Exercise improves the dilatation function of mesenteric arteries in postmyocardial infarction rats via a PI3K/Akt/eNOS pathway-mediated mechanism

2010 ◽  
Vol 299 (6) ◽  
pp. H2097-H2106 ◽  
Author(s):  
Youhua Wang ◽  
Shengpeng Wang ◽  
W. Gil Wier ◽  
Quanjiang Zhang ◽  
Hongke Jiang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Structural Integrity ◽  
Peripheral Resistance ◽  
Mesenteric Arteries ◽  
Ultrastructural Changes ◽  
Sprague Dawley ◽  
Resistance Arteries ◽  
Underlying Mechanisms ◽  
Exercise Induced

Myocardial infarction (MI) has been shown to induce endothelial dysfunction in peripheral resistance arteries and thus increase peripheral resistance. This study was designed to investigate the underlying mechanisms of post-MI-related dysfunctional dilatation of peripheral resistance arteries and, furthermore, to examine whether exercise may restore dysfunctional dilatation of peripheral resistance arteries. Adult male Sprague-Dawley rats were divided into three groups: sham-operated, MI, and MI + exercise. Ultrastructure and relaxation function of the mesenteric arteries, as well as phosphatidylinositol-3 kinase (PI3K), Akt kinases (Akt), endothelial nitric oxide synthase (eNOS) activity, and phosphorylation of PI3K, Akt, and eNOS by ACh were determined. Post-MI rats exhibited pronounced ultrastructural changes in mesenteric artery endothelial cells and endothelial dysfunction. In addition, the activities of PI3K, Akt, and eNOS, and their phosphorylation by ACh were significantly attenuated in mesenteric arteries ( P < 0.05–0.01). After 8 wk of exercise, not only did endothelial cells appeared more normal in structure, but also ameliorated post-MI-associated mesenteric arterial dysfunction, which were accompanied by elevated activities of PI3K, Akt, and eNOS, and their phosphorylation by ACh ( P < 0.05–0.01). Importantly, inhibition of either PI3K or eNOS attenuated exercise-induced restoration of the dilatation function and blocked PI3K, Akt, and eNOS phosphorylation by ACh in the mesenteric arteries. These data demonstrate that MI induces dysfunctional dilation of peripheral resistance arteries by degradation of endothelial structural integrity and attenuating PI3K-Akt-eNOS signaling. Exercise may restore dilatation function of peripheral resistance arteries by protecting endothelial structural integrity and increasing PI3K-Akt-eNOS signaling cascades.

Estrogen replacement attenuates resistance artery adrenergic sensitivity via endothelial vasodilators

1997 ◽  
Vol 272 (5) ◽  
pp. H2264-H2270 ◽  
Author(s):  
M. C. Meyer ◽  
K. Cummings ◽  
G. Osol
Keyword(s):  
Blood Pressure ◽  
Peripheral Resistance ◽  
Mesenteric Arteries ◽  
Muscarinic Agonist ◽  
Estrogen Replacement ◽  
Resistance Artery ◽  
Sprague Dawley ◽  
Resistance Arteries ◽  
Adrenergic Stimulation

The objective of this study was to determine whether chronic estrogen replacement alters adrenergic constriction and endothelium-dependent dilation in resistance arteries from the rat. Resistance-sized (< 200 microns) mesenteric arteries from castrated female Sprague-Dawley rats with (E2; 21 day, 0.5-mg pellet) and without (OvX) estrogen replacement were removed for in vitro study on a pressurized arteriograph system. Sensitivity to alpha-adrenergic constriction and the role of the endothelium in its modulation and of agonist-provoked endothelium-dependent relaxation were determined. Estrogen-treated rats had decreased heart rate as well as systolic and diastolic blood pressure. Arteries from estrogen-replaced rats were fivefold less sensitive to alpha 1-adrenergic stimulation with phenylephrine (50% effective concentration: E2, 3.2 +/- 1.1 microM; OvX, 0.6 +/- 0.2 microM; P < 0.05). This difference was abolished by endothelial denudation, blockade of cyclooxygenase (1 microM ibuprofen), or nitric oxide synthase blockade (0.24 mM N omega-nitro-L-arginine). There was no difference in muscarinic agonist-provoked relaxation or vascular smooth muscle sensitivity to prostacyclin or sodium nitroprusside. These results indicate that estrogen replacement decreases resistance artery adrenergic sensitivity by increasing the basal release of relaxing factors from the endothelium. This effect on small artery function may produce dual cardioprotective effects by decreasing peripheral resistance, blood pressure, and the likelihood of thrombosis.

