Die Rolle der Ca2+ -aktivierten K+ -Kanäle bei Endothelzellproliferation und Angiogenese

Am Anfang der Angiogenese im erwachsenen Organismus und insbesondere der Tumorvaskularisation steht die Aussprossung von Endothelzellen. Proangiogenetische Faktoren wie bFGF und VEGF stimulieren die Proliferation von Endothelzellen in vitro und die Angiogenese in vivo. Auch die tumorinduzierte Angio...

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Bibliographic Details
Main Author: Grgic, Ivica
Contributors: Hoyer, Joachim (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2005
Online Access:PDF Full Text
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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 approximately 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.