Nathalie Ortéga, Helen Hutchings, Jean Plouët

Laboratoire de Biologie Moléculaire Eucaryote, CNRS UPR 9006, 118 Route de Narbonne, 31062 Toulouse cedex, France

1. Abstract

2. Introduction

3. Molecular biology of the VEGF system

3.1. VEGF ligands
3.2. The VEGF receptors

3.2.1. The VEGF binding sites
3.2.2. The VEGF tyrosine kinase receptors
3.2.3. Structural mapping of VEGF/VEGFRs interactions
3.2.4. Signal transduction
3.2.5. Regulation of gene expression

4. Biological functions mediated by each VEGF receptor

4.1. VEGF activity in vitro
4.2. Developmental regulation of the VEGF receptors
4.3. Physiological activation of VEGF receptors in normal adults
4.4. Activation of VEGF receptors in experimental angiogenesis
4.5. VEGF receptor activation in tumoral angiogenesis

5. Potential VEGF receptors based therapeutic agents

6. Perspectives

7. References

1. ABSTRACT

A considerable progress has been made during the past years in elucidating the molecular actors of angiogenesis. Vascular endothelial growth factor turned out to represent the major inducer of angiogenesis. Optional splicing of its pre messenger RNA generates various isoforms which differ not only by their storage in the extracellular matrix but also by their signaling pathways. VEGF binds and activates two tyrosine kinase receptors called VEGFR1 and VEGFR2 and neuropilin-1. The elucidation of the transduction pathways of each receptor suggests that VEGFR1 mediates cell migration whereas VEGFR2 mediates cell proliferation. The construction of internal images of VEGF by the anti-idiotypic antibody strategy allowed us to determine that quiescent endothelial cells need to be activated by so far unknown factors to become competent to respond to mitogenic signals and acquire an angiogenic phenotype. The discovery of the mechanisms of action of the VEGF system has allowed the design of promissing drugs which already entered the pre-clinical or clinical assays.