scholarly journals Polarized Proteins in Endothelium and Their Contribution to Function

2021 ◽  
pp. 1-27
Author(s):  
Abigail G. Wolpe ◽  
Claire A. Ruddiman ◽  
Phillip J. Hall ◽  
Brant E. Isakson
Keyword(s):  
Endothelial Cells ◽  
Endothelial Function ◽  
Planar Cell Polarity ◽  
Protein Localization ◽  
Peripheral Resistance ◽  
Specific Protein ◽  
Resistance Arteries ◽  
Extracellular Stimuli ◽  
Small Resistance ◽  
Signaling Domains

Protein localization in endothelial cells is tightly regulated to create distinct signaling domains within their tight spatial restrictions including luminal membranes, abluminal membranes, and interendothelial junctions, as well as caveolae and calcium signaling domains. Protein localization in endothelial cells is also determined in part by the vascular bed, with differences between arteries and veins and between large and small arteries. Specific protein polarity and localization is essential for endothelial cells in responding to various extracellular stimuli. In this review, we examine protein localization in the endothelium of resistance arteries, with occasional references to other vessels for contrast, and how that polarization contributes to endothelial function and ultimately whole organism physiology. We highlight the protein localization on the luminal surface, discussing important physiological receptors and the glycocalyx. The protein polarization to the abluminal membrane is especially unique in small resistance arteries with the presence of the myoendothelial junction, a signaling microdomain that regulates vasodilation, feedback to smooth muscle cells, and ultimately total peripheral resistance. We also discuss the interendothelial junction, where tight junctions, adherens junctions, and gap junctions all convene and regulate endothelial function. Finally, we address planar cell polarity, or axial polarity, and how this is regulated by mechanosensory signals like blood flow.

scholarly journals Endothelial dysfunction precedes hypertension in diet-induced insulin resistance

1998 ◽  
Vol 275 (3) ◽  
pp. R788-R792 ◽  
Author(s):  
Prasad V. G. Katakam ◽  
Michael R. Ujhelyi ◽  
Margarethe E. Hoenig ◽  
Allison Winecoff Miller
Keyword(s):  
Insulin Resistance ◽  
Endothelial Dysfunction ◽  
Serum Insulin ◽  
Serum Glucose ◽  
Mesenteric Arteries ◽  
Control Group ◽  
Sprague Dawley ◽  
Insulin Resistant ◽  
Glucose Levels

The insulin-resistant (IR) syndrome may be an impetus for the development of hypertension (HTN). Unfortunately, the mechanism by which this could occur is unclear. Our laboratory and others have described impaired endothelium-mediated relaxation in IR, mildly hypertensive rats. The purpose of the current study is to determine if HTN is most likely a cause or result of impaired endothelial function. Sprague-Dawley rats were randomized to receive a fructose-rich diet for 3, 7, 10, 14, 18, or 28 days or were placed in a control group. The control group received rat chow. After diet treatment, animals were instrumented with arterial cannulas, and while awake and unrestrained, their blood pressure (BP) was measured. Subsequently, endothelium-mediated relaxation to acetylcholine was determined (in vitro) by measuring intraluminal diameter of phenylephrine-preconstricted mesenteric arteries (∼250 μM). Serum insulin levels were significantly elevated in all groups receiving fructose feeding compared with control, whereas there were no differences in serum glucose levels between groups. Impairment of endothelium-mediated relaxation starts by day 14 [mean percent maximal relaxation (Emax): 69 ± 10% of baseline] and becomes significant by day 18 (Emax: 52 ± 11% of baseline; P < 0.01). However, the mean BP (mmHg) does not become significantly elevated until day 28 [BP: 132 ± 1 ( day 28) vs. 116 ± 3 (control); P < 0.05]. These findings demonstrate that both IR and endothelial dysfunction occur before HTN in this model and suggest that endothelial dysfunction may be a mechanism linking insulin resistance and essential HTN.

