title: Bone morphogenetic protein receptor II regulates pulmonary artery endothelial cell barrier function.
abstract: Mutations in bone morphogenetic protein receptor II (BMPR-II) underlie most heritable cases of pulmonary arterial hypertension (PAH). However, less than half the individuals who harbor mutations develop the disease. Interestingly, heterozygous null BMPR-II mice fail to develop PAH unless an additional inflammatory insult is applied, suggesting that BMPR-II plays a fundamental role in dampening inflammatory signals in the pulmonary vasculature. Using static- and flow-based in vitro systems, we demonstrate that BMPR-II maintains the barrier function of the pulmonary artery endothelial monolayer suppressing leukocyte transmigration. Similar findings were also observed in vivo using a murine model with loss of endothelial BMPR-II expression. In vitro, the enhanced transmigration of leukocytes after tumor necrosis factor α or transforming growth factor β1 stimulation was CXCR2 dependent. Our data define how loss of BMPR-II in the endothelial layer of the pulmonary vasculature could lead to a heightened susceptibility to inflammation by promoting the extravasation of leukocytes into the pulmonary artery wall. We speculate that this may be a key mechanism involved in the initiation of the disease in heritable PAH that results from defects in BMPR-II expression.
authors: Respiratory Disease Area, Novartis Institutes for BioMedical Research, West Sussex, United Kingdom.
authors: Victoria J
authors: VJ
authors: Burton
authors: Loredana I
authors: LI
authors: Ciuclan
authors: Alan M
authors: AM
authors: Holmes
authors: David M
authors: DM
authors: Rodman
authors: Christoph
authors: C
authors: Walker
authors: David C
authors: DC
authors: Budd
mesh_terms: D000818:Animals; D015153:Blotting, Western; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000037:antagonists & inhibitors / Q000502:physiology*; D002465:Cell Movement; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D019426:Integrases / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009195:Peroxidase / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D052006:Bone Morphogenetic Protein Receptors, Type II; C045073:Cre recombinase; D019426:Integrases