RhoA guanine exchange factor, leading to activation of RhoA. Activated RhoA antagonized Rac1 activity, destabilizing AJs. Inhibition of Rho kinase, a downstream effector of RhoA, reinstated normal endothelial barrier function in FAK-/- ECs and lung vascular integrity in EC-FAK-/- mice. Our findings demonstrate that EC-FAK plays an essential role in maintaining AJs and thereby lung vascular barrier function by establishing the normal balance between RhoA and Rac1 activities. PMID:23771883

  11. Effects of six-month supplementation with beta-hydroxy-beta-methylbutyrate, glutamine, and arginine on vascular endothelial function of older adults

    PubMed Central

    Ellis, Amy; Patterson, Morgan; Dudenbostel, Tanja; Calhoun, David; Gower, Barbara

    2015-01-01

    Background Vascular endothelial function declines with advancing age, due in part to increased oxidative stress and inflammation, and this age-related vascular dysfunction has been identified as an independent risk factor for cardiovascular diseases (CVD). This double-blind, placebo-controlled trial investigated the effects of a dietary supplement containing β-hydroxy-β-methylbutyrate (HMB), glutamine, and arginine on endothelial-dependent vasodilation of older adults. Subjects/Methods Thirty-one community-dwelling men and women aged 65-87 years were randomly assigned to two groups. The treatment group received two doses of the supplement daily (totaling 3g HMB, 14g glutamine, 14g arginine) for six months while the control group received an isocaloric placebo. At baseline and week 24, vascular endothelial function was measured by flow-mediated dilation of the brachial artery, and fasting blood samples were obtained to measure high-sensitivity C-reactive protein (hsCRP) and tumor necrosis factor-α (TNF-α). Results Paired samples t-tests revealed a 27% increase in flow-mediated dilation among the treatment group (p=0.003) while no change was observed in the placebo group (p=0.651). Repeated-measures ANOVA verified a significant time by group interaction (p=0.038). Although no significant changes were observed for hsCRP or TNF-α, a trend was observed for increasing hsCRP among the placebo group only (p=0.059). Conclusions These results suggest that dietary supplementation of HMB, glutamine, and arginine may favorably impact vascular endothelial function in older adults. Additional studies are needed to elucidate whether reduced inflammation or other mechanisms may underlie the benefits of supplementation. PMID:26306566

  12. Vascular Tumors

    PubMed Central

    Sepulveda, Abel; Buchanan, Edward P.

    2014-01-01

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

  13. Implications of Vascular Aging

    PubMed Central

    Barodka, Viachaslau M.; Joshi, Brijen L.; Berkowitz, Dan E.; Hogue, Charles W.; Nyhan, Daniel

    2011-01-01

    Chronological age is a well established risk factor for the development of cardiovascular diseases. The changes that accumulate in the vasculature with age, though, are highly variable. It is now increasingly recognized that indices of vascular health are more reliable than age per se in predicting adverse cardiovascular outcomes. The variation in the accrual of these age-related vascular changes is a function of multiple genetic and environmental factors. In this review, we highlight some of the pathophysiological mechanisms that characterize the vascular aging phenotype. Furthermore, we provide an overview of the key outcome studies that address the value of these vascular health indices in general and discuss potential effects on perioperative cardiovascular outcomes. PMID:21474663

  14. Affect and the Brain's Functional Organization: A Resting-State Connectivity Approach

    PubMed Central

    Rohr, Christiane S.; Okon-Singer, Hadas; Craddock, R. Cameron; Villringer, Arno; Margulies, Daniel S.

    2013-01-01

    The question of how affective processing is organized in the brain is still a matter of controversial discussions. Based on previous initial evidence, several suggestions have been put forward regarding the involved brain areas: (a) right-lateralized dominance in emotional processing, (b) hemispheric dominance according to positive or negative valence, (c) one network for all emotional processing and (d) region-specific discrete emotion matching. We examined these hypotheses by investigating intrinsic functional connectivity patterns that covary with results of the Positive and Negative Affective Schedule (PANAS) from 65 participants. This approach has the advantage of being able to test connectivity rather than activation, and not requiring a potentially confounding task. Voxelwise functional connectivity from 200 regions-of-interest covering the whole brain was assessed. Positive and negative affect covaried with functional connectivity involving a shared set of regions, including the medial prefrontal cortex, the anterior cingulate, the visual cortex and the cerebellum. In addition, each affective domain had unique connectivity patterns, and the lateralization index showed a right hemispheric dominance for negative affect. Therefore, our results suggest a predominantly right-hemispheric network with affect-specific elements as the underlying organization of emotional processes. PMID:23935850

  15. Plant Species and Functional Group Combinations Affect Green Roof Ecosystem Functions

    PubMed Central

    Lundholm, Jeremy; MacIvor, J. Scott; MacDougall, Zachary; Ranalli, Melissa

    2010-01-01

    Background Green roofs perform ecosystem services such as summer roof temperature reduction and stormwater capture that directly contribute to lower building energy use and potential economic savings. These services are in turn related to ecosystem functions performed by the vegetation layer such as radiation reflection and transpiration, but little work has examined the role of plant species composition and diversity in improving these functions. Methodology/Principal Findings We used a replicated modular extensive (shallow growing- medium) green roof system planted with monocultures or mixtures containing one, three or five life-forms, to quantify two ecosystem services: summer roof cooling and water capture. We also measured the related ecosystem properties/processes of albedo, evapotranspiration, and the mean and temporal variability of aboveground biomass over four months. Mixtures containing three or five life-form groups, simultaneously optimized several green roof ecosystem functions, outperforming monocultures and single life-form groups, but there was much variation in performance depending on which life-forms were present in the three life-form mixtures. Some mixtures outperformed the best monocultures for water capture, evapotranspiration, and an index combining both water capture and temperature reductions. Combinations of tall forbs, grasses and succulents simultaneously optimized a range of ecosystem performance measures, thus the main benefit of including all three groups was not to maximize any single process but to perform a variety of functions well. Conclusions/Significance Ecosystem services from green roofs can be improved by planting certain life-form groups in combination, directly contributing to climate change mitigation and adaptation strategies. The strong performance by certain mixtures of life-forms, especially tall forbs, grasses and succulents, warrants further investigation into niche complementarity or facilitation as mechanisms

  16. Vascular Diseases

    MedlinePlus

    ... heart and blood vessels, such as diabetes or high cholesterol Smoking Obesity Losing weight, eating healthy foods, being active and not smoking can help vascular disease. Other treatments include medicines and surgery.