Abstract 637: Hydrogen Sulfide Acts on Endothelial Cells to Elicit Dilation.

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Nancy L Kanagy ◽  
Jessica M Osmond ◽  
Olan Jackson-Weaver ◽  
Benjimen R Walker
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Hydrogen Sulfide ◽  
Mesenteric Arteries ◽  
Direct Effects ◽  
Sprague Dawley ◽  
Imaging Studies ◽  
Knock Out ◽  
Event Frequency ◽  
Sprague Dawley Rats

Hydrogen sulfide (H 2 S), produced by the enzyme cystathionine-γ lyase (CSE), dilates arteries by hyperpolarizing and relaxing vascular smooth muscle cells (VSMC) and CSE knock-out causes hypertension and endothelial dysfunction showing the importance of this system. However, it is not clear if H 2 S-induced VSMC depolarization and relaxation is mediated by direct effects on VSMC or indirectly through actions on endothelial cells (EC). We reported previously that disrupting EC prevents H 2 S-induced vasodilation suggesting H 2 S might act directly on EC. Because inhibiting large-conductance Ca 2+ -activated K + (BK Ca ) channels also inhibits H 2 S-induced dilation, we hypothesized that H 2 S activates EC BK Ca channels to hyperpolarize EC and increase EC Ca 2+ which stimulates release of a secondary hyperpolarizing factor. Small mesenteric arteries from male Sprague-Dawley rats were used for all experiments. We found that EC disruption prevented H 2 S-induced VSMC membrane potential ( E m ) hyperpolarization. Blocking EC BK Ca channels with luminal application of the BK Ca inhibitor, iberiotoxin (IbTx, 100 nM), also prevented NaHS-induced dilation and VSMC hyperpolarization but did not affect resting VSMC E m showing EC specific actions. Sharp electrode recordings in arteries cut open to expose EC demonstrated H 2 S-induced hyperpolarization of EC while Ca 2+ imaging studies in fluor-4 loaded EC showed that H 2 S increases EC Ca 2+ event frequency. Thus H 2 S can act directly on EC. Inhibiting the EC enzyme cytochrome P 450 2C (Cyp2C) with sulfaphenazole also prevented VSMC depolarization and vasodilation. Finally, inhibiting TRPV4 channels to block the target of the Cyp2C product 11,12-EET inhibited NaHS-induced dilation. Combined with our previous report that CSE inhibition decreases BK Ca currents in EC, these results suggest that H 2 S stimulates EC BK Ca channels and activates Cyp2C upstream of VSMC hyperpolarization and vasodilation.

scholarly journals TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure

2009 ◽  
Vol 297 (3) ◽  
pp. H1096-H1102 ◽  
Author(s):  
Scott Earley ◽  
Thierry Pauyo ◽  
Rebecca Drapp ◽  
Matthew J. Tavares ◽  
Wolfgang Liedtke ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Peripheral Resistance ◽  
Muscle Cells ◽  
Mesenteric Arteries ◽  
Transient Receptor Potential Vanilloid ◽  
Resistance Arteries

