This Article Full Text Full Text (PDF) All Versions of this Article: 25/4/704    most recent 01.ATV.0000156399.12787.5cv1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grgic, I. Articles by Köhler, R. Search for Related Content PubMed PubMed Citation Articles by Grgic, I. Articles by Köhler, R.

(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

This article has been cited by other articles:

				I. Grgic, E. Kiss, B. P. Kaistha, C. Busch, M. Kloss, J. Sautter, A. Muller, A. Kaistha, C. Schmidt, G. Raman, et al. Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels PNAS, August 25, 2009; 106(34): 14518 - 14523. [Abstract] [Full Text] [PDF]

				V. G. Romanenko, K. S. Roser, J. E. Melvin, and T. Begenisich The role of cell cholesterol and the cytoskeleton in the interaction between IK1 and maxi-K channels Am J Physiol Cell Physiol, April 1, 2009; 296(4): C878 - C888. [Abstract] [Full Text] [PDF]

				V. Kaushal, P. D. Koeberle, Y. Wang, and L. C. Schlichter The Ca2+-Activated K+ Channel KCNN4/KCa3.1 Contributes to Microglia Activation and Nitric Oxide-Dependent Neurodegeneration J. Neurosci., January 3, 2007; 27(1): 234 - 244. [Abstract] [Full Text] [PDF]

				D. L. Tharp, B. R. Wamhoff, J. R. Turk, and D. K. Bowles Upregulation of intermediate-conductance Ca2+-activated K+ channel (IKCa1) mediates phenotypic modulation of coronary smooth muscle Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2493 - H2503. [Abstract] [Full Text] [PDF]

				G Cruse, S M Duffy, C E Brightling, and P Bradding Functional KCa3.1 K+ channels are required for human lung mast cell migration Thorax, October 1, 2006; 61(10): 880 - 885. [Abstract] [Full Text] [PDF]

				H.-W. Cheng, A.F. James, R.R. Foster, J.C. Hancox, and D.O. Bates VEGF Activates Receptor-Operated Cation Channels in Human Microvascular Endothelial Cells Arterioscler Thromb Vasc Biol, August 1, 2006; 26(8): 1768 - 1776. [Abstract] [Full Text] [PDF]

				J. Ledoux, M. E. Werner, J. E. Brayden, and M. T. Nelson Calcium-Activated Potassium Channels and the Regulation of Vascular Tone Physiology, February 1, 2006; 21(1): 69 - 78. [Abstract] [Full Text] [PDF]

				J. Thompson and T. Begenisich Membrane-delimited Inhibition of Maxi-K Channel Activity by the Intermediate Conductance Ca2+-activated K Channel J. Gen. Physiol., January 30, 2006; 127(2): 159 - 169. [Abstract] [Full Text] [PDF]