Abstract P341: MRTF-A, a Rho-Dependent Coactivator of SRF, Plays a Critical Role in Vascular Remodeling

Abstract

Objective: Rho-ROCK pathway is involved in the progression of pathological vascular remodeling through the regulation of cell proliferation and migration by controlling gene transcription. While a transcriptional co-activator Myocardin-related transcription factor(MRTF)-A transduces Rho-actin signaling to SRF activation in the nucleus, roles of MRTF-A in the process underlying vascular diseases remain unknown. Methods and Results: We found that MRTF-A mRNA and protein expression in femoral arteries 2weeks after wire injury was significantly higher than that in sham-operated arteries of mice. In contrast, the expression of myocardin or MRTF-B was significantly decreased in injured arteries. We then evaluated the role played by MRTF-A in pathological vascular remodeling by creating several vascular disease models of mice lacking MRTF-A (MRTF-A -/- ). Neointima formation induced by ligation in carotid arteries of MRTF-A -/- was significantly smaller than that of MRTF-A +/- . Neointima formation induced by wire injury in femoral arteries of MRTFA -/- was significantly smaller than that of MRTF-A +/+ . Atherosclerotic lesions of MRTF-A -/- ;ApoE -/- was also significantly smaller than those of MRTF-A +/+ ;ApoE -/ . The expression of SRF-target genes involved in cellular migration, such as MMP9 and vinculin,within injured arteries of MRTF-A -/- was significantly attenuated compared to that of MRTF-A +/+ . In cultured, de-differentiated rat aortic vascular smooth muscle cells (RAVSMC), the expression of these genes was decreased by knocking down MRTF-A. Indeed, the promoter activity of vinculin gene was controlled by MRTF-A in RAVSMC. In addition, knocking down MRTF-A in RAVSMC resulted in a significant impairment in migration capacity. Furthermore, treatment with a small molecule CCG1423 inhibiting MRTF-A significantly reduced neointima formation induced by wire injury in femoral arteries of mice. Conclusions: Our study revealed that in de-differentiated vascular smooth muscle cells, in which myocardin and MRTTF-B expression is decreased, increased expression of MRTF-A contributes to the acquisition of migration capacity by maintaining SRF-target genes transcription, thereby promoting stress-induced vascular remodeling.