VEGF₁₄₅, a secreted vascular endothelial growth factor isoform that binds to extracellular matrix

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.