Endothelial PAR2 activation evokes resistance artery relaxation: PAR2 regulation of resistance arteries

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Abstract

Protease-activated receptor-1 & -2 (PAR1 and PAR2) are expressed widely in cardiovascular tissues including endothelial and smooth muscle cells. PAR1 and PAR2 may regulate blood pressure via changes in vascular contraction or relaxation mediated by endothelial Ca 2+ signaling, but the mechanisms are incompletely understood. By using single-cell Ca 2+ imaging across hundreds of endothelial cells in intact blood vessels, we explored PAR-mediated regulation of blood vessel function using PAR1 and PAR2 activators. We show that PAR2 activation evoked multicellular Ca 2+ waves that propagated across the endothelium. The PAR2-evoked Ca 2+ 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-coupled receptor that evokes Ca 2+ release from the IP 3-sensitive store in endothelial cells. A physiological consequence of this PAR2 signaling system is endothelium-dependent relaxation. Conversely, PAR1 activation did not trigger endothelial cell Ca 2+ signaling nor 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 3-mediated Ca 2+ release from the internal store. Sensing mediated by PAR2 receptors is distributed to spatially separated clusters of endothelial cells.

Original languageEnglish
Pages (from-to)776-789
Number of pages14
JournalJournal of Cellular Physiology
Volume238
Issue number4
Early online date15 Feb 2023
DOIs
Publication statusPublished - Apr 2023

Keywords

  • protease activated receptor
  • endothelium
  • calcium signalling
  • vascular relaxation
  • resistance artery

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