New insights into the molecular pathogenesis of pulmonary arterial hypertension: Relevance to novel therapeutic strategies

Abstract

Haploinsufficiency of bone morphogenetic protein receptor-2 (BMPR2) underlies most cases of familial and almost one-half of the idiopathic forms of pulmonary arterial hypertension (PAH). The BMPR2 pathway has been implicated in inhibitory growth regulation of pulmonary artery smooth muscle cells (SMCs), whereas it mediates survival signalling in endothelial cells (ECs). Thus, loss-of-function mutations may contribute to the pathophysiology of PAH by two complementary mechanisms: first, through dysregulated SMC growth leading to medial hyperplasia of pulmonary arteries and arterioles; and, second, by increasing the susceptibility of pulmonary arteriolar ECs to injury and loss in response to various environmental triggers. This hypothesis may represent a ‘double jeopardy' for PAH because apoptosis of pulmonary vascular ECs, particularly at the level of precapillary arterioles, could lead directly to the degeneration of these fragile endothelial structures and loss of efficient perfusion of the distal alveolar capillary bed, while exaggerated SMC proliferation may result in dramatic arterial remodelling. Moreover, EC apoptosis has been suggested to create conditions that favour the emergence of abnormal, apoptosisresistant, hyperproliferative ECs, which may be the genesis of the characteristic plexiform lesions in PAH. This new paradigm suggests that novel strategies aimed at endothelial repair and regeneration may be uniquely effective for the treatment of PAH. The use of endothelial progenitor cells and angiogenic gene therapy, and the results of preclinical proof-of-principle experiments supporting the initiation of a first-in-man clinical trial are reviewed.