Down-regulation of miR-96 by bone morphogenetic protein signaling is critical for vascular smooth muscle cell phenotype modulation.

The bone morphogenetic protein (BMP) signaling pathway is critical for the induction and maintenance of contractile phenotype in vascular smooth muscle cells (VSMCs). Inactivation of BMP signaling is common in abnormalities in vascular development and in vascular proliferative conditions, such as pulmonary artery hypertension. Herein, we identify microRNA-96 (miR-96) as a modulator of the VSMC phenotype in response to BMP4 signaling. We show that miR-96 is down-regulated by BMP4 treatment, which results in the derepression of a novel target, Tribbles-like protein 3 (Trb3). miR-96 targets a partially complementary sequence localized in the 3' UTR of Trb3. Trb3 is an essential positive regulator of the BMP signaling pathway and promotes contractile phenotype in VSMCs. In conclusion, our study demonstrates a novel mechanism of regulation of SMC-specific gene expression and induction of a VSMC contractile phenotype by the BMP4 signaling pathway via suppression of the miR-96-Trb3 axis.