2. Academic Validation
  3. Astrocytic HIF-1α/VEGF induces endothelial PI3K/Akt activation to accelerate post-ischemic angiogenesis upon LCN2 inhibition

Astrocytic HIF-1α/VEGF induces endothelial PI3K/Akt activation to accelerate post-ischemic angiogenesis upon LCN2 inhibition

  • Neurochem Int. 2025 Oct 14:191:106078. doi: 10.1016/j.neuint.2025.106078.
Ning Tian 1,  Xiaoxia Li 1,  Yanlin Jiang 2,  Jungang Deng 2,  Hao Wang 1,  Bing Guo 1,  Meiling Chen 3,  Rujia Liao 4
Affiliations

Affiliations

  • 1 Laboratory of Neuroscience, The First Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guangxi Zhuang Autonomous Region, Guilin, 541000, PR China; Department of Neurology, The First Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guangxi Zhuang Autonomous Region, Guilin, 541000, PR China.
  • 2 Department of Pharmacology, The First Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guangxi Zhuang Autonomous Region, Guilin, 541000, PR China.
  • 3 Department of Neurology, The First Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guangxi Zhuang Autonomous Region, Guilin, 541000, PR China.
  • 4 Laboratory of Neuroscience, The First Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guangxi Zhuang Autonomous Region, Guilin, 541000, PR China; Department of Neurology, The First Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guangxi Zhuang Autonomous Region, Guilin, 541000, PR China. Electronic address: liaorujia@hotmail.com.
PMID: 41101646 DOI: 10.1016/j.neuint.2025.106078
Abstract

Therapeutic angiogenesis represents a pivotal yet underexplored avenue for functional recovery following cerebral ischemia. Although lipocalin-2 (LCN2) participates in neuropathological processes, its cell-type-specific regulation of post-ischemic vascular remodeling remains unknown. Here, we demonstrate that CRISPR/Cas9-mediated C8D1A astrocyte-like cells-specific LCN2 knockout significantly enhances vascular network formation in endothelial co-cultures under oxygen-glucose deprivation/reperfusion (OGD/R). Clinically, elevated LCN2 (GDS4521 dataset) correlates with poor stroke prognosis. Functional analyses revealed that AAV-shRNA-mediated LCN2 knockdown in photothrombotic stroke mice reduced infarct volume, attenuated peri-infarct neuronal loss, increased peri-infarct vascular density, and improved neurobehavioral outcomes at 7 days post-ischemia. Mechanistically, transcriptomic profiling identified hypoxia-inducible factor 1α (HIF-1α) as the master regulator of ischemia-induced angiogenesis. Molecular docking confirmed LCN2-HIF1α interaction. Furthermore, LCN2 ablation unleashes a HIF-1α/VEGF signaling cascade in C8D1A astrocyte-like cells, which activates endothelial phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) via paracrine mechanisms to drive functional revascularization. These findings not only redefine ischemic pathophysiology but also pioneers LCN2 inhibition as a translational strategy to overcome the limitations of current pro-angiogenic therapies in cerebrovascular disease.

Keywords

Angiogenesis; Astrocyte; Cerebral ischemia; Endothelial; Lipocalin-2; Neuroprotection.

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