Faculty Collaboration Database

Reduced pericyte and tight junction coverage in old diabetic rats are associated with hyperglycemia-induced cerebrovascular pericyte dysfunction. Am J Physiol Heart Circ Physiol 2021 Feb 01;320(2):H549-H562

Date

12/12/2020

Pubmed ID

33306445

Pubmed Central ID

PMC8082790

DOI

10.1152/ajpheart.00726.2020

Scopus ID

2-s2.0-85100362190 (requires institutional sign-in at Scopus site)   34 Citations

Abstract

Diabetes mellitus (DM) is one of the primary pathological factors that contributes to aging-related cognitive impairments, but the underlying mechanisms remain unclear. We recently reported that old DM rats exhibited impaired myogenic responses of the cerebral arteries and arterioles, poor cerebral blood flow autoregulation, enhanced blood-brain barrier (BBB) leakage, and cognitive impairments. These changes were associated with diminished vascular smooth muscle cell contractile capability linked to elevated reactive oxygen species (ROS) and reduced ATP production. In the present study, using a nonobese T2DN DM rat, we isolated parenchymal arterioles (PAs), cultured cerebral microvascular pericytes, and examined whether cerebrovascular pericyte in DM is damaged and whether pericyte dysfunction may play a role in the regulation of cerebral hemodynamics and BBB integrity. We found that ROS and mitochondrial superoxide production were elevated in PAs isolated from old DM rats and in high glucose (HG)-treated α-smooth muscle actin-positive pericytes. HG-treated pericytes displayed decreased contractile capability in association with diminished mitochondrial respiration and ATP production. Additionally, the expression of advanced glycation end products, transforming growth factor-β, vascular endothelial growth factor, and fibronectin were enhanced, but claudin 5 and integrin β1 was reduced in the brain of old DM rats and HG-treated pericytes. Further, endothelial tight junction and pericyte coverage on microvessels were reduced in the cortex of old DM rats. These results demonstrate our previous findings that the impaired cerebral hemodynamics and BBB leakage and cognitive impairments in the same old DM model are associated with hyperglycemia-induced cerebrovascular pericyte dysfunction.NEW & NOTEWORTHY This study demonstrates that the loss of contractile capability in pericytes in diabetes is associated with enhanced ROS and reduced ATP production. Enhanced advanced glycation end products (AGEs) in diabetes accompany with reduced pericyte and endothelial tight junction coverage in the cortical capillaries of old diabetic rats. These results suggest our previous findings that the impaired cerebral hemodynamics, BBB leakage, and cognitive impairments in old DM model are associated with hyperglycemia-induced cerebrovascular pericyte dysfunction.

Author List

Liu Y, Zhang H, Wang S, Guo Y, Fang X, Zheng B, Gao W, Yu H, Chen Z, Roman RJ, Fan F

Author

Hongwei Yu MD Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Aging
Animals
Arterioles
Brain
Cells, Cultured
Diabetes Mellitus
Gap Junctions
Glycation End Products, Advanced
Humans
Hyperglycemia
Male
Pericytes
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species
Vasoconstriction