Abstract 14239: Wall Stress-Mediated Rgs5 Expression in Vascular Smooth Muscle Cells Controls Arterial Remodeling During Hypertension
The onset of hypertension is characterized by an increase in arterial wall stress which results in a compensatory remodeling of the vascular wall which ultimately leads to arterial stiffening. While G-protein signaling has been reported to control contraction and differentiation of vascular smooth muscle cells (VSMCs) in this context, the role of the regulators of G-protein signaling (RGS) has not been elucidated in detail. While earlier reports demonstrate that RGS5 regulates biomechanically induced arterial growth (arteriogenesis), we aimed at investigating the relevance of RGS5 for hypertension-induced VSMC responses. In vitro, exposing VSMCs to biomechanical stretch increased RGS5 protein abundance (3.2-fold, p<0.05, n=3). Likewise, RGS5 mRNA expression was augmented in isolated arteries in response to increased wall stress (1.7-fold, p<0.05, n=13). As evidenced by a whole genome microarray, overexpression of RGS5 under these conditions shifted the transcriptome towards expression of RhoA pathway-associated gene products. In fact, the prototypic stretch-stimulated RhoA activity (1.8-fold, p<0.05, n=3) and stress fiber formation (2.8-fold, p<0.05, n=6) in VSMCs was impaired in RGS5-deficient VSMCs. In vivo, both wild type (WT) and RGS5 knockout (RGS5 KO) mice developed hypertension upon DOCA/salt treatment. After ten days, RGS5 mRNA expression (3.5-fold, p<0.05, n=5) as well as RGS5-specific immunofluorescence (1.9-fold, p<0.05, n=4) was increased in the media of WT arteries. Moreover, mRNA expression of RGS16 which inhibits Gα13-mediated RhoA activation was elevated (3.8-fold, p<0.05, n=3) in arteries of hypertensive RGS5 KO but not WT mice. Interestingly, hypertension-induced arterial remodeling was attenuated in RGS5 KO mice as evidenced by decreased VSMC proliferation (3.7-fold, p<0.05, n=4) and VSMC contractile marker analyses. Collectively, these findings suggest that hypertension-induced elevation of wall stress triggers RGS5 expression in VSMCs to balance G-protein activity to promote RhoA-dependent adaptive remodeling. Loss of RGS5 may thus impair RhoA activation presumably as result of increased RGS16 expression and therefore attenuate arterial stiffening as a deleterious consequence of hypertension.
Author Disclosures: C. Arnold: None. E. Demirel: None. G. Genové: None. H. Zhang: None. T. Wieland: None. M. Hecker: None. S. Heximer: None. T. Korff: None.
- © 2016 by American Heart Association, Inc.