Vascular endothelial growth factor-a activates Ca2+-activated K+ channels in human endothelial cells in culture

Vascular endothelial growth factor-A (VEGF-A) is an endothelial-cell specific growth factor and leads to an increase in cytosolic free calcium ([Ca2+](i)) in endothelial cells. Ca2+-activated K+ channels (K-Ca-channels) have been suggested to facilitate calcium influx by hyperpolarising the cell and thus increasing the electrochemical driving force for calcium influx. The patch-clamp technique was used to investigate the effect of VEGF-A on large conductance K-Ca-channels. The role of these channels in VEGF-induced proliferation (cell count. [H-3]thymidine incorporation) was studied using the specific inhibitor iberiotoxin. VEGF-A strongly stimulated K-Ca-channel activity and led to a 14.2 +/- 4.8 fold (SEM. n = 12) increase in activity after 8 min of VEGF-A stimulation. The VEGF-A-induced activation occurred in calcium-free solution as well (16.7 +/- 2.2 fold, SEM, n = 5) whereas carboxyamidotriazole (CAI), an antiangiogenic drug which inhibits both Ca2+ influx and Ca2+ release from intracellular stores, completely blocked VEGF-A-induced K-Ca channel activation. Specific inhibition of K-Ca channel activity with iberiotoxin did not inhibit proliferation of endothelial cells induced by VEGF-A and or basic fibroblast growth factor (bFGF). In conclusion, we show that VEGF-A activates K-Ca-channels in HUVEC. However, K-Ca channel activity is not involved in VEGF-A- or bFGF-induced endothelial-cell proliferation. Since hyperpolarization of endothelial cells secondary to K-Ca-channel activation is electrically transmitted to vascular smooth muscle cells, which relax in response to hyperpolarization, the VEGF-A-induced K-Ca channel activation might contribute to VEGF-A-induced vasorelaxation. (C) 2001 Elsevier Science Ltd. All rights reserved.