Fzd7 (Frizzled-7) Expressed by Endothelial Cells Controls Blood Vessel Formation Through Wnt/β-Catenin Canonical Signaling

Peghaire, Claire; Bats, Marie-Lise; Sewduth, Raj Nayan; Jeanningros, Sylvie; Jaspard, Béatrice; Couffinhal, Thierry; Duplàa, Cécile; Dufourcq, Pascale

doi:10.1161/atvbaha.116.307926

Cited by 28 publications

(58 citation statements)

References 47 publications

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“…44 We verified in vitro that these 2 molecules are able to block mouse Fzd7 (mFzd7) and Fzd7/β-catenin signaling using a TOP-Flash reporter as previously reported. 20 Both Fzd7-CRD and anti-Fzd7 mAb significantly decreased, in a dosedependent manner, the activity of β-catenin reporter gene induced by Wnt3A in EC overexpressing mFzd7 when compared to control conditions ( Figure 4A,B).…”

Section: Validation Of Blocking Fzd7 Signaling With Either An Antibmentioning

confidence: 93%

“…20 Mice were euthanized on P12, P14, and P17 and eyes were enuclated and fixed with 4% paraformaldehyde (PFA)-PBS for 20 min. 20 Mice were euthanized on P12, P14, and P17 and eyes were enuclated and fixed with 4% paraformaldehyde (PFA)-PBS for 20 min.…”

Section: Tissue Immunofluorescencementioning

confidence: 99%

“…20 All experiments were performed in duplicate and differences in cDNA input were compensated by normalization to expression of β-actin. Quantitative PCR (QPCR) was performed as previously described.…”

Section: Rna Preparation and Quantitative Pcrmentioning

confidence: 99%

“…20,43 First, deletion of Fzd7 was induced at P1/P2 by Tamoxifen injections and the retinal vascular phenotype was characterized at different time points to study vaso-obliteration (VO, P12), vessel regrowth and a pathologic formation of extra-retinal neovascularization name tufts (NV) at P14 and P17 ( Figure 2A). We have already characterized this mouse.…”

Section: Specific Fzd7 Deletion In Endothelial Cells Modulates Respmentioning

confidence: 99%

“…[12][13][14][15][16][17] The secreted Wnt proteins (19 members) activate canonical and noncanonical signaling pathways by binding to the cystein-rich domain (CRD) of Frizzled (Fzd) receptors (10 homologous). 21,22 Dysregulation of Wnt signaling is also associated with ocular diseases with an emphasis on DR. 23 Previously, we have demonstrated that Frizzled-7 (Fzd7) signaling controls post natal vessel formation in the retina, 20 however its role in pathological angiogenesis is still unknown. [18][19][20] Moreover, genetic studies have linked familial exudative vitreoretinopathy (FEVR), Norrie disease and Coats' disease with mutations in genes encoding Fzd4, Norrin, or LRP-5 due to impairment in vessel formation/regression.…”

Section: Introductionmentioning

confidence: 99%

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Therapies targeting Frizzled‐7/β‐catenin pathway prevent the development of pathological angiogenesis in an ischemic retinopathy model

et al. 2019

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Retinopathies remain major causes of visual impairment in diabetic patients and premature infants. Introduction of anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF) has transformed therapy for these proliferative retinopathies.However, limitations associated with anti-VEGF medications require to unravel new pathways of vessel growth to identify potential drug targets. Here, we investigated the role of Wnt/Frizzled-7 (Fzd7) pathway in a mouse model of oxygen-induced retinopathy (OIR). Using transgenic mice, which enabled endothelium-specific and time-specific Fzd7 deletion, we demonstrated that Fzd7 controls both vaso-obliteration and neovascular phases (NV). Deletion of Fzd7 at P12, after the ischemic phase of OIR, prevented formation of aberrant neovessels into the vitreous by suppressing proliferation of endothelial cells (EC) in tufts. Next we validated in vitro two Frd7 blocking strategies: a monoclonal antibody (mAbFzd7) against Fzd7 and a soluble Fzd7 receptor (CRD). In vivo a single intravitreal microinjection of mAb-Fzd7 or CRD significantly attenuated retinal neovascularization (NV) in mice with OIR. Molecular analysis revealed that Fzd7 may act through the activation of Wnt/βcatenin and Jagged1 expression to control EC proliferation in extra-retinal neovessels. We identified Fzd7/β-catenin signaling as new regulator of pathological retinal NV. Fzd7 appears to be a potent pharmacological target to prevent or treat aberrant angiogenesis of ischemic retinopathies. K E Y W O R D S

