3‐HKA Promotes Vascular Remodeling After Stroke by Modulating the Activation of A1/A2 Reactive Astrocytes
Abstract Ischemic stroke is the most common cerebrovascular disease and the leading cause of permanent disability worldwide. Recent studies have shown that stroke development and prognosis are closely related to abnormal tryptophan metabolism. Here, significant downregulation of 3‐hydroxy‐kynurenami...
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Wiley
2025-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202412667 |
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| author | Jun‐Min Chen Guang Shi Lu‐Lu Yu Wei Shan Jing‐Yu Sun An‐Chen Guo Jian‐Ping Wu Tie‐Shan Tang Xiang‐Jian Zhang Qun Wang |
| author_facet | Jun‐Min Chen Guang Shi Lu‐Lu Yu Wei Shan Jing‐Yu Sun An‐Chen Guo Jian‐Ping Wu Tie‐Shan Tang Xiang‐Jian Zhang Qun Wang |
| author_sort | Jun‐Min Chen |
| collection | DOAJ |
| description | Abstract Ischemic stroke is the most common cerebrovascular disease and the leading cause of permanent disability worldwide. Recent studies have shown that stroke development and prognosis are closely related to abnormal tryptophan metabolism. Here, significant downregulation of 3‐hydroxy‐kynurenamine (3‐HKA) in stroke patients and animal models is identified. Supplementation with 3‐HKA improved long‐term neurological recovery, reduced infarct volume, and increased ipsilateral cerebral blood flow after distal middle cerebral artery occlusion (MCAO). 3‐HKA promoted angiogenesis, functional blood vessel formation, and blood‐brain barrier (BBB) repair. Moreover, 3‐HKA inhibited A1‐like (neurotoxic) astrocyte activation but promoted A2‐like (neuroprotective) astrocyte polarization. Proteomic analysis revealed that 3‐HKA inhibited AIM2 inflammasome activation after stroke, and co‐labeling studies indicated that AIM2 expression typically increased in astrocytes at 7 and 14 days after stroke. Consistently, in co‐cultures of primary mouse brain microvascular endothelial cells and astrocytes, 3‐HKA promoted angiogenesis after oxygen‐glucose deprivation (OGD). AIM2 overexpression in astrocytes abrogated 3‐HKA‐driven vascular remodeling in vitro and in vivo, suggesting that 3‐HKA may regulate astrocyte‐mediated vascular remodeling by impeding AIM2 inflammasome activation. In conclusion, 3‐HKA may promote post‐stroke vascular remodeling by regulating A1/A2 astrocyte activation, thereby improving long‐term neurological recovery, suggesting that supplementation with 3‐HKA may be an efficient therapy for stroke. |
| format | Article |
| id | doaj-art-275806d40c3348598451ba26bbc72e86 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-275806d40c3348598451ba26bbc72e862025-08-20T02:24:47ZengWileyAdvanced Science2198-38442025-03-011211n/an/a10.1002/advs.2024126673‐HKA Promotes Vascular Remodeling After Stroke by Modulating the Activation of A1/A2 Reactive AstrocytesJun‐Min Chen0Guang Shi1Lu‐Lu Yu2Wei Shan3Jing‐Yu Sun4An‐Chen Guo5Jian‐Ping Wu6Tie‐Shan Tang7Xiang‐Jian Zhang8Qun Wang9Department of Neurology Beijing Tiantan Hospital Capital Medical University Beijing 100070 ChinaDepartment of Neurology Second Hospital of Hebei Medical University Shijiazhuang 050000 ChinaDepartment of Neurology Beijing Tiantan Hospital Capital Medical University Beijing 100070 ChinaDepartment of Neurology Beijing Tiantan Hospital Capital Medical University Beijing 100070 ChinaKey Laboratory of Organ Regeneration and Reconstruction State Key Laboratory of Membrane Biology Institute of Zoology Chinese Academy of Sciences Beijing 100101 ChinaChina National