Cardiovascular system TRPC/Orai-containing channels, Na+/Ca2+ exchanger and Ca2+ handling in hypertension

Abstract

Abnormal vascular Ca2+ regulation in various forms of hypertension has been widely demonstrated. Recent evidence indicates that arterial smooth muscle store- and receptor-operated Ca2+ permeable non-selective cation channels (SOCs and ROCs, respectively), along with type 1 Na+/Ca2+ exchanger (NCX1), play key roles in vasoregulation and the modulation of blood pressure (BP). Members of the canonical TRPC family of seven proteins are prime molecular candidates for SOCs and ROCs, although the recently discovered proteins Orai1 and STIM1 also contribute to store-dependent mechanisms. TRPC/Orai1-containing channels and NCX1 are co-localized at plasma membrane (PM)-sarcoplasmic reticulum (SR) junctions. This arrangement enables these transport systems to function as integrated units that help to regulate Ca2+ signaling and myogenic tone, and are, thus, critical for the determination of vascular resistance in hypertension. In particular, activation of non-selective TRPC6 cation channels (abundantly expressed in the vasculature) induces not only Ca2+ influx, but also Na+ entry, through the channels. The consequent cell depolarization should open voltage-dependent L-type Ca2+ channels and, along with the entering Na+, promote Ca2+ entry through adjacent NCX1. Augmented Ca2+ entry through SOCs, ROCs and NCX1 also contributes to excessive arterial smooth muscle cell (SMC) proliferation and vascular hypertrophy, a major cause of elevated pulmonary vascular resistance in primary pulmonary hypertension. In view of the profound influence of SOCs, ROCs and NCX1 on vascular SMC functions, it is not surprising that abnormal regulation of these transport systems have been implicated in the pathogenesis of systemic and pulmonary arterial hypertension. This review summarizes emerging ideas about the critical roles of TRPC/Orai-containing channels and NCX1 in up-regulated arterial Ca2+ signaling in rat models of essential hypertension and in human idiopathic pulmonary hypertension.