  17. Greater γ-tocopherol status during acute smoking abstinence with nicotine replacement therapy improved vascular endothelial function by decreasing 8-iso-15(S)-prostaglandin F2α.

    PubMed

    Mah, Eunice; Pei, Ruisong; Guo, Yi; Masterjohn, Christopher; Ballard, Kevin D; Taylor, Beth A; Taylor, Alan W; Traber, Maret G; Volek, Jeff S; Bruno, Richard S

    2015-04-01

    Nicotine replacement therapy (NRT) improves the long-term success rate of smoking cessation, but induces oxidative stress and inflammatory responses that may delay the restoration of vascular endothelial function (VEF). No studies have examined co-therapy of NRT-assisted smoking abstinence with γ-tocopherol (γ-T), a vitamin E form with antioxidant and anti-inflammatory activities, on improvements in VEF. In a randomized, double-blind, placebo-controlled study, healthy smokers (25 ± 1 y old; mean ± SEM) received NRT and abstained from smoking for 24 h with placebo (n = 12) or oral administration of γ-T-rich mixture of tocopherols (γ-TmT; n = 11) that provided 500 mg γ-T. Brachial artery flow-mediated dilation (FMD), and biomarkers of nitric oxide metabolism, antioxidant status, inflammation, and lipid peroxidation [8-iso-prostaglandin F2α stereoisomers (8-iso-15(R)-PGF2α and 8-iso-15(S)-PGF2α)] were measured prior to and after 24 h of smoking abstinence. Smoking abstinence with NRT regardless of γ-TmT similarly decreased urinary naphthol (P < 0.05) without affecting plasma cotinine. γ-TmT increased plasma γ-T by 4-times and the urinary metabolite of γ-T, γ-carboxyethyl-chromanol, by three times. Smoking abstinence with γ-TmT, but not smoking abstinence alone, increased FMD without affecting plasma nitrate/nitrite or the ratio of asymmetric dimethylarginine/arginine. Urinary 8-iso-15(S)-PGF2α decreased only in those receiving γ-TmT and was inversely correlated to FMD (R = -0.43, P < 0.05). Circulating markers of inflammation were unaffected by smoking abstinence or γ-TmT. Short-term NRT-assisted smoking abstinence with γ-TmT, but not NRT-assisted smoking abstinence alone, improved VEF by decreasing 8-iso-15(S)-PGF2α, a vasoconstrictor that was otherwise unaffected by NRT-assisted smoking abstinence. PMID:25361769

  18. Functional delineation of rice MADS29 reveals its role in embryo and endosperm development by affecting hormone homeostasis

    PubMed Central

    Kapoor, Sanjay

    2013-01-01

    Rice MADS29 has recently been reported to cause programmed cell death of maternal tissues, the nucellus, and the nucellar projection during early stages of seed development. However, analyses involving OsMADS29 protein expression domains and characterization of OsMADS29 gain-of-function and knockdown phenotypes revealed novel aspects of its function in maintaining hormone homeostasis, which may have a role in the development of embryo and plastid differentiation and starch filling in endosperm cells. The MADS29 transcripts accumulated to high levels soon after fertilization; however, protein accumulation was found to be delayed by at least 4 days. Immunolocalization studies revealed that the protein accumulated initially in the dorsal-vascular trace and the outer layers of endosperm, and subsequently in the embryo and aleurone and subaleurone layers of the endosperm. Ectopic expression of MADS29 resulted in a severely dwarfed phenotype, exhibiting elevated levels of cytokinin, thereby suggesting that cytokinin biosynthesis pathway could be one of the major targets of OsMADS29. Overexpression of OsMADS29 in heterologous BY2 cells was found to mimic the effects of exogenous application of cytokinins that causes differentiation of proplastids to starch-containing amyloplasts and activation of genes involved in the starch biosynthesis pathway. Suppression of MADS29 expression by RNAi severely affected seed set. The surviving seeds were smaller in size, with developmental abnormalities in the embryo and reduced size of endosperm cells, which also contained loosely packed starch granules. Microarray analysis of overexpression and knockdown lines exhibited altered expression of genes involved in plastid biogenesis, starch biosynthesis, cytokinin signalling and biosynthesis. PMID:23929654

  19. Coronary-Heart-Disease-Associated Genetic Variant at the COL4A1/COL4A2 Locus Affects COL4A1/COL4A2 Expression, Vascular Cell Survival, Atherosclerotic Plaque Stability and Risk of Myocardial Infarction

    PubMed Central

    Pu, Xiangyuan; Ren, Meixia; An, Weiwei; Zhang, Ruoxin; Yan, Shunying; Situ, Haiteng; He, Xinjie; Chen, Yequn; Tan, Xuerui; Xiao, Qingzhong; Tucker, Arthur T.; Caulfield, Mark J.; Ye, Shu

    2016-01-01

    Genome-wide association studies have revealed an association between coronary heart disease (CHD) and genetic variation on chromosome 13q34, with the lead single nucleotide polymorphism rs4773144 residing in the COL4A2 gene in this genomic region. We investigated the functional effects of this genetic variant. Analyses of primary cultures of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) from different individuals showed a difference between rs4773144 genotypes in COL4A2 and COL4A1 expression levels, being lowest in the G/G genotype, intermediate in A/G and highest in A/A. Chromatin immunoprecipitation followed by allelic imbalance assays of primary cultures of SMCs and ECs that were of the A/G genotype revealed that the G allele had lower transcriptional activity than the A allele. Electrophoretic mobility shift assays and luciferase reporter gene assays showed that a short DNA sequence encompassing the rs4773144 site interacted with a nuclear protein, with lower efficiency for the G allele, and that the G allele sequence had lower activity in driving reporter gene expression. Analyses of cultured SMCs from different individuals demonstrated that cells of the G/G genotype had higher apoptosis rates. Immunohistochemical and histological examinations of ex vivo atherosclerotic coronary arteries from different individuals disclosed that atherosclerotic plaques with the G/G genotype had lower collagen IV abundance and thinner fibrous cap, a hallmark of unstable, rupture-prone plaques. A study of a cohort of patients with angiographically documented coronary artery disease showed that patients of the G/G genotype had higher rates of myocardial infarction, a phenotype often caused by plaque rupture. These results indicate that the CHD-related genetic variant at the COL4A2 locus affects COL4A2/COL4A1 expression, SMC survival, and atherosclerotic plaque stability, providing a mechanistic explanation for the association between the genetic variant and CHD

