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 (KCa-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 KCa-channels. The role of these channels in VEGF-induced proliferation (cell count, [3H]thymidine incorporation) was studied using the specific inhibitor iberiotoxin. VEGF-A strongly stimulated KCa-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 KCa channel activation. Specific inhibition of KCa 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 KCa-channels in HUVEC. However, KCa channel activity is not involved in VEGF-A- or bFGF-induced endothelial-cell proliferation. Since hyperpolarization of endothelial cells secondary to KCa-channel activation is electrically transmitted to vascular smooth muscle cells, which relax in response to hyperpolarization, the VEGF-A-induced KCa channel activation might contribute to VEGF-A-induced vasorelaxation.
Faehling
M
M
Department of Internal Medicine II/Cardiology, University of Ulm, Medical Center, Robert-Koch-Street 8, D-89081, Ulm, Germany.
Koch
E D
ED
Raithel
J
J
Trischler
G
G
Waltenberger
J
J
D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D006801:Humans; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A
D016228:Endothelial Growth Factors; D015221:Potassium Channels; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D002118:Calcium