Divergent Effects of Aging and Sex on Vasoconstriction to Endothelin in Coronary Arterioles

Abstract

The risk for cardiovascular disease increases with advancing age; however, the chronological development of heart disease differs in males and females. The purpose of this study was to determine whether age-induced alterations in responses of coronary arterioles to the endogenous vasoconstrictor, endothelin, are sex-specific. Coronary arterioles were isolated from young and old male and female rats to assess vasoconstrictor responses to endothelin (ET), and ETa and ETb receptor inhibitors were used to assess receptor-specific signaling. In intact arterioles from males, ET-induced vasoconstriction was reduced with age, whereas age increased vasoconstrictor responses to ET in intact arterioles from female rats. In intact arterioles from both sexes, blockade of either ETa or ETb eliminated age-related differences in responses to ET; however, denudation of arterioles from both sexes revealed age-related differences in ETa-mediated vasoconstriction. In arterioles from male rats, ETa receptor protein decreased, whereas ETb receptor protein increased with age. In coronary arterioles from females, neither ETa nor ETb receptor protein changed with age, suggesting age-related changes in ET signaling occur downstream of ET receptors. Thus, aging-induced alterations in responsiveness of the coronary resistance vasculature to endothelin are sex-specific, possibly contributing to sexual dimorphism in the risk of cardiovascular disease with advancing age.

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

“…There is substantial evidence that male and female mice and humans differ in their vascular function and BP responses 38;39 and MR transcriptional activity was recently found to be modulated by estrogen 40 . Indeed, the coronary response to endothelin-1 is modified by aging in a sex-dependent manner 41 . Thus, additional studies are needed to characterize the role of EC-MR in female mice.…”

Systemically Delivered Adipose Stromal Vascular Fraction Cells Disseminate to Peripheral Artery Walls and Reduce Vasomotor Tone Through a CD11b+ Cell-Dependent Mechanism

“…Saphenous arteries were explanted, taking care to remove the extraneous connective tissue, from anesthetized (5% isoflurane/O 2 balance) recipient mice into cold, filtered physiological saline solution (PSS) (pH 7.4; containing 145 mM NaCl, 4.7 mM KCl, 2.0 mM CaCl 2 , 1.17 mM MgSO 4 , 1.2 mM NaH 2 PO 4 , 5.0 mM glucose, 2.0 mM pyruvate, 0.02 mM EDTA, 3.0 mM 4‐morpholinepropanesulfonic acid buffer, and 1% BSA). The arteries were cannulated on size‐ and resistance‐matched glass pipettes in a Lucite chamber containing warm (37°C) PSS and assessed as previously described [21]. The arteries were preconstricted with phenylephrine (2 µM) to approximately 30% of the resting diameter at 50 mmHg; those that did not constrict were discarded.…”

Sex-Specific Characteristics of the Microcirculation

“…The potent vasoactive peptide endothelin (ET-1) is interesting as plasma levels of ET-1 differ by sex [3, 32, 33], as do the distribution, expression [33, 66], and activation of ET receptors and as do the mediators of the ET system. In females the ratio of ET-1 to ETB receptor activation is primary; in contrast, in males, ET-1/ETA receptor activation is of greatest importance [29].…”

“…In rat coronary arterioles, age, as well as sex, influences the functional response. As females age, coronary arteriolar constriction to ET-1 increases, while in males with aging reduction in the constrictor response to ET-1 is observed [66]. In retinal arterioles, ET-1 sensitivity declines with age, especially in females, while expression levels of the two receptors, ETA and ETB, displayed no differences with either age or sex [71].…”