Vascular endothelial growth factor (VEGF) is one of the key players in the process of angiogenesis. However, its underlying mechanism remains unclear. Mg2+ is the most abundant intracellular divalent cation in the body and plays critical roles in many cell functions. We investigated the effect of VEGF on intracellular Mg2+ in human umbilical vein endothelial cells (HUVECs). VEGF-A(165) increased the intracellular Mg2+ concentration ([Mg2+](i)) in a dose-dependent manner, with or without extracellular Mg2+, and the increase of [Mg2+], was blocked by pretreatment with SU1498, tyrosine kinase inhibitors (tyrphostin A-23 and genistein), phosphatidylinositol 3-kinase (PI3K) inhibitors (wortmannin and LY294002) or phospholipase C gamma (PLC gamma) inhibitor (U73122). In contrast, mitogen-activated protein kinase inhibitors (SB202190 and PD98059) had no effect on the VEGF-induced [Mg2+], increase. These results suggest that VEGF-A165 increases the [Mg2+], from the intracellular Mg2+ stores through the tyrosine kinase/PI3K/PLC gamma-dependent signaling pathways. (c) 2006 Elsevier Inc. All rights reserved.