Angiogenesis: A Team Effort Coordinated by Notch

Abstract

The past two decades of angiogenesis research have identified a wealth of pro- and antiangiogenic signals originating from the tissue environment, which control blood vessel density and function. Understanding when and how blood vessels respond to the combination of signals they encounter to achieve a balanced cellular response is a major challenge for the field of developmental and tumor angiogenesis. This review focuses on how endothelial cell-cell communication via the Notch pathway contributes to this signal integration and is essential for functional vessel patterning.

Cross-talk between endothelial cells and tumor via delta-like ligand4/Notch/PTEN signaling inhibits lung cancer growth

“…Dll4 is usually upregulated by vascular endothelial growth factor in endothelial tip cells, which possess high Dll4 and low Notch (Patel et al, 2005;Hofmann and Luisa Iruela-Arispe, 2007;Benedito et al, 2009). The enhanced Dll4 could activate Notch in the adjacent stalk cells, which exhibit high Notch and low Dll4 (Hofmann and Luisa Iruela-Arispe, 2007;Phng and Gerhardt, 2009). Notch activation sequentially improves the function of microvessels, and lack of Dll4 in stalk cells also permits the proliferation of neighboring tumor cells (Li et al, 2007;Phng and Gerhardt, 2009).…”

“…The enhanced Dll4 could activate Notch in the adjacent stalk cells, which exhibit high Notch and low Dll4 (Hofmann and Luisa Iruela-Arispe, 2007;Phng and Gerhardt, 2009). Notch activation sequentially improves the function of microvessels, and lack of Dll4 in stalk cells also permits the proliferation of neighboring tumor cells (Li et al, 2007;Phng and Gerhardt, 2009). Antiangiogenic therapy for cancer emerged in early 1970s, marked with the publication of the Folkman's hypothesis (Folkman, 1971).…”

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

“…VEGFR and Notch signaling pathways cooperate closely to specify and balance the differentiation of tip and stalk cells during sprouting 8, 9. Stimulating ECs with VEGFA increases the expression of Notch ligand Dll4.…”

“…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. Notch ligands (delta‐like 1, 3, and 4; jagged 1 and 2) activate sequential cleavage of Notch receptors (notch 1–4), executed by ADAM17 and γ‐secretase, to release the Notch intracellular domain (NICD), which translocates into the nucleus and activates the transcription of downstream genes such as Hairy and enhancer of split (Hes) family molecules.…”

Vascular-targeted agents for the treatment of angiosarcoma

“…Studies have shown inhibition of Notch1 in mouse models leads to the formation of vascular tumours, including hepatic angiosarcomas [152,153], and the importance of Notch in branching morphogenesis and in regulating endothelial cell expression of receptors such as VEGFR2 and NRP1 [30], identifies an area worth further study. The be assessed in cell viability and cell differentiation assays.…”