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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:704.)
© 2005 American Heart Association, Inc.

Vascular Biology

Selective Blockade of the Intermediate-Conductance Ca²⁺-Activated K⁺ Channel Suppresses Proliferation of Microvascular and Macrovascular Endothelial Cells and Angiogenesis In Vivo

Ivica Grgic; Ines Eichler; Philipp Heinau; Han Si; Susanne Brakemeier; Joachim Hoyer; Ralf Köhler

From the Department of Nephrology (I.E., S.B.), Charité, Campus Benjamin Franklin, Berlin, and the Department of Internal Medicine-Nephrology (I.G., P.H., H.S., J.H., R.K.), Philipps-University, Marburg, Germany.

Correspondence to Ralf Köhler, Department of Internal Medicine-Nephrology, Philipps-University, Baldingerstrasse, 35033 Marburg, Germany. E-mail rkoehler{at}med.uni-marburg.de

Objective— Ca²⁺-activated K⁺ (K_Ca) channels have been proposed to promote mitogenesis in several cell types. Here, we tested whether the intermediate-conductance K_Ca channel (IKCa1) and the large-conductance K_Ca channel (BK_Ca) contribute to endothelial cell (EC) proliferation and angiogenesis.

Material and Results— Function and expression of IKCa1 and BK_Ca/Slo were investigated by patch-clamp analysis and real-time RT-PCR in human umbilical vein ECs (HUVECs) and in dermal human microvascular ECs 1 (HMEC-1). HMEC-1 expressed IKCa1 and BK_Ca/Slo, whereas HUVECs expressed IKCa1. A 48-hour exposure to basic fibroblast growth factor (bFGF) augmented IKCa1 current amplitudes and induced a 3-fold increase in IKCa1 mRNA expression in HUVECs and HMEC-1. Vascular endothelial growth factor (VEGF) was also effective in upregulating IKCa1. BK_Ca/Slo expression and current amplitudes in HMEC-1 were not altered by bFGF. bFGF- and VEGF-induced EC proliferation was suppressed by charybdotoxin, clotrimazole, or the selective IKCa1 blocker 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), whereas inhibition of BK_Ca/Slo by iberiotoxin was ineffective. In the Matrigel plug assay in mice, administration of TRAM-34 for 2 weeks significantly suppressed angiogenesis by 85%.

Conclusions— bFGF and VEGF upregulate expression of IKCa1 in human ECs. This upregulation of IKCa1 seems to be required for mitogen-induced EC proliferation and angiogenesis in vivo. Selective IKCa1 blocker might be of therapeutic value to prevent tumor angiogenesis.

We tested whether Ca²⁺-activated K⁺ (K_Ca) channels contribute to endothelial cell (EC) proliferation induced by proangiogenic factors. Angiogenic factors augmented mRNA expression and function of intermediate-conductance K_Ca channel (IKCa1). EC proliferation in vitro and angiogenesis in vivo was abolished by IKCa1 blockers, which might be of therapeutic value to prevent tumor angiogenesis.

Key Words: IKCa1 • endothelium • clotrimazole • TRAM-34 • bFGF • angiogenesis

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