Intensive insulin treatment causes a transient worsening of diabetic retinopathy (PDR) (1). Vascular endothelial growth factor (VEGF) upregulation and pathological human retinal pigment epithelial (hRPE) cell proliferation have been implicated in PDR (2,3). Since very little is know about VEGF receptors, we investigated the role of the RAS signaling pathway in VEGF receptor2 (VEGFR2) production in cultured hRPE cells. Cultured hRPE cells were stimulated with insulin and insulin + mevastatin (5µM), an inhibitor of post translation prenylation of the RAS molecule. The effect of insulin and mevastatin on cellular proliferation and cell viability were assessed by measuring 3H-thymidine incorporation (3H-thy) and direct cell counting using the trypan exclusion method (T) respectively. VEGFR2 synthesis was measured by immuno-precipitation of 14C-methionine-VEGFR2 and immunocytochemical methods. Data were analyzed by student t-test. p < 0.05 was considered as significant difference. Insulin stimulated hRPE proliferation and cell viabilty in a dose dependent manner as measured by 3H-thy and T. The addition of mevastatin inhibited insulin-stimulated hRPE proliferation as measured by 3H-thy incorporation in hRPE cells (1033.28 ±67.86 vs 154.65±18.39, CPM ±SEM, N=10, p<0.05). Insulin also stimulated 14C-methionine-VEGFR2 synthesis in hRPE cells in a dose dependent manner as measured by immunoprecipitation assay. The addition of mevastatin inhibited insulin-stimulated VEGFR2 synthesis (1337.38 ±78.47vs 138.12±9.23, CPM ±SEM, N=6, p<0.05) as measured by 14C-methionine-VEGFR2 immunoprecipitation. This was qualitatively confirmed by immunocytochemical staining using anti-VEGFR2 and rhodamine-conjugated anti-rabbit IgG. Insulin is a mitogen for hRPE cells and stimulates intracellular VEGFR2 synthesis. Both hRPE cell proliferation and VEGFR2 synthesis were inhibited by mevastatin. This suggests that RAS signaling plays a key role in regulation of VEGFR2 synthesis and secondarily insulin stimulated hRPE proliferation. Our data suggest that an inhibitor of the RAS pathway may be of therapeutic value in treating PDR.