Angiotensin II type 2 receptor-mediated dilation is greater in the cutaneous microvasculature of premenopausal women compared to men

Abstract

Sex differences in the activation of the renin-angiotensin system (RAS) likely contribute to differences in cardiovascular outcomes in premenopausal women compared to age-matched men. It is established that women have a reduced activation of the vasoconstrictor angiotensin II – angiotensin II type 1 receptor (AT 1 R) pathway. Emerging evidence suggests that this may be mediated by a shift toward the more recently described vasodilatory RAS, including increased sensitivity of the vasodilatory angiotensin II type 2 receptor (AT 2 R). However, few in vivo studies have directly examined sex differences in AT 2 R-mediated dilation, or the balance between AT 1 R- and AT 2 R-mediated vascular responses in humans. Using the cutaneous microcirculation as a model, we hypothesized that AT 2 R-mediated dilation would be greater in premenopausal women compared to men, and that AT 1 R-blockade would augment AT 2 R-mediated dilation to a greater extent in men than in women. Eight healthy women (22±3 years) and 11 healthy men (23±5 years) participated in 1 experimental visit. Two intradermal microdialysis fibers were placed in the skin of the ventral forearm for graded infusions of either compound 21 (C21, AT 2 R agonist; 10 -12 - 10 -3 mol/L) alone or C21 + 43 μmol/L losartan (AT 1 R antagonist). Red blood cell flux was measured over each microdialysis site by laser-Doppler flowmetry. Cutaneous vascular conductance was calculated (CVC=doppler flux/mean arterial pressure) and normalized to maximum (%CVCmax; 28mM SNP+43°C). Women had a greater peak vasodilation response to C21 compared to men (27.2±5.7 versus 18.2±2.7 %CVCmax; p=0.03). AT 1 R-inhibition augmented peak C21-mediated dilation in men (31.3±4.5 versus 18.2±2.7 %CVCmax; p=0.009) but had no effect in women (24.5±6.5 versus 27.2±5.7 %CVCmax; p=0.34). These data suggest that premenopausal women have a greater AT 2 R-mediated vasodilation response than men, and that AT 1 R activation inhibits AT 2 R-mediated dilation in men, but not in women. This study is supported by National Heart, Lung, and Blood Institute Grant R00HL138133. Clinicaltrials.gov identifier: NCT05576155 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.