Department of Cell Biology and Physiology, McAllister Heart Institute, Curriculum in Neurobiology, University of North Carolina at Chapel Hill, NC, USA.
J Cereb Blood Flow Metab. 2020 Sep;40(9):1806-1822. doi: 10.1177/0271678X20924107. Epub 2020 May 19.
Pial collaterals provide protection in stroke. Evidence suggests their formation late during gestation (collaterogenesis) is driven by reduced oxygen levels in the cerebral watersheds. The purpose of this study was to determine if collaterogenesis can be re-activated in the adult to induce formation of additional collaterals ("neo-collateral formation", NCF). Mice were gradually acclimated to reduced inspired oxygen (FIO) and maintained at 12, 10, 8.5 or 7% for two-to-eight weeks. Hypoxemia induced "dose"-dependent NCF and remodeling of native collaterals, and decreased infarct volume after permanent MCA occlusion. In contrast, no formation occurred of addition collateral-like intra-tree anastomoses, PComs, or branches within the MCA tree. Hypoxic NCF, remodeling and infarct protection were durable, i.e. retained for at least six weeks after return to normoxia. Hypoxia increased expression of and . Neo-collateral formation was abolished in mice lacking a novel gene involved in VEGFA→Flk1 signaling and required for formation of collaterals during development, and inhibited by knockdown of , and . -dependent NCF was also induced by permanent MCA occlusion. This is the first report that hypoxia induces new pial collaterals to form. Hypoxia- and occlusion-induced neo-collateral formation provide models to study collaterogenesis in the adult.
软脑膜侧支为中风提供保护。有证据表明，它们在脑分水岭的氧水平降低时形成（侧支生成）。本研究的目的是确定是否可以在成人中重新激活侧支生成以诱导额外侧支的形成（“新侧支形成”，NCF）。小鼠逐渐适应低氧吸入（FIO），并在 12、10、8.5 或 7%的氧浓度下维持 2-8 周。低氧诱导了“剂量”依赖性的 NCF 和天然侧支的重塑，并减少了永久性 MCA 闭塞后的梗死体积。相比之下，MCA 树内没有形成额外的侧支样吻合支、PCoMs 或分支。缺氧 NCF、重塑和梗死保护是持久的，即在返回常氧后至少保留 6 周。低氧增加了 和 的表达。在缺乏一种新型基因（VEGFA→Flk1 信号通路的新基因）的小鼠中，新的侧支形成被废除，该基因在发育过程中形成侧支是必需的，而通过 、 和 的敲低也抑制了 NCF 的形成。永久性 MCA 闭塞也诱导了 -依赖性 NCF。这是首次报道缺氧可诱导新的软脑膜侧支形成。缺氧和闭塞诱导的新侧支形成提供了研究成人侧支生成的模型。
