Microvascular endothelial cells-derived microvesicles imply in ischemic stroke by modulating astrocyte and blood brain barrier function and cerebral blood flow.
Endothelial cell (EC) released microvesicles (EMVs) can affect various target cells by transferring carried genetic information. Astrocytes are the main components of the blood brain barrier (BBB) structure in the brain and participate in regulating BBB integrity and blood flow. The interactions between ECs and astrocytes are essential for BBB integrity in homeostasis and pathological conditions. Here, we studied the effects of human brain microvascular ECs released EMVs on astrocyte functions. Additionally, we investigated the effects of EMVs treated astrocytes on regulating BBB function and cerebral ischemic damage.



EMVs prepared from ECs cultured in normal condition (n-EMVs) or oxygen and glucose deprivation (OGD-EMVs) condition had diverse effects on astrocytes. The n-EMVs promoted, while the OGD-EMVs inhibited the proliferation of astrocytes via regulating PI3K/Akt pathway. Glial fibrillary acidic protein (GFAP) expression (marker of astrocyte activation) was up-regulated by n-EMVs, while down-regulated by OGD-EMVs. Meanwhile, n-EMVs inhibited but OGD-EMVs promoted the apoptosis of astrocytes accompanied by up/down-regulating the expression of Caspase-9 and Bcl-2. In the BBB model of ECs-astrocytes co-culture, the n-EMVs, conversely to OGD-EMVs, decreased the permeability of BBB accompanied with up-regulation of zonula occudens-1(ZO-1) and Claudin-5. In a transient cerebral ischemia mouse model, n-EMVs ameliorated, while OGD-EMVs aggravated, BBB disruption, local cerebral blood flow (CBF) reduction, infarct volume and neurological deficit score.



Our data suggest that EMVs diversely modulate astrocyte functions, BBB integrity and CBF, and could serve as a novel therapeutic target for ischemic stroke.
Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
Qunwen
Q
Pan
Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.|Guangdong Medical University, Zhanjiang, 524001, China.
Caixia
C
He
College of Health Science, Wuhan Sports University, Wuhan, Hubei, 430000, China.
Hua
H
Liu
Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
Xiaorong
X
Liao
Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
Bingyan
B
Dai
Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.|Department of Pharmacology and Toxicology, Wright State University, Dayton, OH, 45435, USA.|Department of Neurology, Boonshoft School of Medicine, Wright State University, Dayton, OH, 45435, USA.
Yanfang
Y
Chen
College of Health Science, Wuhan Sports University, Wuhan, Hubei, 430000, China.
Yi
Y
Yang
Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
Bin
B
Zhao
Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China. ji.bihl@wright.edu.|Department of Pharmacology and Toxicology, Wright State University, Dayton, OH, 45435, USA. ji.bihl@wright.edu.
Ji
J
Bihl
Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China. mxtgdmc@163.com.
Xiaotang
X
Ma
D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000473:pathology / Q000503:physiopathology*; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D053453:Caspase 9 / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D002560:Cerebrovascular Circulation; D062507:Claudin-5 / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D005947:Glucose / Q000172:deficiency; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000473:pathology*; D010100:Oxygen; D010539:Permeability; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020521:Stroke / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
D062507:Claudin-5; D019253:Proto-Oncogene Proteins c-bcl-2; D062826:Zonula Occludens-1 Protein; D019869:Phosphatidylinositol 3-Kinases; D053453:Caspase 9; D005947:Glucose; D010100:Oxygen
Astrocytes; Blood brain barrier; Cerebral blood flow; Cerebral ischemia; Endothelial cells; Gene expression; Microvesicles