Transcriptional Upregulation of α 2 δ-1 Elevates Arterial Smooth Muscle Cell Voltage-Dependent Ca 2+ Channel Surface Expression and Cerebrovascular Constriction in Genetic Hypertension

Abstract

A hallmark of hypertension is an increase in arterial myocyte voltage-dependent Ca 2+ (Ca V 1.2) currents that induces pathological vasoconstriction. Ca V 1.2 channels are heteromeric complexes composed of a pore-forming Ca V 1.2α 1 with auxiliary α 2 δ and β subunits. Molecular mechanisms that elevate Ca V 1.2 currents during hypertension and the potential contribution of Ca V 1.2 auxiliary subunits are unclear. Here, we investigated the pathological significance of α 2 δ subunits in vasoconstriction associated with hypertension. Age-dependent development of hypertension in spontaneously hypertensive rats was associated with an unequal elevation in α 2 δ-1 and Ca V 1.2α 1 mRNA and protein in cerebral artery myocytes, with α 2 δ-1 increasing more than Ca V 1.2α 1 . Other α 2 δ isoforms did not emerge in hypertension. Myocytes and arteries of hypertensive spontaneously hypertensive rats displayed higher surface-localized α 2 δ-1 and Ca V 1.2α 1 proteins, surface α 2 δ-1:Ca V 1.2α 1 ratio, Ca V 1.2 current density and noninactivating current, and pressure- and depolarization-induced vasoconstriction than those of Wistar-Kyoto controls. Pregabalin, an α 2 δ-1 ligand, did not alter α 2 δ-1 or Ca V 1.2α 1 total protein but normalized α 2 δ-1 and Ca V 1.2α 1 surface expression, surface α 2 δ-1:Ca V 1.2α 1 , Ca V 1.2 current density and inactivation, and vasoconstriction in myocytes and arteries of hypertensive rats to control levels. Genetic hypertension is associated with an elevation in α 2 δ-1 expression that promotes surface trafficking of Ca V 1.2 channels in cerebral artery myocytes. This leads to an increase in Ca V 1.2 current-density and a reduction in current inactivation that induces vasoconstriction. Data also suggest that α 2 δ-1 targeting is a novel strategy that may be used to reverse pathological Ca V 1.2 channel trafficking to induce cerebrovascular dilation in hypertension.