Impaired Endothelium-dependent Vasodilation Research Articles

Sexual dimorphism in aortic endothelial function of Zucker diabetic fatty rats: possible involvement of superoxide production (1051.8)

Little is known about the interaction between diabetes and sex in vasculature. This study was designed to investigate whether there were sex differences in rat aortic endothelium‐dependent vasodilation (EDV) in Zucker diabetic fatty (ZDF) rats, and the potential role of superoxide. EDV to acetylcholine (ACh) was measured in aortic rings pre‐contracted with phenylephrine before and after pretreatment with apocynin (100 μM), a NADPH oxidase (Nox) inhibitor. In addition, the level of Nox (a potent source of superoxide) and PKCβ mRNA expression were determined using real‐time RT‐PCR. ACh‐induced relaxations were significantly greater in female lean rats compared with male lean rats. Accordingly, male lean rats had higher PKCβI expression level than female lean rats. Diabetes significantly impaired EDV in aortic rings from female ZDF rats, however, potentiated the relaxation in males. Pre‐incubation of aortic rings with apocynin increased EDV only in diabetic female group, suggesting impairment of EDV in female ZDF aorta was partly due to an increase in the activity of superoxide. Accordingly, the levels of Nox1, Nox4, and PKCβ mRNA expression were substantially enhanced in aorta of female ZDF rats compared to those in lean animals. These data suggest that an elevation of superoxide may partially contribute to the predisposition of the female aorta to injury in type 2 diabetes.Grant Funding Source: NIH/NIDCR

Inhibitory effect of 14,15-EET on endothelial senescence through activation of mTOR complex 2/Akt signaling pathways

Therapies to reverse the vascular endothelial aging process may play as a novel strategy for the treatment of cardiovascular diseases. 14,15-epoxyeicosatrienoic acid (14,15-EET) is a predominant cytochrome P450 epoxygenases-derived arachidonic acid metabolite and possesses multiple biological effects on the vascular system. The present study sought to investigate the roles of mammalian target of rapamycin complex 2 (mTORC2)/Akt signaling pathways in mediating the effect of 14,15-EET on endothelial senescence. By measuring the isometric tension in rat mesenteric arteries, we demonstrated that 14,15-EET improved the impaired endothelium-dependent vasodilatation in aged rats through activating mTORC2/Akt signaling pathway. Meanwhile, by promoting the formation of mTORC2 and the phosphorylation of Akt (Ser473), 14,15-EET inhibited the senescence of rat mesenteric arterial endothelial cells, which was not influenced by rapamycin but was significantly attenuated by Akt1/2 kinase inhibitor. The knockdown of Rictor gene by RNA interference abolished the inhibitory effect of 14,15-EET on endothelial senescence. Furthermore, 14,15-EET down-regulated the expression of p53 protein in aged endothelial cells. Meanwhile, the nuclear translocation of telomerase reverse transcriptase and the nuclear telomerase activity were also enhanced by treatment with 14,15-EET. Therefore, our present study suggests the crucial role of mTORC2/Akt signaling pathways in the inhibitory effects of 14,15-EET on the endothelial senescence. Our findings reveal important mechanistic clues to understanding of the effects of 14,15-EET on the endothelial functions.

Endothelial Dysfunction and the Effects of TNF Inhibitors on the Endothelium in Psoriasis and Psoriatic Arthritis: A Systematic Review

Epidemiologic data support the association of psoriasis and psoriatic arthritis with adverse cardiovascular outcomes. Shared pathogenesis in endothelial dysfunction may underlie psoriasis and atherosclerosis. Tumor necrosis factor (TNF) inhibitors may modulate endothelial dysfunction seen in patients with psoriasis and psoriatic arthritis. To perform a systematic review that investigated endothelial function in psoriasis and psoriatic arthritis and the effect of TNF inhibitors on endothelial function in psoriasis and psoriatic arthritis. MEDLINE (1980-October 2012), Web of Science, the EULAR abstract database, and the AAD annual meeting abstract archive were searched for cross-sectional or longitudinal studies that 1) examined endothelial function in patients with psoriasis or psoriatic arthritis, or 2) investigated the effect of TNF inhibitor therapy on endothelial function. Twenty articles and four abstracts with 2261 patients evaluated endothelial function in psoriasis and psoriatic arthritis, which was measured by pulse wave velocity, flow-mediated dilation, nitroglycerine-induced vasodilation, carotid intima-media thickness, peripheral arterial tonometry, or aortic stiffness parameters. The majority of the data suggests that patients with psoriasis and psoriatic arthritis have significantly increased arterial stiffness, impaired endothelial-dependent vasodilation, increased carotid intima-media thickness, and decreased aortic elasticity compared to the general population. Two out of three studies showed that TNF inhibitors improved endothelial function in psoriasis and psoriatic arthritis. Measurements of endothelial function were not standardized across studies. The preponderance of literature suggests that endothelial function is significantly impaired in patients with psoriasis and psoriatic arthritis compared to the general population. Preliminary evidence suggests that TNF inhibitors may improve endothelial function in the psoriasis and psoriatic arthritis populations.

