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

Differential activation of the renin-angiotensin system (RAS) likely contributes to sex differences in cardiovascular outcomes in premenopausal women compared with age-matched men. Women demonstrate reduced activation of the vasoconstrictor angiotensin II type 1 receptors (AT₁R) compared with men, and evidence suggests that women also likely have increased sensitivity of the vasodilatory angiotensin II type 2 receptors (AT₂R). However, few in vivo studies have directly examined sex differences in AT₂R-mediated dilation, or the balance between AT₁R- and AT₂R-mediated vascular responses in humans. Using the cutaneous microcirculation as a model, we hypothesized that AT₂R-mediated dilation would be greater in premenopausal women compared with men, and that AT₁R-blockade would augment AT₂R-mediated dilation to a greater extent in men than in women. Twelve healthy women (22 ± 3 yr) and 12 men (23 ± 5 yr) had two intradermal microdialysis fibers placed in the ventral forearm for graded infusions of compound 21 (AT₂R agonist; 10^-12 to 10^-8 M) in a control fiber site and a site treated with 43 µM losartan (AT₁R antagonist). Red blood cell flux was measured continuously by laser-Doppler flowmetry, and cutaneous vascular conductance [CVC = flux/mean arterial pressure (MAP)] was normalized to maximum [%max; 28 mM sodium nitroprusside (SNP) + 43 °C]. Women had greater AT₂R-mediated dilation compared with men (women: 25 ± 4 vs. men: 15 ± 2%max, P = 0.03). Local AT₁R inhibition increased AT₂R-mediated dilation in men (losartan: 26 ± 4 vs. control: 15 ± 2%max, P < 0.001) but had no effect in women (losartan: 27 ± 6 vs. control: 25 ± 4%max, P > 0.05). These data suggest that premenopausal women have a greater AT₂R-mediated vasodilation response than men, and that AT₁R activation inhibits AT₂R-mediated dilation in men, but not in women.NEW & NOTEWORTHY Premenopausal women have greater protection against cardiovascular disease than age-matched men. However, the role of vasoconstrictor angiotensin II type 1 receptors (AT₁R) and vasodilatory angiotensin II type 2 receptors (AT₂R) in mediating these sex differences is unclear. Here, we demonstrate that women have greater AT₂R-mediated vasodilation than men and that AT₁R negates AT₂R-mediated dilation in men, but not in women.