  20. Coronary-Heart-Disease-Associated Genetic Variant at the COL4A1/COL4A2 Locus Affects COL4A1/COL4A2 Expression, Vascular Cell Survival, Atherosclerotic Plaque Stability and Risk of Myocardial Infarction.

    PubMed

    Yang, Wei; Ng, Fu Liang; Chan, Kenneth; Pu, Xiangyuan; Poston, Robin N; Ren, Meixia; An, Weiwei; Zhang, Ruoxin; Wu, Jingchun; Yan, Shunying; Situ, Haiteng; He, Xinjie; Chen, Yequn; Tan, Xuerui; Xiao, Qingzhong; Tucker, Arthur T; Caulfield, Mark J; Ye, Shu

    2016-07-01

    Genome-wide association studies have revealed an association between coronary heart disease (CHD) and genetic variation on chromosome 13q34, with the lead single nucleotide polymorphism rs4773144 residing in the COL4A2 gene in this genomic region. We investigated the functional effects of this genetic variant. Analyses of primary cultures of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) from different individuals showed a difference between rs4773144 genotypes in COL4A2 and COL4A1 expression levels, being lowest in the G/G genotype, intermediate in A/G and highest in A/A. Chromatin immunoprecipitation followed by allelic imbalance assays of primary cultures of SMCs and ECs that were of the A/G genotype revealed that the G allele had lower transcriptional activity than the A allele. Electrophoretic mobility shift assays and luciferase reporter gene assays showed that a short DNA sequence encompassing the rs4773144 site interacted with a nuclear protein, with lower efficiency for the G allele, and that the G allele sequence had lower activity in driving reporter gene expression. Analyses of cultured SMCs from different individuals demonstrated that cells of the G/G genotype had higher apoptosis rates. Immunohistochemical and histological examinations of ex vivo atherosclerotic coronary arteries from different individuals disclosed that atherosclerotic plaques with the G/G genotype had lower collagen IV abundance and thinner fibrous cap, a hallmark of unstable, rupture-prone plaques. A study of a cohort of patients with angiographically documented coronary artery disease showed that patients of the G/G genotype had higher rates of myocardial infarction, a phenotype often caused by plaque rupture. These results indicate that the CHD-related genetic variant at the COL4A2 locus affects COL4A2/COL4A1 expression, SMC survival, and atherosclerotic plaque stability, providing a mechanistic explanation for the association between the genetic variant and CHD

  1. Acute Zonal Occult Outer Retinopathy in Japanese Patients: Clinical Features, Visual Function, and Factors Affecting Visual Function

    PubMed Central

    Saito, Saho; Saito, Wataru; Saito, Michiyuki; Hashimoto, Yuki; Mori, Shohei; Noda, Kousuke; Namba, Kenichi; Ishida, Susumu

    2015-01-01

    Purpose To evaluate the clinical features and investigate their relationship with visual function in Japanese patients with acute zonal occult outer retinopathy (AZOOR). Methods Fifty-two eyes of 38 Japanese AZOOR patients (31 female and 7 male patients; mean age at first visit, 35.0 years; median follow-up duration, 31 months) were retrospectively collected: 31 untreated eyes with good visual acuity and 21 systemic corticosteroid-treated eyes with progressive visual acuity loss. Variables affecting the logMAR values of best-corrected visual acuity (BCVA) and the mean deviation (MD) on Humphrey perimetry at initial and final visits were examined using multiple stepwise linear regression analysis. Results In untreated eyes, the mean MD at the final visit was significantly higher than that at the initial visit (P = 0.00002). In corticosteroid-treated eyes, the logMAR BCVA and MD at the final visit were significantly better than the initial values (P = 0.007 and P = 0.02, respectively). The final logMAR BCVA was 0.0 or less in 85% of patients. Variables affecting initial visual function were moderate anterior vitreous cells, myopia severity, and a-wave amplitudes on electroretinography; factors affecting final visual function were the initial MD values, female sex, moderate anterior vitreous cells, and retinal atrophy. Conclusions Our data indicated that visual functions in enrolled patients significantly improved spontaneously or after systemic corticosteroids therapy, suggesting that Japanese patients with AZOOR have good visual outcomes during the follow-up period of this study. Furthermore, initial visual field defects, gender, anterior vitreous cells, and retinal atrophy affected final visual functions in these patients. PMID:25919689

  2. Metacognitive Awareness of Facial Affect in Higher-Functioning Children and Adolescents with Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    McMahon, Camilla M.; Henderson, Heather A.; Newell, Lisa; Jaime, Mark; Mundy, Peter

    2016-01-01

    Higher-functioning participants with and without autism spectrum disorder (ASD) viewed a series of face stimuli, made decisions regarding the affect of each face, and indicated their confidence in each decision. Confidence significantly predicted accuracy across all participants, but this relation was stronger for participants with typical…

  3. Automatic Processing of Emotional Faces in High-Functioning Pervasive Developmental Disorders: An Affective Priming Study

    ERIC Educational Resources Information Center

    Kamio, Yoko; Wolf, Julie; Fein, Deborah

    2006-01-01

    This study examined automatic processing of emotional faces in individuals with high-functioning Pervasive Developmental Disorders (HFPDD) using an affective priming paradigm. Sixteen participants (HFPDD and matched controls) were presented with happy faces, fearful faces or objects in both subliminal and supraliminal exposure conditions, followed…

