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?1-integrin is essential for vasoregulation and smooth muscle survival in vivo.

ABSTRACT: Integrins contribute to vascular morphogenesis through regulation of adhesion and assembly of the extracellular matrix. However, the role of ?1-integrin in the mature vascular wall is less clear.We sought to determine the function of ?1-integrin in mature smooth muscle cells in vivo using a loss of function approach by crossing a tamoxifen-inducible sm22?Cre line to a floxed ?1-integrin transgenic line. Adult mice lacking smooth muscle ?1-integrin survived only 10 weeks post induction. The deletion of ?1-integrin resulted in profound loss of vasomotor control. Histological analysis revealed progressive fibrosis in arteries with associated apoptosis of smooth muscle cells, which was not rescued by adventitial stem cells. Smooth muscle cell apoptosis was detected in arteries with dead cells replaced primarily by collagen. Despite the catastrophic effects on vascular smooth muscle, the deleted visceral smooth muscle remained viable with the exception of a short portion of the colon, indicating that vascular but not visceral smooth muscle is particularly sensitive to changes in ?1-integrin.This study reveals an essential function of ?1-integrin in the maintenance of vasomotor control and highlights a critical role for ?1-integrin in vascular, but not visceral, smooth muscle survival.

SUBMITTER: Turlo KA

PROVIDER: S-EPMC3882010 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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β1-integrin is essential for vasoregulation and smooth muscle survival in vivo.

Turlo Kirsten A KA Scapa Jason J Bagher Pooneh P Jones Allan W AW Feil Robert R Korthuis Ronald J RJ Segal Steven S SS Iruela-Arispe M Luisa ML

Arteriosclerosis, thrombosis, and vascular biology 20130725 10

<h4>Objective</h4>Integrins contribute to vascular morphogenesis through regulation of adhesion and assembly of the extracellular matrix. However, the role of β1-integrin in the mature vascular wall is less clear.<h4>Approach and results</h4>We sought to determine the function of β1-integrin in mature smooth muscle cells in vivo using a loss of function approach by crossing a tamoxifen-inducible sm22αCre line to a floxed β1-integrin transgenic line. Adult mice lacking smooth muscle β1-integrin s ...[more]

PMID: 23887637

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Project description:Voltage-dependent L-type (Ca(V)1.2) Ca(2+) channels are a heteromeric complex formed from pore-forming alpha(1) and auxiliary alpha(2)delta and beta subunits. Ca(V)1.2 channels are the principal Ca(2+) influx pathway in arterial myocytes and regulate multiple physiological functions, including contraction. The macromolecular composition of arterial myocyte Ca(V)1.2 channels remains poorly understood, with no studies having examined the molecular identity or physiological functions of alpha(2)delta subunits.We investigated the functional significance of alpha(2)delta subunits in myocytes of resistance-size (100 to 200 mum diameter) cerebral arteries.alpha(2)delta-1 was the only alpha(2)delta isoform expressed in cerebral artery myocytes. Pregabalin, an alpha(2)delta-1/-2 ligand, and an alpha(2)delta-1 antibody, inhibited Ca(V)1.2 currents in isolated myocytes. Acute pregabalin application reversibly dilated pressurized arteries. Using a novel application of surface biotinylation, data indicated that >95% of Ca(V)1.2 alpha(1) and alpha(2)delta-1 subunits were present in the arterial myocyte plasma membrane. Alpha(2)delta-1 knockdown using short hairpin RNA reduced plasma membrane-localized Ca(V)1.2 alpha(1) subunits, caused a corresponding elevation in cytosolic Ca(V)1.2 alpha(1) subunits, decreased intracellular Ca(2+) concentration, inhibited pressure-induced vasoconstriction ("myogenic tone"), and attenuated pregabalin-induced vasodilation. Prolonged (24-hour) pregabalin exposure did not alter total alpha(2)delta-1 or Ca(V)1.2 alpha(1) proteins but decreased plasma membrane expression of each subunit, which reduced myogenic tone.alpha(2)delta-1 is essential for plasma membrane expression of arterial myocyte Ca(V)1.2 alpha(1) subunits. alpha(2)delta-1 targeting can block Ca(V)1.2 channels directly and inhibit surface expression of Ca(V)1.2 alpha(1) subunits, leading to vasodilation. These data identify alpha(2)delta-1 as a novel molecular target in arterial myocytes, the manipulation of which regulates contractility.

Dataset Information

?1-integrin is essential for vasoregulation and smooth muscle survival in vivo.

Publications

β1-integrin is essential for vasoregulation and smooth muscle survival in vivo.

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