Endothelin-1 overexpression leads to further water accumulation and brain edema after middle cerebral artery occlusion via aquaporin 4 expression in astrocytic end-feet.
Stroke patients have increased levels of endothelin-1 (ET-1), a strong vasoconstrictor, in their plasma or cerebrospinal fluid. Previously, we showed high level of ET-1 mRNA expression in astrocytes after hypoxia/ischemia. It is unclear whether the contribution of ET-1 induction in astrocytes is protective or destructive in cerebral ischemia. Here, we generated a transgenic mouse model that overexpress ET-1 in astrocytes (GET-1) using the glial fibrillary acidic protein promoter to examine the role of astrocytic ET-1 in ischemic stroke by challenging these mice with transient middle cerebral artery occlusion (MCAO). Under normal condition, GET-1 mice showed no abnormality in brain morphology, cerebrovasculature, absolute cerebral blood flow, blood-brain barrier (BBB) integrity, and mean arterial blood pressure. Yet, GET-1 mice subjected to transient MCAO showed more severe neurologic deficits and increased infarct, which were partially normalized by administration of ABT-627 (ET(A) antagonist) 5 mins after MCAO. In addition, GET-1 brains exhibited more Evans blue extravasation and showed decreased endothelial occludin expression after MCAO, correlating with higher brain water content and increased cerebral edema. Aquaporin 4 expression was also more pronounced in astrocytic end-feet on blood vessels in GET-1 ipsilateral brains. Our current data suggest that astrocytic ET-1 has deleterious effects on water homeostasis, cerebral edema and BBB integrity, which contribute to more severe ischemic brain injury.
Lo
Amy C Y
AC
Institute of Molecular Biology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
Chen
Ann Y S
AY
Hung
Victor K L
VK
Yaw
Lai Ping
LP
Fung
Maggie K L
MK
Ho
Maggie C Y
MC
Tsang
Margaret C S
MC
Chung
Stephen S M
SS
Chung
Sookja K
SK
D000818:Animals; D051401:Aquaporin 4; D020346:Aquaporins / Q000096:biosynthesis*; D001253:Astrocytes / Q000378:metabolism* / Q000648:ultrastructure; D001794:Blood Pressure / Q000502:physiology; D001812:Blood-Brain Barrier / Q000502:physiology; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism*; D004396:Coloring Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D005070:Evans Blue; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009422:Nervous System Diseases / Q000209:etiology; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014867:Water / Q000378:metabolism*
C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D020346:Aquaporins; D004396:Coloring Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D005904:Glial Fibrillary Acidic Protein; D014867:Water; D005070:Evans Blue