Abstract 18218: Vascular Dysfunction as a Primary Cause of Hypertension in Mice with Smooth Muscle Specific Deletion of RGS2

Abstract

The etiology of hypertension in most cases is idiopathic. Current dogma states that all forms of hypertension arise from renal abnormalities of sodium handling. We have hypothesized that a primary abnormality of vascular smooth muscle cell (SMC) contraction can cause hypertension. To directly test this hypothesis we created and characterized inducible, SMC-specific RGS2 knockout mice (RGS2-SMC-KO) harboring a SMC-specific deletion of the PKGIα target the GTPase activating protein Regulator of G-protein Signaling 2. In these studies, SMC-specific deletion of RGS2 was induced at 7 weeks of age and Cre-negative mice treated identically as the RGS2-SMC-KO were used as controls. Telemetric blood pressure (BP) studies in ambulatory mice demonstrated that BP was significantly higher in RGS2-SMC-KO vs. control mice (135 ± 5 vs. 122 ± 7 mmHg, respectively. P <0.01), with no change in heart rate. Ex vivo aortic rings of RGS2-SMC-KO mice were hypercontractile in response to phenylephrine (PE) (138 ± 6 vs. 124±4% of pre-existing tone at 6 mM PE, respectively. P <0.05) Hemodynamic studies in anesthetized RGS2-SMC-KO mice revealed increased total systemic vascular resistance (SVR; 3.22x10 4 ± 0.01x10 4 vs. 1.61x10 4 ± 0.55x10 4 , respectively. P <0.001), and significantly higher SBP (106 ± 5 vs. 93 ± 1 mmHg, respectively. P <0.01). Following treatment with the NOS inhibitor L-NAME, BP decreased less in the RGS2-SMC-KO than in the control mice (⋔SBP: 38 ± 7 vs. 47 ± 3 mmHg, P <0.001). We found identical BP responses to changes in dietary sodium intake in the RGS2-SMC-KO mice vs. control, supporting normal renal function in the RGS2-SMC-KO mice. These data support that SMC-specific deletion of RGS2 leads to hypertension, with accompanying loss of RGS2-dependent attenuation of contractile signaling in blood vessels, with increased SVR and hypercontractile arterial function. The hypertension in RGS2-SMC-KO mice together with normal sodium handling supports the hypothesis that high BP can arise from a primary abnormality of vascular smooth muscle cell contractile regulation. Taken together, these data have potentially important implications for the diagnosis and treatment of human vascular diseases and suggest RGS2 as a new therapeutic target for some forms of hypertension.