title: Increased susceptibility to hypoxic pulmonary hypertension in Bmpr2 mutant mice is associated with endothelial dysfunction in the pulmonary vasculature.
abstract: Patients with familial pulmonary arterial hypertension inherit heterozygous mutations of the type 2 bone morphogenetic protein (BMP) receptor BMPR2. To explore the cellular mechanisms of this disease, we evaluated the pulmonary vascular responses to chronic hypoxia in mice carrying heterozygous hypomorphic Bmpr2 mutations (Bmpr2 delta Ex2/+). These mice develop more severe pulmonary hypertension after prolonged exposure to hypoxia without an associated increase in pulmonary vascular remodeling or proliferation compared with wild-type mice. This is associated with defective endothelial-dependent vasodilatation and enhanced vasoconstriction in isolated intrapulmonary artery preparations. In addition, there is a selective decrease in hypoxia-induced, BMP-dependent, endothelial nitric oxide synthase expression and Smad signaling in the intact lungs and in cultured pulmonary microvascular endothelial cells from Bmpr2 delta Ex2/+ mutant mice. These findings indicate that the pulmonary endothelium is a target of abnormal BMP signaling in Bmpr2 delta Ex2/+ mutant mice and suggest that endothelial dysfunction contributes to their increased susceptibility to hypoxic pulmonary hypertension.
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt Univ. School of Medicine, S3223 Medical Center North, 1161 21 St. South, Nashville, TN 37232-2372, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Frank
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lowery
authors.forename: Lynda
authors.initials: L
authors.lastname: Anderson
authors.forename: Monique
authors.initials: M
authors.lastname: Brink
authors.forename: Jeff
authors.initials: J
authors.lastname: Reese
authors.forename: Mark
authors.initials: M
authors.lastname: de Caestecker
mesh_terms: D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D020022:Genetic Predisposition to Disease; D006863:Hydrogen-Ion Concentration; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D011652:Pulmonary Circulation / Q000502:physiology*
chemical_list: C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II