  4. Handgrip Strength, Positive Affect, and Perceived Health Are Prospectively Associated with Fewer Functional Limitations among Centenarians

    ERIC Educational Resources Information Center

    Franke, Warren D.; Margrett, Jennifer A.; Heinz, Melinda; Martin, Peter

    2012-01-01

    This study assessed the association between perceived health, fatigue, positive and negative affect, handgrip strength, objectively measured physical activity, body mass index, and self-reported functional limitations, assessed 6 months later, among 11 centenarians (age = 102 plus or minus 1). Activities of daily living, assessed 6 months prior to…

  5. Weight Reduction in Athletes May Adversely Affect the Phagocytic Function of Monocytes.

    ERIC Educational Resources Information Center

    Kono, Ichiro; And Others

    1988-01-01

    Study of the monocyte phagocytic function in nine competitive athletes before and after a two-week weight reduction (through calorie restriction) program revealed that their pre-program phagocytic activity was higher than in sedentary controls but decreased significantly after the program. This suggests calorie restriction may affect the human…

  6. The performance of single- and multi-proxy transfer functions (testate amoebae, bryophytes, vascular plants) for reconstructing mire surface wetness and pH

    NASA Astrophysics Data System (ADS)

    Mitchell, Edward A. D.; Payne, Richard J.; van der Knaap, Willem O.; Lamentowicz, Łukasz; Gąbka, Maciej; Lamentowicz, Mariusz

    2013-01-01

    Peatlands are widely exploited archives of paleoenvironmental change. We developed and compared multiple transfer functions to infer peatland depth to the water table (DWT) and pH based on testate amoeba (percentages, or presence/absence), bryophyte presence/absence, and vascular plant presence/absence data from sub-alpine peatlands in the SE Swiss Alps in order to 1) compare the performance of single-proxy vs. multi-proxy models and 2) assess the performance of presence/absence models. Bootstrapping cross-validation showing the best performing single-proxy transfer functions for both DWT and pH were those based on bryophytes. The best performing transfer functions overall for DWT were those based on combined testate amoebae percentages, bryophytes and vascular plants; and, for pH, those based on testate amoebae and bryophytes. The comparison of DWT and pH inferred from testate amoeba percentages and presence/absence data showed similar general patterns but differences in the magnitude and timing of some shifts. These results show new directions for paleoenvironmental research, 1) suggesting that it is possible to build good-performing transfer functions using presence/absence data, although with some loss of accuracy, and 2) supporting the idea that multi-proxy inference models may improve paleoecological reconstruction. The performance of multi-proxy and single-proxy transfer functions should be further compared in paleoecological data.

  7. Automatic facial responses to affective stimuli in high-functioning adults with autism spectrum disorder.

    PubMed

    Mathersul, Danielle; McDonald, Skye; Rushby, Jacqueline A

    2013-01-17

    Individuals with autism spectrum disorder (ASD) demonstrate atypical behavioural responses to affective stimuli, although the underlying mechanisms remain unclear. Investigating automatic responses to these stimuli may help elucidate these mechanisms. 18 high-functioning adults with ASDs and 18 typically developing controls viewed 54 extreme pleasant (erotica), extreme unpleasant (mutilations), and non-social neutral images from the International Affective Picture System (IAPS). Two-thirds of images received an acoustic startle probe 3s post-picture onset. Facial electromyography (EMG) activity (orbicularis, zygomaticus, corrugator), skin conductance (SCR) and cardiac responses were recorded. The adults with ASDs demonstrated typical affective startle modulation and automatic facial EMG responses but atypical autonomic (SCRs and cardiac) responses, suggesting a failure to orient to, or a deliberate effort to disconnect from, socially relevant stimuli (erotica, mutilations). These results have implications for neural systems known to underlie affective processes, including the orbitofrontal cortex and amygdala. PMID:23142408

  8. Dietary probucol preserves endothelial function in cholesterol-fed rabbits by limiting vascular oxidative stress and superoxide generation.

    PubMed Central

    Keaney, J F; Xu, A; Cunningham, D; Jackson, T; Frei, B; Vita, J A

    1995-01-01

    Excess vascular oxidative stress and the local formation of oxidized LDL (ox-LDL) have been implicated in the development of impaired endothelium-dependent arterial relaxation in hypercholesterolemia and atherosclerosis. Dietary antioxidants limit LDL oxidation in vitro and treatment of cholesterol-fed rabbits with dietary antioxidants preserves endothelium-derived relaxing factor (EDRF) action. To investigate the mechanism(s) responsible for these observations, we examined EDRF action, vascular oxidative stress, and antioxidant protection in male New Zealand White rabbits using four dietary treatments. Animals consumed standard chow (chow group) or chow supplemented with: (a) 0.5% cholesterol (0.5% cholesterol group); (b) 1% cholesterol (1% cholesterol group); or (c) 1% cholesterol and 1% probucol (probucol group). After 28 d of dietary treatment, segments of thoracic aorta from the 0.5 and 1% cholesterol groups demonstrated impairment of acetylcholine-mediated endothelium-dependent arterial relaxation compared to chow-fed animals (57 +/- 11% and 45 +/- 9% vs 78 +/- 3%, respectively; P < 0.05). In contrast, vessels from the probucol group demonstrated normal relaxation to acetylcholine (83 +/- 5%). Plasma cholesterol levels and the extent of atherosclerosis were similar among all cholesterol-fed groups. Probucol treatment was associated a threefold increase in LDL resistance to copper-induced oxidative modification (P < 0.05) and a reduction in tissue lipid peroxidation (as assessed by thiobarbituric acid-reactive substances; P < 0.05) compared to animals fed cholesterol alone. Most importantly, both of these changes were strongly correlated with preserved EDRF action. Moreover, cholesterol feeding was associated with a dose-dependent increase in vascular superoxide generation and lysophosphatidylcholine content, both of which were prevented by probucol treatment. From these findings, we conclude that probucol, a lipid-soluble antioxidant, preserves EDRF action in

  9. Structural and functional adaptation in the rat myocardium and coronary vascular bed caused by changes in pressure and volume load.

