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Theranostics 2024; 14(1):304-323. doi:10.7150/thno.87633 This issue Cite

Research Paper

Inactivation of ERK1/2 signaling mediates dysfunction of basal meningeal lymphatic vessels in experimental subdural hematoma

Jiangyuan Yuan^1,2†, Xuanhui Liu^1,2†, Meng Nie^1,2†, Yupeng Chen^1,2, Mingqi Liu^1,2, Jinhao Huang^1,2, Weiwei Jiang^1,2, Chuang Gao^1,2, Wei Quan^1,2, Zhitao Gong³, Tangtang Xiang^1,2, Xinjie Zhang^1,2, Zhuang Sha^1,2, Chenrui Wu^1,2, Dong Wang^1,2, Shenghui Li^1,2, Jianning Zhang^1,2✉, Rongcai Jiang^1,2,4✉

1. Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China.
2. Tianjin Neurological Institute, Key Laboratory of Post Neuro-injury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin, Tianjin 300052, China.
3. Department of Rehabilitation Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
4. State Key Laboratory of Experimental Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China.
†These authors contributed equally to this work.

✉ Corresponding authors: Jianning Zhang, jianningzhangcom; Rongcai Jiang, jiangrongcaiedu.cn.

Abstract

Rationale: Meningeal lymphatic vessels (MLVs) are essential for the clearance of subdural hematoma (SDH). However, SDH impairs their drainage function, and the pathogenesis remains unclear. Herein, we aimed to understand the pathological mechanisms of MLV dysfunction following SDH and to test whether atorvastatin, an effective drug for SDH clearance, improves meningeal lymphatic drainage (MLD).

Methods: We induced SDH models in rats by injecting autologous blood into the subdural space and evaluated MLD using Gadopentetate D, Evans blue, and CFSE-labeled erythrocytes. Whole-mount immunofluorescence and transmission electron microscopy were utilized to detect the morphology of MLVs. Phosphoproteomics, western blot, flow cytometry, and in vitro experiments were performed to investigate the molecular mechanisms underlying dysfunctional MLVs.

Results: The basal MLVs were detected to have abundant valves and play an important role in draining subdural substances. Following SDH, these basal MLVs exhibited disrupted endothelial junctions and dilated lumen, leading to impaired MLD. Subsequent proteomics analysis of the meninges detected numerous dephosphorylated proteins, primarily enriched in the adherens junction, including significant dephosphorylation of ERK1/2 within the meningeal lymphatic endothelial cells (LECs). Subdural injection of the ERK1/2 kinase inhibitor PD98059 resulted in dilated basal MLVs and impaired MLD, resembling the dysfunctional MLVs observed in SDH. Moreover, inhibiting ERK1/2 signaling severely disrupted intercellular junctions between cultured LECs. Finally, atorvastatin was revealed to protect the structure of basal MLVs and accelerate MLD following SDH. However, these beneficial effects of atorvastatin were abolished when combined with PD98059.

Conclusion: Our findings demonstrate that SDH induces ERK1/2 dephosphorylation in meningeal LECs, leading to disrupted basal MLVs and impaired MLD. Additionally, we reveal a beneficial effect of atorvastatin in improving MLD.

Keywords: subdural hematoma, meningeal lymphatic vessels, meningeal lymphatic drainage, ERK1/2, atorvastatin

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