Angiotensin II and insulin induce growth of ciliary artery smooth muscle: effects of AT1/AT2 antagonists

PURPOSE: Abnormal growth of smooth muscle cells (SMCs) in small arteries of the eye is associated with hypertension and diabetes, and the complications that they induce. Migration and proliferation of SMCs into the intima are primary mechanisms involved in neointima formation. In aortic SMCs, angiotensin II (AII)-induced proliferation is inhibited by angiotensin type 1 (AT1) receptor antagonist. However, in small artery SMCs, in particular in the circulation of the eye, the effects of AII on migration and proliferation are unknown. METHODS: The effects of AII (10(-6) to 10(-10) M) on migration and proliferation of growth-arrested SMCs of porcine ciliary arteries were studied in the presence and absence of insulin (5 x 10(-10) M) by assaying DNA synthesis (3H-thymidine incorporation), cell number, and movement of SMCs across the membrane of a modified Boyden chamber. RESULTS: In the absence of insulin, only high concentrations (10(-6) to 10(-8) M) of AII induced DNA synthesis and increased cell number (P < 0.05); however, in the presence of insulin (5 x 10(-10) M), AII induced DNA synthesis and cell number at low concentrations (10(-10) M) and in a concentration-dependent manner (P < 0.05). In contrast to proliferation, AII induced SMC migration in a concentration-dependent manner in the absence of insulin (P < 0.05). The AT1 antagonist CGP48933 (10(-8) to 10(-12) M), but not the AT2 antagonist CGP42112 (10(-8) to 10(-12) M), inhibited AII (10(-8) M)-induced proliferation and migration in a concentration-dependent manner (P < 0.05). CONCLUSIONS: Our results suggest that AII is a potent mitogen for SMCs of ophthalmic arteries, an effect that is enhanced in the presence of insulin, and that it may be an important contributor to structural vascular changes in the ophthalmic circulation in hypertension associated with non-insulin dependent diabetes. The inhibition of AII-induced growth by an AT1 antagonist suggests that these drugs may be important therapeutic tools to prevent structural vascular changes in the ophthalmic vasculature under these conditions.