Circulation Research. 2005
Published online before print August 11, 2005, doi: 10.1161/01.RES.0000181152.65534.07
Published online before print August 11, 2005, doi: 10.1161/01.RES.0000181152.65534.07
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Submitted on May 5, 2005
Revised on July 28, 2005
Accepted on July 29, 2005
Bone Morphogenetic Protein 4 Promotes Pulmonary Vascular Remodeling in Hypoxic Pulmonary Hypertension
David B. Frank ;
From the Departments of Cell and Developmental Biology (D.B.F., H.S.B., M.P.d.C.), Medicine (A.A., D.J.Y., A.P., M.P.d.C.), Pathology (S.M., J.E.J.), Biostatistics (Y.S.), and Pediatrics (H.S.B.), Vanderbilt University School of Medicine, Nashville, Tenn.
* To whom correspondence should be addressed. E-mail: mark.de.caestecker{at}vanderbilt.edu.
We show that 1 of the type II bone morphogenetic protein (BMP) receptor ligands, BMP4, is widely expressed in the adult mouse lung and is upregulated in hypoxia-induced pulmonary hypertension (PH). Furthermore, heterozygous null Bmp4lacZ/+ mice are protected from the development of hypoxia-induced PH, vascular smooth muscle cell proliferation, and vascular remodeling. This is associated with a reduction in hypoxia-induced Smad1/5 phosphorylation and Id1 expression in the pulmonary vasculature. In addition, pulmonary microvascular endothelial cells secrete BMP4 in response to hypoxia and promote proliferation and migration of vascular smooth muscle cells in a BMP4-dependent fashion. These findings indicate that BMP4 plays a dominant role in regulating BMP signaling in the hypoxic pulmonary vasculature and suggest that endothelium-derived BMP4 plays a direct, paracrine role in promoting smooth muscle proliferation and remodeling in hypoxic PH.
Key words: bone morphogenetic proteins • endothelial cells • hypoxic pulmonary hypertension • signaling pathways • Smad • vascular remodeling • vascular smooth muscle cell proliferation
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