In vivo two-photon fluorescence microscopy reveals disturbed cerebral capillary blood flow and increased susceptibility to ischemic insults in diabetic mice.
OBJECTIVE
Diabetes mellitus increases the risk of stroke, but the mechanisms are unclear. The present study tested the hypothesis that diabetes mellitus disturbs the brain microcirculation and increases the susceptibility to cerebral damage in a middle cerebral artery occlusion (MCAO) model of ischemia.


METHODS
Diabetes was induced by streptozocin in mice expressing green fluorescent protein in endothelial cells (Tie2-GFP mice). Four weeks later, they were subjected to transient (20 min) MCAO. In vivo blood flow was measured by two-photon laser-scanning microscopy (TPLSM) in cerebral arteries, veins, and capillaries.


RESULTS
There was a significant decrease in red blood cell (RBC) velocity in capillaries in diabetic mice as assessed by TPLSM, yet the regional cerebral blood flow, as assessed by laser Doppler flowmetry, was maintained. Brain capillary flow developed turbulence after MCAO only in diabetic mice. These mice sustained increased neurological deficits after MCAO which were accompanied by an exaggerated degradation of tight junction proteins and blunted CaMKII phosphorylation in cerebral tissues indicating disruption of the blood-brain barrier and disturbed cognitive potential.


CONCLUSIONS
Diabetic mice are more susceptible to disturbances of cerebral capillary blood flow which may predispose them to neurovascular defects following ischemia.
Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Zhejiang University, Hangzhou, China.
Ji-Yun
JY
Huang
Li-Tao
LT
Li
Huan
H
Wang
Shuang-Shuang
SS
Liu
Ying-Mei
YM
Lu
Mei-Hua
MH
Liao
Rong-Rong
RR
Tao
Ling-Juan
LJ
Hong
Kohji
K
Fukunaga
Zhong
Z
Chen
Christopher S
CS
Wilcox
En Yin
EY
Lai
Feng
F
Han
D000704:Analysis of Variance; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000503:physiopathology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002540:Cerebral Cortex / Q000098:blood supply / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004912:Erythrocytes / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology* / Q000503:physiopathology*; D017078:Laser-Doppler Flowmetry; D051379:Mice; D008822:Mice, Transgenic; D042787:Receptor, TIE-2 / Q000235:genetics; D018091:Receptors, AMPA / Q000378:metabolism
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D049452:Green Fluorescent Proteins; D042787:Receptor, TIE-2; D018091:Receptors, AMPA; C079086:Tek protein, mouse
Capillary; Cerebral blood flow; Diabetes; Hyperglycemia; Ischemia; Two-photon laser-scanning microscopy