Dual role of vascular endothelial growth factor-C in post-stroke recovery
Yun Hwa Choi, Martin Hsu, Collin Laaker, Jenna Port, Kristof Kovacs, Melinda Herbáth, Heeyoon Yang, Peter Cismaru, Alexis M. Johnson, Bailey Spellman, Kelsey Wigand, Mátyás Sándor, Zsuzsanna Fábry
Abstract
Cerebrospinal fluid (CSF), antigens, and antigen-presenting cells drain from the central nervous system (CNS) into lymphatic vessels near the cribriform plate and dura, yet the role of these vessels during stroke is unclear. Using a mouse model of ischemic stroke, transient middle cerebral artery occlusion (tMCAO), we demonstrate stroke-induced lymphangiogenesis near the cribriform plate, peaking at day 7 and regressing by day 14. Lymphangiogenesis is restricted to the cribriform plate and deep cervical lymph nodes and is regulated by VEGF-C/VEGFR-3 signaling. The use of a VEGFR-3 inhibitor prevented lymphangiogenesis and led to improved stroke outcomes at earlier time points, with no effects at later time points. VEGF-C delivery after tMCAO did not further increase post-stroke lymphangiogenesis, but instead induced larger brain infarcts. Our data support the damaging role of VEGF-C acutely and a pro-angiogenic role chronically. This nuanced understanding of VEGFR-3 and VEGF-C in stroke pathology advises caution regarding therapeutic VEGF-C use in stroke.