Vascular Bed-Specific Endothelial Dysfunction and Age-Dependent Circadian Hypertension in Mice Lacking the Resolvin D2 Receptor GPR18.

Abstract

G protein-coupled receptor (GPR) 18 is the receptor for the specialized pro-resolving lipid mediator (SPM) RvD2, which has proven efficacy in preventing atherosclerosis in mice. The aim of the present study was to establish direct vascular effects of GPR18 signaling. GPR18 knockout (KO) and wildtype (WT) mice underwent magnetic resonance imaging (MRI) for in vivo determination of endothelial function, and continuous 24 h telemetry for in vivo blood pressure monitoring. Isolated vessels derived from GPR18 KO and wildtype mice were used for determinations of ex vivo vascular reactivity and immunofluorescent quantifications. GPR18 KO mice exhibited endothelial dysfunction in the femoral arterial segment measured by MRI in vivo and in isolated arteries ex vivo as impaired ACh-induced vasodilatation, whereas the sensitivity to exogenous NO was unchanged. Endothelial function was not significantly different in the thoracic aortic segment between GPR18 KO and WT mice, demonstrating vascular bed-specific endothelial dysfunction as a result of GPR18 deletion. A significantly reduced eNOS expression and a larger indomethacin-sensitive component in ACh-induced relaxations observed in femoral arteries derived from GPR18 KO compared with WT mice suggest that the dysfunctional eNOS-mediated femoral endothelial function may be partly compensated by increased relaxant prostanoid modulation. Finally, conscious mean arterial blood pressure recorded by telemetry was significantly higher daytime compared with wildtype mice at 24 h telemetry measures, whereas young mice did not exhibit any significant differences in day- and night-time blood pressure. These observations linking GPR18 to vascular bed-specific endothelial dysfunction and age-dependent hypertension point to beneficial pro-resolving cardiovascular effects through GPR18 during aging.