BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways

We present a novel cell-signaling paradigm in which bone morphogenetic protein 2 (BMP-2) consecutively and interdependently activates the wingless (Wnt)-beta-catenin (beta c) and Wnt planar cell polarity (PCP) signaling pathways to facilitate vascular smooth muscle motility while simultaneously suppressing growth. We show that BMP-2, in a phospho-Akt-dependent manner, induces beta C transcriptional activity to produce fibronectin, which then activates integrin-linked kinase 1 (ILK-1) via alpha 4-integrins. ILK-1 then induces the Wnt-PCP pathway by binding a proline-rich motif in disheveled (Dvl) and consequently activating RhoA-Rac1-mediated motility. Transfection of a Dvl mutant that binds beta C without activating RhoA-Rac1 not only prevents BMP-2 mediated vascular smooth muscle cell motility but promotes proliferation in association with persistent beta C activity. Interfering with the Dvl-dependent Wnt-PCP activation in a murine stented aortic graft injury model promotes extensive neointima formation, as shown by optical coherence tomography and histopathology. We speculate that, in response to injury, factors that subvert BMP-2 mediated tandem activation of Wnt-beta C and Wnt-PCP pathways contribute to obliterative vascular disease in both the systemic and pulmonary circulations.