Altered reactivity of resistance vasculature contributes to hypertension in elastin insufficiency

Elastin (Eln) insufficiency in mice and humans is associated with hypertension and altered structure and mechanical properties of large arteries. However, it is not known to what extent functional or structural changes in resistance arteries contribute to the elevated blood pressure that is characteristic of Eln insufficiency. Here, we investigated how Eln insufficiency affects the structure and function of the resistance vasculature. A functional profile of resistance vasculature in Eln(+/-) mice was generated by assessing small mesenteric artery (MA) contractile and vasodilatory responses to vasoactive agents. We found that Eln haploinsufficiency had a modest effect on phenylephrine-induced vasoconstriction, whereas ANG II-evoked vasoconstriction was markedly increased. Blockade of ANG II type 2 receptors with PD-123319 or modulation of Rho kinase activity with the inhibitor Y-27632 attenuated the augmented vasoconstriction, whereas acute Y-27632 administration normalized blood pressure in Eln(+/-) mice. Sodium nitroprusside- and isoproterenol-induced vasodilatation were normal, whereas ACh-induced vasodilatation was severely impaired in Eln(+/-) MAs. Histologically, the number of smooth muscle layers did not change in Eln(+/-) MAs; however, an additional discontinuous layer of Eln appeared between the smooth muscle layers that was absent in wild-type arteries. We conclude that high blood pressure arising from Eln insufficiency is due partly to permanent changes in vascular tone as a result of increased sensitivity of the resistance vasculature to circulating ANG II and to impaired vasodilatory mechanisms arising from endothelial dysfunction characterized by impaired endothelium-dependent vasodilatation. Eln insufficiency causes augmented ANG II-induced vasoconstriction in part through a novel mechanism that facilitates contraction evoked by ANG II type 2 receptors and altered G protein signaling.

Telmisartan Protects against Vascular Dysfunction with Peroxisome Proliferator-Activated Receptor-γ Activation in Hypertensive 5/6 Nephrectomized Rats

Background/Aims: Telmisartan and losartan, angiotensin II type 1 (AT₁) receptor antagonists, are used to manage hypertension. We previously reported that telmisartan, a partial agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ), exhibited stronger vasoprotection than the same dose of losartan in normotensive chronic kidney disease (CKD) rats. We investigated whether telmisartan could inhibit vascular dysfunction in hypertensive CKD rats, via both AT₁ receptor blockade and PPAR-γ activation, more effectively than losartan, which decreased blood pressure to a similar extent as telmisartan. Methods: Two or three branches of the left renal artery were ligated and the right kidney was removed to make hypertensive CKD rats. Telmisartan (5 mg/kg), losartan (10 mg/kg) or telmisartan plus the PPAR-γ antagonist GW9662 was administered. Results: Blood pressure was increased in CKD rats. Telmisartan and losartan decreased blood pressure to the same levels. Impaired endothelium-dependent vasodilation, hyperplasia and decreased phospho-eNOS (Ser¹¹⁷⁷) expression in CKD rat aortas were improved by telmisartan. The aortic infiltration by macrophages and expression of osteopontin were enhanced in CKD rats and suppressed by telmisartan. GW9662 partly canceled the normalization of vascular dysfunction. While losartan attenuated vascular changes, the extent of this attenuation was greater in the telmisartan-treated group. Conclusion: Telmisartan exhibited vasoprotection via PPAR-γ agonistic properties in hypertensive CKD rats.

