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

• DOI: 10.1084/jem.20221983
• Publication Date: 2024-03-06T17:40:12Z
• Authors: Ligia Simoes Brag...; Luiz Henrique Ger...; Jean Bouchart; Marie-Renee El Ka...; Seyoung Lee; Basavaraju G. San...; 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; Xiaodan 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
• Keywords: Biomedicine; 0303 health sciences; 03 medical and health sciences; Neuroinflammation; Cardiovascular biology; Article; Neuroscience

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.