Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis

  title={Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis},
  author={Mats Hellstr{\"o}m and Li-Kun Phng and Jennifer J. Hofmann and Elisabet Wallgard and Leigh Coultas and Per Lindblom and Jackelyn A. Alva and A K Nilsson and Linda Karlsson and Nicholas R. Gaiano and Keejung Yoon and Janet Rossant and M. Luisa Iruela-Arispe and Mattias Kal{\'e}n and Holger Gerhardt and Christer Betsholtz},
In sprouting angiogenesis, specialized endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of vascular endothelial growth factor (VEGF)-A. VEGF-A is also essential for the induction of endothelial tip cells, but it is not known how single tip cells are selected to lead each vessel sprout, and how tip-cell numbers are determined. Here we present evidence that delta-like 4 (Dll4)–Notch1 signalling regulates the formation of appropriate numbers of tip cells to… 

A study of Notch signalling in developmental angiogenesis

The studies show that Notch signalling regulates endothelial tip cell formation and vessel stability to fine-tune vessel patterning and demonstrate that Nrarp provides a molecular link to Wnt signalling to regulate vessel stability.

Development: Notch mediates the sprouting of tip cells

Whereas VEGFA promotes the sprouting of tip cells, Notch–Dll4 signalling dampens responsiveness to VEG FA in some cells but not in others, thereby mediating tip-cell selection.

Dll4 and Notch signalling couples sprouting angiogenesis and artery formation

Genetic experiments in postnatal mice show that the level of active Notch signalling is more important than the direct Dll4-mediated cell–cell communication between endothelial cells in controlling Notch-dependent vessel growth.

Development: Notch mediates the sprouting of tip cells

Whereas V EGF promotes the sprouting of tip cells, Notch–Dll4 signalling dampens responsiveness to VEGF in some cells but not in others, thereby mediating tip-cell selection, which could mean that inhibitors and modulators of this Notch-Dll 4 pathway might prove to be useful for the treatment of pathological angiogenesis in tumours.

Extrinsic Notch Ligand Delta-Like 1 Regulates Tip Cell Selection and Vascular Branching Morphogenesis

Dll1 acts as an extrinsic cue involved in tip cell selection, which directs vessel sprouting and branch formation in the mouse retina.

Retinal myeloid cells regulate tip cell selection and vascular branching morphogenesis via Notch ligand Delta-like 1

It is shown, using genetic reporter and conditional deletion strategies, that myeloid cells regulate tip cell numbers and Dll4 expression via the Notch ligand Dll1 during vascular development in the retina during angiogenesis.

Flt1 acts as a negative regulator of tip cell formation and branching morphogenesis in the zebrafish embryo

Genetic evidence is presented that flt1 (vegfr1) acts, in a Notch-dependent manner, as a negative regulator of tip cell formation and sprout guidance in the trunk vasculature of zebrafish embryos.

Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor.

It is indicated that the Notch pathway controls lymphatic endothelial quiescence, and explain why LECs are poorly responsive to VEGF compared with V EGF-C.

Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis

It is suggested that blocking ephrin-B2 reverse signalling may be an attractive alternative or combinatorial anti-angiogenic therapy strategy to disrupt VEGFR2 function in tumour angiogenesis.



VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia

It is shown here that VEGF-A controls angiogenic sprouting in the early postnatal retina by guiding filopodial extension from specialized endothelial cells situated at the tips of the vascular sprouts.

Essential Role of Endothelial Notch1 in Angiogenesis

These findings recapitulate the vascular phenotype of global Notch1−/− mutants and indicate an essential cell-autonomous role of Notch2 signaling in the endothelium during vascular development, which may have important clinical implications with regard to notch1 signaling in adult angiogenesis.

Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis.

It is concluded that differential VEGF-A isoform localization in the extracellular space provides a control point for regulating vascular branching pattern.

The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system

It is shown here that the repulsive netrin receptor UNC5B is expressed by endothelial tip cells of the vascular system and functions as a repulsiveNetrin receptor in endothelial cells controlling morphogenesis of theascular system.

Notch function in the vasculature: insights from zebrafish, mouse and man

Vascular development entails multiple cell‐fate decisions to specify a diverse array of vascular structures. Notch proteins are signaling receptors that regulate cell‐fate determination in a variety

Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development.

Dll4 appears to be a major trigger of Notch receptor activities previously implicated in arterial and vascular development, and it may represent a new opportunity for pro- and anti-angiogenic therapies.

Notch signaling is required for arterial-venous differentiation during embryonic vascular development.

The results suggest that notch signaling is required for the proper development of arterial and venous blood vessels, and that a major role of Notch signaling in blood vessels is to repress venous differentiation within developing arteries.

The Notch pathway helps to pattern the tips of the Drosophila tracheal branches by selecting cell fates.

Evidence is presented that the Notch signalling pathway acts directly in the tracheal cells to distinguish individual fates within groups of equivalent cells, and that Delta may activate Notch to specify cell fates at the tips of the developingtracheal branches.

Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance

It is shown that the molecular regulation of two critical elements of self-renewal, inhibition of differentiation and induction of proliferation, can be uncoupled, and Notch signaling is identified as a key factor in inhibiting differentiation.