In addition, collaborative studies of BMPR2 mutation carriers should enable identification of environmental modifiers, biomarkers for disease development and progression, and surrogate markers for efficacy end points in clinical drug development, thereby providing an invaluable resource for trials of PAH prevention.
Circulating angiogenic progenitor numbers in patients with PAH were increased compared with control subjects and functional studies of late-outgrowth progenitor cells from patients with PAH with BMPRII mutations revealed a hyperproliferative phenotype with impaired ability to form vascular networks.
We demonstrate that GDF5 and BMP2 prevent apoptosis induced by serum starvation in mouse embryonic fibroblasts but not in smooth muscle cells via the BMP receptor 2 (BMPR2), which is often mutated in hereditary cases of primary pulmonary hypertension.
Sequence variants in BMPR2 and genes involved in the serotonin and nitric oxide pathways in idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: relation to clinical parameters and comparison with left heart disease.
These cases were compared with 370 patients from the French PAH Network (93 with a bone morphogenetic protein receptor type 2 [BMPR2] mutation and 277 considered as idiopathic cases without identified mutation).
Perhaps the greatest advancement in the last decade has been the discovery of the "PAH gene," bone morphogenetic receptor 2 (Bmpr2), however how the loss-of-function mutations in Bmpr2 lead to PAH is unclear.
We thus hypothesize that BMPR2 mutation thus leads to an impaired ability to terminate the injury repair process, leading to strong predisposition to PAH.
Furthermore, the recent finding that mutations in BMPR2 cause familial forms of pulmonary arterial hypertension and that BMPR2 expression is decreased in secondary forms of PH strongly implicate BMP signaling in the underlying pathophysiology of PH.
We tested this notion using bone marrow-derived macrophages (BMDM; precursors of tissue macrophages) isolated from ROSA26rtTAXTetO(7)-tet-BMPR2(R899X) mice (model of PAH with universal expression of a mutated BMPR2 gene) with and without activation by LPS and in human lung tissue from HPAH with BMPR2 mutations and idiopathic PAH (IPAH).
Our data indicate a high frequency of genetically abnormal subclones within PAH lung vessels and provide the first definitive evidence of a second genetic hit in a patient with a germline BMPR2 mutation.
Gene delivery of BMPR2 has now been shown to ameliorate the development and progression of PAH in animal models, thereby identifying this approach as a therapeutic target.
Our objectives were to assess the effect on PAH of upregulating BMPR2 by targeted adenoviral BMPR2 gene delivery to the pulmonary vascular endothelium.
290 idiopathic (I)PAH patients and 15 heritable (H)PAH were screened to determine the spectrum and rate of BMPR2 mutations in a large Chinese patient group.
These results demonstrate the role of BMPR2 mutation in the pathogenesis of PAH and indicate that variation within the SMAD family represents an infrequent cause of the disease.
Together, these findings suggest that cytoskeletal function is central to the development of BMPR2-associated PAH and that intervention against cytoskeletal defects may reverse established disease.
Heritable and idiopathic pulmonary arterial hypertension (PAH) are phenotypically identical and associated with mutations in several genes related to transforming growth factor (TGF) beta signaling, including bone morphogenetic protein receptor type 2, activin receptor-like kinase 1, endoglin, and mothers against decapentaplegic 9.