Send to

Choose Destination
Circulation. 2019 Oct 22;140(17):1409-1425. doi: 10.1161/CIRCULATIONAHA.119.040629. Epub 2019 Aug 29.

Phenotypically Silent Bone Morphogenetic Protein Receptor 2 Mutations Predispose Rats to Inflammation-Induced Pulmonary Arterial Hypertension by Enhancing the Risk for Neointimal Transformation.

Author information

Veterans Affairs Palo Alto Health Care System, CA (W.T, X.J., Y.K.S., E.S., A.B.T., G.P., Y.K., P.Z., S.P., P.D., M.R.N.).
Stanford University School of Medicine, CA (W.T., X.J., Y.K.S., E.S., T.H.W., P.N.K., A.B.T., A.C., L.W., G.P., Y.K., P.Z., J.C., S.P., P.D., P.M., H.C., R.Z., M.P.S., M.R., M.R.N.).
Faculté de Médecine, Université Paris-Sud and Université Paris-Saclay, Le Kremlin-Bicêtre, France (P.D., M.H.).
Institut National de la Sante Et de la Recherche Medicale UMR_S 999, Le Plessis-Robinson, France (P.D., M.H.).
Pathology Department, Hôpital Marie Lannelongue, Le Plessis-Robinson, Paris, France (P.D.).
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, China (G.P.).
University of Michigan Health System, Ann Arbor (M.P.G.).
Free University Medical Center Amsterdam, the Netherlands (N.F.V.).
AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, Department Hospitalo-Universitaire Thorax Innovation, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (M.H.).



Bmpr2 (bone morphogenetic protein receptor 2) mutations are critical risk factors for hereditary pulmonary arterial hypertension (PAH) with approximately 20% of carriers developing disease. There is an unmet medical need to understand how environmental factors, such as inflammation, render Bmpr2 mutants susceptible to PAH. Overexpressing 5-LO (5-lipoxygenase) provokes lung inflammation and transient PAH in Bmpr2+/- mice. Accordingly, 5-LO and its metabolite, leukotriene B4, are candidates for the second hit. The purpose of this study was to determine how 5-LO-mediated pulmonary inflammation synergized with phenotypically silent Bmpr2 defects to elicit significant pulmonary vascular disease in rats.


Monoallelic Bmpr2 mutant rats were generated and found phenotypically normal for up to 1 year of observation. To evaluate whether a second hit would elicit disease, animals were exposed to 5-LO-expressing adenovirus, monocrotaline, SU5416, SU5416 with chronic hypoxia, or chronic hypoxia alone. Bmpr2-mutant hereditary PAH patient samples were assessed for neointimal 5-LO expression. Pulmonary artery endothelial cells with impaired BMPR2 signaling were exposed to increased 5-LO-mediated inflammation and were assessed for phenotypic and transcriptomic changes.


Lung inflammation, induced by intratracheal delivery of 5-LO-expressing adenovirus, elicited severe PAH with intimal remodeling in Bmpr2+/- rats but not in their wild-type littermates. Neointimal lesions in the diseased Bmpr2+/- rats gained endogenous 5-LO expression associated with elevated leukotriene B4 biosynthesis. Bmpr2-mutant hereditary PAH patients similarly expressed 5-LO in the neointimal cells. In vitro, BMPR2 deficiency, compounded by 5-LO-mediated inflammation, generated apoptosis-resistant and proliferative pulmonary artery endothelial cells with mesenchymal characteristics. These transformed cells expressed nuclear envelope-localized 5-LO consistent with induced leukotriene B4 production, as well as a transcriptomic signature similar to clinical disease, including upregulated nuclear factor Kappa B subunit (NF-κB), interleukin-6, and transforming growth factor beta (TGF-β) signaling pathways. The reversal of PAH and vasculopathy in Bmpr2 mutants by TGF-β antagonism suggests that TGF-β is critical for neointimal transformation.


In a new 2-hit model of disease, lung inflammation induced severe PAH pathology in Bmpr2+/- rats. Endothelial transformation required the activation of canonical and noncanonical TGF-β signaling pathways and was characterized by 5-LO nuclear envelope translocation with enhanced leukotriene B4 production. This study offers an explanation of how an environmental injury unleashes the destructive potential of an otherwise silent genetic mutation.


bmpr2 receptor; endothelial cells; inflammation; lung

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center