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Wnt 信号通路激活蛋白 R-spondin 对血脑屏障功能和卒中后脑损伤的调节作用和分子机制研究

Investigation of the Regulatory Effect and Molecular Mechanism of a Wnt Signaling Agonistic Protein R-spondinon Blood-Brain Barrier Function and Post-Stroke Brain Injury

  • 摘要: 缺血性脑卒中是一种急性脑血管病, 目前主要的治疗手段是及时进行溶栓或取栓治疗以实现血管再通, 但这一过程会对脑血管造成严重的再灌注损伤, 使血脑屏障的结构和功能受到破坏, 增加脑出血的风险。有研究表明 Wnt/β-catenin 信号通路对血脑屏障的功能起重要调节作用, 但Wnt/β-catenin 信号通路激活蛋白 R-spondin 对血脑屏障和脑损伤的调节作用尚不清楚。该文通过体外制备小鼠 R-spondin-1 重组蛋白, 在小鼠原代脑血管内皮细胞中证实了 R-spondin-1 蛋白协同 Wnt3a蛋白对 Wnt/β-catenin 信号通路的激活作用, 并发现 R-spondin-1 能够显著改变血脑屏障功能相关基因Cldn3 和 Plvap 的表达水平;在小鼠脑缺血再灌注模型中, 静脉注射 R-spondin-1 重组蛋白具有降低脑组织梗死和提高小鼠存活率的趋势, 但与生理盐水对照组相比未达到显著性差异。另外, 该文还报道了 R-spondin 蛋白对血脑屏障功能的分子作用机制, 并初步鉴定了其对卒中后脑损伤的治疗效果和临床应用潜力。

     

    Abstract: Ischemic stroke is an acute cerebrovascular disease. Currently, it is treated mainly by timely thrombolysis or mechanical thrombectomy to achieve vascular recanalization, but this process causes serious reperfusion injury to cerebrovasculature, damages the structure and function of the blood-brain barrier (BBB), and increases the risk of cerebral hemorrhage. Studies have shown that the Wnt/β-catenin signaling pathway plays a critical role in regulating the function of BBB, but whether the R-spondin, an agonistic protein of the Wnt/β-catenin signaling pathway, plays a role in regulation of BBB and cerebral injury is unclear. In this study, using mouse recombinant R-spondin-1 protein prepared in vitro, we determined the activation of Wnt/β-catenin signaling pathway induced by combined treatment of the R-spondin-1 protein and Wnt3a protein in mouse primary cerebrovascular endothelial cells, and found that R-spondin1 significantly changed the expression levels of BBB function related genes Cldn3 and Plvap. In a mouse cerebral ischemia/reperfusion model, intravenous injection of recombinant R-spondin-1 protein was inclined to reduce the cerebral infarction and increase mouse survival but did not reach statistical significance compared to phosphate buffer solution controls. Our study reported the molecular mechanisms of BBB function regulation by R-spondin protein, and preliminarily identified its therapeutic effect on cerebral injury following stroke and potential for clinical use.

     

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