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

2024/03/05 by Lígia Simões Braga Boisserand, Ligia Simoes Braga Boisserand, Luiz Henrique Geraldo +40 · 28 citations
Neuroscience · Medicine · #Cerebrospinal fluid and hydrocephalus #Neuroinflammation and Neurodegeneration Mechanisms #Lymphatic System and Diseases

paper · pdf · doi:10.1084/jem.20221983

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.

Citations

• A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules
• Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation

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