Transient receptor potential vanilloid 4 (TRPV4) channels have been implicated as mediators of calcium influx in both endothelial and vascular smooth muscle cells and are potentially important modulators of vascular tone. However, very little is known about the functional roles of TRPV4 in the resistance vasculature or how these channels influence hemodynamic properties. In the present study, we examined arterial vasomotor activity in vitro and recorded blood pressure dynamics in vivo using TRPV4 knockout (KO) mice. Acetylcholine-induced hyperpolarization and vasodilation were reduced by ∼75% in mesenteric resistance arteries from TRPV4 KO versus wild-type (WT) mice. Furthermore, 11,12-epoxyeicosatrienoic acid (EET), a putative endothelium-derived hyperpolarizing factor, activated a TRPV4-like cation current and hyperpolarized the membrane of vascular smooth muscle cells, resulting in the dilation of mesenteric arteries from WT mice. In contrast, 11,12-EET had no effect on membrane potential, diameter, or ionic currents in the mesenteric arteries from TRPV4 KO mice. A disruption of the endothelium reduced 11,12-EET-induced hyperpolarization and vasodilatation by ∼50%. A similar inhibition of these responses was observed following the block of endothelial (small and intermediate conductance) or smooth muscle (large conductance) K+ channels, suggesting a link between 11,12-EET activity, TRPV4, and K+ channels in endothelial and smooth muscle cells. Finally, we found that hypertension induced by the inhibition of nitric oxide synthase was greater in TRPV4 KO compared with WT mice. These results support the conclusion that both endothelial and smooth muscle TRPV4 channels are critically involved in the vasodilation of mesenteric arteries in response to endothelial-derived factors and suggest that in vivo this mechanism opposes the effects of hypertensive stimuli.

scholarly journals Angiotensin-(1-7) and low-dose angiotensin II infusion reverse salt-induced endothelial dysfunction via different mechanisms in rat middle cerebral arteries

2010 ◽  
Vol 299 (4) ◽  
pp. H1024-H1033 ◽  
Author(s):  
Matthew J. Durand ◽  
Gábor Raffai ◽  
Brian D. Weinberg ◽  
Julian H. Lombard
Keyword(s):  
Endothelial Dysfunction ◽  
Receptor Antagonist ◽  
Intravenous Infusion ◽  
Low Dose ◽  
Cerebral Arteries ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Resistance Arteries ◽  
Mas Receptor ◽  
Middle Cerebral Arteries

The goals of this study were to 1) determine the acute effect of ANG-(1-7) on vascular tone in isolated middle cerebral arteries (MCAs) from Sprague-Dawley rats fed a normal salt (NS; 0.4% NaCl) diet, 2) evaluate the ability of chronic intravenous infusion of ANG-(1-7) (4 ng·kg−1·min−1) for 3 days to restore endothelium-dependent dilation to acetylcholine (ACh) in rats fed a high-salt (HS; 4% NaCl) diet, and 3) determine whether the amelioration of endothelial dysfunction by ANG-(1-7) infusion in rats fed a HS diet is different from the protective effect of low-dose ANG II infusion in salt-fed rats. MCAs from rats fed a NS diet dilated in response to exogenous ANG-(1-7) (10−10–10−5 M). Chronic ANG-(1-7) infusion significantly reduced vascular superoxide levels and restored the nitric oxide-dependent dilation to ACh (10−10–10−5 M) that was lost in MCAs of rats fed a HS diet. Acute vasodilation to ANG-(1-7) and the restoration of ACh-induced dilation by chronic ANG-(1-7) infusion in rats fed a HS diet were blocked by the Mas receptor antagonist [d-ALA( 7 )]-ANG-(1-7) or the ANG II type 2 receptor antagonist PD-123319 and unaffected by ANG II type 1 receptor blockade with losartan. The restoration of ACh-induced dilation in MCAs of HS-fed rats by chronic intravenous infusion of ANG II (5 ng·kg−1·min−1) was blocked by losartan and unaffected by d-ALA. These findings demonstrate that circulating ANG-(1-7), working via the Mas receptor, restores endothelium-dependent vasodilation in cerebral resistance arteries of animals fed a HS diet via mechanisms distinct from those activated by low-dose ANG II infusion.

scholarly journals Vascular function in rats with adenine-induced chronic renal failure

2012 ◽  
Vol 302 (12) ◽  
pp. R1426-R1435 ◽  
Author(s):  
Lisa Nguy ◽  
Holger Nilsson ◽  
Jaana Lundgren ◽  
Maria E. Johansson ◽  
Tom Teerlink ◽  
...  
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Vascular Function ◽  
Ex Vivo ◽  
Mesenteric Arteries ◽  
Maximal Response ◽  
Sprague Dawley ◽  
Resistance Arteries ◽  
Severe Renal Failure ◽  
Stress Markers

