Transcriptional Upregulation of α2δ-1 Elevates Arterial Smooth Muscle Cell Voltage-Dependent Ca2+ Channel Surface Expression and Cerebrovascular Constriction in Genetic Hypertension

A hallmark of hypertension is an increase in arterial myocyte voltage-dependent Ca2+ (Ca(v)1.2) currents that induces pathological vasoconstriction. Ca(v)1.2 channels are heteromeric complexes composed of a pore-forming Ca(v)1.2 alpha(1) with auxiliary alpha(2)delta and beta 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 alpha(2)delta subunits in vasoconstriction associated with hypertension. Age-dependent development of hypertension in spontaneously hypertensive rats was associated with an unequal elevation in alpha(2)delta-1 and Ca(v)1.2 alpha(1) mRNA and protein in cerebral artery myocytes, with alpha(2)delta-1 increasing more than Ca(v)1.2 alpha(1). Other alpha(2)delta isoforms did not emerge in hypertension. Myocytes and arteries of hypertensive spontaneously hypertensive rats displayed higher surface-localized alpha(2)delta-1 and Ca(v)1.2 alpha(1) proteins, surface alpha(2)delta-1: Ca(v)1.2 alpha(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 alpha(2)delta-1 ligand, did not alter alpha(2)delta-1 or Ca(v)1.2 alpha(1) total protein but normalized alpha(2)delta-1 and Ca(v)1.2 alpha(1) surface expression, surface alpha(2)delta-1: Ca(v)1.2 alpha(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 alpha(2)delta-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 alpha(2)delta-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. (Hypertension. 2012; 60: 1006-1015.). Online Data Supplement