Regulation of vascular proteoglycan synthesis by angiotensin II type 1 andtype 2 receptors

Recent studies have shown that proteoglycans play an important role in the development of vascular disease and renal failure. In this study, the effec ts of angiotensin II (AngII) type 1 (AT1) and type 2 (AT2) receptor stimula tion on glycosaminoglycan and proteoglycan core protein synthesis in vascul ar smooth muscle cells (VSMC) were examined. Treatment of AT1 receptor-expr essing VSMC with An-II resulted in a dose-dependent and time-dependent incr ease (2- to 4-fold) in H-3-glucosamine/S-35-sulfate incorporation, which wa s abolished by pretreatment with the AT1 receptor antagonist, losartan. The effects of AngII were inhibited by the epidermal growth factor receptor in hibitor, AG1478, and the mitagen-activated protein kinase kinase inhibitor, PD98059, but not the protein kinase C inhibitors, chelerythrine and stauro sporine. AngII treatment also resulted in significant increases in the mRNA of the core proteins, versican, biglycan, and perlecan. The effects of AT2 receptor stimulation were examined by retroviral transfection of VSMC with the AT2 receptor. Stimulation of the AT2 receptor in these VSMC-AT2 cells resulted in a significant (1.3-fold) increase in proteoglycan synthesis, wh ich was abolished by the AT2 receptor antagonist, PD123319, and attenuated by pretreatment with pertussis toxin. These results implicate both AT1 and AT2 receptors in the regulation of proteoglycan synthesis and suggest the i nvolvement of epidermal growth factor receptor-dependent tyrosine kinase pa thways and G alphai/o-mediated mechanisms in the effects of the two recepto rs.