Pathophysiological roles of TRPC6 channels in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive and lethal disease of the pulmonary artery. The pathogenesis of PAH is mainly sustained vasoconstriction and vascular remodeling of the pulmonary artery. These pathogeneses cause progressive elevations in pulmonary vascular resistance and pulmonary arterial pressure in PAH patients. Elevated pulmonary arterial pressure leads to right heart failure and finally death. The vascular remodeling is caused by the enhanced proliferation and reduced apoptosis of pulmonary arterial smooth muscle cells (PASMCs). Excitable abnormality in the pulmonary artery of PAH patients is mostly mediated by an elevated cytosolic Ca2+ concentration. PASMCs express several Ca2+-permeable channels including voltage-dependent Ca2+ channels, store-operated Ca2+ (SOC) channels, and receptor-operated Ca2+ (ROC) channels. The activation and upregulation of these Ca2+ channels have been reported in PASMCs from PAH patients. Here, we analyzed pathophysiological functions of enhanced Ca2+ signaling mediated by SOC and ROC channels using PASMCs from idiopathic PAH patients and animal PAH models. Notch signal enhanced transient receptor potential canonical 6 (TRPC6) "SOC" channels via direct (non-genomic and stimulatory) and indirect (genomic and upregulating) effects in PAH. On the other hand, the activation of Ca2+-sensing receptors evoked Ca2+ influx through TRPC6 "ROC" channels in PAH. In addition, TRPC6 channel blocker and TRPC6 gene deletion inhibited the development of PAH. Specifically, TRPC6 channels potentially form both ROC and SOC channels in PASMCs, which are involved in the pathophysiological events in PAH. Therefore, targeting TRPC6 channels in PASMCs may help develop novel therapeutic approach for PAH.