Abstract 441: Rgs5 Controls Myogenic Responses of Vascular Smooth Muscle Cells
Contraction of vascular smooth muscle cells (VSMCs) in response to an increase in blood pressure is pivotal for maintaining blood flow and constitutes both consequence and cause of chronic hypertension. While a plethora of contraction-mediating mechanisms has been delineated, not much is known about molecular determinants regulating the responses of VSMCs to an increase in wall stress or biomechanical stretch. In this context, we reported that conditional ablation of Junb - a subunit of the transcription factor AP-1 (activator protein 1) - interferes with the expression of myosin light chain 9 and consequently impaired myogenic responses of arteries. We hypothesized that the arterial circumferential wall stress is increased under these conditions which may influence the VSMC phenotype and vessel wall architecture. In fact, Junb-deficient arteries showed structural remodeling as evidenced by a ~2-3-fold decrease in collagen type I and IV content (n=5, p<0.05). cDNA microarray analyses revealed that expression of regulator of G-protein signaling 5 (RGS5) was up-regulated in VSMCs (~6-fold, n=4, p<0.001) isolated from Junb-deficient arteries which was confirmed in vivo but not mediated by AP-1. However, elevation of wall stress by volume-induced hypertension in vivo or exposure of VSMCs to biomechanical stretch in vitro was sufficient to trigger RGS5 expression (3-fold, n=3, p<0.05). Overexpression of this regulator activates RhoA and enhanced stretch-induced responses of VSMCs such as stress fiber formation while its knockdown showed opposite effects. In line with this, RGS5-deficient arteries show an impaired pressure-mediated constriction (n=8, p<0.05) and both the hypertension-induced increase in diastolic blood pressure as well as structural remodeling of the arterial vessel wall were significantly attenuated in RGS5-deficient mice.
Collectively, these findings indicate that biomechanical stretch mediates the expression of RGS5 in VSMCs to enhance stretch-dependent responses as a prerequisite for adequate adaptive vascular remodeling processes. This mechanism may establish RGS5 as a promising target for future strategies to combat, e.g. the deleterious consequences of arterial hypertension such as arterial stiffening.
Author Disclosures: C. Arnold: None. A. Feldner: None. G. Genové: None. S. Schorpp-Kistner: None. P. Angel: None. T. Wieland: None. M. Hecker: None. T. Korff: None.
- © 2015 by American Heart Association, Inc.