Diabetic retinopathy is the primary cause of vision loss in working-age adults. Previous work in the eye has shown that surgical sympathectomy in the retina leads to increased capillary numbers. The goal of this study was to investigate the cellular signaling involved in beta-adrenergic receptor regulation of apoptosis in serum-starved human microvascular retinal endothelial cells (HMREC) cultured in high and low glucose conditions. Cells cultured in high (25 mM) and low glucose (5 mM) conditions were serum starved for 18-24 h, followed by treatment with a beta-1-adrenergic receptor agonist, xamoterol (10 microM), for 15, 30, and 45 min. Non-treated controls were also collected. In addition, high glucose or low glucose serum-starved cells were treated with xamoterol and a Fas inhibitor. Immunoblotting showed a decrease in pro-apoptotic proteins upon xamoterol treatment of cells cultured in high glucose. Caspase-3 levels showed a significant decrease in cells treated with Fas inhibitor alone with further reduction when xamoterol was added, indicating that the apoptosis occurs through Fas signaling. TUNEL labeling confirmed the cleaved caspase-3 data indicating increased apoptosis in cells cultured alone in high glucose compared to a decrease in fluorescence in xamoterol-treated cells. These results indicate that beta-adrenergic receptors regulate protein levels of the Fas signaling cascade in HMREC. This study suggests that maintaining beta-adrenergic receptor signaling in diabetic-like conditions may be protective for the retina.