Zinc improves neurological recovery by promoting angiogenesis via the astrocyte-mediated HIF-1α/VEGF signaling pathway in experimental stroke

Background: Ischemic stroke is a serious cerebrovascular disease with high morbidity and disability. Zinc accumulation has been shown to play a vital role in neuronal death and blood-brain barrier damage following ischemia in acute stage. However, almost nothing is known about whether zinc is involved in neurological recovery in ischemic prolonged period. This study investigates whether zinc promotes neurological recovery through astrocytes-induced angiogenesis during ischemic repair phase. Methods: Sprague-Dawley rats were subjected to 2h ischemia/14, 21, and 28days reperfusion by middle cerebral artery occlusion, then administered ZnCl2 (10mg/kg) via intraperitoneally daily from 7 days to tissue collection to observe brain tissue morphology, neurological function recovery by cortical width index, Adhesive removal test, and Forelimb placing test. Angiogenesis, astrocyte activation, and HIF-1 alpha/VEGF pathway were assessed via Western blot, immunofluorescence, and BrdU method in vivo and in vitro. Results: The results showed that zinc significantly alleviated brain atrophy and improved neurological function recovery during the cerebral ischemia repair stage. Zinc significantly increased the protein levels of HIF-1 alpha, VEGF-A, and VEGF-R2 in astrocytes, and promoted angiogenesis during cerebral ischemia repair. In vitro and in vivo studies confirmed that zinc promoted angiogenesis via the astrocyte-mediated HIF-1 alpha/VEGF signaling pathway. Conclusions: Zinc significantly improves neurological function recovery during the cerebral ischemia repair stage, providing new evidence supporting zinc as a potential therapeutic target for ischemic stroke by promoting astrocyte induced angiogenesis.