The endotoxin/toll-like receptor-4 axis mediates gut microvascular dysfunction associated with post-prandial lipidemia

BackgroundPostprandial lipidemia is important in the development of coronary artery disease (CAD). Consumption of a meal high in monounsaturated fat was correlated with acute impairment of endothelial function. However, the mechanisms underlying impaired endothelial function in the postprandial state have not yet been elucidated. The effects of polyunsaturated fat (corn oil) and monounsaturated fat (olive oil) on vascular dysfunction in intestinal postcapillary venules and arterioles were examined in wild-type (WT) mice, mice genetically deficient in TLR4 (TLR4-/-) and mice pre-treated with antibiotics by intravital microscopy which was performed 1.0, 1.5, 2.0, 2.5 hours after oil administration. After intravital microscopy, samples of jejunum were therefore collected to test TLR4, pNF-kB p65 and SIRT1 protein expression by western blotting.ResultsOur findings showed that feeding mono-unsaturated olive oil or polyunsaturated corn oil promoted leukocyte and platelet trafficking in the gut microvasculature, and impaired endothelium-dependent arteriolar vasodilator responses during postprandial lipidemia. The expression of TLR4, pNF-kB p65 was significantly increased in mice gavaged with olive oil at 2 h and was significantly reduced in mice gavaged for 7 days with antibiotics and in TLR4 knockout (TLR4-/-) mice. At the same time, SIRT1 protein expression is diminished by feeding olive oil for 2 h, a phenomenon that is attenuated in mice pre-treated with antibiotics and in TLR4-/- mice. Corn oil treated mice exhibited a pattern of response similar to olive oil.ConclusionsDietary oils may be negative regulators of SIRT1 which activate the innate immune response through the endotoxin/TLR4 axis. Our findings establish a link between innate immunity (i.e. the endotoxin/TLR4 axis) and epigenetic controls mediated by SIRT1 in the genesis of diet associated vascular stress.

Sexual dimorphism in rat aortic endothelial function of streptozotocin-induced diabetes: Possible involvement of superoxide and nitric oxide production

Little is known of the interactions between diabetes and sex hormones on vascular function. The objectives of this study were to investigate whether there were sex differences in rat aortic endothelial function one week after the induction of streptozotocin (STZ)-diabetes, and to examine the potential roles of superoxide and nitric oxide (NO) in this sex-specific effect. Endothelium-dependent vasodilatation to acetylcholine (ACh) was measured in rat aortic rings before and after treatment with MnTMPyP (25µM), a superoxide dismutase. Contractile responses to phenylephrine (PE) were generated before and after treatment with l-NAME (200μM), a nitric oxide synthase (NOS) inhibitor. The mRNA expression of NADPH oxidase (Nox) and endothelial nitric oxide synthase (eNOS) were also determined. We demonstrated that (1) STZ-diabetes impaired endothelium-dependent vasodilatation to ACh to a greater extent in female than male aortae, (2) inhibition of superoxide enhanced sensitivity to ACh only in diabetic females, and (3) Nox1 and Nox4 mRNA expression were significantly elevated only in aortic tissue of diabetic females. Furthermore, incubation of aortic rings with l-NAME potentiated PE responses in all groups, but aortae from control females showed a greater potentiation of the PE response after NOS inhibition compared with others. STZ-diabetes reduced the extent of PE potentiation after l-NAME and the aortic eNOS mRNA expression in females to the same levels as seen in males. These data suggest that a decrease in NO, resulting from either decreased eNOS or elevated superoxide, may partially contribute to the predisposition of the female aorta to injury early in diabetes.

17‐β Oestradiol prevents cardiovascular dysfunction in post‐menopausal metabolic syndrome by affecting SIRT1/AMPK/H3 acetylation

