Proteinase-activated receptor-2 mediates arterial vasodilation in diabetes.
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.


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.
Roviezzo
Fiorentina
F
Dipartimento di Farmacologia Sperimentale, Università di Napoli Federico II, Italy.
Bucci
Mariarosaria
M
Brancaleone
Vincenzo
V
Di Lorenzo
Annarita
A
Geppetti
Pierangelo
P
Farneti
Silvana
S
Parente
Luca
L
Lungarella
Giuseppe
G
Fiorucci
Stefano
S
Cirino
Giuseppe
G
D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D051379:Mice; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D014664:Vasodilation / Q000502:physiology*
D011453:Prostaglandins; D044464:Receptor, PAR-2; D009569:Nitric Oxide; D051546:Cyclooxygenase 2