TY - JOUR
T1 - Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt -β-catenin and Wnt - RhoA - Rac1 pathways
AU - De Jesus Perez, Vinicio A.
AU - Alastalo, Tero Pekka
AU - Wu, Jenny C.
AU - Axelrod, Jeffrey D.
AU - Cooke, John P.
AU - Amieva, Manuel
AU - Rabinovitch, Marlene
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2009/1/12
Y1 - 2009/1/12
N2 - 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-βces β-catenin (β-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 immunodefi cient mice, we demonstrate that both β-C - and Dvl-mediated RhoA - Rac1 activation are necessary for vascular growth in vivo. These fi ndings suggest that the recruitment of both canonical and noncanonical Wnt pathways is required in BMP-2 - mediated angiogenesis.
AB - 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-βces β-catenin (β-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 immunodefi cient mice, we demonstrate that both β-C - and Dvl-mediated RhoA - Rac1 activation are necessary for vascular growth in vivo. These fi ndings suggest that the recruitment of both canonical and noncanonical Wnt pathways is required in BMP-2 - mediated angiogenesis.
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U2 - 10.1083/jcb.200806049
DO - 10.1083/jcb.200806049
M3 - Article
C2 - 19139264
AN - SCOPUS:59849099675
SN - 0021-9525
VL - 184
SP - 83
EP - 99
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 1
ER -