Mechanisms of ANG (1-7) Mediated Control of Blood Pressure in Males and Females

Abstract

Angiotensin (Ang) (1-7) is a vasodilatory peptide of the renin angiotensin system (RAS). Ang (1-7) levels are greater in females, and Ang (1-7) blunts Ang II-mediated increases in blood pressure (BP) in females compared to males. The molecular mechanism(s) by which Ang (1-7) mediates BP regulation remains largely unknown, although Ang (1-7) has been suggested to increase nitric oxide (NO) levels, suppress proinflammatory markers, and contribute to the BP-lowering effects of RAS-inhibitors. The central hypothesis of my thesis is that Ang (1-7) contributes more to the molecular mechanisms that mediate BP control in females than males. To test this hypothesis, four aims were addressed. Aim 1 tested the hypothesis that the BP in male spontaneously hypertensive rats (SHR) is less sensitive to increases in Ang (1-7) than females. Ang (1-7) levels were pharmacologically increased in male and female SHR, and BP was assessed. However, Ang (1-7) infusion did not alter baseline BP in either sex. Aim 2 tested the hypothesis that Ang (1-7) contributes less to the BP-lowering effects of angiotensin receptor blockers (ARBs) in male than females SHR. To test this hypothesis, BP was measured in male and female SHR in response to an ARB. Males had the greater decrease in basal BP to an ARB than females, although female SHR were more sensitive to ARB-mediated inhibition of Ang II-induced increases in BP. Additional studies indicated that Ang (1-7) contributed to the BP-lowering effect of ARBs to a greater degree in females than in males. vi Aim 3 tested the hypothesis that Ang (1-7) contributes less to NO bioavailability in male than female SHR under basal conditions and following Ang II-hypertension. Ang (1-7) levels were pharmacologically increased or blocked in male and female SHR and the NO pathway was assessed. Renal cortical NO bioavailability was not affected by treatments in either sex. Finally, Aim 4 tested the hypothesis that Ang II infusion will increase renal T cells in both sexes; however, greater Ang (1-7) in females will result in more T regulatory cells (Tregs) relative to male Sprague Dawley (SD) rats. Renal T cells were increased in both males and females following chronic Ang II infusion, however, females exhibited an increase in immune-suppressive Tregs not seen in males. In contrast, males exhibited a greater increase in pro-inflammatory Th17 cells. Inhibition of Ang (1-7) did not alter the sex difference in Tregs, indicating that Ang (1-7) is not responsible for the greater increase in Tregs in females following Ang II-hypertension. In summary, this work examines the role of Ang (1-7) to mediate sex differences in BP regulation, where females are more dependent on Ang (1-7) than males to correct perturbations in the RAS.