Proteinase-activated receptor-2 mediates arterial vasodilation in diabetes

Abstract

Objective - Proteinase-activated receptor-2 is widely expressed in vascular tissue and in highly vascularized organs in humans and other species. Its activation mainly causes endothelium-dependent vasorelaxation in vitro and hypotension in vivo. Here, using nonobese diabetic (NOD) mice at different disease stages, we have evaluated the role of PAR 2 in the arterial vascular response during diabetes progression. Methods and Results - High (NOD-II; 20 to 500 mg/dL) or severe glycosuria (NOD-III; 500 to 1000 mg/dL) provokes a progressive reduction in the response to acetylcholine paralleled by an increase in the vasodilatory response to PAR 2 stimulation. Western blot and quantitative real-time polymerase chain reaction (RT-PCR) studies showed that this effect is tied to an increased expression of PAR 2 coupled to cyclooxygenase-2 expression. Pharmacological dissection performed with specific inhibitors confirmed the functional involvement of cyclooxygenase-2 in PAR 2 vasodilatory effect. This vasodilatory response was confirmed to be dependent on expression of PAR 2 in the smooth muscle component by immunohistochemistry studies performed on aorta isolated by both NOD-III and transgenic PAR 2 mice. Conclusions - Our data demonstrate an important role for PAR 2 in modulating vascular arterial response in diabetes and suggest that this receptor could represent an useful therapeutic target. © 2005 American Heart Association, Inc.