Oestrogen therapy is known to induce cardioprotection in post-menopausal metabolic syndrome (PMS). Hence, we investigated the effect of 17-β oestradiol (E2) on functional responses to angiotensin II and cardiovascular dysfunction in a rat model of PMS. PMS was induced in ovariectomized rats by feeding a high-fat diet for 10 weeks. Isometric tension responses of aortic rings to angiotensin II were recorded using an isometric force transducer. TUNEL assay and immunoblotting was performed to assess apoptosis and protein expression respectively in PMS. Endothelial dysfunction in PMS was characterized by enhanced angiotensin II-induced contractile responses and impaired endothelial dependent vasodilatation. This was associated with an increased protein expression of AT1 receptors in the aorta and heart in PMS. PMS induced cardiac apoptosis by activating Bax and PARP protein expression. These changes were associated with a down-regulation in the expression of silent information regulation 2 homologue (SIRT1)/P-AMP-activated PK (AMPK) and increased H3 acetylation in aorta and heart. E2 partially suppressed angiotensin II-induced contractions, restored the protein expression of SIRT1/P-AMPK and suppressed H3 acetylation. The role of SIRT1/AMPK was further highlighted by administration of sirtinol and compound C (ex vivo), which enhanced angiotensin II contractile responses and ablated the protective effect of E2 on PMS. Our results provide novel mechanisms for PMS-induced cardiovascular dysfunction involving SIRT1/AMPK/ histone H3 acetylation, which was prevented by E2. The study suggests that therapies targeting SIRT1/AMPK/epigenetic modifications may be beneficial in reducing the risk of cardiovascular disorders.

Prenatal Testosterone Induces Sex-Specific Dysfunction in Endothelium-Dependent Relaxation Pathways in Adult Male and Female Rats1

Prenatal testosterone (T) exposure impacts postnatal cardiovascular function, leading to increases in blood pressure with associated decreased endothelium-dependent vascular relaxation in adult females. Endothelial function in males is not known. Furthermore, which of the endothelial pathways contributes to endothelial dysfunction and if there exists sex differences are not known. The objective of this study was to characterize the relative contribution of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) to the impaired endothelium-dependent vasodilation in prenatal T-exposed adult males and females. Offspring of pregnant rats treated with T propionate or its vehicle were examined. Telemetric blood pressure levels and endothelium-dependent vascular reactivity were assessed with wire myography. Levels of nitric oxide synthase (NOS3) and Kcnn3 and Kcnn4 channel expression were examined in mesenteric arteries. Mean arterial pressure was significantly higher in T males and females than in controls. Endothelium-dependent acetylcholine relaxation was significantly lower in both T males and females. EDHF-mediated relaxation was specifically blunted in T males (Emax = 48.64% ± 3.73%) compared to that in control males (Emax = 81.71% ± 3.18%); however, NO-mediated relaxation was specifically impaired in T females (Emax = 36.01% ± 4.29%) compared with that in control females (Emax = 54.56% ± 6.37%). Relaxation to sodium nitroprusside and levcromakalim were unaffected with T-treatment. NOS3 protein was decreased in T females but not in T males. Kcnn3 expression was decreased in both T males and females compared to controls. These findings suggest that prenatal T leads to an increase in blood pressure in the adult offspring, associated with blunting of endothelial cell-associated relaxation and that the effects are sex-specific: EDHF-related in males and NO-related in females.

Contribution of arginase activation to vascular dysfunction in cigarette smoking

BackgroundCigarette smoke increases the risk of several cardiovascular diseases and has synergistic detrimental effects when present with other risks that contribute to its pathogenesis. Oxidative injury to the endothelium via reactive oxygen species (ROS) and nitric oxide (NO) dysregulation is a common denominator of smoking-induced alterations in vascular function. However, the mechanisms underlying ROS and NO dysregulation due to smoking remain unclear. We tested if arginase (Arg) activation/upregulation contributes to this phenomenon by constraining nitric oxide synthase (NOS) activity. MethodsArg2 knockout (Arg2−/−) and control C57BL/6J mice were either exposed to cigarette smoke, 6 h/day/2 weeks (Second Hand Smoking; SHS) or housed in normal environment (Non Smoking; NS). Arg activity, NO and ROS levels were determined by measuring urea production, fluorescent dye (DAF), and dihydroethedium (DHE) respectively in isolated mouse aorta. ResultsArg activity and ROS levels were higher NO lower in SHS compared to NS mice. SHS failed to lower NO levels in Arg2−/− mice. Endothelial dependent vasodilation (EDV) was attenuated in SHS mice as compared to controls (78.80% ± 8 vs 46.58% ± 5). This impaired EDV was abolished in Arg2−/− mice (67.48% ± 7 in SHS vs. 78.80% ± 8 in NS). Vascular stiffness was increased in SHS mice as compared to NS controls but remained unchanged in Arg2−/− mice. ConclusionEndothelial NOS is uncoupled by smoking exposure, leading to endothelial dysfunction and vascular stiffness, a process that is prevented by Arg2 deletion. Hence, we identify Arg2 upregulation as a critical pathogenic factor and target for therapy in oxidative injury following smoking exposure through reciprocal regulation of endothelial NOS.