The aim of the present study was to characterize the function of resistance arteries, and the aorta, in rats with adenine-induced chronic renal failure (A-CRF). Sprague-Dawley rats were randomized to chow with or without adenine supplementation. After 6–10 wk, mesenteric arteries and thoracic aortas were analyzed ex vivo by wire myography. Plasma creatinine concentrations were elevated twofold at 2 wk, and eight-fold at the time of death in A-CRF animals. Ambulatory systolic and diastolic blood pressures measured by radiotelemetry were significantly elevated in A-CRF animals from week 3 and onward. At death, A-CRF animals had anemia, hyperphosphatemia, hyperparathyroidism, and elevated plasma levels of asymmetric dimethylarginine and oxidative stress markers. There were no significant differences between groups in the sensitivity, or maximal response, to ACh, sodium nitroprusside (SNP), norepinephrine, or phenylephrine in either mesenteric arteries or aortas. However, in A-CRF animals, the rate of aortic relaxation was significantly reduced following washout of KCl (both in intact and endothelium-denuded aorta) and in response to ACh and SNP. Also the rate of contraction in response to KCl was significantly reduced in A-CRF animals both in mesenteric arteries and aortas. The media of A-CRF aortas was thickened and showed focal areas of fragmented elastic lamellae and disorganized smooth muscle cells. No vascular calcifications could be detected. These results indicate that severe renal failure for a duration of less than 10 wk in this model primarily affects the aorta and mainly slows the rate of relaxation.

scholarly journals Toll-like receptor 2 mediates high-fat diet-induced impairment of vasodilator actions of insulin

2013 ◽  
Vol 304 (10) ◽  
pp. E1077-E1088 ◽  
Author(s):  
Hyun-Ju Jang ◽  
Hae-Suk Kim ◽  
Daniel H. Hwang ◽  
Michael J. Quon ◽  
Jeong-a Kim
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
High Fat Diet ◽  
Saturated Fatty Acids ◽  
Cardiovascular Complications ◽  
Mesenteric Arteries ◽  
High Fat ◽  
Proinflammatory Response ◽  
Proinflammatory Responses ◽  
Sirna Knockdown

Obesity is characterized by a chronic proinflammatory state that leads to endothelial dysfunction. Saturated fatty acids (SFA) stimulate Toll-like receptors (TLR) that promote metabolic insulin resistance. However, it is not known whether TLR2 mediates impairment of vascular actions of insulin in response to high-fat diet (HFD) to cause endothelial dysfunction. siRNA knockdown of TLR2 in primary endothelial cells opposed palmitate-stimulated expression of proinflammatory cytokines and splicing of X box protein 1 (XBP-1). Inhibition of unfolding protein response (UPR) reduced SFA-stimulated expression of TNFα. Thus, SFA stimulates UPR and proinflammatory response through activation of TLR2 in endothelial cells. Knockdown of TLR2 also opposed impairment of insulin-stimulated phosphorylation of eNOS and subsequent production of NO. Importantly, insulin-stimulated vasorelaxation of mesenteric arteries from TLR2 knockout mice was preserved even on HFD (in contrast with results from arteries examined in wild-type mice on HFD). We conclude that TLR2 in vascular endothelium mediates HFD-stimulated proinflammatory responses and UPR that accompany impairment of vasodilator actions of insulin, leading to endothelial dysfunction. These results are relevant to understanding the pathophysiology of the cardiovascular complications of diabetes and obesity.

scholarly journals Simvastatin Attenuates H2O2-Induced Endothelial Cell Dysfunction by Reducing Endoplasmic Reticulum Stress

