The Wnt/β-Catenin Pathway Modulates Vascular Remodeling and Specification by Upregulating Dll4/Notch Signaling

Corada, Monica; Nyqvist, Daniel; Orsenigo, Fabrizio; Caprini, Andréa; Giampietro, Costanza; Taketo, Makoto Mark; Iruela‐Arispe, M. Luisa; Adams, Ralf H.; Dejana, Elisabetta

doi:10.1016/j.devcel.2010.05.006

Cited by 282 publications

(279 citation statements)

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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%

“…Aberrant activation of components of this pathway in ECs may produce severe vascular phenotypes and result in embryonic lethality in some cases (18)(19)(20)(21)(22)(23). Of relevance, FZD4 and LRP5, which has high homology to LRP6 and shares many biochemical properties (24), have been linked to vascular disorders, including defective intraretinal and cerebellar vascular patterning and arterial network formation (21,23,25).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

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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“…Ectopic overexpression of Wnt-1, a canonical Wnt ligand, in mouse brain microvascular endothelial cells increases cellular proliferation (33). LacZ staining in transgenic mice expressing LacZ gene under the control of the b-catenin-TCF/Lef complex-responsive element reveals the detectable activation in the vasculature during embryonic development (36). However, the relative activation of b-catenin is low in resting vasculature in adults.…”

Section: Canonical Wnt Signaling In Vascular Endothelial Cellsmentioning

confidence: 99%

“…Recently, Wnt/b-catenin pathway involvement in endothelial cell differentiation and vascular remodeling has been reported. Endothelial cell-specific gain-of-function mutation of b-catenin in mice results in upregulation of Notch signaling, thereby altering vascular remodeling during embryonic development (36). Particularly, b-catenin stabilization in endothelial cells increases DLL4 transcription, leading to vascular phenotypes resembling those produced by DLL4 overexpression, including endothelial cell arterialization, lack of vascular remodeling, defects in branching, and loss of venous identity (39) …”

Section: Canonical Wnt Signaling In Vascular Endothelial Cellsmentioning

confidence: 99%

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

et al. 2012

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SummaryThe Wnt signaling pathway is involved in a wide range of developmental and physiological processes, such as cell fate specification, tissue morphogenesis, and homeostasis. Thus, its dysregulation has been found in multiple diseases, including some cardiovascular disorders. The loss or gain of function of Wnt pathway components results in abnormal vascular development and angiogenesis. Further study has revealed that Wnt signaling in endothelial cells appears to contribute to vascular morphogenesis and endothelial cell specification. Owing to the significance of Wnt signaling in angiogenesis, Wnt antagonists have been considered potential treatments for neovascular disorders. In line with this, members of the Dkk protein family (Dkks), well-known Wnt antagonists, have been recently found to regulate angiogenesis. This review summarizes our present knowledge of the roles of Wnt signaling and Wnt antagonists, particularly Dkks, in angiogenic regulation and explores the therapeutic potential of Wnt antagonists.

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“…The cells expressing less VEGFR1 or more VEGFR2 have high probability to be found at the tip position, and VEGFR level-mediated competition is strictly Notch dependent [4]. In addition to negative effects on sprouting, Notch signaling has also been shown to have effects on stabilization of vasculature and vessel remodeling [15][16][17][18][19].…”

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confidence: 99%

Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells

et al. 2013

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Notch is an intercellular signaling pathway related mainly to sprouting neo-angiogenesis. The objective of our study was to evaluate the angiogenic mechanisms involved in the vascular augmentation (sprouting/ intussusception) after Notch inhibition within perfused vascular beds using the chick area vasculosa and MxCreNotch1(lox/lox) mice. In vivo monitoring combined with morphological investigations demonstrated that inhibition of Notch signaling within perfused vascular beds remarkably induced intussusceptive angiogenesis (IA) with resultant dense immature capillary plexuses. The latter were characterized by 40 % increase in vascular density, pericyte detachment, enhanced vessel permeability, as well as recruitment and extravasation of mononuclear cells into the incipient transluminal pillars (quintessence of IA). Combination of Notch inhibition with injection of bone marrow-derived mononuclear cells dramatically enhanced IA with 80 % increase in vascular density and pillar number augmentation by 420 %. Additionally, there was down-regulation of ephrinB2 mRNA levels consequent to Notch inhibition. Inhibition of ephrinB2 or EphB4 signaling induced some pericyte detachment and resulted in upregulation of VEGFRs but with neither an angiogenic response nor recruitment of mononuclear cells. Notably, Tie-2 receptor was down-regulated, and the chemotactic factors SDF-1/CXCR4 were up-regulated only due to the Notch inhibition. Disruption of Notch signaling at the fronts of developing vessels generally results in massive sprouting. On the contrary, in the already existing vascular beds, down-regulation of Notch signaling triggered rapid augmentation of the vasculature predominantly by IA. Notch inhibition disturbed vessel stability and led to pericyte detachment followed by extravasation of mononuclear cells. The mononuclear cells contributed to formation of transluminal pillars with sustained IA resulting in a dense vascular plexus without concomitant vascular remodeling and maturation.

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The Wnt/β-Catenin Pathway Modulates Vascular Remodeling and Specification by Upregulating Dll4/Notch Signaling

Cited by 282 publications

References 49 publications

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

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

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells

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