Tumor necrosis factor-α inhibition improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women

ObjectiveTumor necrosis factor (TNF)-α, a pleiotropic pro-inflammatory cytokine involved in a variety of biological processes including oxidative stress, has been associated with vascular dysfunction in aged and ovariectomized animals. We determined whether acute inhibition of TNF-α improves vascular endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women. MethodsArterial stiffness (carotid artery compliance) and endothelial function (brachial artery flow-mediated dilation [FMD]) were measured in postmenopausal women (n = 23; 57 ± 1 years, mean ± SE) before and following randomization to two days of either transdermal estradiol (0.05 mg/d, N = 12) or placebo (N = 11) alone and following a single subcutaneous injection of the TNF-α inhibitor, etanercept (25 mg), and in premenopausal (n = 9; 33 ± 2 years) before and following etanercept. Results and conclusionsBaseline carotid artery compliance and brachial artery FMD were lower in postmenopausal than premenopausal women (P < 0.0001). In postmenopausal women, carotid artery compliance (n = 12; 0.59 ± 0.05–0.78 ± 0.06 mm2/mmHg × 10−1, P < 0.001) and FMD (4.1 ± 0.6–6.0 ± 0.7%, P = 0.02) increased in response to estradiol but not placebo (n = 11). Carotid artery compliance (0.71 ± 0.06–0.81 ± 0.06 mm2/mmHg × 10−1, P = 0.02) and FMD (5.2 ± 0.7–7.5 ± 0.9%, P = 0.003) increased with etanercept in the placebo group but had no effect in postmenopausal randomized to estradiol or premenopausal women. These results suggest that TNF-α contributes to impaired endothelial-dependent vasodilation and arterial stiffening in estrogen-deficient postmenopausal women.

Abstract 113: Regulation Of Aortic Vasodilation By Sigma-1 Receptor Stimulation In Ovariectomized And Pressure Overloaded Rats.

Objective: We previously reported that sigma-1 receptor ( σ 1 R ) expression in the thoracic aorta decreased after pressure overload (PO) induced by abdominal aortic banding in ovariectomized (OVX) rats. Here, we asked whether stimulation of σ 1 R with the selective agonist SA4503 elicits functional recovery of aortic vasodilation and constriction following vascular injury in OVX rats with PO. Methods: SA4503 (0.3-1.0 mg kg -1 ) and NE-100 (an σ 1 R antagonist, 1.0 mg kg -1 ) were administered orally for 4 weeks (once daily) to OVX-PO rats, starting from the onset of aortic banding. Vascular functions of isolated descending aorta were measured following phenylephrine (PE)- or endothelin-1 (ET-1)-induced vasoconstriction and acetylcholine (ACh)- or clonidine-induced vasodilation. Results: σ 1 R expression in aortic smooth muscle and endothelial cells decreased significantly 4 weeks after PO in OVX rats (vs. Sham or OVX only group). SA4503 administration rescued PO-induced σ 1 R decreases in the descending aorta. SA4503 treatment also rescued PO-induced impairments in ACh- and clonidine-induced vasodilation without affecting PE- and ET-1-induced vasoconstriction. Ameliorated ACh- and clonidine-induced vasodilation was closely associated with increased Akt activity and in turn endothelial nitric oxide synthase (eNOS) phosphorylation. SA4503-mediated improvement of vasodilation was blocked by NE-100 treatment. Conclusions: σ 1 R is downregulated following PO-induced endothelial injury in OVX rats. The selective σ 1 R agonist SA4503 rescues impaired endothelium-dependent vasodilation in the aorta from OVX-PO rats through σ 1 R stimulation, enhancing eNOS-cGMP signaling in vascular endothelial cells. These observations encourage development of novel therapeutics targeting σ 1 R to prevent vascular endothelial injury in postmenopausal woman.