    PubMed

    Friberg, P

    1985-01-01

    The structural and functional characteristics of the myocardium and coronary vessels are major determinants of cardiac function. Both can be influenced by long-term hemodynamic changes, such as sustained alterations of pressure and/or volume load on the heart. The diastolic pressure-volume relationship of the left ventricle (LV) was evaluated in arrested isolated hearts from spontaneously hypertensive rats (SHR), Wistar Kyoto normotensive rats (WKY), pregnant and hyperthyroid SHR and WKY. Such measurements of the LV dimensions were also performed after antihypertensive therapy by hydralazine, felodipine, metoprolol and alpha-methyldopa. Cardiac function was studied in a perfusion system in which external work could be measured at various pre- and afterloads. Coronary flow and O2-extraction could also be determined. LV function was examined in young and aged SHR and WKY, in metoprolol-felodipine treated SHR and in two-kidney, one clip hypertension before and after its reversal by renal artery unclipping. The SHR LV in early established primary hypertension mainly showed eccentric hypertrophy, with increased LV enddiastolic volume for a given filling pressure and a marginal reduction of wall to lumen ratio (w/ri). Hence, a higher stroke volume could be delivered for a given myocardial fibre shortening. Nevertheless, when challenged by high afterloads, LV function in SHR was considerably augmented compared with WKY. The antihypertensive drugs used reduce arterial pressure in different ways, which may differently affect cardiac design. Generally, the results suggest that wall thickness was structurally adapted to keep w/ri balanced to the prevailing blood pressure, while internal radius was adapted to long-term changes in diastolic filling. Thus sympatholytic drugs which lowered arterial pressure by reducing cardiac output, induced a reduction of wall thickness at a minor change of internal radius, while drugs which reduced pressure by systemic vasodilation increased

  10. Small but Powerful: Top Predator Local Extinction Affects Ecosystem Structure and Function in an Intermittent Stream

    PubMed Central

    Rodríguez-Lozano, Pablo; Verkaik, Iraima; Rieradevall, Maria; Prat, Narcís

    2015-01-01

    Top predator loss is a major global problem, with a current trend in biodiversity loss towards high trophic levels that modifies most ecosystems worldwide. Most research in this area is focused on large-bodied predators, despite the high extinction risk of small-bodied freshwater fish that often act as apex consumers. Consequently, it remains unknown if intermittent streams are affected by the consequences of top-predators’ extirpations. The aim of our research was to determine how this global problem affects intermittent streams and, in particular, if the loss of a small-bodied top predator (1) leads to a ‘mesopredator release’, affects primary consumers and changes whole community structures, and (2) triggers a cascade effect modifying the ecosystem function. To address these questions, we studied the top-down effects of a small endangered fish species, Barbus meridionalis (the Mediterranean barbel), conducting an enclosure/exclosure mesocosm experiment in an intermittent stream where B. meridionalis became locally extinct following a wildfire. We found that top predator absence led to ‘mesopredator release’, and also to ‘prey release’ despite intraguild predation, which contrasts with traditional food web theory. In addition, B. meridionalis extirpation changed whole macroinvertebrate community composition and increased total macroinvertebrate density. Regarding ecosystem function, periphyton primary production decreased in apex consumer absence. In this study, the apex consumer was functionally irreplaceable; its local extinction led to the loss of an important functional role that resulted in major changes to the ecosystem’s structure and function. This study evidences that intermittent streams can be affected by the consequences of apex consumers’ extinctions, and that the loss of small-bodied top predators can lead to large ecosystem changes. We recommend the reintroduction of small-bodied apex consumers to systems where they have been

  11. Small but powerful: top predator local extinction affects ecosystem structure and function in an intermittent stream.

    PubMed

    Rodríguez-Lozano, Pablo; Verkaik, Iraima; Rieradevall, Maria; Prat, Narcís

    2015-01-01

    Top predator loss is a major global problem, with a current trend in biodiversity loss towards high trophic levels that modifies most ecosystems worldwide. Most research in this area is focused on large-bodied predators, despite the high extinction risk of small-bodied freshwater fish that often act as apex consumers. Consequently, it remains unknown if intermittent streams are affected by the consequences of top-predators' extirpations. The aim of our research was to determine how this global problem affects intermittent streams and, in particular, if the loss of a small-bodied top predator (1) leads to a 'mesopredator release', affects primary consumers and changes whole community structures, and (2) triggers a cascade effect modifying the ecosystem function. To address these questions, we studied the top-down effects of a small endangered fish species, Barbus meridionalis (the Mediterranean barbel), conducting an enclosure/exclosure mesocosm experiment in an intermittent stream where B. meridionalis became locally extinct following a wildfire. We found that top predator absence led to 'mesopredator release', and also to 'prey release' despite intraguild predation, which contrasts with traditional food web theory. In addition, B. meridionalis extirpation changed whole macroinvertebrate community composition and increased total macroinvertebrate density. Regarding ecosystem function, periphyton primary production decreased in apex consumer absence. In this study, the apex consumer was functionally irreplaceable; its local extinction led to the loss of an important functional role that resulted in major changes to the ecosystem's structure and function. This study evidences that intermittent streams can be affected by the consequences of apex consumers' extinctions, and that the loss of small-bodied top predators can lead to large ecosystem changes. We recommend the reintroduction of small-bodied apex consumers to systems where they have been extirpated, to restore

  12. High signal intensity in dentate nucleus and globus pallidus on unenhanced T1-weighted MR images in three patients with impaired renal function and vascular calcification.

