MRTF-A, a rho-dependent co-activator of SRF, regulates phenotypic modulation of vascular smooth muscle cells and plays an important role in vascular remodeling
K. Kuwahara, T. Minami, J. Shibata, C. Yamada, Y. Kuwabara, K. Nakao, H. Kinoshita, S. Usami, Y. Nakagawa, T. Nishikimi & K. Nakao
Myocardin-related transcription factor (MRTF)-A is a Rho signaling-responsive co-activator of serum response factor (SRF). In this study we investigated roles of MRTF-A in the process underlying vascular diseases by using two different mouse models of vascular diseases. MRTF-A expression was significantly higher in the wire-injured femoral arteries of wild-type mice and in the atherosclerotic aortic tissues of ApoE−/− mice than in healthy control tissues, whereas myocardin expression was significantly lower. In MRTF-A−/− mice, neointimal formation induced by wire injury in femoral artery was significantly smaller than that in MRTF-A+/+ mice (neointima to media ratio: 2.09±0.17 in MRTF-A+/+ vs 0.96±0.10 in MRTF-A−/−, P<0.05). Diet-induced atherosclerotic lesions in MRTF-A−/−; ApoE−/− mice was also significantly smaller than those in MRTF-A+/+; ApoE−/− mice (% area of atherosclerotic lesions: 11.8% in MRTF-A+/+; ApoE−/− vs 2.5% in MRTF-A−/−; ApoE−/−, P<0.05). Expression of vinculin, MMP-9 and integrin beta1, three SRF targets and key regulators of cell migration, in injured arteries was significantly weaker in Mkl1−/− mice than in wild-type mice. Knocking down MRTF-A using siRNA in cultured rat aortic vascular smooth muscle cells reduced expression of these genes, resulting in a significant impairment in PDGF-BB-induced migration. Underlying the increased MRTF-A expression in dedifferentiated vascular smooth muscle cells was the downregulation of microRNA-1 concomitant with a decrease in myocardin expression. Collectively, these results demonstrate that MRTF-A plays a critical role in vascular remodeling by regulating vascular smooth muscle cells migration.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.