title: Frizzled 4 regulates arterial network organization through noncanonical Wnt/planar cell polarity signaling.
abstract: BACKGROUND
  A growing body of evidence supports the hypothesis that the Wnt/planar cell polarity (PCP) pathway regulates endothelial cell proliferation and angiogenesis, but the components that mediate this regulation remain elusive.
  
  
  OBJECTIVE
  We investigated the involvement of one of the receptors, Frizzled4 (Fzd4), in this process because its role has been implicated in retinal vascular development.
  
  
  RESULTS
  We found that loss of fzd4 function in mice results in a striking reduction and impairment of the distal small artery network in the heart and kidney. We report that loss of fzd4 decreases vascular cell proliferation and migration and decreases the ability of the endothelial cells to form tubes. We show that fzd4 deletion induces defects in the expression level of stable acetylated tubulin and in Golgi organization during migration. Deletion of fzd4 favors Wnt noncanonical AP1-dependent signaling, indicating that Fzd4 plays a pivotal role favoring PCP signaling. Our data further demonstrate that Fzd4 is predominantly localized on the top of the plasma membrane, where it preferentially induces Dvl3 relocalization to promote its activation and α-tubulin recruitment during migration. In a pathological mouse angiogenic model, deletion of fzd4 impairs the angiogenic response and leads to the formation of a disorganized arterial network.
  
  
  CONCLUSIONS
  These results suggest that Fzd4 is a major receptor involved in arterial formation and organization through a Wnt/PCP pathway.
authors.affiliation: Inserm U1034, 125 Av du Haut lévèque, 33 600 Pessac, France.
authors.forename: Betty
authors.initials: B
authors.lastname: Descamps
authors.forename: Raj
authors.initials: R
authors.lastname: Sewduth
authors.forename: Nancy
authors.initials: N
authors.lastname: Ferreira Tojais
authors.forename: Béatrice
authors.initials: B
authors.lastname: Jaspard
authors.forename: Annabel
authors.initials: A
authors.lastname: Reynaud
authors.forename: Fabien
authors.initials: F
authors.lastname: Sohet
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacolley
authors.forename: Cécile
authors.initials: C
authors.lastname: Allières
authors.forename: Jean-Marie Daniel
authors.initials: JM
authors.lastname: Lamazière
authors.forename: Catherine
authors.initials: C
authors.lastname: Moreau
authors.forename: Pascale
authors.initials: P
authors.lastname: Dufourcq
authors.forename: Thierry
authors.initials: T
authors.lastname: Couffinhal
authors.forename: Cécile
authors.initials: C
authors.lastname: Duplàa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D001158:Arteries / Q000166:cytology* / Q000502:physiology; D001160:Arterioles / Q000166:cytology / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology*; D049109:Cell Proliferation; D000072261:Dishevelled Proteins; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D051157:Frizzled Receptors / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D055879:Gene Knock-In Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008870:Microtubules / Q000502:physiology; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; C000606585:Dvl3 protein, mouse; D051157:Frizzled Receptors; C498581:Fzd4 protein, mouse; D010750:Phosphoproteins; D051153:Wnt Proteins