Browsing by Author "Del Vecchio, Angelica R."

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    Antecubital venous endothelial ETB receptor protein expression is preserved with aging in men
    (American Journal of Physiology - Heart and Circulatory Physiology, 2024-01-01) Tummala, Saumya; Kuczmarski, Andrew V.; Del Vecchio, Angelica R.; Schwab, Allyson I.; Edwards, David G.; Wenner, Megan M.
    Changes in endothelial function precede the development of cardiovascular disease (CVD). We have previously shown that age-related declines in endothelial function in women are due in part to a reduction in endothelial cell endothelin-B receptor (ETBR) protein expression. However, it is not known if ETBR protein expression changes with aging in men. The purpose of this study was to test the hypothesis that ETBR protein expression is attenuated in older men (OM) compared with younger men (YM). Primary endothelial cells were harvested from the antecubital vein of 14 OM (60 ± 6 yr; 26 ± 3 kg/m2) and 17 YM (24 ± 5 yr; 24 ± 2 kg/m2). Cells were stained with 4′,6-diamidino-2-phenylindole, vascular endothelial cadherin, and ETBR. Images were quantified using immunocytochemistry. Endothelial function was assessed using brachial artery flow-mediated dilation (FMD). Systolic BP was similar (OM, 123 ± 11 vs. YM, 122 ± 10 mmHg) whereas diastolic BP was higher in OM (OM, 77 ± 7 vs. YM, 70 ± 6 mmHg; P < 0.01). Total testosterone was lower in OM (OM, 6.28 ± 4.21 vs. YM, 9.10 ± 2.68 ng/mL; P = 0.03). As expected, FMD was lower in OM (OM, 3.85 ± 1.51 vs. YM, 6.40 ± 2.68%; P < 0.01). However, ETBR protein expression was similar between OM and YM (OM, 0.39 ± 0.17 vs. YM, 0.42 ± 0.17 AU; P = 0.66). These data suggest that ETBR protein expression is not altered with age in men. These findings contrast with our previous data in women and further support sex differences in the endothelin system. NEW & NOTEWORTHY Our laboratory has previously shown that age-related declines in endothelial function are associated with a reduction in endothelial cell ETBR protein expression in women. However, it is unclear if endothelial cell ETBR protein expression is reduced with aging in men. This study demonstrates that endothelial cell ETBR protein expression is preserved with aging in men, and provides additional evidence for sex differences in the endothelin system.
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    Short-term estradiol administration does not restore endothelin‐B receptor‐mediated vasodilation in postmenopausal women
    (American Journal of Physiology - Heart and Circulatory Physiology, 2025-02-01) Nuckols, Virginia R.; Shoemaker, Leena N.; Kuczmarski, Andrew V.; Haigh, Katherine M.; McGinty, Shane J.; Del Vecchio, Angelica R.; Schwab, Allyson I.; Edwards, David G.; Taylor, Hugh S.; Wenner, Megan M.
    The endothelin-B receptor (ETBR) mediates vasodilation in young women, an effect that is absent in postmenopausal women. We have previously demonstrated that ETBR-mediated vasodilation is regulated by estradiol (E2) in young women; however, the impact of E2 on ETBR function in postmenopausal women remains unknown. Accordingly, the objective of this study was to test the hypothesis that E2 exposure restores ETBR-mediated dilation in postmenopausal women. Ten healthy postmenopausal women (55 ± 2 yr of age, 5 ± 3 years since menopause) completed the study. E2 was administered by transdermal patch for 7 days (0.1 mg/day, Vivelle-Dot patch). Vasodilation in the cutaneous microcirculation (microvascular endothelial function) was measured via local heating (42°C) using laser Doppler flowmetry combined with intradermal microdialysis perfusions of lactated Ringer’s (control) and ETBR antagonist (BQ-788, 300 nM) at baseline and after E2 administration. There was no effect of E2 on ETBR function [hormone × site, F(1,9) = 0.77, P = 0.40]. These data demonstrate that in contrast to findings in premenopausal women, E2 administration does not restore ETBR function in postmenopausal women. NEW & NOTEWORTHY The vascular endothelial endothelin-B receptor (ETBR) mediates vasodilation in premenopausal women, an effect modulated by estradiol. ETBR-mediated vasodilation is lost in postmenopausal women, but the effect of exogenous estradiol administration on ETBR function in postmenopausal women is not known. During estradiol administration, ETBR blockade did not affect cutaneous microvascular vasodilatory response to local heating. We demonstrate that exogenous estradiol administration does not restore ETBR-mediated vasodilation in postmenopausal women.