Lack of Association of Homocysteine Concentrations with Oxidative Stress, Alterations in Carotid Intima Media Thickness and Endothelial Reactivity in Prepubertal Children

Background and Aims: Our purpose was to assess the presence of risk factors for cardiovascular diseases (alterations in the lipid profile, fasting glycaemia, high arterial pressure values, oxidative stress, increased intima media thickness and impaired endothelium-dependent vasodilation) in prepubertal children with elevated homocysteine (Hcy) levels. Methods: In a cross-sectional study, 35 children with Hcy levels ≥7.3 μmol/l were matched by gender and age with 29 children with Hcy levels ≤4.1 μmol/l. Our collected data included weight, height, waist circumference, systemic arterial pressure, lipid profile, fasting glycaemia and oxidative stress markers. A Doppler ultrasound was performed to measure the carotid intima media thickness and the endothelium-dependent vasodilation of the brachial artery. Results: There were no statistically significant differences between the groups regarding the lipid profile and fasting glycaemia, blood pressure or oxidative stress. Overweight and obesity (body mass index z-score > +1) were more frequent in the group with Hcy ≥7.3 μmol/l when compared to the group with Hcy ≤4.1 μmol/l [13/35 (37.1%) vs. 4/29 (13.8%); p = 0.035]. After adjusting for nutritional status, there were no differences in the intima media thickness and endothelium-dependent vasodilation between children with high and low Hcy levels. Conclusions: Among the cardiovascular risk factors investigated in the present study, which was based on prepubertal children, only overweight and obesity were associated with increased Hcy concentrations (≥7.3 μmol/l).

High-density lipoprotein cholesterol affects early endothelial progenitor cell number and endothelial function in obese women

In order to improve our understanding of high-density lipoprotein cholesterol (HDL-C) cardiovascular (CV) impact in obesity, the association of HDL-C plasma level with circulating early endothelial progenitor cell (early-EPC) number and endothelium-dependent vasodilatation (EDV) in obese women with normal or high low-density lipoprotein cholesterol (LDL-C) plasma levels was evaluated. One hundred thirteen obese female subjects and a control group of 78 healthy female subjects were recruited. Circulating early-EPC were assessed by single- and two-color flow cytometric analyses with a fluorescence activated cell sorting (FACScan) flow cytometer. EDV was evaluated as response to ischemia by strain gauge plethysmography. Both early-EPC number and EDV were significantly decreased in obese women compared with the control group. Obese women with low HDL-C showed a further decrease of early-EPC and EDV in the presence of both high or normal LDL-C plasmatic levels. In the normal HDL-C level subgroup, hypercholesterolemic and nonhypercholesterolemic subjects showed no difference in early-EPC number, whereas slight EDV impairment was present in hypercholesterolemic subjects. In obese women, low HDL-C is associated to decreased early-EPC number and impaired EDV, suggesting the need to assess whether evaluation of early-EPC and EDV may increase HDL-C prognostic value in the stratification of CV risk.

THU0053 Reduced endothelium-independent vascular reactivity is indicative of carotid atherosclerosis in patients with rheumatoid arthritis without overt cardiovascular disease

BackgroundBrachial artery reactivity is one of the early surrogate markers of atherosclerosis. The association of impaired endothelium-dependent (EDVD) and endothelium-independent vasodilatation (EIVD) with structural measures of subclinical atherosclerosis in patients...

症例 血管内皮細胞機能:特に内皮依存性血管拡張反応の低下について

症例 血管内皮細胞機能:特に内皮依存性血管拡張反応の低下について

Add Another Killer for Interfered Vascular Function

The predominant physiological role of the renin–angiotensin system is to regulate blood pressure and water/sodium homeostasis. Excessive angiotensin II (Ang II), the major bioactive angiotensin peptide of this system, leads to vascular dysfunction that contributes to many cardiovascular diseases. Increasing evidence supports a concept that overactivation of the renin–angiotensin system disrupts normal immune/inflammatory responses. Although this overview of adverse responses to Ang II is widely accepted, how alterations in inflammation contribute to vascular dysfunction is not completely understood. See accompanying article on page 1313 Alterations in immune responses to vascular function were reported >4 decades ago but less advancement in understanding how immune-mediated or inflammation-induced responses have been identified.1 Recently, Guzik et al2 reported that RAG-1−/− mice, lacking both functional T and B lymphocytes, were protected from Ang II–induced loss of endothelium-dependent vasodilatation. Conversely, adoptive transfer of T lymphocytes led to vascular dysfunction that were attributed to impaired endothelium-dependent vasodilatation and an increase in vascular superoxide production in response to Ang II. The authors interpreted these findings as one mechanism of Ang II–induced high blood pressure. After this initial report, other groups have confirmed contribution of immune/inflammation to Ang II–induced vascular dysfunction beyond …

