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

Authors:
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
In:
Source: J Cell Biol
Publication Date: (2011)
Issue: 192(1): 171-88
Research Area:
Gene Expression
Cells used in publication:
SMC, aortic (AoSMC), human
Species: human
Tissue Origin: aortic
SMC, pul.artery (PASMC), human
Species: human
Tissue Origin: artery
Platform:
Nucleofector™ I/II/2b
Abstract
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.