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PAR1 and PAR2 may regulate blood pressure via changes in vascular contraction or relaxation mediated by endothelial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling, but the mechanisms are incompletely understood. By using single\u2010cell Ca\n                    <jats:sup>2+<\/jats:sup>\n                    imaging across hundreds of endothelial cells in intact blood vessels, we explored PAR\u2010mediated regulation of blood vessel function using PAR1 and PAR2 activators. We show that PAR2 activation evoked multicellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    waves that propagated across the endothelium. The PAR2\u2010evoked Ca\n                    <jats:sup>2+<\/jats:sup>\n                    waves were temporally distinct from those generated by muscarinic receptor activation. PAR2 activated distinct clusters of endothelial cells, and these cells were different from those activated by muscarinic receptor stimulation. These results indicate that distinct cell clusters facilitate spatial segregation of endothelial signal processing. We also demonstrate that PAR2 is a phospholipase C\u2010coupled receptor that evokes Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release from the IP\n                    <jats:sub>3<\/jats:sub>\n                    \u2010sensitive store in endothelial cells. A physiological consequence of this PAR2 signaling system is endothelium\u2010dependent relaxation. Conversely, PAR1 activation did not trigger endothelial cell Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling\u00a0nor relax or contract mesenteric arteries. Neither did PAR1 activators alter the response to PAR2 or muscarinic receptor activation. Collectively, these results suggest that endothelial PAR2 but not PAR1 evokes mesenteric artery relaxation by evoking IP\n                    <jats:sub>3<\/jats:sub>\n                    \u2010mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release from the internal store. Sensing mediated by PAR2 receptors is distributed to spatially separated clusters of endothelial cells.\n                  <\/jats:p>","DOI":"10.1002\/jcp.30973","type":"journal-article","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T13:09:38Z","timestamp":1676466578000},"page":"776-789","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Endothelial PAR2 activation evokes resistance artery relaxation"],"prefix":"10.1002","volume":"238","author":[{"given":"Xun","family":"Zhang","sequence":"first","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D.","family":"Lee","sequence":"additional","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Buckley","sequence":"additional","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morley D.","family":"Hollenberg","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology and Department of Medicine University of Calgary Cumming School of Medicine Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calum","family":"Wilson","sequence":"additional","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3302-3984","authenticated-orcid":false,"given":"John G.","family":"McCarron","sequence":"additional","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,2,15]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2011.01.003"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14748"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.83.11.1115"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20062354"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2840-13-31"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-09-355958"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.12.018"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.7847"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.80.6.838"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1718600115"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(03)00565-0"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.00-0633fje"},{"key":"e_1_2_7_14_1","doi-asserted-by":"crossref","unstructured":"Cicala C. 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