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 ␣ or transforming growth factor ␤1 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. (Blood. 2011;117(1):333-341)

Transient Receptor Potential Channel 4 Encodes a Vascular Permeability Defect and High-Frequency Ca2+ Transients in Severe Pulmonary Arterial Hypertension

“…28 These findings are contradicted by studies addressing the role of bone morphogenetic protein receptor type 2 (BMPR2) mutations in familial pulmonary arterial hypertension, where silencing of BMPR2 in human endothelial cells increases permeability, 36 and mice transfected with mutated BMPR2 exhibit substantial vascular leak in vivo. 37 Herein, we demonstrated a TRPC4-dependent increase in the permeability of isolated lungs from PAH Fischer rats after store depletion with thapsigargin.…”

“…Furthermore, BMPR2 silencing and Sugen models of PAH exhibit interaction with respect to permeability, indicating that vascular endothelial growth factor receptor and BMPR pathways are linked in regulating endothelial barrier function. 36 We suggest that increased vascular permeability may be a distinguishing feature of a subset of PAH patients, and therefore warrants further study.…”

Heterozygous Null Bone Morphogenetic Protein Receptor Type 2 Mutations Promote SRC Kinase-dependent Caveolar Trafficking Defects and Endothelial Dysfunction in Pulmonary Arterial Hypertension

“…Heterozygous Bmpr2 mutant mice have pulmonary endothelial cell (PEC) dysfunction with decreased endothelium-dependent relaxation in isolated intrapulmonary pulmonary artery preparations (8). In addition, mice with conditional deletion of Bmpr2 in the endothelium develop spontaneous pulmonary hypertension and have endothelial barrier dysfunction associated with increased pulmonary vascular leak and perivascular inflammation (11)(12)(13). Increased perivascular inflammation also occurs in patients with pulmonary hypertension (14 -16).…”

RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension

“…Reduced BMPR2 expression and function is also described in patients with IPAH or with APAH who do not have a mutation (8). Loss of BMPR2 impairs PAEC survival (2)(3)(4)(5) and barrier function (11). Our previous studies demonstrated that BMPR2 signaling activates b-catenin/peroxisome proliferator-activated receptor (PPAR) g-mediated transcription of PAEC genes, such as apelin (3,4).…”