    PubMed

    Barbieri, Sebastiano; Schroeder, Christophe; Froehlich, Johannes M; Pasch, Andreas; Thoeny, Harriet C

    2016-05-01

    Gadolinium-based contrast agents (primarily those with linear chelates) are associated with a dose-dependent signal hyperintensity in the dentate nucleus and the globus pallidus on unenhanced T1-weighted MRI following administration to selected patients with normal renal function. The accumulation of gadolinium has also been reported in the skin, heart, liver, lung, and kidney of patients with impaired renal function suffering from nephrogenic systemic fibrosis (NSF). Here we report on three patients with impaired renal function and vascular calcification (two with confirmed NSF) whose unenhanced T1-weighted MRIs showed conspicuous high signal intensity in the dentate nucleus and the globus pallidus after they had been exposed to relatively low doses of linear gadolinium-based contrast agents (0.27, 0.45, and 0.68 mmol/kg). Signal ratios between dentate nucleus and pons and between globus pallidus and thalamus were comparable with previously reported measurements in subjects without renal impairment. Of note, all three analysed patients suffered from transient signs of neurological disorders of undetermined cause. In conclusion, the exposure to 0.27-0.68 mmol/kg of linear gadolinium-based contrast agent was associated with probable gadolinium accumulation in the brain of three patients suffering from impaired renal function and vascular calcification. © 2016 The Authors. Contrast Media & Molecular Imaging published by John Wiley & Sons Ltd. PMID:26929131

  13. Antioxidants and vascular health.

    PubMed

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

    2015-12-15

    Oxygen free radicals and other reactive oxygen species (ROS) are common products of normal aerobic cellular metabolism, but high levels of ROS lead to oxidative stress and cellular damage. Increased production of ROS favors vascular dysfunction, inducing altered vascular permeability and inflammation, accompanied by the loss of vascular modulatory function, the imbalance between vasorelaxation and vasoconstriction, and the aberrant expression of inflammatory adhesion molecules. Inflammatory stimuli promote oxidative stress generated from the increased activity of mitochondrial nicotinamide adenine dinucleotide phosphate oxidase, particularly of the Nox4 isoform, with the consequent impairment of mitochondrial β-oxidation. Vascular dysfunction due to the increase in Nox4 activity and ROS overproduction leads to the progression of cardiovascular diseases, diabetes, inflammatory bowel disease, and neurological disorders. Considerable research into the development of effective antioxidant therapies using natural derivatives or new synthetic molecules has been conducted. Antioxidants may prevent cellular damage by reducing ROS overproduction or interfering in reactions that involve ROS. Vitamin E and ascorbic acid are well known as natural antioxidants that counteract lipid peroxidative damage by scavenging oxygen-derived free radicals, thus restoring vascular function. Recently, preliminary studies on natural antioxidants such as goji berries, thymus, rosemary, green tea ginseng, and garlic have been conducted for their efficacy in preventing vascular damage. N-acetyl-cysteine and propionyl-L-carnitine are synthetic compounds that regulate ROS production by replacing endogenous antioxidants in both endothelial and smooth muscle cells. In this review, we consider the molecular mechanisms underlying the generation of oxidative stress-induced vascular dysfunction as well as the beneficial effects of antioxidant therapies. PMID:26585821

  14. Genetic Pathways of Vascular Calcification

    PubMed Central

    Bowman, Marion A. Hofmann; McNally, Elizabeth M.

    2012-01-01

    Vascular calcification is an independent risk factor for cardiovascular disease. Arterial calcification of the aorta, coronary, carotid and peripheral arteries becomes more prevalent with age. Genomewide association studies have identified regions of the genome linked to vascular calcification, and these same regions are linked to myocardial infarction risk. The 9p21 region linked to vascular disease and inflammation also associates with vascular calcification. In addition to these common variants, rare genetic defects can serve as primary triggers of accelerated and premature calcification. Infancy-associated calcific disorders are caused by loss of function mutations in ENPP1 an enzyme that produces extracellular pyrophosphate. Adult onset vascular calcification is linked to mutations NTE5, another enzyme that regulates extracellular phosphate metabolism. Common conditions that secondarily enhance vascular calcification include atherosclerosis, metabolic dysfunction, diabetes, and impaired renal clearance. Oxidative stress and vascular inflammation, along with biophysical properties, converge with these predisposing factors to promote soft tissue mineralization. Vascular calcification is accompanied by an osteogenic profile, and this osteogenic conversion is seen within the vascular smooth muscle itself as well as the matrix. Herein we will review the genetic causes of medial calcification in the smooth muscle layer, focusing on recent discoveries of gene mutations that regulate extracellular matrix phosphate production and the role of S100 proteins as promoters of vascular calcification. PMID:23040839

  15. Cholinergic and serotonergic modulations differentially affect large-scale functional networks in the mouse brain.

    PubMed

    Shah, Disha; Blockx, Ines; Keliris, Georgios A; Kara, Firat; Jonckers, Elisabeth; Verhoye, Marleen; Van der Linden, Annemie

    2016-07-01

    Resting-state functional MRI (rsfMRI) is a widely implemented technique used to investigate large-scale topology in the human brain during health and disease. Studies in mice provide additional advantages, including the possibility to flexibly modulate the brain by pharmacological or genetic manipulations in combination with high-throughput functional connectivity (FC) investigations. Pharmacological modulations that target specific neurotransmitter systems, partly mimicking the effect of pathological events, could allow discriminating the effect of specific systems on functional network disruptions. The current study investigated the effect of cholinergic and serotonergic antagonists on large-scale brain networks in mice. The cholinergic system is involved in cognitive functions and is impaired in, e.g., Alzheimer's disease, while the serotonergic system is involved in emotional and introspective functions and is impaired in, e.g., Alzheimer's disease, depression and autism. Specific interest goes to the default-mode-network (DMN), which is studied extensively in humans and is affected in many neurological disorders. The results show that both cholinergic and serotonergic antagonists impaired the mouse DMN-like network similarly, except that cholinergic modulation additionally affected the retrosplenial cortex. This suggests that both neurotransmitter systems are involved in maintaining integrity of FC within the DMN-like network in mice. Cholinergic and serotonergic modulations also affected other functional networks, however, serotonergic modulation impaired the frontal and thalamus networks more extensively. In conclusion, this study demonstrates the utility of pharmacological rsfMRI in animal models to provide insights into the role of specific neurotransmitter systems on functional networks in neurological disorders. PMID:26195064

  16. An investigation on pharmacy functions and services affecting satisfaction of patients with prescriptions in community pharmacies.

