Canonical and Noncanonical Vascular Endothelial Growth Factor Pathways

Abstract

The last five years have witnessed a significant expansion in our understanding of VEGF signaling. In particular, the process of canonical activation of VEGFR tyrosine kinases by homodimeric VEGF molecules have now been broadened by the realization that heterodimeric ligands and receptors are also active participants in the signaling process. While heterodimer receptors were described two decades ago, their impact, along with the effect of additional cell surface partners and novel autocrine VEGF signaling pathways, are only now starting to be clarified. Furthermore, ligand-independent signaling (non-canonical) has been identified which occurs through galectin and gremlin binding, and upon rise of intracellular levels of reactive oxygen species. Activation of the VEGF receptors in the absence of ligand holds immediate implications for therapeutic approaches that exclusively target VEGF. The present review provides a concise summary of the recent developments in both canonical and non-canonical VEGF signaling and places these findings in perspective to their potential clinical and biological ramifications.

Rapid treatment of full‐thickness skin loss using ovine tendon collagen typeIscaffold with skin cells

“…Previously, Loh and Choong () demonstrated the enhancement of cell migration on porous 3D scaffolds. The involvement of cell–cell contact (involving the release of soluble factors) and cell–scaffold interaction (specifically binding to the cell receptors or presented by noncanonical signalling action; Domigan, Ziyad, & Iruela‐Arispe, ) could contribute to abovementioned behaviour. Thus, as presented in Figure e,f, the penetrated cells could be the HDF and the cells on the surface could be HEK.…”

Release of endothelial cell associated VEGFR2 during TGF-β modulated angiogenesis in vitro

“…There is growing evidence that VEGFR2 signals cells in an ‘autocrine’ or ‘intracrine’ fashion, leading to increased receptor activity within the cytosolic (endosome) and/or nuclear compartments [33–36]. Endothelial cells can also release exosomes containing sequestered molecules that then modulate neighbouring cells [37–39].…”

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

“…miR‐342‐5p could inhibit EC proliferation through 2 mechanisms. One is that miR‐342‐5p attenuated VEGF‐induced Akt phosporylation, which is a major signal transduction event downstream from VEGFR2 during angiogenesis 6, 7. Moreover, Wei et al reported that miR‐342‐5p directly targets Akt1 through its 3′ UTR.…”

“…Vascular endothelial growth factor (VEGF) receptors, a class of receptor tyrosine kinases, regulate vascular permeability and endothelial proliferation, migration, survival, and differentiation 6. VEGFA is the major ligand for VEGFR and binds to VEGFR2 to trigger receptor dimerization and autophosphorylation at several tyrosine residues, which in turn activate the downstream phospholipase C‐γ–protein kinase pathway, leading to activation of the c‐Raf, MEK, and mitogen‐activated protein kinase cascade and the phosphoinositide 3‐kinase and Akt pathway 6, 7. Notch signaling is an evolutionarily highly conserved pathway mediating contact‐dependent signaling between neighboring cells 8.…”