VEGF-C prophylaxis favors lymphatic drainage and modulates neuroinflammation in a stroke model.

Meningeal lymphatic vessels (MLVs) promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelial growth factor-C (VEGF-C) regulates MLV development and maintenance and has therapeutic potential for treating neurological disorders. Herein, we investigated the effects of VEGF-C overexpression on brain fluid drainage and ischemic stroke outcomes in mice. Intracerebrospinal administration of an adeno-associated virus expressing mouse full-length VEGF-C (AAV-mVEGF-C) increased CSF drainage to the deep cervical lymph nodes (dCLNs) by enhancing lymphatic growth and upregulated neuroprotective signaling pathways identified by single nuclei RNA sequencing of brain cells. In a mouse model of ischemic stroke, AAV-mVEGF-C pretreatment reduced stroke injury and ameliorated motor performances in the subacute stage, associated with mitigated microglia-mediated inflammation and increased BDNF signaling in brain cells. Neuroprotective effects of VEGF-C were lost upon cauterization of the dCLN afferent lymphatics and not mimicked by acute post-stroke VEGF-C injection. We conclude that VEGF-C prophylaxis promotes multiple vascular, immune, and neural responses that culminate in a protection against neurological damage in acute ischemic stroke. © 2024 Boisserand et al.

Citation

Ligia Simoes Braga Boisserand, Luiz Henrique Geraldo, Jean Bouchart, Marie-Renee El Kamouh, Seyoung Lee, Basavaraju G Sanganahalli, Myriam Spajer, Shenqi Zhang, Sungwoon Lee, Maxime Parent, Yuechuan Xue, Mario Skarica, Xiangyun Yin, Justine Guegan, Kevin Boyé, Felipe Saceanu Leser, Laurent Jacob, Mathilde Poulet, Mingfeng Li, Xiodan Liu, Sofia E Velazquez, Ruchith Singhabahu, Mark E Robinson, Michael H Askenase, Artem Osherov, Nenad Sestan, Jiangbing Zhou, Kari Alitalo, Eric Song, Anne Eichmann, Lauren H Sansing, Helene Benveniste, Fahmeed Hyder, Jean-Leon Thomas. VEGF-C prophylaxis favors lymphatic drainage and modulates neuroinflammation in a stroke model. The Journal of experimental medicine. 2024 Apr 01;221(4)

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PMID: 38442272

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