Vascular AT1 Receptors Control Blood Pressure by Augmenting Peripheral Vascular Resistance in Female Mice

Angiotensin (Ang) II is a major mediator of hypertension pathogenesis and end organ damage. Our understanding of how Ang II elicits these effects on a cellular level continues to evolve. However, the majority of these studies utilize male subjects, despite the awareness that males and females differ in mechanisms of BP regulation. Here we investigated the role of vascular smooth muscle cell (VSMC) AT1A receptors to BP control in female mice. Using Loxp technology and Cre transgenes, we created female mice with cell-specific deletion of AT 1A receptors in smooth muscle cells (SMKO mice). We found that elimination of these receptors led to a significant (8 mmHg) reduction in baseline BP in female SMKO mice (similar to male SMKO mice) compared with controls (108±2 versus 116±1 mmHg; P =0.004) with no effect on modulating sodium sensitivity in female SMKO mice (unlike male SMKO mice in which sodium sensitivity was enhanced). Over a 4-week Ang II infusion, the severity of Ang II - dependent hypertension was minimally affected during the first 2 weeks of Ang II infusion, corresponding to no difference in sodium excretion. However, female SMKO mice had a 35% less BP elevation compared to controls over the final 2 weeks of Ang II infusion (SMKO, 20±2 versus control, 30±3 Change in SBP mmHg; P =0.01). The acute vasoconstrictor responses to Ang II in the systemic vasculature were reduced (by approximately 50-75%) in female SMKO mice (0.1 μg/kg- SMKO, 3.6±1.2 mmHg versus control, 7.3±0.7 mmHg; P =0.01, 0.3 μg/kg- SMKO, 3.3±1.8 mmHg versus control, 12.1 ± 1.3 mmHg; P =0.0008, 1.0 μg/kg- SMKO, 8.5±1.9 mmHg versus control, 19.4±2.0 mmHg; P =0.002). In addition, the acute Ang II reduction in renal tissue perfusion was nearly eliminated in female SMKO mice. In contrast, we previously reported that in male SMKO mice have a much larger (50%) reduction in BP during chronic Ang II infusion associated with increased natriuresis, but relatively preserved vasoconstrictor response (25% reduction) during acute Ang II infusions. These findings suggest that in female mice, direct actions of AT 1A receptors in VSMCs are essential for regulation of basal BP and Ang II-dependent hypertension. However, this effect is mediated by reductions in peripheral vascular resistance rather than sodium retention.