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

Abstract

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.

• Authors: Nikki Cheng, Dana M Brantley, Hua Liu, Qin Lin, Miriam Enriquez, Nick Gale, George Yancopoulos, Douglas Pat Cerretti, Thomas O Daniel, Jin Chen
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 1 Issue 1 Pg. 2-11 (Nov 2002) ISSN: 1541-7786 [Print] United States
• PMID: 12496364 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Angiogenesis Inhibitors
• Endothelial Growth Factors
• Ephrin-A1
• Intercellular Signaling Peptides and Proteins
• Lymphokines
• Oligonucleotides, Antisense
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• Fibroblast Growth Factor 2
• Receptor, EphA2

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Apoptosis (drug effects)
• Cell Division (drug effects)
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Corneal Neovascularization
• Endothelial Growth Factors (antagonists & inhibitors)
• Endothelium, Vascular (cytology, drug effects, physiology)
• Enzyme Activation (physiology)
• Ephrin-A1 (metabolism, pharmacology)
• Fibroblast Growth Factor 2 (pharmacology)
• Humans
• Intercellular Signaling Peptides and Proteins
• Lymphokines (antagonists & inhibitors)
• Mice
• Mice, Inbred C57BL
• Neovascularization, Physiologic (drug effects)
• Oligonucleotides, Antisense (pharmacology)
• Phosphorylation
• Receptor, EphA2 (antagonists & inhibitors, metabolism)
• Umbilical Veins (cytology)
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors