Hyperglycemia and advanced glycation end products disrupt BBB and promote occludin and claudin-5 protein secretion on extracellular microvesicles

• Published in: Scientific reports 2020-04, Vol.10 (1), p.7274-7274, Article 7274
• Main Authors: Rom, Slava, Heldt, Nathan A., Gajghate, Sachin, Seliga, Alecia, Reichenbach, Nancy L., Persidsky, Yuri
• Format: Article
• Language: English
• Subjects: 631/378/1341; 692/699/2743/137; Advanced glycosylation end products; Animals; Blood-brain barrier; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; Claudin-5 - metabolism; Cognitive ability; Connexin 43; Diabetes mellitus; Endothelium; Extracellular vesicles; Extracellular Vesicles - metabolism; Extracellular Vesicles - pathology; Gene Expression Regulation; Glycation End Products, Advanced - metabolism; Glycosylation; Humanities and Social Sciences; Hyperglycemia; Hyperglycemia - metabolism; Hyperglycemia - pathology; Leukocyte migration; Male; Membrane permeability; Mice; Microvasculature; multidisciplinary; Occludin - biosynthesis; Occludin - metabolism; Pericytes; Pericytes - metabolism; Pericytes - pathology; Permeability; Platelet-derived growth factor; Science; Science (multidisciplinary); Tight junctions
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-64349-x

Cognitive impairment is a well-known complication of diabetes mellitus (DM). Microvascular compromise was described one DM complication. Recently we showed blood brain barrier (BBB) permeability and memory loss are associated with diminution of tight junctions (TJ) in brain endothelium and pericyte coverage and inflammation in cerebral microvessels and brain tissue paralleling hyperglycemia in mice of both DM types. The current study demonstrates that exposure of brain microvessels to hyperglycemic conditions or advanced glycation end products (AGEs) ex vivo resulted in significant abnormalities in membranous distribution of TJ proteins. We found significant increase in the amount of extracellular vesicles (EVs) isolated from DM mice and enhanced presence of TJ proteins, occludin and claudin-5, on EVs. Exposure of BMVECs to high glucose and AGEs led to significant augmentation of ICAM and VCAM expression, elevated leukocyte adhesion to and migration across BMVEC monolayers, and increased BBB permeability in vitro . Pericytes exposed to hyperglycemia and AGEs displayed diminished expression of integrin α1, PDGF-R1β and connexin-43. Our findings indicate BBB compromise in DM ex vivo , in vitro and in vivo models in association with BMVEC/pericyte dysfunction and inflammation. Prevention of BBB injury may be a new therapeutic approach to avert cognitive demise in DM.