    PubMed

    Sakurai, Hidehiko; Nakajima, Fumio; Tada, Yuichirou; Yoshikawa, Emi; Iwahashi, Yoshiki; Fujita, Kenji; Hayase, Yukitoshi

    2009-05-01

    Various functions expected by patient expects are needed with progress in the system for separation of dispensing and prescribing functions. In this investigation, the relationship between patient satisfaction and pharmacy function were analyzed quantitatively. A questionnaire survey was conducted in 178 community pharmacies. Questions on pharmacy functions and services totaled 87 items concerning information service, amenities, safety, personnel training, etc. The questionnaires for patients had five-grade scales and composed 11 items (observed variables). Based on the results, "the percentage of satisfied patients" was determined. Multivariate analysis was performed to investigate the relationship between patient satisfaction and pharmacy functions or services provided, to confirm patient's evaluation of the pharmacy, and how factors affected comprehensive satisfaction. In correlation analysis, "the number of pharmacists" and "comprehensive satisfaction" had a negative correlation. Other interesting results were obtained. As a results of factor analysis, three latent factors were obtained: the "human factor," "patients' convenience," and "environmental factor," Multiple regression analysis showed that the "human factor" affected "comprehensive satisfaction" the most. Various pharmacy functions and services influence patient satisfaction, and improvement in their quality increases patient satisfaction. This will result in the practice of patient-centered medicine. PMID:19420889

  17. Functions and sources of perceived social support among children affected by HIV/AIDS in China.

    PubMed

    Zhao, Guoxiang; Li, Xiaoming; Fang, Xiaoyi; Zhao, Junfeng; Hong, Yan; Lin, Xiuyun; Stanton, Bonita

    2011-06-01

    While the relationship between perceived social support (PSS) and psychosocial well-being has been well documented in the global literature, existing studies also suggest the existence of multiple domains in definition and measurement of PSS. The current study, utilizing data from 1299 rural children affected by HIV/AIDS in central China, examines the relative importance of PSS functional measures (informational/emotional, material/tangible, affectionate, and social interaction) and PSS structural measures (family/relatives, teachers, friends, and significant others) in predicting psychosocial outcomes including internalizing problems, externalizing problems, and educational resilience. Both functional and structural measures of PSS provided reliable measures of related but unique aspects of PSS. The findings of the current study confirmed the previous results that PSS is highly correlated with children's psychosocial well-being and such correlations vary by functions and sources of the PSS as well as different psychosocial outcomes. The findings in the current study suggested the roles of specific social support functions or resources may need to be assessed in relation to specific psychosocial outcome and the context of children's lives. The strong association between PSS and psychosocial outcomes underscores the importance of adequate social support to alleviate stressful life events and improve psychosocial well-being of children affected by HIV/AIDS. Meanwhile, the study findings call for gender and developmentally appropriate and situation-specific social support for children and families affected by HIV/AIDS. PMID:21287421

  18. Multi-modal magnetic resonance imaging and histology of vascular function in xenografts using macromolecular contrast agent hyperbranched polyglycerol (HPG-GdF).

    PubMed

    Baker, Jennifer H E; McPhee, Kelly C; Moosvi, Firas; Saatchi, Katayoun; Häfeli, Urs O; Minchinton, Andrew I; Reinsberg, Stefan A

    2016-01-01

    Macromolecular gadolinium (Gd)-based contrast agents are in development as blood pool markers for MRI. HPG-GdF is a 583 kDa hyperbranched polyglycerol doubly tagged with Gd and Alexa 647 nm dye, making it both MR and histologically visible. In this study we examined the location of HPG-GdF in whole-tumor xenograft sections matched to in vivo DCE-MR images of both HPG-GdF and Gadovist. Despite its large size, we have shown that HPG-GdF extravasates from some tumor vessels and accumulates over time, but does not distribute beyond a few cell diameters from vessels. Fractional plasma volume (fPV) and apparent permeability-surface area product (aPS) parameters were derived from the MR concentration-time curves of HPG-GdF. Non-viable necrotic tumor tissue was excluded from the analysis by applying a novel bolus arrival time (BAT) algorithm to all voxels. aPS derived from HPG-GdF was the only MR parameter to identify a difference in vascular function between HCT116 and HT29 colorectal tumors. This study is the first to relate low and high molecular weight contrast agents with matched whole-tumor histological sections. These detailed comparisons identified tumor regions that appear distinct from each other using the HPG-GdF biomarkers related to perfusion and vessel leakiness, while Gadovist-imaged parameter measures in the same regions were unable to detect variation in vascular function. We have established HPG-GdF as a biocompatible multi-modal high molecular weight contrast agent with application for examining vascular function in both MR and histological modalities. PMID:26268906

  19. Scaffold porosity and oxygenation of printed hydrogel constructs affect functionality of embedded osteogenic progenitors.

    PubMed

    Fedorovich, Natalja E; Kuipers, Elske; Gawlitta, Debby; Dhert, Wouter J A; Alblas, Jacqueline

    2011-10-01

    Insufficient supply of oxygen and nutrients throughout the graft is considered one of the principal limitations in development of large, tissue-engineered bone grafts. Organ or tissue printing by means of three-dimensional (3D) fiber deposition is a novel modality in regenerative medicine that combines pore formation and defined cell placement, and is used here for development of cell-laden hydrogel structures with reproducible internal architecture to sustain oxygen supply and to support adequate tissue development. In this study we tested the effect of porosity on multipotent stromal cells (MSCs) embedded in hydrogel constructs printed with a 3D fiber deposition (3DF) machine. For this, porous and solid alginate hydrogel scaffolds, with MSCs homogeneously dispersed throughout the construct, were printed and analyzed in vitro for the presence of hypoxia markers, metabolism, survival, and osteogenic differentiation. We demonstrated that porosity promotes oxygenation of MSCs in printed hydrogel scaffolds and supported the viability and osteogenic differentiation of embedded cells. Porous and solid printed constructs were subsequently implanted subcutaneously in immunodeficient mice to analyze tissue formation in relation to hypoxia responses of embedded cells. Implantation of printed grafts resulted in ingrowth of vascularized tissue and significantly enhanced oxygenation of embedded MSCs. In conclusion, the introduction of pores significantly enhances the conductive properties of printed hydrogel constructs and contributes to the functionality of embedded osteogenic progenitors. PMID:21599540

  20. Vascular-targeted TNFα improves tumor blood vessel function and enhances antitumor immunity and chemotherapy in colorectal cancer.

