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Pulmonary hypertension (PH) encompasses a group of conditions which ultimately lead to elevated pulmonary arterial pressure. PH is classified into five subgroups, of which Group 1 pulmonary arterial hypertension (PAH), is the most extensively studied. Numerous causal genes have been identified in PAH, most notably germline mutations in bone morphogenetic protein receptor type 2 (BMPR2) and the wider BMP pathway. Often when considering the genetics of PH, sporadic idiopathic and heritable PAH dominates the discussion. There are a number of reviews that elegantly describe the ‘state of the art’ in respect to group 1 PAH, however this focus misses the wider context of genetic conditions where PH is a feature, but outside of the framework of classical ‘idiopathic or heritable’ PAH. In addition to variants in genes within the TGF-β/BMP signaling pathway, genes which regulate ion channels, the extracellular matrix, inflammation, angiogenesis, and mitochondrial dysfunction have been shown to play a significant role in PH pathogenesis across different PH groups. In this review, we aim to cast the net wider to understand what we can learn from the spectrum of genetic conditions where PH is an acknowledged feature or complication, and what this tells us about the important cellular, molecular and systems physiology features that predispose to PH and consequently might be treatment targets.

Summary: Concentric lung vascular wall thickening due to enhanced proliferation of pulmonary arterial smooth muscle cells is an important pathological cause for the elevated pulmonary vascular resistance reported in patients with pulmonary arterial hypertension. We identified a differential role of mammalian target of rapamycin (mTOR) complex 1 and complex 2, two functionally distinct mTOR complexes, in the development of pulmonary hypertension (PH). Inhibition of mTOR complex 1 attenuated the development of PH; however, inhibition of mTOR complex 2 caused spontaneous PH, potentially due to up-regulation of platelet-derived growth factor receptors in pulmonary arterial smooth muscle cells, and compromised the therapeutic effect of the mTOR inhibitors on PH. In addition, we describe a promising therapeutic strategy using combination treatment with the mTOR inhibitors and the platelet-derived growth factor receptor inhibitors on PH and right ventricular hypertrophy. The data from this study provide an important mechanism-based perspective for developing novel therapies for patients with pulmonary arterial hypertension and right heart failure. Key Words: mTOR, pulmonary hypertension, Raptor, Rictor, right ventricle