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Growth factor alterations in advanced diabetic retinopathy: a possible role of blood retina barrier breakdown
A Pfeiffer1, J Spranger, R Meyer-Schwickerath
1Department of Internal Medicine, Berufsgenossenschaftliche Kliniken Bergmannsheil, Ruhr-Universität Bochum, Germany. andreas.pfeiffer@ruhr-uni-bechum.de
Abstract:
Chronic hyperglycemia may cause growth factor alterations that are likely to participate in tissue remodeling typical for diabetic late complications. However, few details of such events are known. The ocular vitreous fluid allows studies of growth factor levels in human eyes (after vitrectomy). The vitreous is highly inert and protected by the blood-retina barrier and thus probably reflects growth factor production by the normal retina. Vitreous from patients with proliferative diabetic retinopathy (PDR) was compared with vitreous obtained from patients with nonproliferative eye disease and with vitreous from patients without diabetes but with marked neovascular proliferations due to ischemia. This design permits us to distinguish diabetes-related from non-diabetes-related alterations. Insulin-like growth factor I (IGF-I), IGF-II, IGF binding protein 2 (IGFBP-2), and IGFBP-3 were elevated 3- to 13-fold in nondiabetic retinal ischemia and 1.5- to 3-fold in PDR, indicating that the changes were not restricted to diabetes. These changes may partially be explained by leakage of serum into the vitreous, since IGFs and IGFBPs are 20- to 50-fold higher in serum than in vitreous, and vitreous protein content was 1.5-fold elevated in PDR subjects and 5-fold in ischemia patients compared with control subjects. TGF-beta is a proposed antiangiogenic factor in the eye. TGF-beta2 was the predominant subtype in vitreous, and its total amount was not altered in PDR patients. More importantly, the active fraction of TGF-beta was decreased by 30 and 70% in PDR and nondiabetic retinal ischemia patients, respectively. Since plasmin may control TGF-beta activation, the serum protein alpha2-antiplasmin was measured and found to be significantly elevated to 150 and 250% of control values in PDR and ischemia patients, respectively. Thus, influx of serum proteins due to microvascular disturbances and hypoxia is proposed as a possible cause for vitreous alterations of IGF-I and of active TGF-beta. These changes seem to occur late in the sequence of events leading to PDR and are not specific for diabetes, but they were also observed in other diseases characterized by retinal hypoxia.
Insights
Diabetic retinopathy and retinal ischemia alter vitreous growth factors, with changes potentially caused by serum protein influx due to microvascular issues and hypoxia. These findings are not exclusive to diabetes.
Area of Science:
- Ophthalmology
- Endocrinology
- Vascular Biology
Background:
- Chronic hyperglycemia in diabetes can lead to late-stage complications involving tissue remodeling.
- Growth factor alterations in the eye's vitreous humor are implicated in these processes, but details remain scarce.
- The vitreous humor offers a unique window into ocular biochemical changes, protected by the blood-retina barrier.
Purpose of the Study:
- To investigate alterations in vitreous growth factors and related proteins in proliferative diabetic retinopathy (PDR).
- To differentiate diabetes-specific changes from those caused by retinal ischemia in general.
- To explore the role of serum protein influx and hypoxia in these vitreous alterations.
Main Methods:
- Vitreous fluid samples were collected from patients undergoing vitrectomy for PDR, nonproliferative eye disease, and retinal ischemia due to non-diabetic causes.
- Levels of Insulin-like Growth Factor I (IGF-I), IGF-II, IGF Binding Protein 2 (IGFBP-2), IGFBP-3, and Transforming Growth Factor-beta (TGF-beta) subtypes and activity were measured.
- Concentrations of serum proteins, including alpha2-antiplasmin, were analyzed to assess potential leakage from blood vessels.
Main Results:
- Elevated levels of IGF-I, IGF-II, IGFBP-2, and IGFBP-3 were observed in both PDR and non-diabetic retinal ischemia, suggesting non-diabetic origins for some changes.
- The active fraction of TGF-beta2 was significantly decreased in both PDR and ischemia groups.
- Increased levels of alpha2-antiplasmin in PDR and ischemia indicate enhanced serum protein influx, correlating with observed vitreous changes.
Conclusions:
- Vitreous alterations in growth factors like IGFs and active TGF-beta in PDR are not solely diabetes-specific and may result from microvascular disturbances and hypoxia.
- Influx of serum proteins into the vitreous appears to be a significant factor contributing to these late-stage ocular complications.
- These findings suggest a common pathway involving hypoxia and vascular leakage in various retinal neovascularization diseases.