title: Wnt signaling mediates pathological vascular growth in proliferative retinopathy.
abstract: BACKGROUND
  Ischemic proliferative retinopathy, characterized by pathological retinal neovascularization, is a major cause of blindness in working-age adults and children. Defining the molecular pathways distinguishing pathological neovascularization from normal vessels is critical to controlling these blinding diseases with targeted therapy. Because mutations in Wnt signaling cause defective retinal vasculature in humans with some characteristics of the pathological vessels in retinopathy, we investigated the potential role of Wnt signaling in pathological retinal vascular growth in proliferative retinopathy.
  
  
  RESULTS
  In this study, we show that Wnt receptors (Frizzled4 and low-density lipoprotein receptor-related protein5 [Lrp5]) and activity are significantly increased in pathological neovascularization in a mouse model of oxygen-induced proliferative retinopathy. Loss of Wnt coreceptor Lrp5 and downstream signaling molecule dishevelled2 significantly decreases the formation of pathological retinal neovascularization in retinopathy. Loss of Lrp5 also affects retinal angiogenesis during development and formation of the blood-retinal barrier, which is linked to significant downregulation of tight junction protein claudin5 in Lrp5(-/-) vessels. Blocking claudin5 significantly suppresses Wnt pathway-driven endothelial cell sprouting in vitro and developmental and pathological vascular growth in retinopathy in vivo.
  
  
  CONCLUSIONS
  These results demonstrate an important role of Wnt signaling in pathological vascular development in retinopathy and show a novel function of Cln5 in promoting angiogenesis.
authors.affiliation: Department of Ophthalmology, Harvard Medical School/Children's Hospital Boston, Boston MA 02115, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Andreas
authors.initials: A
authors.lastname: Stahl
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Krah
authors.forename: Molly R
authors.initials: MR
authors.lastname: Seaward
authors.forename: Roberta J
authors.initials: RJ
authors.lastname: Dennison
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
authors.forename: Jing
authors.initials: J
authors.lastname: Hua
authors.forename: Colman J
authors.initials: CJ
authors.lastname: Hatton
authors.forename: Aimee M
authors.initials: AM
authors.lastname: Juan
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Aderman
authors.forename: Keirnan L
authors.initials: KL
authors.lastname: Willett
authors.forename: Karen I
authors.initials: KI
authors.lastname: Guerin
authors.forename: Akiko
authors.initials: A
authors.lastname: Mammoto
authors.forename: Matthew
authors.initials: M
authors.lastname: Campbell
authors.forename: Lois E H
authors.initials: LE
authors.lastname: Smith
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology*; D051157:Frizzled Receptors / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000096:biosynthesis / Q000502:physiology*; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D060490:Receptors, Wnt / Q000096:biosynthesis / Q000502:physiology*; D012160:Retina / Q000254:growth & development / Q000473:pathology* / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: C488572:Cln5 protein, mouse; D051157:Frizzled Receptors; C498581:Fzd4 protein, mouse; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D060490:Receptors, Wnt