We examined effects of 17ß-estradiol (E2) on human vascular smooth muscle cell (VSMC) proliferation under normal (5 mmol/L) and high (25 mmol/L) glucose concentrations. Platelet-derived growth factor (PDGF) BB (20 ng/mL)- induced increases in DNA synthesis and proliferation were greater in high than normal glucose concentrations; the difference in DNA synthesis was abolished by a protein kinase C (PKC) -ß inhibitor LY379196 (30 nmol/L). Western blotting showed that PKC-ß1 protein increased in cells exposed to high glucose, while PKC- protein and total PKC activity remained unchanged, in comparison with normal glucose cultures. In normal glucose, E2(1-100 nmol/L) inhibited PDGF- induced DNA synthesis by 18-37% and cell proliferation by 16-22% in a concentration-dependent manner. The effects of E2 were blocked by the ER antagonist ICI 182780, indicating ER-dependence. In high glucose, the inhibitory effect of E2 on VSMC proliferation was abolished, but restored in the presence of the PKC-ß inhibitor LY379196. Thus, high glucose enhances human VSMC proliferation and attenuates the antiproliferative effect of E2 in VSMC via activation of PKC-ß.