Regulation of angiogenesis by homotypic and heterotypic notch signalling in endothelial cells and pericytes: from basic research to potential therapies.
The notch-signalling pathway regulates cell fate and differentiation through cell-cell communication. In recent years, several in vitro and in vivo studies have demonstrated that notch-signalling functions as a negative feedback mechanism downstream of the VEGF-signalling pathway that acts to finely shape the vascular network. Notch activation by the Jagged-1 and Delta-like 4 ligands regulates different steps of blood vessel development ranging from proliferation and survival of endothelial cells, to vessel branching and arterial-venous differentiation. In addition, heterotypic notch signalling from endothelial cells to pericytes is critical for vessel stabilization and maturation. Interestingly, several studies have demonstrated that blocking the notch pathway can delay tumour growth. Unexpectedly however, tumour growth inhibition by Notch was caused by an increased number of non-functional vessels, which resulted in poor tumour perfusion. This approach of modulating notch signalling, combined with the extended knowledge acquired on the basic vascular role of notch signalling, will aid the development of treatments targetting human pathologies such as tissue ischaemia and solid tumour formation.
Sainson
Richard C A
RC
Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS, UK. richard.sainson@imm.ox.ac.uk
Harris
Adrian L
AL
D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020286:Pericytes / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D051880:Receptors, Notch