Transcriptional upregulation of α2δ-1 elevates arterial smooth muscle cell voltage-dependent Ca2+ channel surface expression and cerebrovascular constriction in genetic hypertension

John P. Bannister, Simon Bulley, Damodaran Narayanan, Candice Thomas-Gatewood, Patrik Luzny, Judith Pachuau, Jonathan H. Jaggar

Research output: Contribution to journalArticle

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Abstract

A hallmark of hypertension is an increase in arterial myocyte voltage-dependent Ca (CaV1.2) currents that induces pathological vasoconstriction. CaV1.2 channels are heteromeric complexes composed of a pore-forming CaV1.2α1 with auxiliary α2δ and β subunits. Molecular mechanisms that elevate CaV1.2 currents during hypertension and the potential contribution of CaV1.2 auxiliary subunits are unclear. Here, we investigated the pathological significance of α2δ subunits in vasoconstriction associated with hypertension. Age-dependent development of hypertension in spontaneously hypertensive rats was associated with an unequal elevation in α2δ-1 and CaV1.2α1 mRNA and protein in cerebral artery myocytes, with α2δ-1 increasing more than CaV1.2α1. Other α2δ isoforms did not emerge in hypertension. Myocytes and arteries of hypertensive spontaneously hypertensive rats displayed higher surface-localized α2δ-1 and CaV1.2α1 proteins, surface α2δ-1:CaV1.2α1 ratio, CaV1.2 current density and noninactivating current, and pressure- and depolarization-induced vasoconstriction than those of Wistar-Kyoto controls. Pregabalin, an α2δ-1 ligand, did not alter α2δ-1 or CaV1.2α1 total protein but normalized α2δ-1 and CaV1.2α1 surface expression, surface α2δ-1:CaV1.2α1, CaV1.2 current density and inactivation, and vasoconstriction in myocytes and arteries of hypertensive rats to control levels. Genetic hypertension is associated with an elevation in α2δ-1 expression that promotes surface trafficking of CaV1.2 channels in cerebral artery myocytes. This leads to an increase in CaV1.2 current-density and a reduction in current inactivation that induces vasoconstriction. Data also suggest that α2δ-1 targeting is a novel strategy that may be used to reverse pathological CaV1.2 channel trafficking to induce cerebrovascular dilation in hypertension.

Original languageEnglish (US)
Pages (from-to)1006-1015
Number of pages10
JournalHypertension
Volume60
Issue number4
DOIs
StatePublished - Oct 1 2012

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Constriction
Smooth Muscle Myocytes
Up-Regulation
Vasoconstriction
Hypertension
Muscle Cells
Cerebral Arteries
Inbred SHR Rats
Arteries
Dilatation
Protein Isoforms
Membrane Proteins
Proteins
Ligands
Pressure
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Internal Medicine

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Transcriptional upregulation of α2δ-1 elevates arterial smooth muscle cell voltage-dependent Ca2+ channel surface expression and cerebrovascular constriction in genetic hypertension. / Bannister, John P.; Bulley, Simon; Narayanan, Damodaran; Thomas-Gatewood, Candice; Luzny, Patrik; Pachuau, Judith; Jaggar, Jonathan H.

In: Hypertension, Vol. 60, No. 4, 01.10.2012, p. 1006-1015.

Research output: Contribution to journalArticle

Bannister, John P. ; Bulley, Simon ; Narayanan, Damodaran ; Thomas-Gatewood, Candice ; Luzny, Patrik ; Pachuau, Judith ; Jaggar, Jonathan H. / Transcriptional upregulation of α2δ-1 elevates arterial smooth muscle cell voltage-dependent Ca2+ channel surface expression and cerebrovascular constriction in genetic hypertension. In: Hypertension. 2012 ; Vol. 60, No. 4. pp. 1006-1015.
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AU - Thomas-Gatewood, Candice

AU - Luzny, Patrik

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AU - Jaggar, Jonathan H.

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