2. Academic Validation
  3. Meningeal lymphatic dysfunction drives cognitive impairment after experimental subarachnoid hemorrhage

Meningeal lymphatic dysfunction drives cognitive impairment after experimental subarachnoid hemorrhage

  • Neurotherapeutics. 2025 Dec 12:e00819. doi: 10.1016/j.neurot.2025.e00819.
Yichen Cai 1,  Yanxin Shao 2,  Hui Yuan 2,  Lina Feng 3,  Jing Wang 2,  Mingfeng Yang 2,  Cong Li 4,  Baoliang Sun 5,  Leilei Mao 6
Affiliations

Affiliations

  • 1 The Second Affiliated Hospital, College of Medical Information and Artificial Intelligence, Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China; Department of Neurology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang 161002, China.
  • 2 The Second Affiliated Hospital, College of Medical Information and Artificial Intelligence, Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China.
  • 3 Departmentof Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China.
  • 4 The Second Affiliated Hospital, College of Medical Information and Artificial Intelligence, Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China. Electronic address: [email protected].
  • 5 The Second Affiliated Hospital, College of Medical Information and Artificial Intelligence, Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China. Electronic address: [email protected].
  • 6 The Second Affiliated Hospital, College of Medical Information and Artificial Intelligence, Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China; State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, 20032, China. Electronic address: [email protected].
PMID: 41390288 DOI: 10.1016/j.neurot.2025.e00819
Abstract

More than half of subarachnoid hemorrhage (SAH) survivors develop delayed cognitive dysfunction, but the underlying mechanisms remain elusive. This study investigated the role of meningeal lymphatic vessels (mLVs) in this complication by examining their structural integrity, drainage capacity, and association with cognitive deficits post-SAH. In adult male C57BL/6J mice in which SAH was induced by intracisternal injection of autologous blood, spatial learning and memory, and hippocampal CA1 neuronal activity were impaired as early as 1 month post-surgery, with a marked exacerbation of these deficits at 2 months. SAH induced mLV fragmentation and atrophy, subsequent cerebrospinal and interstitial fluid drainage impairment, metabolite accumulation, and ultimately delayed cognitive dysfunction. Notably, lymphatic vessel ablation exacerbated these pathologies. In vitro experiments confirmed that vascular endothelial growth factor C (VEGF-C) reduced oxyhemoglobin-induced lymphatic endothelial cell Apoptosis. Furthermore, in vivo studies demonstrated that VEGF-C therapy inhibited Amyloid-β (Aβ) deposition in the hippocampal CA1 region and ameliorated cognitive dysfunction. Additional studies revealed that VEGF-C's protective effect on mLVs may be mediated via PI3K-AKT pathway activation. Collectively, these findings indicate that disrupted mLV integrity and drainage contribute to post-SAH cognitive impairment. Activation of VEGF-C-mediated PI3K-AKT signaling may preserve mLV function and represent a potential therapeutic strategy for preventing delayed cognitive impairment after SAH.

Keywords

Cognitive impairment; Meningeal lymphatic vessels; PI3K-AKT pathway; Subarachnoid hemorrhage; VEGF-C.

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