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Abstract

Genetic alterations in pulmonary arterial hypertension (PAH) have become increasingly recognized in both known familial or heritable and sporadic or idiopathic PAH (IPAH). Unrecognized genetic alterations have now been found in up to 40% of the IPAH in which no familial predisposition is apparent.1 Bone morphogenetic protein (BMP) receptor II (BMPR-II) is the most common gene implicated in this hereditary form of PAH; furthermore, it is implicated in the pathogenesis of nonhereditary forms of PAH with a significant reduction in the expression of BMPR-II in both IPAH and experimental animal models of pulmonary hypertension (PH).2 BMPs represent the largest group of cytokines in the transforming growth factor-β superfamily and regulate growth, differentiation, and apoptosis in multiple cell types, whereas BMPR-II has been shown to have unique roles in differing cells. Article, see p 1159 BMPR-II is constitutively active at the cell membrane, and ligand stimulation initiates cross-linking with BMPR-I to form a receptor complex that is necessary to activate intracellular signaling. BMPR-II is most highly expressed in endothelial cells in the pulmonary vasculature, and BMPR-II activation leads to the increased proliferation and decreased apoptosis through Smad signaling.3,4 This is in contrast to pulmonary arterial smooth muscle cells, where BMP activation leads to the inhibition of proliferation and increased apoptosis through Smad signaling in large vessels, although in small pulmonary arteries, a proliferative effect is seen through activation of extracellular signal–regulated kinase and mitogen-activated protein kinase, which inhibits Smad signaling.5,6 It is these unique yet complementary functions that make BMPR-II mutations particularly damaging in the pulmonary circulation, leading to development of PAH. A dysfunctional mutation of BMPR-II, as in heritable PAH, or downregulation of protein expression, as in IPAH and animal models, can lead to endothelial dysfunction hallmarked by abnormal barrier function through …