title: Fzd7 (Frizzled-7) Expressed by Endothelial Cells Controls Blood Vessel Formation Through Wnt/β-Catenin Canonical Signaling.
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.
  
  
  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 fzd7ECKOvascular 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.
authors.affiliation: 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.).
authors.forename: Claire
authors.initials: C
authors.lastname: Peghaire
authors.affiliation: 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.).
authors.forename: Marie Lise
authors.initials: ML
authors.lastname: Bats
authors.affiliation: 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.).
authors.forename: Raj
authors.initials: R
authors.lastname: Sewduth
authors.affiliation: 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.).
authors.forename: Sylvie
authors.initials: S
authors.lastname: Jeanningros
authors.affiliation: 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.).
authors.forename: Beatrice
authors.initials: B
authors.lastname: Jaspard
authors.affiliation: 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.).
authors.forename: Thierry
authors.initials: T
authors.lastname: Couffinhal
authors.affiliation: 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.).
authors.forename: Cécile
authors.initials: C
authors.lastname: Duplàa
authors.affiliation: 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.). pascale.dufourcq@u-bordeaux.fr.
authors.forename: Pascale
authors.initials: P
authors.lastname: Dufourcq
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000831:Animals, Newborn; D002135:Calcium-Binding Proteins; D049109:Cell Proliferation; D002478:Cells, Cultured; D000072261:Dishevelled Proteins / Q000172:deficiency / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D051157:Frizzled Receptors; D005838:Genotype; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010641:Phenotype; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D015861:Retinal Neovascularization / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D012171:Retinal Vessels / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495267:CTNNB1 protein, mouse; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; C000606585:Dvl3 protein, mouse; D051157:Frizzled Receptors; C492041:Fzd7 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D043562:Receptors, G-Protein-Coupled; D051880:Receptors, Notch; D051176:beta Catenin; D018021:Lithium Chloride
keywords: cardiovascular diseases; endothelial cells; frizzled receptor; neovascularization; transgenic mice