Functional characterization and sex differences in small mesenteric arteries of the estrogen receptor-β knockout mouse

Abstract

The role of the estrogen receptor (ER) subtypes in the modulation of vascular function is poorly understood. The aim of this study was to characterize ex vivo the functional properties of small arteries and their response to estrogens in the mesenteric circulation of female and male ER-beta knockout mice (beta-ERKO) and their wild-type (WT) littermates. Responses to changes in intraluminal flow and pressure were obtained before and after incubation with 17beta-estradiol or ER-alpha agonist propyl-pyrazole-triol (3 h; 10 nM). Cumulative concentration-response curves to acetylcholine, norepinephrine, and passive distensibility were compared with respect to sex and genotype. The collagen and elastin content within the vascular wall and ER expression were also determined. Endothelial morphology was visualized by scanning electron microscopy. 17beta-Estradiol and propyl-pyrazole-triol-treated arteries from female beta-ERKO and WT mice showed enhanced flow-mediated dilation, but this was not evident in males. Distensibility was decreased in arteries from beta-ERKO females. Sex differences in myogenic tone were observed in 17beta-estradiol-treated arteries, but were similar between beta-ERKO and WT mice. Acetylcholine- and norepinephrine-induced responses were similar between groups and sexes. ER-alpha was similarly expressed in the endothelium and media of arteries from all groups studied, as well as ER-beta in WT animals. Endothelial morphology was similar in arteries from animals of both sexes and genotype; however, arterial elastin content was decreased, and collagen content was increased in beta-ERKO male compared with WT male and with beta-ERKO female. We suggest that ERs play a sex-specific role in estrogen-mediated flow responses and distensibility, and that deletion of ER-beta affects artery structure but only in male animals. Further studies in beta-ERKO mice with established hypertension and in alpha-ERKO mice are warranted.

Vascular Actions of Estrogens: Functional Implications

“…For example, only the selective ER␣ agonist, DPN, induces acute NOdependent vasodilation (Bolego et al, 2005). Likewise, in small mesenteric arteries from female mice, PPT increased flow-mediated relaxation; interestingly, there was no effect of PPT in arteries from males (Douglas et al, 2008). These studies using selective ER agonists support the conclusion that ER␣ is the principal form 214 MILLER AND DUCKLES involved in mediating the actions of estrogen on vascular function.…”

Essential role of ER-α-dependent NO production in resveratrol-mediated inhibition of restenosis

“…Note that female animals were selected for these studies so as to maximize responses. However, 1) since male animals also express ERs in the vasculature (13,18), 2) since it is now recognized that ER-␣ contributes to physiological function in the male vasculature (9,27), and 3) since our prior studies in male compared with female vascular smooth muscle cells showed similar responses for Resv (14), we expect similar responses in male mice. In studies involving a pharmacological inhibition of NOS, the mice were administered N G -nitro-L-arginine methyl ester (L-NAME, 50 mg/kg) in their drinking water, starting 7 days before the denudation procedure, continuing through 14 days postdenudation.…”

Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease

“…Studies with selective ER agonists suggest that ERα may mediate most of the vascular actions of estrogen. PPT increases flow-mediated relaxation in small mesenteric arteries from female, but not male mice [64]. Diarylpropionitrile (DPN) is a potent ERβ agonist with a 30- to 70-fold selectivity over ERα [41].…”