Acute ischemic stroke damages the regional brain blood vessel (BV) network. Acute recovery of basic blood flows, which is carried out by the earliest regenerated BVs, are critical to improve clinical outcomes and minimize lethality. Although the late-regenerated BVs form via growing along the meninge-derived ingrown lymphatic vessels (iLVs), mechanisms underlying the early, acute 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, the LV-to-BV transdifferentiation occurs exclusively in the stand-alone iLVs through Notch activation. In the track iLVs adhered by late-regenerated BVs, transdifferentiation never occurs because the BV-expressing EphrinB2a paracellularly activates the iLV-expressing EphB4a to inhibit Notch activation. Suppression of LV-to-BV transdifferentiation blocks acute BV regeneration and becomes lethal. These results demonstrate that acute BV regeneration occurs via lymphatic transdifferentiation, suggesting this process and key regulatory molecules EphrinB2a/EphB4a/Notch as new postischemic therapeutic targets.

急性缺血性中风会损害区域脑血管 (BV) 网络。由最早再生的 BV 进行的基本血流的急性恢复对于改善临床结果和最大限度地降低死亡率至关重要。尽管晚期再生的 BV 是通过沿脑膜衍生的向内生长的淋巴管 (iLV) 生长形成的，但早期急性 BV 再生的机制仍然难以捉摸。使用斑马鱼脑血管损伤模型，我们表明最早再生的 BV 来自淋巴转分化，这是脊椎动物中迄今为止未被重视的过程。从机制上讲，LV 到 BV 的转分化仅发生在独立的 iLV 中，通过 Notch 激活。在后期再生 BV 附着的轨道 iLV 中，转分化从未发生，因为表达 BV 的 EphrinB2a 细胞旁激活表达 iLV 的 EphB4a 以抑制 Notch 激活。LV-to-BV 转分化的抑制会阻止急性 BV 再生并变得致命。这些结果表明急性 BV 再生通过淋巴转分化发生，表明该过程和关键调节分子 EphrinB2a/EphB4a/Notch 是新的缺血后治疗靶点。