Normalization of non-canonical Wnt signalings does not compromise blood-brain barrier protection conferred by upregulating endothelial Wnt/β-catenin signaling following ischemic stroke.
Normalization of non-canonical Wnt signalings does not compromise blood-brain barrier protection conferred by upregulating endothelial Wnt/β-catenin signaling following ischemic stroke.
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非经典 Wnt 信号转导的正常化不会损害缺血性中风后上调内皮 Wnt/β-连环蛋白信号转导所赋予的血脑屏障保护。
DOI：
10.1111/cns.13661
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发表时间：
2021-05-31
影响因子：
5.5
通讯作者：
Chang J
中科院分区：
文献类型：
--
作者：
Ji YB;Wang TX;Gao Q;Huang XW;Chang J
内皮细胞经典信号（Wnt/β-catenin）和非经典信号（Wnt/PCP和Wnt/Ca 2+）促进血脑屏障（BBB）发育并相互拮抗。然而，缺血性卒中对内皮细胞经典和非经典Wnt信号传导的影响尚不清楚。此外，尚未研究非经典Wnt信号传导如何受到内皮Wnt/β-连环蛋白信号传导上调的影响，并随后影响缺血性卒中后的BBB功能。首先，我们确定了Wnt信号传导标志物的水平，包括TCF/LEF 1转录活性、Axin 2 mRNA、磷酸化JNKThr 183/Tyr 185和脑内皮细胞（EC）中的NFAT，其中Wnt受体Frizzled（Fzd）4或Fzd 6（脑EC中两种最丰富的Fzd）缺失。接下来，我们观察了缺血/再灌注损伤对脑EC和成年小鼠Wnt信号的影响。最后，我们评估了具有内皮β-catenin激活的小鼠（β-cat小鼠）中缺血性卒中早期非经典Wnt信号传导和BBB损伤的变化。 Fzd 4或Fzd 6缺失抑制了Wnt/β-catenin和Wnt/PCP信号传导，但增强了脑EC中的Wnt/Ca 2+信号传导。在体外和体内缺血/再灌注损伤后，脑EC中的经典和非经典Wnt信号均下调。在β-cat小鼠中上调内皮Wnt/β-catenin信号传导使下调的非经典Wnt信号传导正常化，这不会损害其对缺血性卒中后BBB完整性和内皮紧密连接的保护作用。在缺血性卒中早期，内皮Wnt/β-catenin信号上调诱导的BBB保护可能不受非经典Wnt信号正常化的干扰。在缺血性卒中早期，Wnt/β-catenin信号上调诱导的BBB保护可能不受非经典Wnt信号正常化的干扰。
Endothelial canonical (Wnt/β‐catenin) and non‐canonical Wnt signalings (Wnt/PCP and Wnt/Ca2+) promote blood‐brain barrier (BBB) development and antagonize each other. However, the effects of ischemic stroke on endothelial canonical and non‐canonical Wnt signalings are unclear. Further, how non‐canonical Wnt signalings are influenced by upregulation of endothelial Wnt/β‐catenin signaling and subsequently affect BBB function following ischemic stroke have not been studied. First, we determined the levels of Wnt signaling markers including TCF/LEF1 transcription activity, Axin2 mRNA, phospho‐JNKThr183/Tyr185, and NFAT in brain endothelial cells (ECs) with the deletion of Wnt receptor Frizzled (Fzd)4 or Fzd6, the two most abundant Fzds in brain ECs. Next, we observed the effect of ischemia/reperfusion injury on Wnt signalings in brain ECs and adult mice. Last, we assessed the changes of non‐canonical Wnt signalings and BBB injury in the early stage of ischemic stroke in mice with endothelial β‐catenin activation (β‐cat mice). Fzd4 or Fzd6 deletion dampened both Wnt/β‐catenin and Wnt/PCP signalings but enhanced Wnt/Ca2+ signaling in brain ECs. Both canonical and non‐canonical Wnt signalings in brain ECs were downregulated after ischemia/reperfusion injury in vitro and in vivo. Upregulating endothelial Wnt/β‐catenin signaling in β‐cat mice normalized the downregulated non‐canonical Wnt signalings, which did not compromise its protective effects on BBB integrity and endothelial tight junction following ischemic stroke. The BBB protection induced by upregulation of endothelial Wnt/β‐catenin signaling may be not interfered by the normalization of non‐canonical Wnt signalings in the early stage of ischemic stroke. The BBB protection induced by upregulation of Wnt/β‐catenin signaling may be not interfered by the normalization of non‐canonical Wnt signalings in the early stage of ischemic stroke.
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影响因子：
5.5
作者：
Chen, Wei;Ju, Xing-Zhu;Chen, Jia-Wei
通讯作者：
Chen, Jia-Wei
Wnt/β-catenin信号传导控制血脑屏障的发展。
影响因子：
7.8
作者：
Liebner, Stefan;Corada, Monica;Bangsow, Thorsten;Babbage, Jane;Taddei, Andrea;Czupalla, Cathrin J.;Reis, Marco;Felici, Angelina;Wolburg, Hartwig;Fruttiger, Marcus;Taketo, Makoto M.;von Melchner, Harald;Plate, Karl Heinz;Gerhardt, Holger;Dejana, Elisabetta
通讯作者：
Dejana, Elisabetta
影响因子：
5.5
作者：
Gao M;Lu W;Shu Y;Yang Z;Sun S;Xu J;Gan S;Zhu S;Qiu G;Zhuo F;Xu S;Wang Y;Chen J;Wu X;Huang J
通讯作者：
Huang J
影响因子：
82.9
作者：
Chang J;Mancuso MR;Maier C;Liang X;Yuki K;Yang L;Kwong JW;Wang J;Rao V;Vallon M;Kosinski C;Zhang JJ;Mah AT;Xu L;Li L;Gholamin S;Reyes TF;Li R;Kuhnert F;Han X;Yuan J;Chiou SH;Brettman AD;Daly L;Corney DC;Cheshier SH;Shortliffe LD;Wu X;Snyder M;Chan P;Giffard RG;Chang HY;Andreasson K;Kuo CJ
通讯作者：
Kuo CJ
影响因子：
6.3
作者：
Manaenko, Anatol;Yang, Peng;Tang, Jiping
通讯作者：
Tang, Jiping