Progesterone induces vascular endothelial growth factor on retinal pigment epithelial cells in culture

Diabetic retinopathy is known to frequently deteriorate during pregnancy but the cause remains obscure. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a potent vascular endothelial cell mitogen which is mainly up-regulated by hypoxia, and is closely associated with the development and progression of diabetic retinopathy. To examine the influence of the drastic hormonal alterations during pregnancy on the worsening of diabetic retinopathy, we examined the effects of estradiol (E(2)) and progesterone (P-4) on the production of VEGF/VPF in bovine retinal pigment epithelial cells in culture. The VEGF/VPF production was significantly elevated (214.5+/-28.3 ng/g protein, P<0.01) by 48 h of exposure to a high concentration of P-4(10 mu M), which is still within the physiological range during pregnancy, compared to that of the control group (147.7+/-17.9 ng/g protein). However, E(2) significantly stimulated the production of VEGF/VPF only at concentrations (100 mu M) much higher than normally encountered during pregnancy. These two hormones were not observed to have a synergistic effect, at least at physiological concentrations. As the increase in serum P-4 levels during pregnancy is reported to be greater in pregnant diabetic patients with progressive retinopathy, our findings suggest that P-4 may contribute to the worsening of diabetic retinopathy during pregnancy by up-regulating intraocular VEGF levels.