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Section: Validation Of Blocking Fzd7 Signaling With Either An Antibmentioning

confidence: 93%

Section: Tissue Immunofluorescencementioning

confidence: 99%

Section: Rna Preparation and Quantitative Pcrmentioning

confidence: 99%

Section: Specific Fzd7 Deletion In Endothelial Cells Modulates Respmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Therapies targeting Frizzled‐7/β‐catenin pathway prevent the development of pathological angiogenesis in an ischemic retinopathy model

et al. 2019

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Long noncoding RNA HOTTIP promotes endothelial cell proliferation and migration via activation of the Wnt/β‐catenin pathway

Liao

Chen

Feng

et al. 2017

J of Cellular Biochemistry

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Atherosclerosis is the major cause of stroke and heart disease. However, the course and pathogenesis of atherosclerosis remains unknown. The proliferation and migration of endothelial cell play important roles in the inition and pathological progression of atherosclerosis. In this study, we demonstrated that long noncoding RNA (lncRNA) HOXA transcript at the distal tip (HOTTIP) expression level was higher in coronary artery disease (CAD) tissues than in normal arterial tissues. The expression level of HOTTIP was upregulated in the proliferating endothelial cells induced by TNF-α or PDGF-BB. Ectopic expression of HOTTIP promoted endothelial cell proliferation and also increased the expression of proliferating makers cyclin D1 and PCNA. Moreover, elevated expression of HOTTIP promoted endothelial cell migration. Downregulation expression of HOTTIP suppressed endothelial cell proliferation and migration. Furthermore, we determined that overexpression of HOTTIP induced β-catenin expression and enhanced the downstream protein c-Myc expression in the endothelial cell. Ectopic expression of HOTTIP increased endothelial cell proliferation and migration via activation of the Wnt/β-catenin pathway. These results suggested that HOTTIP might manipulate the endothelial cell proliferation and migration via activation of the Wnt/β-catenin pathway.

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Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of Angpt2 and Flt1

et al. 2018

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AimsFormation of a functional vascular system is essential and its formation is a highly regulated process initiated during embryogenesis, which continues to play important roles throughout life in both health and disease. In previous studies, Fzd5 was shown to be critically involved in this process and here we investigated the molecular mechanism by which endothelial loss of this receptor attenuates angiogenesis.Methods and resultsUsing short interference RNA-mediated loss-of-function assays, the function and mechanism of signaling via Fzd5 was studied in human endothelial cells (ECs). Our findings indicate that Fzd5 signaling promotes neovessel formation in vitro in a collagen matrix-based 3D co-culture of primary vascular cells. Silencing of Fzd5 reduced EC proliferation, as a result of G0/G1 cell cycle arrest, and decreased cell migration. Furthermore, Fzd5 knockdown resulted in enhanced expression of the factors Angpt2 and Flt1, which are mainly known for their destabilizing effects on the vasculature. In Fzd5-silenced ECs, Angpt2 and Flt1 upregulation was induced by enhanced PKC signaling, without the involvement of canonical Wnt signaling, non-canonical Wnt/Ca2+-mediated activation of NFAT, and non-canonical Wnt/PCP-mediated activation of JNK. We demonstrated that PKC-induced transcription of Angpt2 and Flt1 involved the transcription factor Ets1.ConclusionsThe current study demonstrates a pro-angiogenic role of Fzd5, which was shown to be involved in endothelial tubule formation, cell cycle progression and migration, and partly does so by repression of PKC/Ets1-mediated transcription of Flt1 and Angpt2.Electronic supplementary materialThe online version of this article (10.1007/s10456-018-9625-6) contains supplementary material, which is available to authorized users.

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Fzd7 (Frizzled-7) Expressed by Endothelial Cells Controls Blood Vessel Formation Through Wnt/β-Catenin Canonical Signaling

Cited by 28 publications

References 47 publications

Therapies targeting Frizzled‐7/β‐catenin pathway prevent the development of pathological angiogenesis in an ischemic retinopathy model

Therapies targeting Frizzled‐7/β‐catenin pathway prevent the development of pathological angiogenesis in an ischemic retinopathy model

Long noncoding RNA HOTTIP promotes endothelial cell proliferation and migration via activation of the Wnt/β‐catenin pathway

Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of Angpt2 and Flt1

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