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Gangaraju Rajashekhar, Abby Marin, Vidhya R. Rao, Sangly P. Srinivas, Uday B. Kompella, Matthias Clauss; Chronic Endothelial Activation In Transgenic tie2-tmTNF Mice Triggers Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2103.
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Although in rodent models the metabolic and physiologic abnormalities associated with hyperglycemia has been shown to cause degeneration of the retinal blood vessels with increased permeability and leukostasis, mice only display early stages of diabetic retinopathy (DR) possibly due to much less vaso-obliteration. Therefore, we hypothesize that the vascular damage in short lived hyperglycemic rodents is not sufficient to reach a threshold of inflammation and damage seen in larger animal models and human patients. Thus, we tested the onset of DR in diabetic mice, which are transgenic for endothelial TNF expression, leading to constant endothelial activation and chronic inflammation.
We employed an in vivo endothelial TNF-alpha pro-inflammatory transgenic model and induced hyperglycemia by streptozotocin (STZ). In vitro, retinal endothelial cells were exposed to chronic TNF-alpha and high glucose. Vascular permeability was assessed by the albumin extravasation assay and in vitro by dynamic changes in trans-endothelial electrical resistance. Increased vascular remodeling was assessed by isolectin staining in retinal whole mounts and by capillary sprout formation assay in vitro. Increased pro-angiogenic genes and matrix metalloproteinases were assessed by realtime RT-PCR and zymography, respectively.
Within four weeks of STZ induced hyperglycemia in tie2-tmTNF mice, a significant increase in retinal vascular permeability and aberrant vessel density, were noted. Furthermore, only the diabetic tie2-tmTNF mice developed microhemorrhagic vessels as evidenced by extravasated RBCs. In vitro, retinal endothelial cells subjected to chronic activation by a low dose TNF-alpha at high glucose levels led to increased sprout formation, pro-angiogenic genes, matrix metalloproteinases, and Hsp-27.
For the first time, we demonstrated a mouse model of DR phenotype with intraretinal microhemorrhages in addition to increased vascular permeability and vessel remodeling. Endothelial activation and hyperglycemia synergistically induced a DR phenotype with increased pro-angiogenic genes and matrixmetalloproteinases in vitro. Understanding the causal relationship between increased vascular permeability, aberrant vascular remodeling and microhemorrhages to capillary and neurodegeneration in this mouse model needs further investigation.
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