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.

Endothelial cells and the IGF system

“…Overexpression of IGF1 in the retina resulted in changes similar to those of diabetic retinopathy (Ruberte et al 2004). Subsequently, intraocular overexpression of IGF1 has been shown to result in breakdown of the blood-retinal barrier and increased retinal vascular permeability (Haurigot et al 2009).…”

Insulin-like Growth Factor I (IGF-I)-induced Chronic Gliosis and Retinal Stress Lead to Neurodegeneration in a Mouse Model of Retinopathy

“…Transgenic mice overexpressing Igf-I in photoreceptors (TgIGF-I) have increased intraocular VEGF levels and develop many of the retinal vascular alterations characteristic of human diabetic eye disease, despite not being hyperglycemic (14,15). Nonproliferative vascular alterations are found in young animals (2-3 months), and the phenotype progresses to overt preretinal neovascularization in adult mice (7-8 months) (14).…”

“…reports describing the presence of gliosis in the retinas of TgIGF-I mice (14,15). To determine whether there is a temporal progression of glial alterations, GFAP immunohistochemistry was performed at different ages.…”

Immunological Risk Factors for the Development and Progression of Diabetic Retinopathy

“…Intravitreal administration of IGF-I increased retinal factors AKT, JNK, HIF-1alpha, NF-κB, AP-1 activity, and VEGF levels. Haurigot et al, 2009 demonstrated that high intra-ocular concentration of IGF-I in retina is sufficient to activate processes leading to disruption of blood-retina barrier and increase in vascular permeability as a consequence of high expression of IGF-I in retina.…”