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1782 ◽  
Author(s):  
Zhiqiang He ◽  
Xuanhong He ◽  
Menghan Liu ◽  
Lingyue Hua ◽  
Tian Wang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Endothelial Cells ◽  
Endoplasmic Reticulum ◽  
Endothelial Dysfunction ◽  
Er Stress ◽  
Umbilical Vein ◽  
Primary Role ◽  
Intracellular Cholesterol ◽  
Underlying Mechanisms ◽  
Umbilical Vein Endothelial Cells

Atherosclerosis is the pathological basis of cardiovascular disease, whilst endothelial dysfunction (ED) plays a primary role in the occurrence and development of atherosclerosis. Simvastatin has been shown to possess significant anti-atherosclerosis activity. In this study, we evaluated the protective effect of simvastatin on endothelial cells under oxidative stress and elucidated its underlying mechanisms. Simvastatin was found to attenuate H2O2-induced human umbilical vein endothelial cells (HUVECs) dysfunction and inhibit the Wnt/β-catenin pathway; however, when this pathway was activated by lithium chloride, endothelial dysfunction was clearly enhanced. Further investigation revealed that simvastatin did not alter the expression or phosphorylation of LRP6, but reduced intracellular cholesterol deposition and inhibited endoplasmic reticulum (ER) stress. Inducing ER stress with tunicamycin activated the Wnt/β-catenin pathway, whereas reducing ER stress with 4-phenylbutyric acid inhibited it. We hypothesize that simvastatin does not affect transmembrane signal transduction in the Wnt/β-catenin pathway, but inhibits ER stress by reducing intracellular cholesterol accumulation, which blocks intracellular signal transduction in the Wnt/β-catenin pathway and ameliorates endothelial dysfunction.

Cholesterol-Induced Suppression of Endothelial Kir Channels Is a Driver of Impairment of Arteriolar Flow-Induced Vasodilation in Humans

Hypertension ◽  
2021 ◽  
Author(s):  
Sang Joon Ahn ◽  
Ibra S. Fancher ◽  
Sara T. Granados ◽  
Natalia F. Do Couto ◽  
Chueh-Lung Hwang ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Significant Negative Correlation ◽  
Dominant Negative ◽  
Mesenteric Arteries ◽  
Resistance Arteries ◽  
Knock Out ◽  
Major Mechanism

Dyslipidemia-induced endothelial dysfunction is an important factor in the progression of cardiovascular disease; however, the underlying mechanisms are unclear. Our recent studies demonstrated that flow-induced vasodilation (FIV) is regulated by inwardly rectifying K + channels (Kir2.1) in resistance arteries. Furthermore, we showed that hypercholesterolemia inhibits Kir2.1-dependent vasodilation. In this study, we introduced 2 new mouse models: (1) endothelial-specific deletion of Kir2.1 to demonstrate the role of endothelial Kir2.1 in FIV and (2) cholesterol-insensitive Kir2.1 mutant to determine the Kir2.1 regulation in FIV under hypercholesterolemia. FIV was significantly reduced in endothelial-specific Kir2.1 knock-out mouse mesenteric arteries compared with control groups. In cholesterol-insensitive Kir2.1 mutant mice, Kir2.1 currents were not affected by cyclodextrin and FIV was restored in cells and arteries, respectively, with a hypercholesterolemic background. To extend our observations to humans, 16 healthy subjects were recruited with LDL (low-density lipoprotein)-cholesterol ranging from 51 to 153 mg/dL and FIV was assessed in resistance arteries isolated from gluteal adipose. Resistance arteries from participants with >100 mg/dL LDL (high-LDL) exhibited reduced FIV as compared with those participants with <100 mg/dL LDL (low-LDL). A significant negative correlation was observed between LDL cholesterol and FIV in high-LDL. Expressing dominant-negative Kir2.1 in endothelium blunted FIV in arteries from low-LDL but had no further effect on FIV in arteries from high-LDL. The Kir2.1-dependent vasodilation more negatively correlated to LDL cholesterol in high-LDL. Overexpressing wild-type Kir2.1 in endothelium fully recovered FIV in arteries from participants with high-LDL. Our data suggest that cholesterol-induced suppression of Kir2.1 is a major mechanism underlying endothelial dysfunction in hypercholesterolemia.

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