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Bone morphogenetic protein receptor II regulates pulmonary artery endothelial cell barrier function.

Authors
  • Burton, Victoria J
  • Ciuclan, Loredana I
  • Holmes, Alan M
  • Rodman, David M
  • Walker, Christoph
  • Budd, David C
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Jan 06, 2011
Volume
117
Issue
1
Pages
333–341
Identifiers
DOI: 10.1182/blood-2010-05-285973
PMID: 20724539
Source
Medline
License
Unknown

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.

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