Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-beta-catenin and Wnt-RhoA-Rac1 pathways.
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.
de Jesus Perez
Vinicio A
VA
Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Alastalo
Tero-Pekka
TP
Wu
Jenny C
JC
Axelrod
Jeffrey D
JD
Cooke
John P
JP
Amieva
Manuel
M
Rabinovitch
Marlene
M
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D055396:Bone Morphogenetic Protein 2 / Q000502:physiology*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002465:Cell Movement; D049109:Cell Proliferation; D000072261:Dishevelled Proteins; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D051176:beta Catenin / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; C495270:CTNNB1 protein, human; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; C497399:SMAD1 protein, human; D051898:Smad1 Protein; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D052006:Bone Morphogenetic Protein Receptors, Type II; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein