Distinct endothelial pathways underlie sexual dimorphism in vascular auto‐regulation

Chan, Melissa; Bubb, Kristen J.; Noyce, Alastair J.; Villar, Inmaculada Concepción; Duchêne, Johan; Hobbs, Adrian J.; Scotland, Ramona S.; Ahluwalia, Amrita

doi:10.1111/j.1476-5381.2012.02012.x

Cited by 37 publications

(34 citation statements)

References 55 publications

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“…As published previously,14, 15 in control female mice without risk factors, EDH was a greater contributor to endothelial‐dependent relaxation than NO (Figure 5A and 5D). When exposed to obesity or hyperlipidemia, female resistance vessels exhibited a significant decline in the EDH component of acetylcholine‐induced relaxation (Figure 5B and 5C).…”

Section: Resultssupporting

confidence: 84%

“…The data reveal profound differences in the effects of cardiometabolic risk factors on the components of endothelial dilation in females versus males. In males (Figure 4), in the absence of risk factors, both eNOS and EDH contribute to vasodilation, with NOS contributing a greater proportion of mesenteric vasodilatory function than EDH (Figure 4A and 4D), consistent with prior studies 14, 15. Exposure of male mice to obesity, with or without hyperlipidemia, resulted in profound impairment in eNOS‐mediated relaxation of resistance vessels.…”

Section: Resultssupporting

confidence: 82%

“…Hydrogen peroxide (H 2 O 2 ) is an additional vasodilator that activates potassium channels to contribute to EDH 12, 13. Sex differences have been described in the relative contribution of these endothelium‐derived relaxing factors to resistance vessel function in rodent models 14, 15. However, how these components are modulated in resistance vessels in response to cardiometabolic risk factors and whether there are sex differences in those responses have not been directly investigated.…”

Section: Introductionmentioning

confidence: 99%

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Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

Davel

Lü

Moss

et al. 2018

JAHA

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BackgroundThe incidence of obesity is rising, particularly among women. Microvascular dysfunction is more common with female sex, obesity, and hyperlipidemia and predicts adverse cardiovascular outcomes, but the molecular mechanisms are unclear. Because obesity is associated with mineralocorticoid receptor (MR) activation, we tested the hypothesis that MR in endothelial cells contribute to sex differences in resistance vessel dysfunction in response to cardiometabolic risk factors.Methods and ResultsMale and female endothelial cell–specific MR knockout mice and MR‐intact littermates were randomized to high‐fat‐diet–induced obesity or obesity with hyperlipidemia induced by adeno‐associated virus–based vector targeting transfer of the mutant stable form (DY mutation) of the human PCSK9 (proprotein convertase subtilisin/kexin type 9) gene and compared with control diet. Female but not male mice were sensitive to obesity‐induced endothelial dysfunction, whereas endothelial function was impaired in obese hyperlipidemic males and females. In males, obesity or hyperlipidemia decreased the nitric oxide component of vasodilation without altering superoxide production or endothelial nitric oxide synthase expression or phosphorylation. Decreased nitric oxide content in obese males was overcome by enhanced endothelium‐derived hyperpolarization–mediated relaxation along with increased SK3 expression. Conversely, in females, endothelium‐derived hyperpolarization was significantly impaired by obesity with lower IK1 expression and by hyperlipidemia with lower IK1 and SK3 expression, loss of H2O2‐mediated vasodilation, and increased superoxide production. Endothelial cell–MR deletion prevented endothelial dysfunction induced by risk factors only in females. Rather than restoring endothelium‐derived hyperpolarization in females, endothelial cell–MR deletion enhanced nitric oxide and prevented hyperlipidemia‐induced oxidative stress.ConclusionsThese data reveal distinct mechanisms driving resistance vessel dysfunction in males versus females and suggest that personalized treatments are needed to prevent the progression of vascular disease in the setting of obesity, depending on both the sex and the metabolic profile of each patient.

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Section: Resultssupporting

confidence: 84%

Section: Resultssupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

Davel

Lü

Moss

et al. 2018

JAHA

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“…30 Tadalafi l, the agent used in the current study, is a phosphodiesterase type 5 inhibitor that enhances NO signaling by impeding the catabolism of cyclic guanosine monophosphate (cGMP), whose downstream eff ects lead to vasorelaxation. In a study by Chan and colleagues, 31 NO-mediated vasodilatation in murine mesenteric arteries exhibited sex-specifi c responses to stimulation of the NO-soluble guanylate cyclase (sGC) pathway. Specifi cally, these investigators found that in male mice, NO-mediated vasodilatation was solely through the NO-sGC-cGMP pathway.…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in Response to Tadalafil in Pulmonary Arterial Hypertension

Mathai

Hassoun

Puhan

et al. 2015

Chest

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BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease with high rates of morbidity and mortality. Current therapies improve symptoms, functional capacity, and, in select cases, survival. Little is known about patient factors that may predict the likelihood of patient-important, clinically relevant responses to therapy such as the 6-min walk distance (6MWD) and health-related quality of life (HRQoL).

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“…This may be likely due to an augmenting effect of female sex hormones on the function of Kcnn3 channels [50].…”

Section: Androgens In Sex-specific Endothelial Dysfunctionmentioning

confidence: 99%

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

Chinnathambi

Yallampalli

Sathishkumar

2013

Biology of Reproduction

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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.

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Distinct endothelial pathways underlie sexual dimorphism in vascular auto‐regulation

Cited by 37 publications

References 55 publications

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

Sex Differences in Response to Tadalafil in Pulmonary Arterial Hypertension

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

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