학술논문
VEGF-C prophylaxis favors lymphatic drainage and modulates neuroinflammation in a stroke model
Document Type
Article
Author
Boisserand, Ligia Simoes Braga; Geraldo, Luiz Henrique; Bouchart, Jean; El Kamouh, Marie-Renee; Lee, Seyoung; Sanganahalli, Basavaraju G.; Spajer, Myriam; Zhang, Shenqi; Lee, Sungwoon; Parent, Maxime; Xue, Yuechuan; Skarica, Mario; Yin, Xiangyun; Guegan, Justine; Boyé, Kevin; Saceanu Leser, Felipe; Jacob, Laurent; Poulet, Mathilde; Li, Mingfeng; Liu, Xiodan; Velazquez, Sofia E.; Singhabahu, Ruchith; Robinson, Mark E.; Askenase, Michael H.; Osherov, Artem; Sestan, Nenad; Zhou, Jiangbing; Alitalo, Kari; Song, Eric; Eichmann, Anne; Sansing, Lauren H.; Benveniste, Helene; Hyder, Fahmeed; Thomas, Jean-Leon
Source
The Journal of Experimental Medicine; April 2024, Vol. 221 Issue: 4 pe20221983-e20221983, 1p
Subject
Language
ISSN
00221007; 15409538
Abstract
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.