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Original Research

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

Claire Peghaire, Marie Lise Bats, Raj Sewduth, Sylvie Jeanningros, Beatrice Jaspard, Thierry Couffinhal, Cécile Duplàa, Pascale Dufourcq
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https://doi.org/10.1161/ATVBAHA.116.307926
Arteriosclerosis, Thrombosis, and Vascular Biology. 2016;ATVBAHA.116.307926
Originally published October 6, 2016
Claire Peghaire
From the Biology of Cardiovascular Diseases, INSERM U1034, Pessac, France (M.L.B., S.J., B.J., T.C., C.D., P.D.); Biology of Cardiovascular Diseases, University of Bordeaux, U1034, France (M.L.B., B.J., T.C., C.D., P.D.); Service des Maladies cardiaques et vasculaires (T.C.) and Service de Biochimie clinique (M.L.B.), CHU de Bordeaux, France; National Heart and Lung Institute, Vascular Science, Imperial Center for Translational and Experimental Medicine, Imperial College London, Hammersmith Hospital, United Kingdom (C.P.); and Laboratorium voor Endotheliale Moleculaire Biologie, Vesalius Research Center, Leuven, Belgium (R.S.).
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Marie Lise Bats
From the Biology of Cardiovascular Diseases, INSERM U1034, Pessac, France (M.L.B., S.J., B.J., T.C., C.D., P.D.); Biology of Cardiovascular Diseases, University of Bordeaux, U1034, France (M.L.B., B.J., T.C., C.D., P.D.); Service des Maladies cardiaques et vasculaires (T.C.) and Service de Biochimie clinique (M.L.B.), CHU de Bordeaux, France; National Heart and Lung Institute, Vascular Science, Imperial Center for Translational and Experimental Medicine, Imperial College London, Hammersmith Hospital, United Kingdom (C.P.); and Laboratorium voor Endotheliale Moleculaire Biologie, Vesalius Research Center, Leuven, Belgium (R.S.).
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Raj Sewduth
From the Biology of Cardiovascular Diseases, INSERM U1034, Pessac, France (M.L.B., S.J., B.J., T.C., C.D., P.D.); Biology of Cardiovascular Diseases, University of Bordeaux, U1034, France (M.L.B., B.J., T.C., C.D., P.D.); Service des Maladies cardiaques et vasculaires (T.C.) and Service de Biochimie clinique (M.L.B.), CHU de Bordeaux, France; National Heart and Lung Institute, Vascular Science, Imperial Center for Translational and Experimental Medicine, Imperial College London, Hammersmith Hospital, United Kingdom (C.P.); and Laboratorium voor Endotheliale Moleculaire Biologie, Vesalius Research Center, Leuven, Belgium (R.S.).
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Sylvie Jeanningros
From the Biology of Cardiovascular Diseases, INSERM U1034, Pessac, France (M.L.B., S.J., B.J., T.C., C.D., P.D.); Biology of Cardiovascular Diseases, University of Bordeaux, U1034, France (M.L.B., B.J., T.C., C.D., P.D.); Service des Maladies cardiaques et vasculaires (T.C.) and Service de Biochimie clinique (M.L.B.), CHU de Bordeaux, France; National Heart and Lung Institute, Vascular Science, Imperial Center for Translational and Experimental Medicine, Imperial College London, Hammersmith Hospital, United Kingdom (C.P.); and Laboratorium voor Endotheliale Moleculaire Biologie, Vesalius Research Center, Leuven, Belgium (R.S.).
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Beatrice Jaspard
From the Biology of Cardiovascular Diseases, INSERM U1034, Pessac, France (M.L.B., S.J., B.J., T.C., C.D., P.D.); Biology of Cardiovascular Diseases, University of Bordeaux, U1034, France (M.L.B., B.J., T.C., C.D., P.D.); Service des Maladies cardiaques et vasculaires (T.C.) and Service de Biochimie clinique (M.L.B.), CHU de Bordeaux, France; National Heart and Lung Institute, Vascular Science, Imperial Center for Translational and Experimental Medicine, Imperial College London, Hammersmith Hospital, United Kingdom (C.P.); and Laboratorium voor Endotheliale Moleculaire Biologie, Vesalius Research Center, Leuven, Belgium (R.S.).
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Thierry Couffinhal
From the Biology of Cardiovascular Diseases, INSERM U1034, Pessac, France (M.L.B., S.J., B.J., T.C., C.D., P.D.); Biology of Cardiovascular Diseases, University of Bordeaux, U1034, France (M.L.B., B.J., T.C., C.D., P.D.); Service des Maladies cardiaques et vasculaires (T.C.) and Service de Biochimie clinique (M.L.B.), CHU de Bordeaux, France; National Heart and Lung Institute, Vascular Science, Imperial Center for Translational and Experimental Medicine, Imperial College London, Hammersmith Hospital, United Kingdom (C.P.); and Laboratorium voor Endotheliale Moleculaire Biologie, Vesalius Research Center, Leuven, Belgium (R.S.).
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Cécile Duplàa
From the Biology of Cardiovascular Diseases, INSERM U1034, Pessac, France (M.L.B., S.J., B.J., T.C., C.D., P.D.); Biology of Cardiovascular Diseases, University of Bordeaux, U1034, France (M.L.B., B.J., T.C., C.D., P.D.); Service des Maladies cardiaques et vasculaires (T.C.) and Service de Biochimie clinique (M.L.B.), CHU de Bordeaux, France; National Heart and Lung Institute, Vascular Science, Imperial Center for Translational and Experimental Medicine, Imperial College London, Hammersmith Hospital, United Kingdom (C.P.); and Laboratorium voor Endotheliale Moleculaire Biologie, Vesalius Research Center, Leuven, Belgium (R.S.).
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Pascale Dufourcq
From the Biology of Cardiovascular Diseases, INSERM U1034, Pessac, France (M.L.B., S.J., B.J., T.C., C.D., P.D.); Biology of Cardiovascular Diseases, University of Bordeaux, U1034, France (M.L.B., B.J., T.C., C.D., P.D.); Service des Maladies cardiaques et vasculaires (T.C.) and Service de Biochimie clinique (M.L.B.), CHU de Bordeaux, France; National Heart and Lung Institute, Vascular Science, Imperial Center for Translational and Experimental Medicine, Imperial College London, Hammersmith Hospital, United Kingdom (C.P.); and Laboratorium voor Endotheliale Moleculaire Biologie, Vesalius Research Center, Leuven, Belgium (R.S.).
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Abstract

