Delta-like ligand 4–Notch signaling regulates bone marrow–derived pericyte/vascular smooth muscle cell formation

Stewart, Keri Schadler; Zhou, Zhichao; Zweidler‐McKay, Patrick A.; Kleinerman, Eugenie S.

doi:10.1182/blood-2010-05-284869

Cited by 34 publications

(41 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Collectively, these data suggest a critical dosage sensitivity requirement for Notch signaling in angiogenesis and that perturbations in either direction are deleterious to the overall process. In keeping with our data, recent studies in Ewings sarcoma xenograft models report that blockade of Dll4 using either shRNA or a mouse cross-reactive antiDll4 antibody is associated with a decrease in pericyte/ VSMC coverage (13,35). Taken together, our findings are consistent with a role for Dll4-Notch signaling in pericyte/vSMC development and, in future studies, it will be interesting to further elucidate the role of Dll4 relative to other Notch pathway members (e.g., Notch3) in pericyte recruitment and vessel maturation.…”

Section: Discussionsupporting

confidence: 71%

MEDI0639: A Novel Therapeutic Antibody Targeting Dll4 Modulates Endothelial Cell Function and Angiogenesis In Vivo

Jenkins

Ross

Veldman-Jones

et al. 2012

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The Notch signaling pathway has been implicated in cell fate determination and differentiation in many tissues. Accumulating evidence points toward a pivotal role in blood vessel formation, and the importance of the Delta-like ligand (Dll) 4-Notch1 ligand-receptor interaction has been shown in both physiological and tumor angiogenesis. Disruption of this interaction leads to a reduction in tumor growth as a result of an increase in nonfunctional vasculature leading to poor perfusion of the tumor. MEDI0639 is an investigational human therapeutic antibody that targets Dll4 to inhibit the interaction between Dll4 and Notch1. The antibody crossreacts to cynomolgus monkey but not mouse species orthologues. In vitro MEDI0639 inhibits the binding of Notch1 to Dll4, interacting via a novel epitope that has not been previously described. Binding to this epitope translates into MEDI0639 reversing Notch1-mediated suppression of human umbilical vein endothelial cell growth in vitro. MEDI0639 administration resulted in stimulation of tubule formation in a three-dimensional (3D) endothelial cell outgrowth assay, a phenotype driven by disruption of the Dll4-Notch signaling axis. In contrast, in a two-dimensional endothelial cell-fibroblast coculture model, MEDI0639 is a potent inhibitor of tubule formation. In vivo, MEDI0639 shows activity in a human endothelial cell angiogenesis assay promoting human vessel formation and reducing the number of vessels with smooth muscle actin-positive mural cells coverage. Collectively, the data show that MEDI0639 is a potent modulator of Dll4-Notch signaling pathway.

show abstract

Section: Discussionsupporting

confidence: 71%

MEDI0639: A Novel Therapeutic Antibody Targeting Dll4 Modulates Endothelial Cell Function and Angiogenesis In Vivo

Jenkins

Ross

Veldman-Jones

et al. 2012

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Additionally, it has been suggested that notch signalling can stabilise newly formed blood vessels by affecting pericytes. For example, pericyte marker expression in cells cultured from bone marrow increases with notch signalling (Stewart et al, 2011), and a recent study suggested that the stabilising effect of ANG1/TIE2 signalling between pericytes and ECs is mediated via induction of DLL4 expression in ECs (Fig. 5) (Zhang et al, 2011).…”

Section: Network Formation: Remodelling and Maturationmentioning

confidence: 99%

Coordinating cell behaviour during blood vessel formation

2011

View full text Add to dashboard Cite

SummaryThe correct development of blood vessels is crucial for all aspects of tissue growth and physiology in vertebrates. The formation of an elaborate hierarchically branched network of endothelial tubes, through either angiogenesis or vasculogenesis, relies on a series of coordinated morphogenic events, but how individual endothelial cells adopt specific phenotypes and how they coordinate their behaviour during vascular patterning is unclear. Recent progress in our understanding of blood vessel formation has been driven by advanced imaging techniques and detailed analyses that have used a combination of powerful in vitro, in vivo and in silico model systems. Here, we summarise these models and discuss their advantages and disadvantages. We then review the different stages of blood vessel development, highlighting the cellular mechanisms and molecular players involved at each step and focusing on cell specification and coordination within the network.

show abstract

“…Other groups provided evidence of Dll4 enhancing pericyte coverage of tumor vessels, 29,30 and defective vessel maturation and perfusion is a result of Dll4 ablation. 31 Defective recruitment of pericytes, hyperproliverative angiogenesis, enhanced permeability, insufficient maturation and perfusion are all well-known aspects in CCM pathology and underline the relevance of Dll4-Notch3 signaling in this neurological entity.…”

Section: May 2015mentioning

confidence: 99%

Cerebral Cavernous Malformation-1 Protein Controls DLL4-Notch3 Signaling Between the Endothelium and Pericytes

Schulz

Wieland

Wüstehube-Lausch

et al. 2015

Stroke

View full text Add to dashboard Cite

Background and Purpose— Cerebral cavernous malformation (CCM) is a neurovascular dysplasia characterized by conglomerates of enlarged endothelial channels in the central nervous system, which are almost devoid of pericytes or smooth muscle cells. This disease is caused by loss-of-function mutations in CCM1 , CCM2 , or CCM3 genes in endothelial cells, making blood vessels highly susceptible to angiogenic stimuli. CCM1 - and CCM3 -silenced endothelial cells have a reduced expression of the Notch ligand Delta-like 4 (DLL4) resulting in impaired Notch signaling and irregular sprouting angiogenesis. This study aimed to address if DLL4, which is exclusively expressed on endothelial cells, may influence interactions of endothelial cells with pericytes, which express Notch3 as the predominant Notch receptor. Methods— Genetic manipulation of primary human endothelial cells and brain pericytes. Transgenic mouse models were also used. Results— Endothelial cell–specific ablation of Ccm1 and Ccm2 in different mouse models led to the formation of CCM-like lesions, which were poorly covered by periendothelial cells. CCM1 silencing in endothelial cells caused decreased Notch3 activity in cocultured pericytes. DLL4 proteins stimulated Notch3 receptors on human brain pericytes. Active Notch3 induced expression of PDGFRB2, N-Cadherin , HBEGF , TGFB1, NG2 , and S1P genes. Notch3 signaling in pericytes enhanced the adhesion strength of pericytes to endothelial cells, limited their migratory and invasive behavior, and enhanced their antiangiogenic function. Pericytes silenced for Notch3 expression were more motile and could not efficiently repress angiogenesis. Conclusions— The data suggest that Notch signaling in pericytes is important to maintain the quiescent vascular phenotype. Deregulated Notch signaling may, therefore, contribute to the pathogenesis of CCM.

show abstract

Delta-like ligand 4–Notch signaling regulates bone marrow–derived pericyte/vascular smooth muscle cell formation

Cited by 34 publications

References 25 publications

MEDI0639: A Novel Therapeutic Antibody Targeting Dll4 Modulates Endothelial Cell Function and Angiogenesis In Vivo

MEDI0639: A Novel Therapeutic Antibody Targeting Dll4 Modulates Endothelial Cell Function and Angiogenesis In Vivo

Coordinating cell behaviour during blood vessel formation

Cerebral Cavernous Malformation-1 Protein Controls DLL4-Notch3 Signaling Between the Endothelium and Pericytes

Contact Info

Product

Resources

About