Novel Cellular and Molecular Regulation of Collateral Remodeling in Ischemic Stroke

摘要 软脑膜侧支循环和重塑最近成为治疗高血压的有力靶点。 中风后的神经恢复性治疗。脑血管闭塞阻止了足够的血液流向神经 组织区域导致神经细胞丢失和严重的感觉运动障碍。发生逆行再灌流 有足够侧支反应的患者，无论是在再通之前或之后，都可以帮助稳定 脑血流量(CBF)和辅助半影区组织保护。然而，细胞和分子 这种侧支壁龛患者不同反应的机制(S)尚不清楚。证据 提示内皮细胞(ECs)排列在侧支血管壁上，主动地对血流的变化做出反应 以下阻碍和帮助协调侧支重塑过程。我们新的临床前发现 展示了一种称为EphR的细胞间接触蛋白及其膜 结合的肾上腺素配体(S)存在于脑侧支内皮细胞上，并在限制其反应中发挥核心作用 在中风后的小鼠大脑中。本申请中概述的研究目标侧重于新的增长 EphR信号对侧支重构和神经功能恢复的抑制机制(S)。欧共体- EphR的特定缺失导致显著的神经保护和CBF的恢复，这反映了 侧枝生长和促动脉生成因子产生的巨大变化。我们假设 EphR信号的激活通过抑制EC介导急性神经组织损伤和功能障碍 卒中后侧支重构过程中的反应。为了测试这一点，我们将使用细胞特异性诱导基因敲除 和骨髓嵌合小鼠。我们还将调查损伤诱导的相关性和机制(S)。 使用功能丧失和功能逆转的微渗透输注方法在神经恢复中的侧支重塑。 这些研究将揭示一种抑制中风侧支反应的新机制，并提供 以此通路为靶点治疗和管理缺血性卒中的治疗支持。

ABSTRACT Leptomeningeal collateral circulation and remodeling has recently emerged as a powerful therapeutic target for neurorestorative therapy following stroke. Cerebral vascular occlusion prevents adequate blood flow to neural tissue regions resulting in neuronal cell loss and severe sensorimotor deficits. Retrograde reperfusion occurring in patients with a sufficient collateral response, either prior to or following recanalization, can help stabilize cerebral blood flow (CBF) and aide in penumbral tissue protection. However, the cellular and molecular mechanism(s) underlying this differential patient response in the collateral niche remains unclear. Evidence suggests that endothelial cells (ECs) lining the collateral vessel wall actively respond to changes in blood flow following obstruction and help orchestrate the collateral remodeling process. Our novel pre-clinical findings demonstrate, cell-to-cell contact proteins called Eph receptor tyrosine kinases (EphR), and their membrane bound ephrin ligand(s), are present on cerebral collateral ECs and play a central role in limiting their response in the murine brain following stroke. The research objectives outlined in this application focus on the novel growth suppressive mechanism(s) of EphR signaling on collateral remodeling and neural functional recovery. EC- specific deletion of EphR results in significant neuroprotection and restoration of CBF which reflects a monumental change in collateral growth and production of pro-arteriogenic factors. We hypothesize that activation of EphR signaling mediates acute neural tissue damage and dysfunction by suppressing the EC response during collateral remodeling after stroke. To test this, we will employ cell-specific inducible knockout and bone marrow chimeric mice. We will also investigate the relevance and mechanism(s) of injury-induced collateral remodeling in neural recovery using loss- and reverse-of-function mini-osmotic infusion approaches. These studies will reveal a novel mechanism suppressing the collateral response to stroke and provide therapeutic support for targeting this pathway for the treatment and management of ischemic stroke.