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Samuel Alexander Mills, Andrew Ian Jobling, Bang V Bui, Zheng He, Ursula Greferath, Joe Wang, Flora Hui, Erica L Fletcher; The relationship between retinal blood flow, neuronal function and glia in the early diabetic retina,. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3215.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal glia maintain and regulate retinal vascular tone in response to neuronal demand. While it is known that changes in retinal blood flow and neuronal function are among the earliest signs of diabetic retinopathy (DR), it is unclear whether the primary cause of retinal degeneration is vascular, neuronal or glial in origin. Using a rat model of diabetes retinal blood flow, neuronal function, and retinal glia were assessed in early diabetes.
Hyperglycaemia was induced in adult Dark Agouti rats using streptozotocin (STZ, 55mg/kg). After 4 weeks of insulin controlled diabetes, the blood flow kinetics of arterioles, capillaries and venules were quantified by sodium fluorescein video angiography (n=21) under anaesthesia (60:5 mg/kg ketamine:xylazine). Electroretinogram (ERG) was performed on anesthetised dark adapted animals (n=9). Blood vessel diameters were measured from fundus images, while immunohistochemistry was used to quantify vessel density and the association of microglia (Ionized calcium binding adaptor molecule 1), astrocytes (glial fibrillary acidic protein), and pericytes (Chondroitin Sulfate Proteoglycan) with each vessel type (Isolectin B4)(n=11)
After 4 weeks of STZ-diabetes, blood vessels showed slower fluorescein filling rates compared to controls (arterioles: -23.1% [95% CI= -6.8% to -36.8%]; capillaries: -18.1% [-5.2% to -31.0%]; venules: -14.5% [-3.7% to -25.3%]) and even slower drainage rates (arterioles: -52.6% [-26.6% to -78.5%]; capillaries: -48.1% [-18.1% to -78.0%]; venules: -48.8% [-24.9% to -72.6%]). Arteriole to venous ratios remained unchanged in diabetes and there was no loss of capillary density. ERG showed a reduction in the ganglion cell response (-27.4% [-17.4% to -37.5%]), without affecting other waveforms. Astrocytes showed no change in vessel coverage or density, and there was no loss of pericytes. Retinal microglia showed an increased association with capillaries and pericytes within the central retina (319 cells/mm2 vessel [38.7 to 601.0]; 24 cells/mm2retina [2.7 to 46])
Early in DR, increased contact of microglia with capillaries and pericytes may be the initial stage of capillary loss and pericyte dropout, both early symptoms of DR observed in humans. Hyperglycaemia induced a decline primarily in ganglion cell activity and retinal blood flow, which preceded any structural changes to inner retinal macroglia.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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