LAUSR

Since the discovery of mutations in BMPR2 (bone morphogenetic protein receptor type II) gene in patients with pulmonary arterial hypertension (PAH), growing evidence from human genetics has supported a critical role for imbalanced signaling of the TGF-β (transforming growth factor-β) family, such that deficient BMP and maladaptive TGF-β signaling appear to contribute. BMPRII expression is not only reduced in PAH patients harboring mutations in BMPR2 but also in mutation-negative idiopathic PAH, suggesting additional environmental or epigenetic factors may downregulate this receptor. Several possible mechanisms have been proposed, including estrogen signaling, interleukin-6–mediated inflammation, TNFα (tumor necrosis factor-α)-induced cleavage, and other factors driving the ubiquitination and degradation of BMPRII. The reduced penetrance of PAH-associated BMPR2 mutations is consistent with the need for additional factors, such as vascular injury or inflammation for triggering disease. In search of this missing link, Abdul-Salam et al describe in the current issue a novel pathway that may integrate hypoxia and inflammation to regulate endothelial BMPRII expression and the balance between BMP and TGF-β signaling.