Abstract 16024: Selective Inhibition of G12/13 Prevents Vascular Smooth Muscle Cell Activation and Neointima Formation in Response to Balloon Angioplasty
Several G protein coupled receptor (GPCR) agonists including angiotensin II (AngII) and certain growth factor receptor agonists such as platelet-derived growth factor (PDGF) have been shown to activate heterotrimeric G proteins, G12 and G13 leading to cell migration. We have recently shown that G12/13 are required for VSMC migration in response to stimulation of the AngII AT1 receptor. Activation of G12/13 also resulted in Rho-kinase activation and subsequent sensitization for smooth muscle contraction. Thus, critical requirement of G12/13 for development of hypertension has been recently demonstrated. However, whether G12/13 have any role in mediating pathological vascular remodeling remains unclear. Here we attempted to answer this question by utilizing an adenovirus vector encoding the RGS-domain of p115 RhoGEF, a selective G12/13 inhibitor. In cultured rat VSMCs, AngII and PDGF-BB rapidly activated G12/13 as detected with a TPR-pull down assay. Adenoviral expression of p115RGS (100 moi) inhibited c-jun/c-fos protein and mRNA induction and c-jun promoter activation by AngII in VSMCs. p115RGS (100 moi) attenuated VSMC migration stimulated by AngII or PDGF-BB. It also inhibited serum-induced VSMC proliferation. Moreover, adenoviral expression of p115RGS markedly inhibited neointima formation in rat carotid artery 2 weeks after a balloon injury. These data suggest that G12/13 are required for VSMC activation stimulated not only by GPCR agonists but also by growth factors, which may play critical roles in pathological vascular remodeling.
- © 2010 by American Heart Association, Inc.