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[Cancer Research 57, 3852-3859, September 1, 1997]
© 1997 American Association for Cancer Research
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Up-Regulation of flk-1/Vascular Endothelial Growth Factor Receptor 2 by Its Ligand in a Cerebral Slice Culture System1

Christine Kremer, Georg Breier, Werner Risau and Karl H. Plate2

Department of Neuropathology, Neurocenter, Freiburg University Medical School, Breisacherstrasse 64, 79106 Freiburg [C. K., K. H. P.], and Department of Molecular Cell Biology, Max-Planck-Institute for Physiological and Clinical Research, 61231 Bad Nauheim [G. B., W. R.], Germany

Vascular endothelial growth factor (VEGF) and its tyrosine kinase receptors VEGFR-1 (flt-1) and VEGFR-2 (flk-1/KDR) are key mediators of physiological and pathological angiogenesis. They are expressed in most tissues during embryonic development but are down-regulated in the adult, when angiogenesis ceases. Up-regulation of VEGFR-2 and of VEGF are observed in many pathological conditions under which angiogenesis is reinduced. A major regulator of VEGF expression is hypoxia. Although the temporal expression pattern of VEGFR-2 parallels VEGF expression to a high extent, little is known about its regulation. Here, we show that VEGFR-2 is highly expressed in early postnatal mouse brain but is down-regulated commencing at postnatal day 15 (P15) of mouse brain development and is hardly detectable in P30 mouse brain. Using P30 mouse brain slices, we observed that hypoxia up-regulates VEGFR-2 in the slices but not in human umbilical vein endothelial cells, suggesting the presence of a hypoxia-inducible factor in the murine neuroectoderm that up-regulates VEGFR-2. To identify the factors involved, normoxic P30 cerebral slices were cultured with growth factors that are either hypoxia-inducible (e.g., PDGF-BB, erythropoietin, and VEGF) and/or are known to act on endothelial cells (e.g., PDGF-BB, VEGF, and PIGF). Exogenously added recombinant VEGF led to an up-regulation of VEGFR-2 expression, which could be inhibited by preincubation with a neutralizing anti-VEGF antibody. Addition of PDGF-BB, PIGF, and erythropoietin had no effect on VEGFR-2 expression. Our results suggest a differential but synergistic regulation by hypoxia of VEGF and VEGFR-2: a direct induction of VEGF that subsequently up-regulates VEGFR-2 in endothelial cells. This autoenhancing system may represent an important mechanism of tumor angiogenesis.

1 This work was supported by a grant from the Dr. Mildred-Scheel-Stiftung (Deutsche Krebshilfe; to K. H. P. and W. R.).

2 To whom requests for reprints should be addressed. Phone: 49-761-270-5107; Fax: 49-761-270-5050; E-mail: plate@nzll.ukl.uni-freiburg.de.

Received 3/ 7/97. Accepted 7/ 3/97.




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Copyright © 1997 by the American Association for Cancer Research.