title: Hypoxia Response Element-Regulated MMP-9 Promotes Neurological Recovery via Glial Scar Degradation and Angiogenesis in Delayed Stroke.
abstract: Matrix metalloproteinase 9 (MMP-9) plays a beneficial role in the delayed phase of middle cerebral artery occlusion (MCAO). However, the mechanism is obscure. Here, we constructed hypoxia response element (HRE)-regulated MMP-9 to explore its effect on glial scars and neurogenesis in delayed ischemic stroke. Adult male Institute of Cancer Research (ICR) mice underwent MCAO and received a stereotactic injection of lentivirus carrying HRE-MMP-9 or normal saline (NS)/lentivirus-GFP 7 days after ischemia. We found that HRE-MMP-9 improved neurological outcomes, reduced ischemia-induced brain atrophy, and degraded glial scars (p < 0.05). Furthermore, HRE-MMP-9 increased the number of microvessels in the peri-infarct area (p < 0.001), which may have been due to the accumulation of endogenous endothelial progenitor cells (EPCs) in the peri-infarct area after glial scar degradation. Finally, HRE-MMP-9 increased the number of bromodeoxyuridine-positive (BrdU+)/NeuN+cells and the expression of PSD-95 in the peri-infarct area (p < 0.01). These changes could be blocked by vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor SU5416 and MMP-9 inhibitor 2-[[(4-phenoxyphenyl)sulfonyl]methyl]-thiirane (SB-3CT). Our results provided a novel mechanism by which glial scar degradation and vascular endothelial growth factor (VEGF)/VEGFR2-dependent angiogenesis may be key procedures for neurological recovery in delayed ischemic stroke after HRE-MMP-9 treatment. Therefore, HRE-MMP-9 overexpression in the delayed ischemic brain is a promising approach for neurological recovery.
authors.affiliation: Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Neurology, Yangzhou University Affiliated Hospital, Yangzhou No. 1 People's Hospital, Jiangsu Province, 225000, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Cai
authors.affiliation: Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Neuroscience and Neuroengineering Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Neuroscience and Neuroengineering Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Neuroscience and Neuroengineering Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Mu
authors.affiliation: Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Neuroscience and Neuroengineering Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Neuroscience and Neuroengineering Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.affiliation: Neuroscience and Neuroengineering Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Yongting
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Neuroscience and Neuroengineering Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China. Electronic address: gyyang0626@gmail.com.
authors.forename: Guo-Yuan
authors.initials: GY
authors.lastname: Yang
authors.affiliation: Neuroscience and Neuroengineering Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China. Electronic address: zhangzhij@gmail.com.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001284:Atrophy; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000235:genetics*; D055495:Neurogenesis / Q000235:genetics; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D020218:Response Elements; D020521:Stroke / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000071939:Stroke Rehabilitation
chemical_list: D020780:Matrix Metalloproteinase 9
keywords: HRE-MMP-9; angiogenesis; glial scar; neurogenesis; stroke