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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2349.)
© 2005 American Heart Association, Inc.

Vascular Biology

Proteinase-Activated Receptor-2 Mediates Arterial Vasodilation in Diabetes

Fiorentina Roviezzo; Mariarosaria Bucci; Vincenzo Brancaleone; Annarita Di Lorenzo; Pierangelo Geppetti; Silvana Farneti; Luca Parente; Giuseppe Lungarella; Stefano Fiorucci; Giuseppe Cirino

From Dipartimento di Farmacologia Sperimentale (F.R., M.B., V.B., A.D.L., G.C.), Università di Napoli Federico II; Dipartimento di Scienze Farmaceutiche (L.P.), Università di Salerno; Dipartimento di Aria Critica Medico Chirurgica (P.G.), Università di Firenze; Dipartimento di Medicina Sperimentale (S.F., S.Fiorucci), Università di Perugia; Dipartimento di Fisiopatologia e Medicina Sperimentale (G.L.), Università di Siena.

Correspondence to Giuseppe Cirino, PhD, Dipartimento di Farmacologia Sperimentale, via Domenico Montesano 49 80131 Napoli, Italy. E-mail cirino{at}unina.it

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 (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 PAR₂ stimulation. Western blot and quantitative real-time 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.

On diabetes development in NOD mice there is a diminished vasodilatory response to acetylcholine that is counterbalanced by an increased expression of PAR-2 both as protein and message. The expression is mainly localized on the smooth muscle cell component as demonstrated by the immunohistochemistry and functional studies

Key Words: cyclooxygenase-2 • diabetes, type I • proteinase-activated receptor-2 • smooth muscle