Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-beta-catenin and Wnt-RhoA-Rac1 pathways. Academic Article uri icon

Overview

abstract

  • Mutations in bone morphogenetic protein (BMP) receptor II (BMPRII) are associated with pulmonary artery endothelial cell (PAEC) apoptosis and the loss of small vessels seen in idiopathic pulmonary arterial hypertension. Given the low penetrance of BMPRII mutations, abnormalities in other converging signaling pathways may be necessary for disease development. We hypothesized that BMPRII supports normal PAEC function by recruiting Wingless (Wnt) signaling pathways to promote proliferation, survival, and motility. In this study, we report that BMP-2, via BMPRII-mediated inhibition of GSK3-beta, induces beta-catenin (beta-C) accumulation and transcriptional activity necessary for PAEC survival and proliferation. At the same time, BMP-2 mediates phosphorylated Smad1 (pSmad1) or, with loss of BMPRII, pSmad3-dependent recruitment of Disheveled (Dvl) to promote RhoA-Rac1 signaling necessary for motility. Finally, using an angiogenesis assay in severe combined immunodeficient mice, we demonstrate that both beta-C- and Dvl-mediated RhoA-Rac1 activation are necessary for vascular growth in vivo. These findings suggest that the recruitment of both canonical and noncanonical Wnt pathways is required in BMP-2-mediated angiogenesis.

publication date

  • January 12, 2009

Research

keywords

  • Bone Morphogenetic Protein 2
  • Pulmonary Artery
  • Signal Transduction
  • Wnt Proteins

Identity

PubMed Central ID

  • PMC2615088

Scopus Document Identifier

  • 59849099675

Digital Object Identifier (DOI)

  • 10.1126/stke.2002.151.pe40

PubMed ID

  • 19139264

Additional Document Info

volume

  • 184

issue

  • 1