¹F.Roviezzo ¹L. De Gruttola, ¹A. Bertolino; ¹V.Vellecco, ²B.D’Agostino, V. Brancaleone,  ¹MR. Bucci and G. Cirino<sup>1

1</sup>Dipartimento di Farmacologia Sperimentale, Università di Napoli Federico II, ²Dipartimento di Medicina Sperimentale, Sezione di Farmacologia L. Donatelli, Seconda Università degli Studi di Napoli
 

Proteinase-Activated receptors 2 (PAR-2) is one of four members of a G protein-coupled receptors family (PARs). PAR₂ is involved in the endothelium dependent vasorelaxation. Several literature data suggest a role for PAR-2 in cardiovascular inflammation, but it is still unclear whether the activation of this receptor plays a pathological or compensatory role. Here we have evaluated the role of PAR-2 in systemic sclerosis (SSc), a systemic inflammatory disorder characterized by three histopathologic features: 1)structural and functional vascular lesions; 2) perivascular and tissue infiltration of mononuclear inflammatory cells; 3) increased synthesis and excessive deposition of extracellular matrix, resulting in fibrotic destruction of internal organ. The experiments have been performed using the tight skin (TSK) mice, a spontaneous dominant mutant of the inbred B10.D2 (58N) Sn mouse strain that shares many features with the human pathology. The results of our studies indicate that arterial expression of PAR₂ increases following diseases progression and it is coupled to an increased vasorelaxant effect following challenge with PAR activating peptides as opposite to the endothelin 1. The endothelin system has vasoconstrictor and profibrotic properties and it is know to be activated in systemic sclerosis. Thus the PAR-2 increased response appear to counterbalance the ET-1 effect. This hypothesis is further supported by the fining that blockage of PAR-2 with a specific antagonist increases endothelin-1 induced contractions while an ET-1 antagonist further increases PAR-2-induced vasorelaxation. These functional interaction has been also confirmed by using PAR-2^+/+ and PAR-2-/- mice. In these mice there was an increased vasoconstrictor response to endothelin-1, when PAR-2 was not expressed while it was significantly reduced in PAR-2+/+ mice. In conclusion our results suggest that development of PAR₂ agonist might be helpful in treating vascular dysfunction in SS.