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The interplay between hyperglycemia and endothelial activation in inducing endoplasmic reticulum (ER) stress pathways and visual deficits in DR is not fully understood. To address this, we used a mouse model of chronic vascular activation using endothelial\u2010specific tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1)\u2010expressing (tie2\u2010TNF) mice to induce diabetes with streptozotocin. At 4 weeks post streptozotocin, a significant 2\u2010fold to 10\u2010fold increase in retinal neurovascular inflammatory gene transcript response in tie2\u2010TNF mice was further increased in diabetic tie2\u2010TNF mice. A decrease in visual acuity and scotopic b\u2010wave amplitude in tie2\u2010TNF mice was further accentuated in diabetic tie2\u2010TNF mice and these changes correlated with a multi\u2010fold increase in retinal ER stress markers and a reduction in adherens junctions. Cultured retinal endothelial cells showed a significant decrease in trans\u2010endothelial resistance as well as VE\u2010cadherin expression under TNF\u2010\u03b1 and high glucose stress. These changes were partly rescued by tauroursodeoxycholic acid, a potent ER stress inhibitor. Taken together, constant endothelial activation induced by TNF\u2010\u03b1 further exacerbated by hyperglycemia results in activation of ER stress and chronic proinflammation in a feed forward loop ultimately resulting in endothelial junction protein alterations leading to visual deficits in the retina. Inhibition of ER stress and endothelial activation may prove to be a novel therapeutic target in DR.<\/jats:p>","DOI":"10.1002\/jcb.27072","type":"journal-article","created":{"date-parts":[[2018,7,28]],"date-time":"2018-07-28T05:18:25Z","timestamp":1532755105000},"page":"8460-8471","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Critical role of endoplasmic reticulum stress in chronic endothelial activation\u2212induced visual deficits in tie2\u2010tumor necrosis factor mice"],"prefix":"10.1002","volume":"119","author":[{"given":"Raji","family":"Lenin","sequence":"first","affiliation":[{"name":"Department of Ophthalmology University of Tennessee Health Science Center  Memphis Tennessee"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter G.","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology University of Tennessee Health Science Center  Memphis 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