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C. Gustavsson, E. Agardh, M. Gomez, M.-L. Schmidt, C.-D. Agardh; Decreased VCAM-1 Expression in Retinal Vessels From Diabetic Mouse Is Restored by TNF- Deletion. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5364.
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Several studies have demonstrated up-regulation of angiogenic cytokines in microvascular complications of diabetes. Tumor necrosis factor- (TNF-) is an angiogenic and inflammatory cytokine associated with diabetic retinopathy. Thus regulation of TNF- activity may be of therapeutic interest. In the present study we hypothesized that diabetes induced endothelial dysfunction might depend on TNF-. To test this, we studied the effect of diabetes on the expression of VCAM-1, an early marker for endothelial activation, in retinal vessels from TNF--/- mice, both on a normal (C57Bl6) and a dyslipidemic (Apoe-/-) background.
Wild type (wt) and three genetically modified mouse strains (Apoe-/-, TNF--/- and Apoe-/-/TNF--/-) were made diabetic by an intraperitoneal injection of streptozocin (STZ). After 8 weeks, the expression of VCAM-1 in the endothelium of retinal vessels was assessed by inmunofluorescence confocal microscopy. The number of VCAM-1 positive vessels and their mean fluorescence intensity were analyzed and statistically differences were determined using Chi2/Fisher’s exact test and one way Anova with Bonferroni post hoc correction, respectively.
Diabetes reduced the intensity and the number of VCAM-1 positive vessels in wt and Apoe-/- mice whereas no differences were observed in vessels from TNF- deficient mice, regardless the background. VCAM-1 intensity was positively correlated to vessel diameter (Spearman R=0.284, p=0.01), but not to blood glucose, total cholesterol or triglyceride levels.
Contrary to our expectations, VCAM-1-expression did not increase in diabetic TNF--competent mice, instead it decreased. This was not the case in TNF--deficient strains. The mechanism behind the decreased VCAM-1 expression found in diabetic mice is not clear. One possible explanation could be that diabetes-induced leukostasis enhances adherence of leukocytes to VCAM-1 in the walls of small vessels thereby preventing the binding of VCAM-1 antibody to their epitopes, and that this does not occur in TNF- deficient strains. We are currently investigating this hypothesis.
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