Objective
We and others have previously shown that RhoA-dependent stimulation of myocardin related transcription factor (MRTF) nuclear localization promotes smooth muscle cell (SMC) marker gene expression. The goal of the present study was to provide direct in vivo evidence that actin polymerization by the diaphanous-related formins contributes to the regulation of SMC differentiation and/or phenotype.
Approach and Results
Conditional cre-based genetic approaches were used to over-express a well-characterized dominant negative variant of mDia1 (DNmDia) in SMC. DNmDia expression in SM22 expressing cells resulted in embryonic and perinatal lethality in ~20% of mice due to defects in myocardial development and SMC investment of peripheral vessels. While most DNmDia+/SM22Cre+ mice exhibited no overt phenotype, the re-expression of SMC differentiation marker gene expression that occurs following carotid artery ligation was delayed, and this effect was accompanied by a significant decrease in MRTF-A nuclear localization. Interestingly, neointima growth was inhibited by expression of DNmDia in SMC and this was likely due to a defect in directional SMC migration and not to defects in SMC proliferation or survival. Finally, by using the tamoxifen-inducible SM MHCCreERT2 line, we showed that SMC-specific induction of DNmDia in adult mice decreased SMC marker gene expression.
Conclusions
Our demonstration that diaphanous-related formin signaling plays a role in heart and vascular development and the maintenance of SMC phenotype provides important new evidence that Rho/actin/MRTF signaling plays a critical role in cardiovascular function.