Genetic Ablation of the Bmpr2 Gene in Pulmonary Endothelium Is Sufficient to Predispose to Pulmonary Arterial Hypertension

Abstract

Background Pulmonary arterial hypertension (PAH) is a rare but fatal lung disease of diverse etiologies. PAH is now further subclassified as idiopathic (IPAH), familial (FPAH) and associated (APAH) varieties. Heterozygous mutations in BMPR2 can be detected in 50-70% of patients with FPAH and 10-40% of patients with IPAH. Although endothelial cells have been suspected as the cellular origin of PAH pathogenesis, no direct in vivo evidence has been clearly presented. The present study was designed to investigate whether endothelial Bmpr2 deletion can predispose to PAH. Methods and Results The Bmpr2 gene was deleted in pulmonary endothelial cells (pECs) using Bmpr2 conditional knockout mice and a novel endothelial Cre transgenic mouse line. Wide ranges of right ventricular systolic pressure (RVSP) were observed in mice with heterozygous (21.7 - 44.1 mmHg, median: 23.7 mmHg) and homozygous (20.7- 56.3 mmHg, median: 27 mmHg) conditional deletion of Bmpr2 in pECs in comparison with control mice (19.9 - 26.7 mmHg, median: 23 mmHg) at two to seven months of age. A subset of mice with RVSP greater than 30 mmHg exhibited right ventricular hypertrophy and an increase in the number and wall thickness of muscularized distal pulmonary arteries. In the lungs of these high RVSP mice, expression of proteins involved in the pathogenesis of PAH, such as serotonin transporter and tenacin-C, were elevated in distal arteries, and had a high incidence of perivascular leukocyte infiltration and in situ thrombosis. Conclusions Conditional hetero or homozygous Bmpr2 deletion in pECs predisposes mice to develop PAH.

Putting skin in the game: dermis-derived stem cells provide insight into familial pulmonary hypertension

“…Several studies have reported mutations or polymorphisms that affect TGF-β signaling as being either protective against or associated with the development of FPAH, but the events determining disease penetrance remain poorly understood for most families (4,5). Endothelial cell-line specific mutation of BMPR2 in mice also leads to pulmonary hypertension, consistent with other data highlighting endothelial cells as a key factor in FPAH pathogenesis (6).…”

Coagulation and the Vessel Wall in Pulmonary Embolism

“…104 Recent data have shown that genetic ablation of the BMPR2 gene in pulmonary endothelium induces in situ thrombosis, suggesting a role for the TGF-β pathway in thrombus organization. 105 …”

Cellular microparticles in the pathogenesis of pulmonary hypertension

“…Taken together, all these experimental findings support the notion that circulating microparticles could contribute to both initiation and/or amplification of the pulmonary endothelial dysfunction during PH and encourage further studies of the precise pathogenic mechanism underlying this phenomenon. Moreover, we cannot exclude that the generation of microparticles and their migration to the systemic circulation could mediate a crosstalk between the pulmonary and systemic endothelium and, therefore, explain the peripheral endothelial dysfunction observed during PH [21,24,25].…”

“…In addition, alterations of endothelial cell monolayer integrity in mice, such as a selective disruption of the endothelial peroxisome proliferator-activated receptor-c or of the endothelial BMPR2 signalling, are sufficient to predispose to PH [20,21].…”