Involvement of VEGFR-2 (kdr/flk-1) but not VEGFR-1 (flt-1) in VEGF-A and VEGF-C-induced tube formation by human microvascular endothelial cells in fibrin matrices in vitro |
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Authors: | Pieter Koolwijk Erna Peters Bea van der Vecht Carsten Hornig Herbert A. Weich Kari Alitalo Daniel J. Hicklin Yan Wu Larry Witte Victor W.M. van Hinsbergh |
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Affiliation: | (1) Gaubius Laboratory TNO-PG, Leiden, The Netherlands;(2) GBF, Braunschweig, Germany;(3) Haartman Institute, University of Helsinki, Helsinki, Finland;(4) ImClone Systems, Inc., New York, USA;(5) Department of Physiology, Institute for Cardiovascular Research, Vrije Universiteit, Amsterdam, The Netherlands |
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Abstract: | Different forms of vascular endothelial growth factor (VEGF) and their cellular receptors (VEGFR) are associated with angiogenesis, as demonstrated by the lethality of VEGF-A, VEGFR-1 or VEGFR-2 knockout mice. Here we have used an in vitro angiogenesis model, consisting of human microvascular endothelial cells (hMVEC) cultured on three-dimensional (3D) fibrin matrices to investigate the roles of VEGFR-1 and VEGFR-2 in the process of VEGF-A and VEGF-C-induced tube formation. Soluble VEGFR-1 completely inhibited the tube formation induced by the combination of VEGF-A and TNFα (VEGF-A/TNFα). This inhibition was not observed when tube formation was induced by VEGF-C/TNFα or bFGF/TNFα. Blocking monoclonal antibodies specific for VEGFR-2, but not antibodies specifically blocking VEGFR-1, were able to inhibit the VEGF-A/TNFα-induced as well as the VEGF-C/TNFα-induced tube formation in vitro. PlGF-2, which interacts only with VEGFR-1, neither induced tube formation in combination with TNFα, nor inhibited or stimulated by itself the VEGF-A/TNFα-induced tube formation in vitro. These data indicate that VEGF-A or VEGF-C activation of the VEGFR-2, and not of VEGFR-1, is involved in the formation of capillary-like tubular structures of hMVEC in 3D fibrin matrices used as a model of repair-associated or pathological angiogenesis in vitro. This revised version was published online in June 2006 with corrections to the Cover Date. |
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Keywords: | human microvascular endothelial cells in vitro angiogenesis VEGF-A VEGF-C VEGF receptors |
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