Aging Inhibits Emergency Angiogenesis and Exacerbates Neuronal Damage by Downregulating DARS2

Dan Liu,1 Meilin Weng,2 Rui Wang,3 Wenchao Fu,1 Lijuan Zhang,1 Cheng Wang,4 Mingsen Liu,1 Tao Shen,1 Jirui Ren,1 Yinfei Song,1 Jiayu Li,1 Xianzhang Zeng1,5 1Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, The Heilongjiang Key Laboratory of Anesthesia and Intensive Care Research, Harbin Medical University, Harbin, People’s Republic of China; 2Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China; 4Department of Environmental Hygiene, School of Public Health, Harbin Medical University, Harbin, People’s Republic of China; 5Department of Anesthesiology, Chongqing University Affiliated Cancer Hospital, Chongqing, People’s Republic of ChinaCorrespondence: Xianzhang Zeng, Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, The Heilongjiang key Laboratory of Anesthesia and Intensive Care Research, Harbin Medical University, Health Road, Nangang District, Harbin, Heilongjiang, People’s Republic of China, Email [email protected] Meilin Weng, Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China, Email [email protected]: Early vascular regeneration is important for the speedy recovery of neurological function following ischemic stroke. M2-like microglia polarization decreases and vascular regeneration weakens with aging. The function of mitochondrial respiratory chain is dependent on M2-like polarization in microglia. DARS2 gene is a marker for mitochondrial respiratory chain function, but its specific molecular mechanism affecting acute angiogenesis of microglia during ischemic stroke in elderly individuals remains unclear.Methods: A murine model of middle cerebral artery occlusion (MCAO) was used to perform animal behavioral assessments, immunoblotting, tube formation and chick embryo chorioallantoic membrane assays. A D-galactose-induced cellular senescence model was established in BV2 cells.Results: Aging significantly exacerbates acute brain injury 24 hours post-cerebral ischemia-reperfusion, with increased expression of M1-like microglial markers and a concomitant decrease in M2-like microglial markers. Additionally, aging can inhibit DARS2 protein expression, adversely affect angiogenesis and reduce brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor A (VEGFA) expression. In vitro, oxygen-glucose deprivation/reoxygenation and re-glucose (OGD/R) demonstrated that DARS2 gene knockout in young microglia replicates the phenotypic characteristics observed in aged microglia.Conclusion: This study suggests that aging impedes M2-like microglial polarization by downregulating DARS2 expression in microglia, thereby impairing emergency angiogenesis during acute ischemic stroke and exacerbating neuronal damage.Keywords: ischemic stroke, angiogenesis, DARS2, microglia