The central role of VEGF (vascular endothelial growth factor A) in angiogenesis is dependent upon its ability to co-ordinately regulate multiple endothelial functions. The multifunctionality of VEGF at the cellular level results from its ability to initiate a diverse, complex and integrated network of signalling pathways via its major receptor, kinase-insert-domain-containing receptor (KDR). Activation of phospholipase C-γ, protein kinase C, Ca2+, ERK (extracellular-signal-regulated protein kinase), Akt, Src, focal adhesion kinase and calcineurin pathways has been implicated in mediating multiple VEGF functions, including survival, proliferation, migration, vascular permeability, tubulogenesis, NO and prostanoid synthesis, and gene expression. NO and prostanoids in turn play paracrine and autocrine roles in linking post-receptor signalling to biological functions. Integration between biologically important signalling cascades occurs at several points. Akt and ERK, for example, are key junction points linking together signal transduction involved in survival and NO generation, and proliferation and prostanoid biosynthesis. Together, the multiplicity, functional versatility and integration of VEGF signalling provide a useful framework for understanding the mechanisms underlying the endothelial biological response to this key factor.
- kinase-insert-domain-containing receptor (KDR)
- mitogen-activated protein kinase (MAPK)
- vascular endothelial growth factor (VEGF)
679th Meeting of the Biochemical Society held at the University of Essex, Colchester, 2–4 July 2003
Abbreviations used: eNOS, endothelial constitutive nitric oxide synthase; ERK, extracellular-signal-regulated protein kinase; FAK, focal adhesion kinase; HUVEC, human umbilical vein endothelial cell; KDR, kinase-insert-domain-containing receptor; VE, vascular endothelial; PGI2, prostacyclin; VEGF, vascular endothelial growth factor A; VEGFR, VEGF receptor; PLC, phospholipase C; PlGF, placenta growth factor; RTK, receptor tyrosine kinase; SH2, Src homology 2; PI 3-kinase, phosphoinositide 3´-kinase; MEK, mitogen-activated protein kinase/ERK kinase; PKC, protein kinase C; JNK, c-Jun N-terminal protein kinase; cPLA2, cytosolic phospholipase A2; COX, cyclo-oxygenase; NP, neuropilin; Ang1, angiopoietin 1.
- © 2003 Biochemical Society