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Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension
Author(s) -
Caestecker Mark Peter,
Anderson Lynda,
Jones Mark,
Lowery Jonathan
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1023.3
Subject(s) - bmpr2 , hypoxia (environmental) , enos , pulmonary hypertension , bone morphogenetic protein 2 , medicine , bone morphogenetic protein receptor , bone morphogenetic protein , endocrinology , pulmonary artery , biology , chemistry , nitric oxide , biochemistry , oxygen , nitric oxide synthase , gene , in vitro , organic chemistry
Patients with Familial Pulmonary Hypertension have mutations in the BMP receptor, BMPR2, but it is unknown how these mutations cause disease. These observations also raise questions as to the role of BMPR2 signaling in other forms of pulmonary hypertension (PH). To address this, we evaluated the regulation and function of Bmpr2 ligands in a mouse model of hypoxic PH. Pulmonary Bmp2 and Bmp4 are up‐regulated by hypoxia: Bmp2 is up‐regulated in the peripheral pulmonary vasculature, while Bmp4 is widely expressed in respiratory epithelia. Loss of hypoxia‐induced Bmp4 in Bmp4 +/− mice is associated with reduced PH and decreased pulmonary vascular remodeling. This contrasts with Bmpr2 ΔEx2/+ mice which show greater susceptibility to hypoxic PH, and suggests that an alternative ligand regulates Bmpr2‐dependent effects in the vasculature. Unlike Bmp4 +/− mice, Bmp2 +/− mice develop more severe hypoxic PH than wild type littermates. There is also reduced eNOS expression and activity in the pulmonary vasculature of hypoxic Bmp2 +/− , but not Bmp4 +/− mice. Bmp2 also up‐regulates eNOS expression and activity in intrapulmonary artery and endothelial cell preparations, indicating that eNOS is a target of Bmp2 in the pulmonary vasculature. These data indicate that Bmp2 and Bmp4 exert opposing roles in hypoxic PH, and suggest that protective effects of Bmp2 are mediated by increasing eNOS activity in the pulmonary vasculature.