title: VE-cadherin Y685F knock-in mouse is sensitive to vascular permeability in recurrent angiogenic organs.
abstract: Covalent modifications such as tyrosine phosphorylation are associated with the breakdown of endothelial cell junctions and increased vascular permeability. We previously showed that vascular endothelial (VE)-cadherin was tyrosine phosphorylated in vivo in the mouse reproductive tract and that Y685 was a target site for Src in response to vascular endothelial growth factor in vitro. In the present study, we aimed to understand the implication of VE-cadherin phosphorylation at site Y685 in cyclic angiogenic organs. To achieve this aim, we generated a knock-in mouse carrying a tyrosine-to-phenylalanine point mutation of VE-cadherin Y685 (VE-Y685F). Although homozygous VE-Y685F mice were viable and fertile, the nulliparous knock-in female mice exhibited enlarged uteri with edema. This phenotype was observed in 30% of females between 4 to 14 mo old. Histological examination of longitudinal sections of the VE-Y685F uterus showed an extensive disorganization of myometrium and endometrium with highly edematous uterine glands, numerous areas with sparse cells, and increased accumulation of collagen fibers around blood vessels, indicating a fibrotic state. Analysis of cross section of ovaries showed the appearance of spontaneous cysts, which suggested increased vascular hyperpermeability. Electron microscopy analysis of capillaries in the ovary showed a slight but significant increase in the gap size between two adjacent endothelial cell membranes in the junctions of VE-Y685F mice (wild-type, 11.5 ± 0.3, n = 78; and VE-Y685F, 12.48 ± 0.3, n = 65; P = 0.045), as well as collagen fiber accumulation around capillaries. Miles assay revealed that either basal or vascular endothelial growth factor-stimulated permeability in the skin was increased in VE-Y685F mice. Since edema and fibrotic appearance have been identified as hallmarks of initial increased vascular permeability, we conclude that the site Y685 in VE-cadherin is involved in the physiological regulation of capillary permeability. Furthermore, this knock-in mouse model is of potential interest for further studies of diseases that are associated with abnormal vascular permeability.
authors.affiliation: INSERM, U1036, Biology of Cancer and Infection, Grenoble, France; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France;
authors.forename: Adama
authors.initials: A
authors.lastname: Sidibé
authors.affiliation: INSERM, U1036, Biology of Cancer and Infection, Grenoble, France; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France;
authors.forename: Helena
authors.initials: H
authors.lastname: Polena
authors.affiliation: Grenoble Institute of Neurosciences, Grenoble, France; INSERM U836, Electron microscopy platform, Grenoble, France; and.
authors.forename: Karin
authors.initials: K
authors.lastname: Pernet-Gallay
authors.affiliation: INSERM, U1036, Biology of Cancer and Infection, Grenoble, France; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France;
authors.forename: Jeremy
authors.initials: J
authors.lastname: Razanajatovo
authors.affiliation: INSERM, U1036, Biology of Cancer and Infection, Grenoble, France; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France;
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Mannic
authors.affiliation: INSERM, U1036, Biology of Cancer and Infection, Grenoble, France; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chaumontel
authors.affiliation: INSERM, U1036, Biology of Cancer and Infection, Grenoble, France; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France;
authors.forename: Soumalamaya
authors.initials: S
authors.lastname: Bama
authors.affiliation: INSERM, U1036, Biology of Cancer and Infection, Grenoble, France; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France;
authors.forename: Irène
authors.initials: I
authors.lastname: Maréchal
authors.affiliation: INSERM, U1036, Biology of Cancer and Infection, Grenoble, France; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Huber
authors.affiliation: INSERM, U1036, Biology of Cancer and Infection, Grenoble, France; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France;
authors.forename: Danielle
authors.initials: D
authors.lastname: Gulino-Debrac
authors.affiliation: INSERM, U1036, Biology of Cancer and Infection, Grenoble, France; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France; Division of Internal Medicine, Grenoble University Hospital, Grenoble, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Bouillet
authors.affiliation: INSERM, U1036, Biology of Cancer and Infection, Grenoble, France; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France; ivilgrain@cea.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vilgrain
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D002199:Capillary Permeability; D004487:Edema / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D055879:Gene Knock-In Techniques; D005838:Genotype; D006720:Homozygote; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D010053:Ovary / Q000098:blood supply*; D010641:Phenotype; D010766:Phosphorylation; D014443:Tyrosine; D014599:Uterus / Q000098:blood supply*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D014443:Tyrosine; D000099152:Cadherin 5
keywords: VE-cadherin phosphorylation; knock-in mouse; mouse estrous cycle; tyrosine kinase; vascular permeability