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| The EMBO Journal
(1999) 18, 363–374, doi:10.1093/emboj/18.2.363 |
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| A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases |
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| Marlene Meyer1, Matthias Clauss2, Albrecht Lepple-Wienhues3, Johannes Waltenberger4, Hellmut G. Augustin5, Marina Ziche6, Christa Lanz1, Mathias Büttner7, Hanns-Joachim Rziha7 and Christoph Dehio1 |
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1 Department of Infection Biology, Max Planck Institute for Biology, Spemannstra e 34, D-72076 Tübingen, Germany2 Department of Molecular Cell Biology, Max Planck Institute for Physiological and Clinical Research, 61231 Bad Nauheim, Germany 3 Department of Physiology, University Tübingen, 72076 Tübingen, Germany 4 Department of Internal Medicine II, Ulm University Medical Center, 89081 Ulm, Germany 5 Department of Gynaecology and Obstetrics, University of Göttingen Medical School, 37075 Göttingen, Germany 6 Department of Pharmacology, University of Florence, 50134 Florence, Italy 7 Federal Research Centre for Virus Diseases of Animals, Institute for Vaccines, 72076 Tübingen, Germany To whom correspondence should be addressed Christoph Dehio, christoph.dehio@tuebingen.mpg.de Received 21 October 1998; Revised 19 November 1998; Accepted 24 November 1998. |
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| Abstract |
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| The different members of the vascular endothelial growth factor (VEGF) family act as key regulators of endothelial cell function controlling vasculogenesis, angiogenesis, vascular permeability and endothelial cell survival. In this study, we have functionally characterized a novel member of the VEGF family, designated VEGF-E. VEGF-E sequences are encoded by the parapoxvirus Orf virus (OV). They carry the characteristic cysteine knot motif present in all mammalian VEGFs, while forming a microheterogenic group distinct from previously described members of this family. VEGF-E was expressed as the native protein in mammalian cells or as a recombinant protein in Escherichia coli and was shown to act as a heat-stable, secreted dimer. VEGF-E and VEGF-A were found to possess similar bioactivities, i.e. both factors stimulate the release of tissue factor (TF), the proliferation, chemotaxis and sprouting of cultured vascular endothelial cells in vitro and angiogenesis in vivo. Like VEGF-A, VEGF-E was found to bind with high affinity to VEGF receptor-2 (KDR) resulting in receptor autophosphorylation and a biphasic rise in free intracellular Ca2+ concentration, whilst in contrast to VEGF-A, VEGF-E did not bind to VEGF receptor-1 (Flt-1). VEGF-E is thus a potent angiogenic factor selectively binding to VEGF receptor-2. These data strongly indicate that activation of VEGF receptor-2 alone can efficiently stimulate angiogenesis. |
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| Keywords: angiogenesis, Flt-1, KDR, Orf virus, VEGF |
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