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Protecting Cerebral Microvascular Endothelial Cells in Diabetes Mellitus
Author(s) -
Bidasee Keshore R,
Alomar Fadhel,
Rozanski George J,
Mayhan William,
Padanilam Babu,
Singh Jaipaul
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.836.17
Subject(s) - medicine , ischemia , inflammation , endocrinology , endothelial stem cell , oxidative stress , methylglyoxal , endothelial dysfunction , gliosis , pharmacology , pathology , biology , biochemistry , in vitro , enzyme
Endothelial cell‐mediated vasodilatation of cerebral arterioles is impaired in individuals with diabetes mellitus (DM). This defect, which compromises hemodynamics can lead to hypoxia, oxidative stress, vascular leakage/microbleeds, inflammation, and exaggerated ischemia‐reperfusion injuries. Excessive production of the mitochondrial toxin methylglyoxal (MG) has emerged as a leading cause for endothelial cell dysfunction in DM. However, why/how MG increases in the brain during DM remains undefined. Here tissue from different brain regions from Type 1 and Type 2 DM patients and from Type 1 DM rats were used to assess expression and activities of the MG synthesizing and degradation enzymes, vascular adhesion protein‐1 (VAP‐1) and glyoxalase‐I (Glo‐I), respectively. Type 1 DM rats were also used to determine if increasing Glo‐I in cerebral microvascular smooth muscle cells (cSMCs) would blunt endothelial cell dysfunction and the resultant cerebral defects. In brains of patients and rats with DM, VAP‐1 was upregulated and Glo‐I was downregulated in cSMCs. MG and its metabolite argpyrimidine were also upregulated. In DM rats, endothelial cell‐mediated vasodilatation of cerebral arterioles was compromised and cerebral microvascular leakage/microbleeds, gliosis, oxidative stress, infiltration of macrophage/neutrophil in brain parenchyma, and inflammation (NF‐kB activation and TNF‐α) were increased. The density of microvessel perfused was also reduced and a transient occlusion of a mid‐cerebral artery resulted in exaggerated ischemia‐reperfusion injuries. Restoring Glo‐I protein in cSMCs of Type 1 DM to control levels using a custom‐designed adeno‐associated virus, lowered MG, its metabolite argpyrimidine and prevented endothelial cell dysfunction. It also attenuated upregulation of VAP‐1 and MG production in cSMCs, blunted oxidative stress, microvascular leakage, gliosis, macrophage/neutrophil infiltration, NF‐κB activation, TNF‐α production, and restored perfusion of cerebral microvessels. From these new data we conclude that the supra‐physiologic level of MG that triggers dysregulation of endothelial cells in the cerebral microvasculature in DM is arising from increased expression of VAP‐1 and decreased Glo‐I in cSMCs. They also suggest that lowering MG in cSMCs could be a viable therapeutic strategy to preserve cECs function and prevent deleterious cerebral deficits in DM.