eprintid: 10157967 rev_number: 7 eprint_status: archive userid: 699 dir: disk0/10/15/79/67 datestamp: 2022-10-26 10:56:54 lastmod: 2022-10-26 10:56:54 status_changed: 2022-10-26 10:56:54 type: article metadata_visibility: show sword_depositor: 699 creators_name: Morris, Gavin E creators_name: Denniff, Matthew J creators_name: Karamanavi, Elisavet creators_name: Andrews, Sarah A creators_name: Kostogrys, Renata B creators_name: Bountziouka, Vasiliki creators_name: Ghaderi-Najafabadi, Maryam creators_name: Shamkhi, Noor creators_name: McConnell, George creators_name: Kaiser, Michael A creators_name: Carleton, Laura creators_name: Schofield, Christine creators_name: Kessler, Thorsten creators_name: Rainbow, Richard D creators_name: Samani, Nilesh J creators_name: Webb, Thomas R title: The integrin ligand SVEP1 regulates GPCR-mediated vasoconstriction via integrins α9β1 and α4β1 ispublished: pub divisions: UCL divisions: G25 divisions: D13 divisions: B02 keywords: blood pressure, integrin alpha 4 beta 1, integrin alpha 9 beta 1, SVEP1, vasoconstriction note: Copyright © 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited. abstract: 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. date: 2022-11 date_type: published publisher: WILEY official_url: https://doi.org/10.1111/bph.15921 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1964915 doi: 10.1111/bph.15921 medium: Print-Electronic lyricists_name: Bountziouka, Vasiliki lyricists_id: VBOUN85 actors_name: Bountziouka, Vasiliki actors_id: VBOUN85 actors_role: owner funding_acknowledgements: PG/20/10056 [British Heart Foundation (BHF)]; SP16/4/32697 [British Heart Foundation (BHF)]; SP/19/2/344612 [BHF-DZHK VIAgenomics]; HEALTHF2-2013-601456 [European Union Seventh Framework Programme FP7/2007-2013]; [van Geest Heart and Cardiovascular Diseases Research Fund] full_text_status: public publication: British Journal of Pharmacology volume: 179 number: 21 pagerange: 4958-4973 pages: 16 event_location: England issn: 0007-1188 citation: Morris, Gavin E; Denniff, Matthew J; Karamanavi, Elisavet; Andrews, Sarah A; Kostogrys, Renata B; Bountziouka, Vasiliki; Ghaderi-Najafabadi, Maryam; ... Webb, Thomas R; + view all <#> Morris, Gavin E; Denniff, Matthew J; Karamanavi, Elisavet; Andrews, Sarah A; Kostogrys, Renata B; Bountziouka, Vasiliki; Ghaderi-Najafabadi, Maryam; Shamkhi, Noor; McConnell, George; Kaiser, Michael A; Carleton, Laura; Schofield, Christine; Kessler, Thorsten; Rainbow, Richard D; Samani, Nilesh J; Webb, Thomas R; - view fewer <#> (2022) The integrin ligand SVEP1 regulates GPCR-mediated vasoconstriction via integrins α9β1 and α4β1. British Journal of Pharmacology , 179 (21) pp. 4958-4973. 10.1111/bph.15921 <https://doi.org/10.1111/bph.15921>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10157967/1/P100_Morris%20et%20al_SVEP1%20regulates%20GPCR_British%20J%20Pharmacology%202022.pdf