Vascular Endothelial Growth Factor-Induced Genes in Human Umbilical Vein Endothelial Cells. Relative Roles of KDR and Flt-1 Receptors

doi:10.1161/01.ATV.0000038995.31179.24

Published Online
on September 26, 2002

Arteriosclerosis, Thrombosis, and Vascular Biology. 2002
Published online before print September 26, 2002, doi: 10.1161/01.ATV.0000038995.31179.24

A more recent version of this article appeared on November 1, 2002

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Submitted on September 4, 2002
Accepted on September 9, 2002

Vascular Endothelial Growth Factor-Induced Genes in Human Umbilical Vein Endothelial Cells. Relative Roles of KDR and Flt-1 Receptors

Suya Yang ; Karen Toy ; Gladys Ingle ; Constance Zlot ; P. Mickey Williams ; Germaine Fuh ; Bing Li ; Abraham de Vos ; and Mary E. Gerritsen ^*

From the Departments of Cardiovascular Research (S.Y., G.I., C.Z., M.E.G.), Structural Chemistry (G.F., B.L., A.d.V.), and Molecular Biology (K.T., P.M.W.), Genentech Inc, South San Francisco, Calif.

^* To whom correspondence should be addressed. E-mail: meg570{at}attbi.com.

Objective—This study evaluated the relative roles of the vascular endothelial growth factor (VEGF) receptors KDR and Flt-1 in the mediation of altered gene expression elicited by VEGF.

Methods and Results—We used mutants of VEGF selective for the KDR and Flt-1 receptors to differentiate gene expression patterns mediated by wild-type VEGF (VEGFwt) in human umbilical vein endothelial cells. RNA was extracted from cells treated for 24 hours with 1 nmol/L of each ligand, and gene expression was monitored by using oligonucleotide arrays (Affymetrix U95A). We report that activation of KDR was sufficient to upregulate all the genes induced by VEGFwt. In contrast, there were no genes selectively upregulated by the Flt-selective mutant. However, high concentrations of the Flt-selective mutant could augment the expression of some genes induced by submaximal concentrations of VEGFwt but not the KDR-selective mutant.

Conclusions—The binding of VEGF to its receptor, KDR, is necessary and sufficient to induce the gene expression profile induced by this growth factor. Furthermore, in human umbilical vein endothelial cells, the Flt-1 receptor appears to act as a decoy receptor, tempering the response to lower concentrations of VEGF.

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