Vascular Pharmacology ( IF 3.5 ) Pub Date : 2021-11-13 , DOI: 10.1016/j.vph.2021.106941
Junyu Mu 1 , Yuhui Que 1 , Xu Li 1 , Feier Zhou 1 , Lai Jin 1 , Shengnan Li 1 , Chao Zhu 1
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Corticotrophin-releasing hormone (CRH) has been demonstrated to participate in vascular inflammation and permeability. Our previous studies have shown that blockade of S1PR2 or CRHR1 inhibited H2O2-induced brain endothelial hyperpermeability via inhibiting cPLA2 phosphorylation. However, little is known about the linkage between S1PRs and CRHR1 in oxidative stress-induced cerebrovascular endothelial hyperpermeability. Here we observed the opposite effects of S1PR2 to those of S1PR3 on the monolayer permeability of bEnd3 cells in response to H2O2. Interestingly, activation of CRHR1 was found to reverse the effects resulting from blockade/silencing of both S1PR2 and S1PR3. In bEnd3 monolayer, blockade/knockdown of S1PR2 reduced the endothelial hyperpermeability and suppressed the tight junction protein ZO-1 redistribution caused by H2O2, along with the inhibition of p38, ERK and cPLA2 phosphorylation. On the contrary, suppression/silencing of S1PR3 further promoted H2O2-induced endothelial hyperpermeability and ZO-1 redistribution, accompanied by the increased phosphorylation of p38, ERK and cPLA2. In the presence of CRH, the effects resulting from the suppression of both S1PR2 and S1PR3 were abolished. Our results elucidate a possible linkage between CRHR1 and S1PR2/S1PR3 involving in the regulation of endothelial monolayer permeability under oxidative stress condition.
中文翻译:

CRH/CRHR1 调节氧化应激下与 S1PR2 和 S1PR3 相关的脑血管内皮细胞通透性
已证明促肾上腺皮质激素释放激素 (CRH) 参与血管炎症和通透性。我们之前的研究表明,阻断 S1PR2 或 CRHR1通过抑制 cPLA 2磷酸化来抑制 H 2 O 2诱导的脑内皮细胞通透性过高。然而,关于 S1PRs 和 CRHR1 在氧化应激诱导的脑血管内皮高通透性中的联系知之甚少。在这里,我们观察到 S1PR2 与 S1PR3 对 bEnd3 细胞响应 H 2 O 2的单层渗透性的相反影响. 有趣的是,发现 CRHR1 的激活可以逆转 S1PR2 和 S1PR3 的阻断/沉默所产生的影响。在 bEnd3 单层中,S1PR2 的阻断/敲低降低了内皮细胞的高通透性并抑制了由 H 2 O 2引起的紧密连接蛋白 ZO-1 再分布,同时抑制了 p38、ERK 和 cPLA 2磷酸化。相反,S1PR3 的抑制/沉默进一步促进了 H 2 O 2诱导的内皮通透性过高和 ZO-1 再分布,伴随着 p38、ERK 和 cPLA 2的磷酸化增加. 在存在 CRH 的情况下,抑制 S1PR2 和 S1PR3 所产生的影响被消除了。我们的结果阐明了 CRHR1 和 S1PR2/S1PR3 之间可能存在的联系,涉及在氧化应激条件下调节内皮单层通透性。