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 PAR₂ in the arterial vascular response during diabetes progression.

Methods and Results--High (NODII; 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 PAR₂ stimulation. Western blot and quantitative reverse-transcription polymerase chain reaction (RT-PCR) studies showed that this effect is tied to an increased expression of PAR₂ coupled to cyclooxygenase-2 expression. Pharmacological dissection performed with specific inhibitors confirmed the functional involvement of cyclooxygenase-2 in PAR₂ vasodilatory effect. This vasodilatory response was confirmed to be dependent on expression of PAR₂ in the smooth muscle component by immunohistochemistry studies performed on aorta isolated by both NOD III and transgenic PAR₂ mice.

Conclusions--Our data demonstrate an important role for PAR₂ in modulating vascular arterial response in diabetes and suggest that this receptor could represent an useful therapeutic target.