ANGIOTENSIN-II AND INSULIN INDUCE GROWTH OF CILIARY ARTERY SMOOTH-MUSCLE - EFFECTS OF AT(1) AT(2) ANTAGONISTS/

PURPOSE. Abnormal growth of smooth muscle cells (SMCs) in small arteri es of the eye is associated with hypertension and diabetes, and the co mplications that they induce. Migration and proliferation of SMCs into the intima are primary mechanisms involved in neointima formation. In aortic SMCs, angiotensin IT (AII)-induced proliferation is inhibited by angiotensin type 1 (AT(i)) receptor antagonist. However, in small a rtery SMCs, in particular in the circulation of the eye, the effects o f AII on migration and proliferation are unknown. METHODS. The effects of All (10(-6) to 10(-10) M) on migration and proliferation of growth -arrested SMCs of porcine ciliary arteries were studied in the presenc e and absence of insulin (5 X 10(-10) M) by assaying DNA synthesis (H- 3-thymidine incorporation), cell number, and movement of SMCs across t he membrane of a modified Boyden chamber. RESULTS. In the absence of i nsulin, only high concentrations (10(-6) to 10(-8) M) of AII induced D NA synthesis and increased cell number (P < 0.05); however, in the pre sence of insulin(5 X 10(-10) M), Ail induced DNA synthesis and cell nu mber at low concentrations (10(-10) M) and in a concentration-dependen t manner (P < 0.05). In contrast to proliferation, AII induced SMC mig ration in a concentration-dependent manner in the absence of insulin ( P < 0.05). The AT, antagonist CGP48933 (10(-8) to 10(-12) M), but not the AT, antagonist CGP42112 (10(-8) to 10(-12) M), inhibited AII (10-8 IM)-induced proliferation and migration in a concentration-dependent manner (P < 0.05), CONCLUSIONS. Our results suggest that AII is a pote nt mitogen for SMCs of ophthalmic arteries, an effect that is enhanced in the presence of insulin, and that it may be an important contribut or to structural vascular changes in the ophthalmic circulation in hyp ertension associated with noninsulin dependent diabetes. The inhibitio n of AII-induced growth by an AT(1) antagonist suggests that these dru gs may be important therapeutic tools to prevent structural vascular c hanges in the ophthalmic vasculature under these conditions.