Key result
PAR2 and muscarinic receptors selectively elicit two elementary Ca2+ signals in single endothelial cells, with PAR2-selective IP3R-dependent peripheral Ca2+-release mechanisms remaining identical between healthy and diseased states.
PAR2-mediated calcium signaling in endothelial cells is preserved during AngII-induced endothelial dysfunction, unlike muscarinic receptor-mediated signaling.
PAR2 preserves endothelial vasodilation where muscarinic responses decline; leaves open therapeutic targeting pending human validation.
Endothelial cell (EC)-dependent vasodilation by proteinase-activated receptor 2 (PAR2) is preserved in small caliber arteries in disease states where vasodilation by muscarinic receptors is decreased. In this study, we identified and characterized the PAR2-mediated intracellular calcium (Ca(2+))-release mechanisms in EC from small caliber arteries in healthy and diseased states. Mesenteric arterial EC were isolated from PAR2 wild-type (WT) and null mice, after saline (controls) or angiotensin II (AngII) infusion, for imaging intracellular calcium and characterizing the calcium-release system by immunofluorescence. EC Ca(2+) signals comprised two forms of Ca(2+)-release events that had distinct spatial-temporal properties and occurred near either the plasmalemma (peripheral) or center of EC. In healthy EC, PAR2-dependent increases in the densities and firing rates of both forms of Ca(2+)-release were abolished by inositol 1,4,5- trisphosphate receptor (IP3R) inhibitor, but partially reduced by transient potential vanilloid channels inhibitor ruthenium red (RR). Acetylcholine (ACh)-induced less overall Ca(2+)-release than PAR2 activation, but enhanced selectively the incidence of central events. PAR2-dependent Ca(2+)-activity, inhibitors sensitivities, IP3R, small- and intermediate-conductance Ca(2+)-activated potassium channels expressions were unchanged in EC from AngII WT. However, the same cells exhibited decreases in ACh-induced Ca(2+)-release, RR sensitivity, and endothelial nitric oxide synthase expression, indicating AngII-induced dysfunction was differentiated by receptor, Ca(2+)-release, and downstream targets of EC activation. We conclude that PAR2 and muscarinic receptors selectively elicit two elementary Ca(2+) signals in single EC. PAR2-selective IP3R-dependent peripheral Ca(2+)-release mechanisms are identical between healthy and diseased states. Further study of PAR2-selective Ca(2+)-release for eliciting pathological and/or normal EC functions is warranted.
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Hennessey et al. (2015) studied Endothelial dysfunction. Angiotensin II infusion vs. Saline was evaluated on Intracellular calcium (Ca2+) release mechanisms. PAR2 and muscarinic receptors selectively elicit two elementary Ca2+ signals in single endothelial cells, with PAR2-selective IP3R-dependent peripheral Ca2+-release mechanisms remaining identical between healthy and diseased states.
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