    PubMed

    Lu, Lan; Li, Zhi Jie; Li, Long Fei; Wu, William Ka Kei; Shen, Jing; Zhang, Lin; Chan, Ruby Lok Yi; Yu, Le; Liu, Ya Wei; Ren, Shun Xiang; Chan, Kam Ming; Cho, Chi Hin

    2015-07-28

    Delivery and penetration of chemotherapeutic drugs into neoplasm through the tumor vasculature are essential mechanisms to enhance the efficiency of chemotherapy. "Vascular targeting" strategy focuses on promoting the infiltration of chemotherapeutic drugs into neoplastic tissues. In this study, we achieved a targeted therapy by coupling tumor necrosis factor α (TNFα) with TCP-1, a novel vascular-targeting peptide, in an orthotopic colorectal cancer model in mice. High dose of TCP-1-conjugated TNFα (TCP-1/TNFα: 5μg/mouse) displayed potent antitumor activity by inducing apoptosis and reducing microvessel number in tumors than unconjugated TNFα, with no evidence of increased toxicity. In the combined therapy, the antitumor action of 5-fluorouracil (5-FU) was potentiated when the mice were pretreated with a low dose of TNFα (1ng/mouse) and to a greater extent by the same concentration of TCP-1/TNFα. In this regard, TCP-1/TNFα combined with 5-FU synergistically inhibited the tumor growth, induced apoptosis and reduced cell proliferation. More importantly, TCP-1/TNFα normalized the tumor vasculature and facilitated the infiltration of immune cells to neoplasm as well as attenuated the immunosuppressing effects of TNFα in bone marrow and spleen. At the same time, TCP-1/TNFα significantly improved 5-FU absorption into the tumor mass. Taken together, these findings underscore the therapeutic potential of TCP-1 as a drug carrier in cancer therapy. TCP-1 is a novel vascular-targeting peptide and appears to be a promising agent for drug delivery. TCP-1 fused with TNFα holds great promise for colorectal cancer therapy. PMID:26003042

  1. Cognitive Function in Adolescent Patients with Anorexia Nervosa and Unipolar Affective Disorders.

    PubMed

    Sarrar, Lea; Holzhausen, Martin; Warschburger, Petra; Pfeiffer, Ernst; Lehmkuhl, Ulrike; Schneider, Nora

    2016-05-01

    Studies have shown impairments in cognitive function among adult patients with anorexia nervosa (AN) and affective disorders (AD). The association between cognitive dysfunctions, AN and AD as well as the specificity for these psychiatric diagnoses remains unclear. Therefore, we examined cognitive flexibility and processing speed in 47 female adolescent patients with AN, 21 female adolescent patients with unipolar affective disorders and 48 female healthy adolescents. All participants completed a neuropsychological test battery. There were no significant group differences regarding cognitive function, except for psychomotor processing speed with poorer performance in patients with AN. A further analysis revealed that all groups performed with the normal range, although patients with AN were over represented in the poorest performing quartile. We found no severe cognitive impairments in either patient group. Nevertheless, belonging to the AN group contributed significantly to poor performances in neuropsychological tasks. Therefore, we conclude that the risk for cognitive impairments is slightly higher for patients with AN. PMID:26695683

  2. The relationship between sleep-wake cycle and cognitive functioning in young people with affective disorders.

    PubMed

    Carpenter, Joanne S; Robillard, Rébecca; Lee, Rico S C; Hermens, Daniel F; Naismith, Sharon L; White, Django; Whitwell, Bradley; Scott, Elizabeth M; Hickie, Ian B

    2015-01-01

    Although early-stage affective disorders are associated with both cognitive dysfunction and sleep-wake disruptions, relationships between these factors have not been specifically examined in young adults. Sleep and circadian rhythm disturbances in those with affective disorders are considerably heterogeneous, and may not relate to cognitive dysfunction in a simple linear fashion. This study aimed to characterise profiles of sleep and circadian disturbance in young people with affective disorders and examine associations between these profiles and cognitive performance. Actigraphy monitoring was completed in 152 young people (16-30 years; 66% female) with primary diagnoses of affective disorders, and 69 healthy controls (18-30 years; 57% female). Patients also underwent detailed neuropsychological assessment. Actigraphy data were processed to estimate both sleep and circadian parameters. Overall neuropsychological performance in patients was poor on tasks relating to mental flexibility and visual memory. Two hierarchical cluster analyses identified three distinct patient groups based on sleep variables and three based on circadian variables. Sleep clusters included a 'long sleep' cluster, a 'disrupted sleep' cluster, and a 'delayed and disrupted sleep' cluster. Circadian clusters included a 'strong circadian' cluster, a 'weak circadian' cluster, and a 'delayed circadian' cluster. Medication use differed between clusters. The 'long sleep' cluster displayed significantly worse visual memory performance compared to the 'disrupted sleep' cluster. No other cognitive functions differed between clusters. These results highlight the heterogeneity of sleep and circadian profiles in young people with affective disorders, and provide preliminary evidence in support of a relationship between sleep and visual memory, which may be mediated by use of antipsychotic medication. These findings have implications for the personalisation of treatments and improvement of functioning in

  3. The Relationship between Sleep-Wake Cycle and Cognitive Functioning in Young People with Affective Disorders

    PubMed Central

    Carpenter, Joanne S.; Robillard, Rébecca; Lee, Rico S. C.; Hermens, Daniel F.; Naismith, Sharon L.; White, Django; Whitwell, Bradley; Scott, Elizabeth M.; Hickie, Ian B.

    2015-01-01

    Although early-stage affective disorders are associated with both cognitive dysfunction and sleep-wake disruptions, relationships between these factors have not been specifically examined in young adults. Sleep and circadian rhythm