Signal transduction induced in endothelial cells by growth factor receptors involved in angiogenesis

Abstract

New vessel formation during development and in the adult is triggered by concerted signals of largely endothelial-specific receptors for ligands of the VEGF, angiopoietin and ephrin families. The signals and genes induced by these receptors operate in the context of additional signals transduced by non-endothelial specific growth factor receptors, inflammatory cytokine receptors as well as adhesion molecules. We summarize here available data on characteristic signaling of the VEGF receptor-2 and the current state of knowledge regarding the additional different receptor tyrosine kinases of the VEGF, Tie and Ephrin receptor families. Furthermore, the potential cross-talk with signals induced by other growth factors and inflammatory cytokines as well as the modulation by VE-cadherin is discussed.

Figure 1. Signal transduction by VEGF-A/VEGF receptor-2

Major characteristic pathways activated by VEGF-A/VEGF receptor-2 and in part distinct from pathways induced by the IL-1 and EGF receptors in endothelial cells are shown. VEGF-A couples via Tyr1175 to PLC-γ (43, 55) activating the Ca⁺⁺/calcineurin and PKC/MAPK pathways. This leads to the induction of the transcription factors NFAT and EGR-1, which are important for part of the VEGF-induced gene repertoire and the angiogenic/proliferative response (45-47, 53) (G. Schabbauer and E. Hofer, in preparation). Other pathways activated lead via PI3K/Akt, TsAd, Src and p38 to the promotion of survival, migration and potentially permeability, respectively (41, 57, 112, 115). The IL-1 receptor induces genes to a large extent via NF-κB (103, 104). A significant fraction of the NF-κB-induced genes appears to be also upregulated by VEGF-A-induced NFAT. EGF seems to induce the MAPK pathway via Ras and does not activate NFAT (53) (Schweighofer B and Hofer E, in preparation). Neither VEGF-A nor EGF trigger NF-κB activation to a significant extent (45).