Differences in TRPC3 and TRPC6 channels assembly in mesenteric vascular smooth muscle cells in essential hypertension

Abstract

Increased vascular tone in essential hypertension involves a sustained rise in total peripheral resistance. A model has been proposed in which the combination of membrane depolarization and higher L-type Ca²⁺ channel activity generates augmented Ca²⁺ influx into vascular smooth muscle cells (VSMCs), contraction and vasoconstriction. The search for culprit ion channels responsible of membrane depolarization has provided several candidates, including members of the TRPC family. TRPC3 and TRPC6 are DAG–activated, non-selective cationic channels contributing to stretch- or agonist-induced depolarization. Conflicting information exists regarding changes in TRPC3/TRPC6 functional expression in hypertension. However, although TRPC3-TRPC6 channels can heteromultimerize, the possibility that differences in their association pattern may change their functional contribution to vascular tone is largely unexplored. We probe this hypothesis using a model of essential hypertension (BPH mice) and its normotensive control (BPN mice). First, non-selective cationic currents through homo and heterotetramers recorded from transfected CHO cells indicated that TRPC currents were sensitive to the selective antagonist Pyr10 only when TRPC6 was present, while intracellular anti-TRPC3 antibody selectively blocked TRPC3-mediated currents. In mesenteric VSMCs, basal and agonist-induced currents were more sensitive to Pyr3 and Pyr10 in BPN cells. Consistently, myography studies showed a larger Pyr3/10-induced vasodilation in BPN mesenteric arteries. mRNA and protein expression data supported changes in TRPC3 and TRPC6 proportion and assembly, with a higher TRPC3 channel contribution in BPH VSMCs which could favour cell depolarization. These differences in functional and pharmacological properties of TRPC3 and TRPC6 channels depending on their assembly could represent novel therapeutical opportunities.

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