Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis.

Cheng N, Brantley DM, Liu H, Lin Q, Enriquez M, Gale N, Yancopoulos G, Cerretti DP, Daniel TO, Chen J
Mol Cancer Res. 2002 1 (1): 2-11

PMID: 12496364

Angiogenesis is a multistep process involving a diverse array of molecular signals. Ligands for receptor tyrosine kinases (RTKs) have emerged as critical mediators of angiogenesis. Three families of ligands, vascular endothelial cell growth factors (VEGFs), angiopoietins, and ephrins, act via RTKs expressed in endothelial cells. Recent evidence indicates that VEGF cooperates with angiopoietins to regulate vascular remodeling and angiogenesis in both embryogenesis and tumor neovascularization. However, the relationship between VEGF and ephrins remains unclear. Here we show that interaction between EphA RTKs and ephrinA ligands is necessary for induction of maximal neovascularization by VEGF. EphA2 RTK is activated by VEGF through induction of ephrinA1 ligand. A soluble EphA2-Fc receptor inhibits VEGF-, but not basic fibroblast growth factor-induced endothelial cell survival, migration, sprouting, and corneal angiogenesis. As an independent, but complementary approach, EphA2 antisense oligonucleotides inhibited endothelial expression of EphA2 receptor and suppressed ephrinA1- and VEGF-induced cell migration. Taken together, these data indicate an essential role for EphA receptor activation in VEGF-dependent angiogenesis and suggest a potential new target for therapeutic intervention in pathogenic angiogenesis.

MeSH Terms (25)

Angiogenesis Inhibitors Animals Apoptosis Cell Division Cell Movement Cells, Cultured Cell Survival Corneal Neovascularization Endothelial Growth Factors Endothelium, Vascular Enzyme Activation Ephrin-A1 Fibroblast Growth Factor 2 Humans Intercellular Signaling Peptides and Proteins Lymphokines Mice Mice, Inbred C57BL Neovascularization, Physiologic Oligonucleotides, Antisense Phosphorylation Receptor, EphA2 Umbilical Veins Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors

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