title: Increased intraocular insulin-like growth factor-I triggers blood-retinal barrier breakdown.
abstract: Blood-retinal barrier (BRB) breakdown is a key event in diabetic retinopathy and other ocular disorders that leads to increased retinal vascular permeability. This causes edema and tissue damage resulting in visual impairment. Insulin-like growth factor-I (IGF-I) is involved in these processes, although the relative contribution of increased systemic versus intraocular IGF-I remains controversial. Here, to elucidate the role of this factor in BRB breakdown, transgenic mice with either local or systemic elevations of IGF-I have been examined. High intraocular IGF-I, resulting from overexpression of IGF-I in the retina, increased IGF-I receptor content and signaling and led to accumulation of vascular endothelial growth factor. This was parallel to up-regulation of vascular Intercellular adhesion molecule I and retinal infiltration by bone marrow-derived microglial cells. These alterations resulted in increased vessel paracellular permeability to both low and high molecular weight compounds in IGF-I-overexpressing retinas and agreed with the loss of vascular tight junction integrity observed by electron microscopy and the altered junctional protein content. In contrast, mice with chronically elevated serum IGF-I did not show alterations in the retinal vasculature structure and permeability, indicating that circulating IGF-I cannot initiate BRB breakdown. Consistent with a key role of IGF-I signaling in retinal diseases, a strong up-regulation of the IGF-I receptor in human retinas with marked gliosis was also observed. Thus, this study demonstrates that intraocular IGF-I, but not systemic IGF-I, is sufficient to trigger processes leading to BRB breakdown and increased retinal vascular permeability. Therefore, therapeutic interventions designed to counteract local IGF-I effects may prove successful to prevent BRB disruption.
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Haurigot
authors.forename: Pilar
authors.initials: P
authors.lastname: Villacampa
authors.forename: Albert
authors.initials: A
authors.lastname: Ribera
authors.forename: Cristina
authors.initials: C
authors.lastname: Llombart
authors.forename: Assumpcio
authors.initials: A
authors.lastname: Bosch
authors.forename: Victor
authors.initials: V
authors.lastname: Nacher
authors.forename: David
authors.initials: D
authors.lastname: Ramos
authors.forename: Eduard
authors.initials: E
authors.lastname: Ayuso
authors.forename: José C
authors.initials: JC
authors.lastname: Segovia
authors.forename: Juan A
authors.initials: JA
authors.lastname: Bueren
authors.forename: Jesus
authors.initials: J
authors.lastname: Ruberte
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch
mesh_terms: D000369:Aged, 80 and over; D000818:Animals; D001813:Blood-Retinal Barrier / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D015153:Blotting, Western; D002417:Cattle; D005260:Female; D005911:Gliosis / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism* / Q000473:pathology
chemical_list: D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1