The integrin ligand SVEP1 regulates GPCR‐mediated vasoconstriction via.pdf (27.79 MB)
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The integrin ligand SVEP1 regulates GPCR-mediated vasoconstriction via integrins alpha 9 beta 1 and alpha 4 beta 1

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journal contribution
posted on 22.11.2022, 10:42 authored by Gavin E Morris, Matthew J Denniff, Elisavet Karamanavi, Sarah A Andrews, Renata B Kostogrys, Vasiliki Bountziouka, Maryam Ghaderi-Najafabadi, Noor Shamkhi, George McConnell, Michael A Kaiser, Laura Carleton, Christine Schofield, Thorsten Kessler, Richard D Rainbow, Nilesh J Samani, Thomas R Webb
Background and Purpose: Vascular tone is regulated by the relative contractile state of vascular smooth muscle cells (VSMCs). Several integrins directly modulate VSMC contraction by regulating calcium influx through L-type voltage-gated Ca2+ channels (VGCCs). Genetic variants in ITGA9, which encodes the α9 subunit of integrin α9β1, and SVEP1, a ligand for integrin α9β1, associate with elevated blood pressure; however, neither SVEP1 nor integrin α9β1 has reported roles in vasoregulation. We determined whether SVEP1 and integrin α9β1 can regulate VSMC contraction. Experimental Approach: SVEP1 and integrin binding were confirmed by immunoprecipitation and cell binding assays. Human induced pluripotent stem cell-derived VSMCs were used in in vitro [Ca2+]i studies, and aortas from a Svep1+/− knockout mouse model were used in wire myography to measure vessel contraction. Key Results: We confirmed the ligation of SVEP1 to integrin α9β1 and additionally found SVEP1 to directly bind to integrin α4β1. Inhibition of SVEP1, integrin α4β1 or α9β1 significantly enhanced [Ca2+]i levels in isolated VSMCs to Gαq/11-vasoconstrictors. This response was confirmed in whole vessels where a greater contraction to U46619 was seen in vessels from Svep1+/− mice compared to littermate controls or when integrin α4β1 or α9β1 was inhibited. Inhibition studies suggested that this effect was mediated via VGCCs, PKC and Rho A/Rho kinase dependent mechanisms. Conclusions and Implications: Our studies reveal a novel role for SVEP1 and the integrins α4β1 and α9β1 in reducing VSMC contractility. This could provide an explanation for the genetic associations with blood pressure risk at the SVEP1 and ITGA9 loci.

Funding

Functional investigation of the coronary artery disease associated gene SVEP1 in vascular smooth muscle contraction

British Heart Foundation

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British Heart Foundation (BHF) (SP16/4/32697)

BHF-DZHK VIAgenomics (SP/19/2/344612)

European Union Seventh Framework Programme FP7/2007-2013 under grant agreement number HEALTH-F2-2013-601456

van Geest Heart and Cardiovascular Diseases Research Fund, administered by the Department of Cardiovascular Sciences, University of Leicester.

History

Author affiliation

Department of Cardiovascular Sciences, University of Leicester

Version

VoR (Version of Record)

Published in

BRITISH JOURNAL OF PHARMACOLOGY

Volume

179

Issue

21

Pagination

4958 - 4973

Publisher

WILEY

issn

0007-1188

eissn

1476-5381

Copyright date

2022

Available date

22/11/2022

Spatial coverage

England

Language

English