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    The role of angiotensin-(1-7) in regulating vascular endothelial function in postmenopausal women
    (University of Delaware, 2025) Del Vecchio, Angelica R.
    Postmenopausal women (PMW) exhibit reduced endothelial function compared to younger, premenopausal women (YW). This is mainly attributed to the loss of estrogen with menopause but the mechanisms underlying the decline in endothelial function remain unclear. Angiotensin-(1-7) [Ang-(1-7)] induces vasodilation through the Mas receptor (MasR) and has been shown to restore endothelium-dependent dilation in women with endothelial dysfunction. Animal studies suggest menopause and aging reduce vascular sensitivity to Ang-(1-7) which may cause a compensatory upregulation of MasR. However, the role of the Ang-(1-7)/MasR axis has not yet been studied in humans. The central hypothesis of this dissertation was that the Ang-(1-7)/MasR axis is a main regulator of vascular function in women and that there is dysfunction in this pathway that occurs during menopause which leads to the pathologies associated with the onset of CVD. We hypothesize that PMW would have decreased vascular sensitivity to Ang-(1-7), local administration of Ang-(1-7) would improve endothelial function, and PMW would show a compensatory-based upregulation of MasR on endothelial cells. Methods: Blood flow was measured using laser Doppler flowmetry. To assess vascular sensitivity, Ang-(1-7) was locally administered in escalating doses in the presence and absence of L-NAME via cutaneous microdialysis to elicit a dose-dependent response. Dose response curves were fit to a sigmoidal curve and the ED50, slope, area under the curve, and peak response were compared between groups. To assess endothelial function, local heating of the cutaneous circulation to 42°C – which elicits an endothelium-dependent dilation – was performed during microdialysis perfusions of lactated Ringers (control) or Ang-(1-7). All skin blood flow data are expressed as cutaneous vascular conductance as a percentage of the maximum dilation elicited by sodium nitroprusside perfusions with heating to 43°C (CVC%max). Separately, venous endothelial cells were collected from PMW and YW and stained for MasR using immunocytochemistry and are expressed as protein expression arbitrary units (A.U.) following normalization to a positive control. All data are presented as mean+SD and alpha was set to P<0.05. Results: As expected PMW were significantly older than YW and showed elevated diastolic blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, and blood glucose that is characteristic with aging and menopause in this population. There were no differences in the dose-dependent response to Ang-(1-7) (Top: (YW: 99.93+17.32 vs. PMW: 97.58+31.32), LogED50 (YW: 9.34+10.5 vs PMW: 8.40+3.96), HillSlope (YW: 0.18+0.24 vs PMW: 0.25+0.21), or area under the curve (YW: 73.76+19.83, vs PMW: 67.35+12.01); p>0.05 for all variables). There was also no significant difference in NO-dependent dilation to Ang-(1-7) between YW and PMW (YW: 7.56+26.36 AUC vs. PMW: 17.40+25.75 AUC; p=0.48). PMW displayed a blunted endothelial function shown by a significantly attenuated response to local heating in the control site (YW: 91.26+4.87 CVC%max vs. PMW: 85.97+5.63 CVC%max; p=0.03), however, there was no impact of Ang-(1-7) on the response to local heating in either group (YW: 89.23+10.35 CVC%max vs. PMW 87.19+9.57 CVC%max; p=0.88). Lastly, there were no differences in endothelial MasR expression between groups (YW: 0.36+0.08 A.U. vs. PMW: 0.35+0.13 A.U.; p=0.77). Conclusion: The Ang-(1-7)/MasR axis does not appear to contribute to endothelial function in PMW as was hypothesized. These data are first to examine the impact of Ang-(1-7)/MasR axis on endothelial function in PMW and provide an important first step for future research examining the relationship between this pathway and the physiological changes that occur with menopause.