Background Vascular occlusion and complex plexiform lesions are hallmarks of the pathology of severe pulmonary arterial hypertension (PAH) in patients. However, mechanisms of obliterative vascular remodeling remain elusive and hence current therapies have not targeted the fundamental disease modifying mechanisms and result in only modest improvement in morbidity and mortality. Methods and Results Mice with Tie2Cre-mediated disruption of Egln1 (encoding prolyl-4 hydroxylase 2, PHD2) (Egln1Tie2) in endothelial cells (ECs) and hematopoietic cells exhibited spontaneous severe PAH with extensive pulmonary vascular remodeling including vascular occlusion and plexiform-like lesions resembling the hallmarks of the pathology of clinical PAH. As seen in idiopathic PAH patients, Egln1Tie2 mice exhibited unprecedented right ventricular hypertrophy and failure and progressive mortality. Consistently, PHD2 expression was diminished in lung ECs of obliterated pulmonary vessels in idiopathic PAH patients. Genetic deletions of both Egln1 and Hif1a or Egln1 and Hif2a identified hypoxia-inducible factor-2α (HIF-2α) as the critical mediator of severe PAH seen in Egln1Tie2 mice. We also observed altered expression of many PH-causing genes in Egln1Tie2 lungs which was also normalized in Egln1Tie2/Hif2aTie2 lungs. PHD2-deficient ECs promoted smooth muscle cell proliferation in part through HIF-2α-activated CXCL12 expression. Genetic deletion of Cxcl12 attenuated PAH in Egln1Tie2 mice. Conclusions These studies defined an unexpected role of PHD2 deficiency in the mechanisms of severe PAH and identified the first genetically modified mouse model with obliterative vascular remodeling and pathophysiology recapitulating clinical PAH. Thus, targeting PHD2/HIF-2α signaling is a promising strategy to reverse vascular remodeling for treatment of severe PAH.

Pulmonary arterial hypertension (PAH) is a devastating disease that involves pulmonary vasoconstriction, small vessel obliteration, large vessel thickening and obstruction, and development of plexiform lesions. PAH vasculopathy leads to progressive increases in pulmonary vascular resistance, right heart failure, and ultimately, premature death. Besides other cell types that are known to be involved in PAH pathogenesis (e.g. smooth muscle cells, fibroblasts, and leukocytes), recent studies demonstrate a crucial role of endothelial cells (ECs) in the initiation and progression of PAH. The EC-specific role in PAH is multi-faceted and impacts upon numerous pathophysiological processes including vasoconstriction, inflammation, coagulation, metabolism, and oxidative/nitrative stress, as well as cell viability, growth, and differentiation. In this review, we describe how EC dysfunction and cell signalling regulate the pathogenesis of PAH. We also highlight areas of research that warrant attention in future studies, and discuss potential molecular signalling pathways in ECs that could be targeted therapeutically in the prevention and treatment of PAH.