Regulation of angiogenesis by homotypic and heterotypic notch signalling in endothelial cells and pericytes: from basic research to potential therapies

Abstract

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.

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

“…15,16 Despite lacking the characteristic Delta, Serrate and Lag-2 (DSL) domain of canonical Notch ligands, DLK1 and DLK2 interact with Notch1 and serve as antagonists to DLL4-and Jagged1-mediated activation of Notch signaling [17][18][19] that are required for normal vascular maturation. 20 Consistent with previous reports that the Dlk1 and Dlk2 genes reciprocally regulate each other's expression, 16 we report that targeted therapeutic vaccination against DLK1 in RENCAbearing mice leads to the loss of DLK1 expression in the TME, but also to a compensatory increase in the expression of DLK2 by tumor-associated vascular pericytes. We also show that combined vaccination against DLK1 and DLK2 leads to improved antitumor benefits when compared with vaccination against either single antigen in both the RENCA and B16 melanoma tumor models.…”

The miR-143/145 Cluster Is a Novel Transcriptional Target of Jagged-1/Notch Signaling in Vascular Smooth Muscle Cells

“…Additionally, our present and published studies show that expression of an activated Notch1 or Notch2 receptor also recapitulates the VSMC contractile phenotype (5,29) and therefore may also activate miR-143/145. Homotypic and heterotypic Notch signaling have been shown to be critical in defining vascular tone, maintaining vascular homeostasis, recruitment of mural cells and communication during angiogenesis (40). While Jag-1 expression in the endothelium activates Notch3 receptors in adjacent VSMC and promotes a mature contractile phenotype (15), Notch signaling between VSMC is also critical for mediating vascular remodeling after injury (41).…”

Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells

“…Among the complex angiogenic processes regulated by Notch signaling, interactions between endothelial cells and mural cells (pericytes and vascular smooth muscle cells) have recently come into focus as central processes in vascular formation, stabilization, remodeling, and function [20][21][22]. Up-regulation of Notch signaling in mural cells induces expression of smooth muscle cell (SMC) marker genes, contributes to vessel stabilization and finally to formation of robust and mature vascular networks [23].…”