Smooth muscle-generated methylglyoxal impairs endothelial cell-mediated vasodilatation of cerebral microvessels in type 1 diabetic rats.
Endothelial cell-mediated 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-reperfusion 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).



Endothelial cell-mediated vasodilatation, vascular transcytosis inflammation, hypoxia and ischaemia-reperfusion injury were assessed in brains of male Sprague-Dawley rats with streptozotocin-induced diabetes and compared with those in diabetic rats with increased expression of methylglyoxal-degrading enzyme glyoxalase-I (Glo-I) in cSMCs.



After 7-8 weeks of T1D, endothelial cell-mediated vasodilatation of cerebral arterioles was impaired. Microvascular leakage, gliosis, macrophage/neutrophil infiltration, NF-κB activity and TNF-α levels were increased, and density of perfused microvessels was reduced. Transient occlusion of a mid-cerebral artery exacerbated ischaemia-reperfusion injury. In cSMCs, Glo-I protein was decreased, and the methylglyoxal-synthesizing enzyme, vascular adhesion protein 1 (VAP-1) and methylglyoxal were increased. Restoring Glo-I protein in cSMCs of diabetic rats to control levels via gene transfer, blunted VAP-1 and methylglyoxal increases, cECs dysfunction, microvascular leakage, inflammation, ischaemia-reperfusion injury and increased microvessel perfusion.



Methylglyoxal generated by cSMCs induced cECs dysfunction, inflammation, hypoxia and exaggerated ischaemia-reperfusion 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.
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.|Department of Pharmacology, University of Dammam, Dammam, Saudi Arabia.
Fadhel
F
Alomar
School of Forensic and Applied Science, University of Central Lancashire, Preston, UK.
Jaipaul
J
Singh
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA.
Hee-Seong
HS
Jang
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA.|Nebraska Redox Biology Center, Lincoln, NE, USA.
George J
GJ
Rozanzki
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
Chun Hong
CH
Shao
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA.
Babu J
BJ
Padanilam
Department of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.
William G
WG
Mayhan
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.|Department of Environmental, Agricultural and Occupational Health, University of Nebraska Medical Center, Omaha, NE, USA.|Nebraska Redox Biology Center, Lincoln, NE, USA.
Keshore R
KR
Bidasee
D000818:Animals; D001160:Arterioles / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D008297:Male; D055806:Microvessels / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011765:Pyruvaldehyde / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology; D013311:Streptozocin; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D013311:Streptozocin; D011765:Pyruvaldehyde