Increased intraocular insulin-like growth factor-I triggers blood-retinal barrier breakdown

Virginia Haurigot, Pilar Villacampa, Albert Ribera, Critina Llombart, Assumpcio Bosch, Victor Nacher, David Ramos, Eduard Ayuso, José C. Segovia, Juan A. Bueven, Jesus Ruberte, Fatima Bosch

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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. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
Original languageEnglish
Pages (from-to)22961-22969
JournalJournal of Biological Chemistry
Volume284
Issue number34
DOIs
Publication statusPublished - 21 Aug 2009

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    Haurigot, V., Villacampa, P., Ribera, A., Llombart, C., Bosch, A., Nacher, V., Ramos, D., Ayuso, E., Segovia, J. C., Bueven, J. A., Ruberte, J., & Bosch, F. (2009). Increased intraocular insulin-like growth factor-I triggers blood-retinal barrier breakdown. Journal of Biological Chemistry, 284(34), 22961-22969. https://doi.org/10.1074/jbc.M109.014787