ET_Breceptor contribution to vascular dysfunction in postmenopausal women

Abstract

Endothelin-1 (ET-1) contributes to age-related endothelial dysfunction in men via the ET receptor. However, there are sex differences in the ET-1 system, and ET receptors are modulated by sex hormones. The purpose of this study was to test the hypothesis that ET receptors contribute to impaired vasodilatory function in postmenopausal women (PMW). We measured flow-mediated dilation (FMD) using ultrasound, and cutaneous nitric oxide-mediated vasodilation during local heating (42°C) via laser Doppler flowmetry in 18 young women (YW; 22 ± 1 yr) and 16 PMW (56 ± 1 yr). Cutaneous microdialysis perfusions of lactated Ringer (control), an ET receptor antagonist (BQ-788, 300 nM), and an ET receptor antagonist (BQ-123, 500 nM), were done through separate fibers, followed by perfusions of sodium nitroprusside (28 mM) and local heating to 43°C (max). Cutaneous vascular conductance (CVC) was calculated as cutaneous blood flow/mean arterial pressure and expressed as a percent of maximal dilation. FMD (YW: 7.5 ± 0.5 vs. PMW: 5.6 ± 0.6%) and cutaneous vasodilation (YW: 93 ± 2 vs. PMW: 83 ± 4%CVC) were lower in PMW (both < 0.05). Blockade of ET receptors decreased cutaneous vasodilation in YW (87 ± 2%CVC; < 0.05 vs. control) but increased vasodilation in PMW (93 ± 1%CVC; < 0.05 vs. control). ET receptor blockade had minimal effect in YW (92 ± 1%CVC) but increased cutaneous vasodilation in PMW (91 ± 2%CVC; < 0.05 vs. control). In conclusion, ET receptors mediate vasodilation in YW, but this effect is lost after menopause. Impaired vasodilatory function in PMW is due in part to a loss of ET-mediated dilation.

Alterations in endothelin type B receptor contribute to microvascular dysfunction in women who have had preeclampsia

“…In order to examine the role of augmented ET B R function in this attenuated microvascular vasodilator response, we locally administered the ET B R-specific antagonist BQ-788 during assessments of pharmacologically (exogenous ACh) and physiologically (local heating of the skin) stimulated endothelium- and NO-dependent dilation. Consistent with previous reports of an endothelium-dependent vasodilator role of ET B R in healthy premenopausal women(35, 36, 43), we found that ET B R-inhibition attenuated endothelium-dependent dilation via reduced NO-dependent dilation in HC. However, we found that ET B R-inhibition increased endothelium-dependent dilation, independent of NO-dependent mechanisms, in PrEC.…”

“…Cutaneous vascular conductance was calculated (CVC = laser Doppler flux/mean arterial pressure) and normalized to a percentage of site-specific baseline (% base) for constriction and site-specific maximum (% max) for vasodilation as per standard normalization procedures(20, 41-43). In the local heating protocol, within-site NO-dependent dilation was calculated as the difference between the local heating plateau and the post-L-NAME plateau.…”

Minimally modified low-density lipoprotein upregulates the ETB and α1 receptors in mouse mesenteric arteries in vivo by activating the PI3K/Akt pathway

“…Under a normal physiological state, the ET B receptor is primarily expressed on vascular endothelial cells to mediate dilation. In pathological conditions, the ET B receptor is expressed in vascular smooth muscle to mediate the vasoconstriction reaction, during which the ET B receptor undergoes a process from absence to presence on vascular smooth muscle . However, the mechanism underlying the intracellular change remains unclear .…”

Sex-Specific Contributions of Endothelin to Hypertension

“…Webb et al found that short-term intracoronary administration of estradiol resulted in a significant decrease in coronary sinus concentrations of ET-1 in postmenopausal women with coronary artery disease [25]. A recent study has shown that ET B -mediated vasodilatory capacity is decreased in postmenopausal women, compared to young women (Figure 1)[26]. This interesting finding suggests that impaired ET B -mediated vasodilatory function may be responsible, at least in part, for endothelial dysfunction manifested after menopause [26].…”