Nrarp Coordinates Endothelial Notch and Wnt Signaling to Control Vessel Density in Angiogenesis

Phng, Li Kun; Potente, Michael; Leslie, Jonathan D.; Babbage, Jane W; Nyqvist, Daniel; Lobov, Ivan B.; Ondr, Jennifer K.; Rao, Sujata; Lang, Richard A.; Thurston, Gavin; Gerhardt, Holger

doi:10.1016/j.devcel.2008.12.009

Cited by 315 publications

(298 citation statements)

References 53 publications

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“…In the presence of VEGF-A, MEDI0639 was capable of inducing endothelial cell sprouting. This effect is consistent with previously published studies that highlight the role of Dll4 as a negative regulator of angiogenesis and the phenotypic consequence of inhibition being an increase in vessel branching due to an increase in the number of tip cells (18,19,30). Second, MEDI0639 was evaluated in a 2D coculture assay, in which endothelial tubes form on top of a fibroblast monolayer.…”

Section: Discussionsupporting

confidence: 73%

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

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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.

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Section: Discussionsupporting

confidence: 73%

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

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“…Emerging evidence also implicates the WNT/β-catenin pathway in angiogenesis and arteriogenesis. In endothelium, β-catenin-dependent gene expression is essential for balancing Notch-induced vessel stability via Dll4 (20) or, alternatively, via Nrarp (a Notch-regulated gene), which differentially modulates Notch and WNT signaling activity to balance tip and stalk cell proliferation during network formation (20,34). Of clinical relevance, components of this pathway, FZD4 and LRP5/6, have been associated with inherited vascular diseases, Norrie disease, and familial exudative viteoretinopathy, which manifests in most cases with blindness at birth, persistence of fetal vasculature, and progressive hearing loss (21,23).…”

Section: Discussionmentioning

confidence: 99%

Endothelial miR-17∼92 cluster negatively regulates arteriogenesis via miRNA-19 repression of WNT signaling

Landskroner-Eiger

Qiu

Perrotta

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The contribution of endothelial-derived miR-17∼92 to ischemiainduced arteriogenesis has not been investigated in an in vivo model. In the present study, we demonstrate a critical role for the endothelial-derived miR-17∼92 cluster in shaping physiological and ischemiatriggered arteriogenesis. Endothelial-specific deletion of miR-17∼92 results in an increase in collateral density limbs and hearts and in ischemic limbs compared with control mice, and consequently improves blood flow recovery. Individual cluster components positively or negatively regulate endothelial cell (EC) functions in vitro, and, remarkably, ECs lacking the cluster spontaneously form cords in a manner rescued by miR-17a, -18a, and -19a. Using both in vitro and in vivo analyses, we identified FZD4 and LRP6 as targets of miR-19a/b. Both of these targets were up-regulated in 17∼92 KO ECs compared with control ECs, and both were shown to be targeted by miR-19 using luciferase assays. We demonstrate that miR-19a negatively regulates FZD4, its coreceptor LRP6, and WNT signaling, and that antagonism of miR-19a/b in aged mice improves blood flow recovery after ischemia and reduces repression of these targets. Collectively, these data provide insights into miRNA regulation of arterialization and highlight the importance of vascular WNT signaling in maintaining arterial blood flow.endothelium | arteriogenesis | vascular | microRNA

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“…We examined whether the reduction in vasculature in MCL1 mutants was caused by increased vessel regression, a common consequence of EC apoptosis. 5,10,19,20 We quantified vessel regression in mutant and control retinas based on the presence of collagen IV sleeves devoid of PECAM1 signal, which mark sites of vessel regression 21,22 ( Figure 3c). Vessel regression was quantified in the region of the remodeling vein and in the sprouting region as these were sites of significantly increased apoptosis in the mutants (see below), but we saw no difference in the amount of vessel regression in either location irrespective of genotype (Figures 3d and e).…”

Section: Mcl1 Is Essential For Ec Development Germline Loss Ofmentioning

confidence: 99%

Endothelial cell survival during angiogenesis requires the pro-survival protein MCL1

Whitehead

Adams

et al. 2016

Cell Death Differ

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Angiogenesis is essential to match the size of blood vessel networks to the metabolic demands of growing tissues. While many genes and pathways necessary for regulating angiogenesis have been identified, those responsible for endothelial cell (EC) survival during angiogenesis remain largely unknown. We have investigated the in vivo role of myeloid cell leukemia 1 (MCL1), a pro-survival member of the BCL2 family, in EC survival during angiogenesis. EC-specific deletion of Mcl1 resulted in a dosedependent increase in EC apoptosis in the angiogenic vasculature and a corresponding decline in vessel density. Our results suggest this apoptosis was independent of the BH3-only protein BIM. Despite the known link between apoptosis and blood vessel regression, this was not the cause of reduced vessel density observed in the absence of endothelial MCL1. Rather, the reduction in vessel density was linked to ectopic apoptosis in regions of the angiogenic vasculature where EC proliferation and new vessel growth occurs. We have therefore identified MCL1 as an essential survival factor for ECs that is required for blood vessel production during angiogenesis.

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Nrarp Coordinates Endothelial Notch and Wnt Signaling to Control Vessel Density in Angiogenesis

Cited by 315 publications

References 53 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

Endothelial miR-17∼92 cluster negatively regulates arteriogenesis via miRNA-19 repression of WNT signaling

Endothelial cell survival during angiogenesis requires the pro-survival protein MCL1

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