Potassium in Hypertension and Cardiovascular Disease

The increased prevalence of hypertension and cardiovascular disease in industrialized societies undoubtedly is associated with the modern high-sodium/low-potassium diet. Extensive experimental and clinical data strongly link potassium intake to cardiovascular outcome. Most studies suggest that the sodium-to-potassium intake ratio is a better predictor of cardiovascular outcome than either nutrient individually. A high-sodium/low-potassium environment results in significant abnormalities in central hemodynamics, leading to potential target organ damage. Altered renal sodium handling, impaired endothelium-dependent vasodilatation, and increased oxidative stress are important mediators of this effect. It remains of paramount importance to reinforce consumption of a low-sodium/high-potassium diet as a critical strategy for prevention and treatment of hypertension and cardiovascular disease.

Role of Endothelial Soluble Epoxide Hydrolase in Cerebrovascular Function and Ischemic Injury

Soluble Epoxide Hydrolase (sEH) is a key enzyme in the metabolism and termination of action of epoxyeicosatrienoic acids, derivatives of arachidonic acid, which are protective against ischemic stroke. Mice lacking sEH globally are protected from injury following stroke; however, little is known about the role of endothelial sEH in brain ischemia. We generated transgenic mice with endothelial-specific expression of human sEH (Tie2-hsEH), and assessed the effect of transgenic overexpression of endothelial sEH on endothelium-dependent vascular reactivity and ischemic injury following middle cerebral artery occlusion (MCAO). Compared to wild-type, male Tie2-hsEH mice exhibited impaired vasodilation in response to stimulation with 1 µM acetylcholine as assessed by laser-Doppler perfusion monitoring in an in-vivo cranial window preparation. No difference in infarct size was observed between wild-type and Tie2-hsEH male mice. In females, however, Tie2-hsEH mice sustained larger infarcts in striatum, but not cortex, compared to wild-type mice. Sex difference in ischemic injury was maintained in the cortex of Tie2-hsEH mice. In the striatum, expression of Tie2-hsEH resulted in a sex difference, with larger infarct in females than males. These findings demonstrate that transgenic expression of sEH in endothelium results in impaired endothelium-dependent vasodilation in the cerebral circulation, and that females are more susceptible to enhanced ischemic damage as a result of increased endothelial sEH than males, especially in end-arteriolar striatal region.

Role of K‐Channels in Microvascular Flow‐ Induced Dilation of Subcutaneous and Visceral Arterioles in Human Obesity

Altered vascular tone, a characteristic of human obesity, has been associated with impaired endothelium‐dependent vasodilation. Prior data suggest that visceral adipose tissue (VAT) is associated to endothelial dysfunction compared to subcutaneous adipose tissue (SAT). The aim of this study was to determine the contribution of vascular potassium channels to flow‐induced dilation (FID) in human VAT and SAT resistance arteries. Microvessels were obtained from VAT and SAT biopsies during bariatric surgery (OB; BMI&gt;;48). Isolated vessels were cannulated for vascular reactivity to flow (pressure gradient 10–100 cmH2O) in the absence and presence of the 4‐aminopyridine (4‐AP; KV channel blocker), BaCl2 (KIR channel blocker), tetraethylammonium (TEA; BKCa channel blocker) and glybenclamide (KATP channel blocker). Dilations to papaverine (10–4M) were determined in each vessel. FID was reduced in VAT compared to SAT (at 60 cmH2O, 56±6% vs. 71±8%, p&lt;0.05). There was no effect of TEA or glybenclamide on FID in SAT of OB subjects, but 4‐AP (p&lt;0.05) and BaCl2 reduced FID in SAT of OB ( at 60 cmH2O and 100 cmH2O; p&lt;0.05) vs. baseline. These data suggest that 1) FID is reduced in visceral compared to subcutaneous fat of obese patients and 2) Kir and Kv channels may be dysfunctional in VAT arterioles of obese subjects since 4‐AP and BaCl2 don't affect vasodilation of them while still reduce it in SAT arterioles.