MicroRNA miR145 Regulates TGFBR2 Expression and Matrix Synthesis in Vascular Smooth Muscle Cells

Abstract

Rationale: MicroRNA miR145 has been implicated in vascular smooth muscle cell differentiation, but its mechanisms of action and downstream targets have not been fully defined. Objective: Here, we sought to explore and define the mechanisms of miR145 function in smooth muscle cells. Methods and Results: Using a combination of cell culture assays and in vivo mouse models to modulate miR145, we characterized its downstream actions on smooth muscle phenotypes. Our results show that the miR-143/145 gene cluster is induced in smooth muscle cells by coculture with endothelial cells. Endothelial cell–induced expression of miR-143/145 is augmented by Notch signaling and accordingly expression is reduced in Notch receptor–deficient cells. Screens to identify miR145-regulated genes revealed that the transforming growth factor (TGF)-β pathway has a significantly high number of putative target genes, and we show that TGFβ receptor II is a direct target of miR145. Extracellular matrix genes that are regulated by TGFβ receptor II were attenuated by miR145 overexpression, and miR145 mutant mice exhibit an increase in extracellular matrix synthesis. Furthermore, activation of TGFβ signaling via angiotensin II infusion revealed a pronounced fibrotic response in the absence of miR145. Conclusions: These data demonstrate a specific role for miR145 in the regulation of matrix gene expression in smooth muscle cells and suggest that miR145 acts to suppress TGFβ-dependent extracellular matrix accumulation and fibrosis, while promoting TGFβ-induced smooth muscle cell differentiation. Our findings offer evidence to explain how TGFβ signaling exhibits distinct downstream actions via its regulation by a specific microRNA.