VEGF145, a Secreted Vascular Endothelial Growth Factor Isoform That Binds to Extracellular Matrix

doi:10.1074/jbc.272.11.7151

VEGF₁₄₅, a Secreted Vascular Endothelial Growth Factor Isoform That Binds to Extracellular Matrix*

From the ^‡ Department of Biology and the
^§ Department of Food Engineering and Biotechnology and the
^¶ B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 32000, Israel, the
^∥ Department of Oncology, Hadassah University Hospital, Jerusalem 91120, Israel, and the
** Department of Molecular Biology, The Hebrew University-Hadassah Medical School, Jerusalem 91010, Israel

^‡‡ To whom correspondence should be addressed.

Abstract

A vascular endothelial growth factor (VEGF) mRNA species containing exons 1-6 and 8 of the VEGF gene was found to be expressed as a major VEGF mRNA form in several cell lines derived from carcinomas of the female reproductive system. This mRNA is predicted to encode a VEGF form of 145 amino acids (VEGF₁₄₅). Recombinant VEGF₁₄₅ induced the proliferation of vascular endothelial cells and promoted angiogenesis in vivo VEGF₁₄₅ was compared with previously characterized VEGF species with respect to interaction with heparin-like molecules, cellular distribution, VEGF receptor recognition, and extracellular matrix (ECM) binding ability. VEGF₁₄₅ shares with VEGF₁₆₅ the ability to bind to the KDR/flk-1 receptor of endothelial cells. It also binds to heparin with an affinity similar to that of VEGF₁₆₅. However, VEGF₁₄₅ does not bind to two additional endothelial cell surface receptors that are recognized by VEGF₁₆₅ but not by VEGF₁₂₁. VEGF₁₄₅ is secreted from producing cells as are VEGF₁₂₁ and VEGF₁₆₅. However, VEGF₁₂₁ and VEGF₁₆₅ do not bind to the ECM produced by corneal endothelial cells, whereas VEGF₁₄₅ binds efficiently to this ECM. Basic fibroblast growth factor (bFGF)-depleted ECM containing bound VEGF₁₄₅ induces proliferation of endothelial cells, indicating that the bound VEGF₁₄₅ is active. The mechanism by which VEGF₁₄₅ binds to the ECM differs from that of bFGF. Digestion of the ECM by heparinase inhibited the binding of bFGF to the ECM and released prebound bFGF, whereas the binding of VEGF₁₄₅ was not affected by heparinase digestion. It therefore seems that VEGF₁₄₅ possesses a unique combination of biological properties distinct from those of previously characterized VEGF species.

Footnotes

↵* This work was supported by a Joint Angiogenesis Research Center grant from the Israel Academy of Sciences (to G. N., I. V., and E. K.), a grant from the German-Israeli Binational Foundation, and a grant from the Israel Ministry of Health (to G. N.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

VEGF

vascular endothelial growth factor

BCE

bovine corneal endothelial

bFGF

basic fibroblast growth factor

ECM

extracellular matrix

HUVEC

human umbilical vein-derived endothelial cell

PCR

polymerase chain reaction

PAGE

polyacrylamide gel electrophoresis.
↵² G. Neufeld, unpublished results.
- Received August 2, 1996.
- Revision received November 20, 1996.