{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T08:35:58Z","timestamp":1775810158333,"version":"3.50.1"},"reference-count":64,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2016,10,14]],"date-time":"2016-10-14T00:00:00Z","timestamp":1476403200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Endothelial cell\u2010mediated vasodilatation of cerebral arterioles is impaired in individuals with Type 1 diabetes (T1D). This defect compromises haemodynamics and can lead to hypoxia, microbleeds, inflammation and exaggerated ischaemia\u2010reperfusion injuries. The molecular causes for dysregulation of cerebral microvascular endothelial cells (cECs) in T1D remains poorly defined. This study tests the hypothesis that cECs dysregulation in T1D is triggered by increased generation of the mitochondrial toxin, methylglyoxal, by smooth muscle cells in cerebral arterioles (cSMCs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Endothelial cell\u2010mediated vasodilatation, vascular transcytosis inflammation, hypoxia and ischaemia\u2010reperfusion injury were assessed in brains of male Sprague\u2010Dawley rats with streptozotocin\u2010induced diabetes and compared with those in diabetic rats with increased expression of methylglyoxal\u2010degrading enzyme glyoxalase\u2010I (Glo\u2010I) in cSMCs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>After 7\u20138\u00a0weeks of T1D, endothelial cell\u2010mediated vasodilatation of cerebral arterioles was impaired. Microvascular leakage, gliosis, macrophage\/neutrophil infiltration, NF\u2010\u03baB activity and TNF\u2010\u03b1 levels were increased, and density of perfused microvessels was reduced. Transient occlusion of a mid\u2010cerebral artery exacerbated ischaemia\u2010reperfusion injury. In cSMCs, Glo\u2010I protein was decreased, and the methylglyoxal\u2010synthesizing enzyme, vascular adhesion protein 1 (VAP\u20101) and methylglyoxal were increased. Restoring Glo\u2010I protein in cSMCs of diabetic rats to control levels via gene transfer, blunted VAP\u20101 and methylglyoxal increases, cECs dysfunction, microvascular leakage, inflammation, ischaemia\u2010reperfusion injury and increased microvessel perfusion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Methylglyoxal generated by cSMCs induced cECs dysfunction, inflammation, hypoxia and exaggerated ischaemia\u2010reperfusion injury in diabetic rats. Lowering methylglyoxal produced by cSMCs may be a viable therapeutic strategy to preserve cECs function and blunt deleterious downstream consequences in T1D.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13617","type":"journal-article","created":{"date-parts":[[2016,9,9]],"date-time":"2016-09-09T18:15:46Z","timestamp":1473444946000},"page":"3307-3326","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Smooth muscle\u2010generated methylglyoxal impairs endothelial cell\u2010mediated vasodilatation of cerebral microvessels in type 1 diabetic rats"],"prefix":"10.1111","volume":"173","author":[{"given":"Fadhel","family":"Alomar","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center  Omaha NE USA"},{"name":"Department of Pharmacology University of Dammam  Dammam Saudi 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