Vascular type 1 angiotensin receptors control blood pressure by augmenting peripheral vascular resistance in female mice

Abstract

Angiotensin II (ANG II) is a major mediator of hypertension pathogenesis. In addition, there are well-documented differences in expression of the renin-angiotensin system (RAS) components and ANG II responses between males and females, which may explain sex differences in blood pressure (BP) and hypertension epidemiology. We previously showed that type 1A angiotensin (AT) receptors in vascular smooth muscle cells (VSMCs) play a critical role in BP regulation and hypertension pathogenesis, but these studies were carried out in male mice. Therefore, the major goal of the current studies was to examine the impact of VSMC AT receptors on BP and hypertension pathogenesis in female mice. We found that elimination of VSMC AT receptors in female mice reduced (≈8 mmHg) baseline BP without altering sodium sensitivity. The severity of ANG II-induced hypertension was diminished (≈33% reduction in BP), particularly during the last 2 wk of chronic ANG II infusion, compared with controls, but natriuresis was not altered during the first 5 days of ANG II infusion. Urinary norepinephrine levels were enhanced in female SMKO compared with control mice. There was a virtually complete elimination of ANG II-induced kidney hemodynamic responses with attenuation of acute vasoconstrictor responses in the systemic vasculature. These findings demonstrate that direct vascular actions of AT receptors play a prominent role in BP control and hypertension pathogenesis in female mice.

Vascular control of kidney epithelial transporters

“…In previous studies, we confirmed an important direct contribution of AT 1 receptors in VSMCs to blood pressure control and hypertension pathogenesis using mice with cell-specific deletion of AT 1A receptors, the major murine AT 1 receptor isoform (20), from smooth muscle (SMKO mice) (21,22). These SMKO mice lacking AT 1A receptors in VSMCs have lower baseline blood pressures, preserved renal blood flow (RBF), and attenuated hypertensive responses to chronic ANG II administration (21,22). Furthermore, they exhibit enhanced natriuresis during chronic ANG II infusion, which we posited was a key mechanism in their resistance to hypertension (21).…”

“…6). In previous studies, we found that SMKO mice had attenuated hypertension, exaggerated natriuresis, and diminished cardiac hypertrophy in response to chronic ANG II infusion (21,22,40). Furthermore, we have reported in this model (40) and others (9) that the magnitude of cardiac hypertrophy is directly correlated with the extent of blood pressure elevation in ANG II hypertension.…”

“…In this regard, previous studies have clearly shown that direct actions of AT 1 receptors in specific kidney epithelial lineages control the expression of Na þ transporters, impairing natriuresis and contributing to the development of hypertension (1,9,11). Similarly, powerful vasoconstrictor effects of AT 1 receptors in VSMCs can directly influence blood pressure by increasing peripheral vascular resistance (22) or by complex effects in the kidney circulation to promote solute reabsorption (1). Here, we demonstrate an unexpected interaction of vascular AT 1 receptors with the kidney tubular epithelium resulting in alterations of transporter abundance, impacting blood pressure.…”

“…In three published studies, we have reported that basal blood pressures are reduced by %7-8 mmHg in mice with cell-specific deletion of AT 1A receptors from VSMCs (SMKO mice) compared with control mice (21,22,40). Although this alteration in blood pressure might be explained by kidney hemodynamic changes (21), the magnitude of these effects is sufficiently large and durable such that we considered whether altered abundance and activity of key Na þ transporters might also be contributing.…”

“…To examine the changes in Na þ transporter (cotransporter and channel) abundance in mice lacking vascular AT 1A receptors, we used mice with specific deletion of AT 1A receptors from smooth muscle cell lineages, SMKO (KISm22a-Cre pos ; Agtr1a flox/flox ) and control (KISm22a-Cre neg ;Agtr1a flox/flox ), as previously described (21,22,31). All mice used in these experiments were male and age-matched littermates (age: 10-20 wk) on an inbred C57BL/6 background.…”