BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways
Perez VA, Ali Z, Alastalo TP, Ikeno F, Sawada H, Lai YJ, Kleisli T, Spiekerkoetter E, Qu X, Rubinos LH, Ashley E, Amieva M, Dedhar S, Rabinovitch M
J Cell Biol
Cells used in publication:
SMC, aortic (AoSMC), human
Tissue Origin: aortic
SMC, pul.artery (PASMC), human
Tissue Origin: artery
Smooth Muscle Growth Medium-2
We present a novel cell-signaling paradigm in which bone morphogenetic protein 2 (BMP-2) consecutively and interdependently activates the wingless (Wnt)-ß-catenin (ßC) 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 ßC transcriptional activity to produce fibronectin, which then activates integrin-linked kinase 1 (ILK-1) via a4-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 ßC without activating RhoA-Rac1 not only prevents BMP-2-mediated vascular smooth muscle cell motility but promotes proliferation in association with persistent ßC 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-ßC and Wnt-PCP pathways contribute to obliterative vascular disease in both the systemic and pulmonary circulations.
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