title: Dystrophin Dp71 gene deletion induces retinal vascular inflammation and capillary degeneration.
abstract: We have previously shown that the deletion of the dystrophin Dp71 gene induces a highly permeable blood-retinal barrier (BRB). Given that BRB breakdown is involved in retinal inflammation and the pathophysiology of many blinding eye diseases, here we investigated whether the absence of Dp71 brings out retinal vascular inflammation and vessel loss by using specific Dp71-null mice. The expression of vascular endothelial growth factor (VEGF), quantified by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay methods, was higher in the retina of Dp71-null mice than in wild-type mice. In contrast, no differences were observed in VEGFR-2 and tumor necrosis factor-α expression. Moreover, mRNA expression of water channel, aquaporin 4 (AQP4) was increased after Dp71 deletion. The Dp71 deletion was also associated with the overexpression of intercellular adhesion molecule 1, which is expressed on endothelial cells surface to recruit leukocytes. Consistent with these findings, the total number of adherent leukocytes per retina, assessed after perfusion with fluorescein isothiocyanate-conjugated concanavalin A, was increased in the absence of Dp71. Finally, a significant increase in capillary degeneration quantified after retinal trypsin digestion was observed in mice lacking Dp71. These data illustrate for the first time that the deletion of Dp71 was associated with retinal vascular inflammation, vascular lesions with increased leukocyte adhesion and capillary degeneration. Thus, dystrophin Dp71 could play a critical role in retinal vascular inflammation disease, and therefore represent a potential therapeutic target.
authors.affiliation: Institut de la Vision/INSERM/UPMC, Univ Paris 06/CNRS/CHNO des Quinze-Vingts, Paris, France, Sanofi Fovea-Ophthalmology, Paris, France.
authors.forename: Brahim
authors.initials: B
authors.lastname: El Mathari
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Sene
authors.affiliation: Institut de la Vision/INSERM/UPMC, Univ Paris 06/CNRS/CHNO des Quinze-Vingts, Paris, France.
authors.forename: Hugo
authors.initials: H
authors.lastname: Charles-Messance
authors.affiliation: Institut de la Vision/INSERM/UPMC, Univ Paris 06/CNRS/CHNO des Quinze-Vingts, Paris, France.
authors.forename: Ophélie
authors.initials: O
authors.lastname: Vacca
authors.affiliation: Institut de la Vision/INSERM/UPMC, Univ Paris 06/CNRS/CHNO des Quinze-Vingts, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Guillonneau
authors.affiliation: Sanofi Fovea-Ophthalmology, Paris, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Grepin
authors.affiliation: Institut de la Vision/INSERM/UPMC, Univ Paris 06/CNRS/CHNO des Quinze-Vingts, Paris, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Sennlaub
authors.affiliation: Institut de la Vision/INSERM/UPMC, Univ Paris 06/CNRS/CHNO des Quinze-Vingts, Paris, France, Fondation Ophtalmologique Adolphe de Rothschild, Paris, France, Institute of Ophthalmology, University College of London, UK, Académie des Sciences-Institut de France, Paris, France and.
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: Institut de la Vision/INSERM/UPMC, Univ Paris 06/CNRS/CHNO des Quinze-Vingts, Paris, France.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Rendon
authors.affiliation: Institut de la Vision/INSERM/UPMC, Univ Paris 06/CNRS/CHNO des Quinze-Vingts, Paris, France, Ophthalmology Department, Hôpital Lariboisière (AP-HP) 2, Université Paris 7, Sorbonne Paris Cité, rue Ambroise Paré, 75010 Paris, France ramin.tadayoni@lrb.aphp.fr.
authors.forename: Ramin
authors.initials: R
authors.lastname: Tadayoni
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics / Q000378:metabolism; D001813:Blood-Retinal Barrier; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D016189:Dystrophin / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D017353:Gene Deletion; D005904:Glial Fibrillary Acidic Protein; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000473:pathology*; D012164:Retinal Diseases / Q000235:genetics; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; C494827:Bax protein, mouse; D016189:Dystrophin; D005904:Glial Fibrillary Acidic Protein; C090509:Icam1 protein, mouse; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C085339:apo-dystrophin 1; D051028:bcl-2-Associated X Protein; C528900:glial fibrillary astrocytic protein, mouse; D018799:Intercellular Adhesion Molecule-1; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; C505409:Casp3 protein, mouse; D053148:Caspase 3