Urgent Brain Vascular Regeneration Occurs via Lymphatic Transdifferentiation

Acute ischemic stroke damages regional brain blood vessel (BV) network. Urgent recovery of basic blood flows, which represents the earliest regenerated BVs, are critical to improve clinical outcomes and minimize lethality. Although the late-regenerated BVs have been implicated to form via growing along the meninge-derived lymphatic vessels (iLVs), mechanisms underlying the early, urgent BV regeneration remain elusive. Using zebrafish cerebrovascular injury models, we show that the earliest regenerated BVs come from lymphatic transdifferentiation, a hitherto unappreciated process in vertebrates. Mechanistically, LV-to-BV transdifferentiation occurs exclusively in the stand-alone iLVs through Notch activation. In the track iLVs adhered by nascent BVs, transdifferentiation never occurs because the BV-expressing EphrineB2a paracellularly activates the iLV-expressing EphB4a to inhibit Notch activation. Suppression of LV-to-BV transdifferentiation blocks early BV regeneration and becomes lethal. These results demonstrate that urgent BV regeneration occurs via lymphatic transdifferentiation, suggesting this process and key regulatory molecules EphrinB2a/EphB4a/Notch as new post-ischemic therapeutic targets.