title: Perivascular gene transfer of dominant-negative N19RhoA attenuates neointimal formation via inhibition of TGF-beta1-Smad2 signaling in rats after carotid artery balloon injury.
abstract: 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-beta1-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 14days 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 14days after balloon injury. Ad-N19RhoA-hrGFP administration also inhibited adventitial Smad2 phosphorylation, but did not alter local TGF-beta1 and total-Smad2 expression after injury. Our results provide evidence that perivascular gene transfer of dominant-negative N19RhoA blocks TGF-beta1-Smad2-induced differentiation of adventitial fibroblasts to myofibroblasts, which contributes to intimal hyperplasia after balloon injury.
authors.affiliation: Shanghai Key Laboratory of Vascular Biology at Ruijin Hospital and Shanghai Institute of Hypertension, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: WenDong
authors.initials: W
authors.lastname: Chen
authors.forename: YuFeng
authors.initials: Y
authors.lastname: Chu
authors.forename: DingLiang
authors.initials: D
authors.lastname: Zhu
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.forename: JianJun
authors.initials: J
authors.lastname: Liu
authors.forename: KaiDa
authors.initials: K
authors.lastname: Ji
authors.forename: PingJin
authors.initials: P
authors.lastname: Gao
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000256:Adenoviridae; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D002339:Carotid Arteries / Q000601:surgery; D020212:Carotid Artery Injuries / Q000473:pathology*; D002454:Cell Differentiation; D005347:Fibroblasts / Q000473:pathology*; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D006965:Hyperplasia / Q000473:pathology; D008297:Male; D008840:Microfilament Proteins / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D051899:Smad2 Protein / Q000037:antagonists & inhibitors*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors*; D020742:rhoA GTP-Binding Protein / Q000235:genetics*; D000096985:Calponins
chemical_list: D000199:Actins; D002135:Calcium-Binding Proteins; D049452:Green Fluorescent Proteins; D008840:Microfilament Proteins; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D020742:rhoA GTP-Binding Protein; D000096985:Calponins; C498862:Acta2 protein, rat