Clinical Research Center for Neurological Diseases Beijing 100070 ChinaDepartment of Neurology Beijing Tiantan Hospital Capital Medical University Beijing 100070 ChinaKey Laboratory of Organ Regeneration and Reconstruction State Key Laboratory of Membrane Biology Institute of Zoology Chinese Academy of Sciences Beijing 100101 ChinaDepartment of Neurology Second Hospital of Hebei Medical University Shijiazhuang 050000 ChinaDepartment of Neurology Beijing Tiantan Hospital Capital Medical University Beijing 100070 ChinaAbstract Ischemic stroke is the most common cerebrovascular disease and the leading cause of permanent disability worldwide. Recent studies have shown that stroke development and prognosis are closely related to abnormal tryptophan metabolism. Here, significant downregulation of 3‐hydroxy‐kynurenamine (3‐HKA) in stroke patients and animal models is identified. Supplementation with 3‐HKA improved long‐term neurological recovery, reduced infarct volume, and increased ipsilateral cerebral blood flow after distal middle cerebral artery occlusion (MCAO). 3‐HKA promoted angiogenesis, functional blood vessel formation, and blood‐brain barrier (BBB) repair. Moreover, 3‐HKA inhibited A1‐like (neurotoxic) astrocyte activation but promoted A2‐like (neuroprotective) astrocyte polarization. Proteomic analysis revealed that 3‐HKA inhibited AIM2 inflammasome activation after stroke, and co‐labeling studies indicated that AIM2 expression typically increased in astrocytes at 7 and 14 days after stroke. Consistently, in co‐cultures of primary mouse brain microvascular endothelial cells and astrocytes, 3‐HKA promoted angiogenesis after oxygen‐glucose deprivation (OGD). AIM2 overexpression in astrocytes abrogated 3‐HKA‐driven vascular remodeling in vitro and in vivo, suggesting that 3‐HKA may regulate astrocyte‐mediated vascular remodeling by impeding AIM2 inflammasome activation. In conclusion, 3‐HKA may promote post‐stroke vascular remodeling by regulating A1/A2 astrocyte activation, thereby improving long‐term neurological recovery, suggesting that supplementation with 3‐HKA may be an efficient therapy for stroke.https://doi.org/10.1002/advs.2024126673‐hydroxy‐kynurenamineAIM2 inflammasomesischemic strokereactive astrocytesvascular remodeling |
| spellingShingle | Jun‐Min Chen Guang Shi Lu‐Lu Yu Wei Shan Jing‐Yu Sun An‐Chen Guo Jian‐Ping Wu Tie‐Shan Tang Xiang‐Jian Zhang Qun Wang 3‐HKA Promotes Vascular Remodeling After Stroke by Modulating the Activation of A1/A2 Reactive Astrocytes Advanced Science 3‐hydroxy‐kynurenamine AIM2 inflammasomes ischemic stroke reactive astrocytes vascular remodeling |
| title | 3‐HKA Promotes Vascular Remodeling After Stroke by Modulating the Activation of A1/A2 Reactive Astrocytes |
| title_full | 3‐HKA Promotes Vascular Remodeling After Stroke by Modulating the Activation of A1/A2 Reactive Astrocytes |
| title_fullStr | 3‐HKA Promotes Vascular Remodeling After Stroke by Modulating the Activation of A1/A2 Reactive Astrocytes |
| title_full_unstemmed | 3‐HKA Promotes Vascular Remodeling After Stroke by Modulating the Activation of A1/A2 Reactive Astrocytes |
| title_short | 3‐HKA Promotes Vascular Remodeling After Stroke by Modulating the Activation of A1/A2 Reactive Astrocytes |
| title_sort | 3 hka promotes vascular remodeling after stroke by modulating the activation of a1 a2 reactive astrocytes |
| topic | 3‐hydroxy‐kynurenamine AIM2 inflammasomes ischemic stroke reactive astrocytes vascular remodeling |
| url | https://doi.org/10.1002/advs.202412667 |
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