Astrocytic endothelin-1 overexpression impairs learning and memory ability in ischemic stroke via altered hippocampal neurogenesis and lipid metabolism

Vascular etiology is the second most prevalent cause of cognitive impairment globally. Endothelin-1, which is produced and secreted by endothelial cells and astrocytes, is implicated in the pathogenesis of stroke. However, the way in which changes in astrocytic endothelin-1 lead to poststroke cognitive deficits following transient middle cerebral artery occlusion is not well understood. Here, using mice in which astrocytic endothelin-1 was overexpressed, we found that the selective overexpression of endothelin-1 by astrocytic cells led to ischemic stroke-related dementia (1 hour of ischemia; 7 days, 28 days, or 3 months of reperfusion). We also revealed that astrocytic endothelin-1 overexpression contributed to the role of neural stem cell proliferation but impaired neurogenesis in the dentate gyrus of the hippocampus after middle cerebral artery occlusion. Comprehensive proteome profiles and western blot analysis confirmed that levels of glial fibrillary acidic protein and peroxiredoxin 6, which were differentially expressed in the brain, were significantly increased in mice with astrocytic endothelin-1 overexpression in comparison with wild-type mice 28 days after ischemic stroke. Moreover, the levels of the enriched differentially expressed proteins were closely related to lipid metabolism, as indicated by Kyoto Encyclopedia of Genes and Genomes pathway analysis. Liquid chromatography-mass spectrometry nontargeted metabolite profiling of brain tissues showed that astrocytic endothelin-1 overexpression altered lipid metabolism products such as glycerol phosphatidylcholine, sphingomyelin, and phosphatidic acid. Overall, this study demonstrates that astrocytic endothelin-1 overexpression can impair hippocampal neurogenesis and that it is correlated with lipid metabolism in poststroke cognitive dysfunction.