Objective—Vessel formation requires precise orchestration of a series of morphometric and molecular events controlled by a multitude of angiogenic factors and morphogens. Wnt/frizzled signaling is required for proper vascular formation. In this study, we investigated the role of the Fzd7 (frizzled-7) receptor in retinal vascular development and its relationship with the Wnt/β-catenin canonical pathway and Notch signaling.

Approach and Results—Using transgenic mice, we demonstrated that Fzd7 is required for postnatal vascular formation. Endothelial cell (EC) deletion of fzd7 (fzd7ECKO) delayed retinal plexus formation because of an impairment in tip cell phenotype and a decrease in stalk cell proliferation. Dvl (dishevelled) proteins are a main component of Wnt signaling and play a functionally redundant role. We found that Dvl3 depletion in dvl1−/− mice mimicked the fzd7ECKO vascular phenotype and demonstrated that Fzd7 acted via β-catenin activation by showing that LiCl treatment rescued impairment in tip and stalk cell phenotypes induced in fzd7 mutants. Deletion of fzd7 or Dvl1/3 induced a strong decrease in Wnt canonical genes and Notch partners’ expression. Genetic and pharmacological rescue strategies demonstrated that Fzd7 acted via β-catenin activation, upstream of Notch signaling to control Dll4 and Jagged1 EC expression.

Conclusions—Fzd7 expressed by EC drives postnatal angiogenesis via activation of Dvl/β-catenin signaling and can control the integrative interaction of Wnt and Notch signaling during postnatal angiogenesis.

  • cardiovascular diseases
  • cell polarity
  • cytosol
  • endothelial cells
  • transgenic mice
  • Received May 5, 2016.
  • Accepted September 22, 2016.
  • © 2016 American Heart Association, Inc.
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    Fzd7 (Frizzled-7) Expressed by Endothelial Cells Controls Blood Vessel Formation Through Wnt/β-Catenin Canonical Signaling
    Claire Peghaire, Marie Lise Bats, Raj Sewduth, Sylvie Jeanningros, Beatrice Jaspard, Thierry Couffinhal, Cécile Duplàa and Pascale Dufourcq
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2016;ATVBAHA.116.307926, originally published October 6, 2016
    https://doi.org/10.1161/ATVBAHA.116.307926

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    Fzd7 (Frizzled-7) Expressed by Endothelial Cells Controls Blood Vessel Formation Through Wnt/β-Catenin Canonical Signaling
    Claire Peghaire, Marie Lise Bats, Raj Sewduth, Sylvie Jeanningros, Beatrice Jaspard, Thierry Couffinhal, Cécile Duplàa and Pascale Dufourcq
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2016;ATVBAHA.116.307926, originally published October 6, 2016
    https://doi.org/10.1161/ATVBAHA.116.307926
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