Cerebrovascular damages induce lymphatic invasion into brain parenchyma to guide vascular regeneration

Damage to regional brain vasculature and neuronal tissues occurs during acute cerebrovascular diseases, such as ischemic stroke. Promoting vascular regeneration is the most promising therapeutic approach. To understand cellular and molecular mechanisms underlying brain vascular regeneration, we developed two zebrafish cerebrovascular injury models using genetic ablation and photochemical thrombosis. Although brain parenchyma is physiologically devoid of lymphatic vasculature, we found that cerebrovascular injuries induce rapid ingrowth of meningeal lymphatics into the injured parenchyma. The ingrown lymphatics on one hand become lumenized to drain interstitial fluid to resolve brain oedema, on the other hand act as "growing tracks" for nascent blood vessels and produce Vegfa to promote the neoangiogenesis. The ingrown lymphatic vessels undergo apoptosis and clearance after cerebrovascular regeneration. This study reveals a pathological function of meningeal lymphatics, through previously unexpected ingrowth into brain parenchyma and a newly identified lymphatic function as vascular "growing tracks".