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.
05 - 09 May 2012
European Society of Endocrinology