Perivascular gene transfer of dominant-negative N19RhoA attenuates neointimal formation via inhibition of TGF-β1-Smad2 signaling in rats after carotid artery balloon injury

Phenotypic differentiation of adventitial fibroblasts to myofibroblasts is an essential feature of vascular remodeling. Here, we carried Out perivascular gene transfer of dominant-negative N19RhoA to investigate whether antagonism of RhoA signaling attenuates neointimal formation following rat carotid artery balloon injury and alters TGF-beta 1-Smad2-induced differentiation of adventitial fibroblasts to myofibroblasts. Perivascular delivery of an adenovirus coexpressing dominant-negative N19RhoA and humanized Renilla green fluorescent protein (hrGFP) (Ad-N19RhoA-hrGFP), as demonstrated by hrGFP staining, suppressed neointimal formation at 7 and 14 days post-injury. Ad-N19RhoA-hrGFP administration inhibited neointimal alpha-smooth muscle-actin and Calponin expression, as markers of myofibroblast differentiation and perivascular collagen deposition, at 14 days after balloon injury. Ad-N19RhoA-hrGFP administration also inhibited adventitial Smad2 phosphorylation, but did not alter local TGF-beta 1 and total-Smad2 expression after injury. Our results provide evidence that perivascular gene transfer of dominant-negative N19RhoA blocks TGF-beta 1-Smad2-induced differentiation of adventitial fibroblasts to myofibroblasts, which contributes to intimal hyperplasia after balloon injury. (C) 2009 Elsevier Inc. All rights reserved.