3-HKA Promotes Vascular Remodeling After Stroke by Modulating the Activation of A1/A2 Reactive Astrocytes

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.