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.
Highlights
The BRB5 is a selective diffusion barrier that isolates the retina from the blood, maintaining the appropriate milieu for optimal retinal function and excluding potentially harmful stimuli, acting as a critical protective barrier
In mice with intraocular accumulation of IGF-I, IGF-IR was increased predominantly in Muller cells, leading to increased IGF-I signaling and accumulation of vascular endothelial growth factor (VEGF), whose levels increase as animals age [9]
The disruption of tight junctions (TJs) complexes that control flux through the paracellular route was confirmed by electron microscopy studies, in which horseradish peroxidase (HRP) was detected within interendothelial spaces and accumulated in cells of the vessel wall of TgIGF-I
Summary
Animals—CD1 or C57Bl6/SJL heterozygous mice overexpressing IGF-I in the retina [9] were used for permeability studies or as recipients of bone marrow (BM) transplantation, respectively. Human Samples—Human retinas were obtained from corpses donated to Universitat Autonoma de Barcelona Medical School. Donors 1, 3, and 5 were 83-, 99-, and 85-year-old males. Donors 2 and 4 were females of 86 and 89 years of age. Formalin-fixed paraffin-embedded eye sections were incubated with antiIGF-I receptor, anti-ICAM-1, anti-VEGF, and anti-GFAP. Whole-mount formalin-fixed retinas were incubated with antiZO-1 (61–7300, Zymed Laboratories Inc.), anti-collagen type IV (AB756P, Chemicon), or anti-green fluorescent protein (GFP; ab6673, Abcam). Images were obtained with a laser-scanning confocal microscope (TCs SP2; Leica Microsystems GmbH). In vivo BRB evaluation was performed after intravascular injection of Cy5.5 (Amersham Biosciences). Differences were considered statistically significant at p values less than 0.05
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