The Notch pathway: a crossroad between the life and death of the endothelium

The endothelium is attracting increasing attention from oncologists and cardiologists. Inhibition of angiogenesis in tumours by the induction of endothelial injury is considered a promising therapeutic approach. Conversely, endothelial injury is implicated in atherosclerosis, thrombosis, hypertension, and diabetes. Endothelial death occurs by apoptosis and the regenerative capacity of mature endothelial cells is limited: wherever an imbalance between death and regeneration of the endothelium occurs, its integrity and function is threatened and the origin and progression of cardiovascular disease is favoured. Notch signalling is involved in the cell fate decision and, directly or by cross-talking with other pathways, has been shown to regulate apoptosis, regeneration, proliferation, and migration of endothelial cells.1,2 Inhibition of the Notch pathways is useful in oncology to repress angiogenesis in tumours3,4 but its manipulation could be useful in cardiology to reduce endothelial apoptosis and to favour angiogenesis. The leitmotiv of this short review is a cross-talk between a cell biologist, an oncologist, and a cardiologist with the goal to examine data relevant to the role of the Notch system on the endothelium. It is a highly conserved pathway from invertebrates to mammals5 that controls cell fate decisions. It is a short range communication system between two adjacent cells based on a ligand-activated receptor. Mammals express four highly homologous receptors (Notch 1, 2, 3, and 4) and five canonical ligands (Delta-like 1,3, 4 and Jagged 1, 2). Both receptors and ligands are membrane-spanning proteins ( Figure 1 ). Ligand binding separates the extracellular domain of Notch from the transmembrane domain allowing the first proteolytic cut by a surface protease, ADAM10 (A Disintegrin And Metalloprotease), which removes the extracellular portion of Notch and creates a membrane-tethered intermediate that is a substrate for γ-secretase, an intramembranous aspartylprotease complex. γ-Secretase in turn generates the active form …