Previous studies have shown that dietary copper deficiency causes cardiac hypertrophy and depression of vascular epithelial growth factor (VEGF) expression in mouse model. Copper replenishment in the diet reverses cardiac hypertrophy and restores VEGF expression. The present study was undertaken to specifically determine the role of VEGF in copper effect on cell hypertrophy. Embryonic rat cardiac H9c2 cells were exposed to hydrogen peroxide to develop hypertrophy, determined by increases in cell size and total protein content. Copper addition at 5 microM in cultures suppressed cell hypertrophy. In the presence of anti-VEGF antibody, copper inhibitory effect on cell hypertrophy was blunted, and VEGF alone mimicked the inhibitory effect of copper. The results thus demonstrated that VEGF is critically involved in copper inhibition of cell hypertrophy induced by hydrogen peroxide in the H9c2 cells.