Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation.
Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation.
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DOI：
10.1007/s10456-021-09781-x
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发表时间：
2021-08
期刊：
影响因子：
9.8
通讯作者：
Margadant C
中科院分区：
文献类型：
--
作者：
Amado-Azevedo J;van Stalborch AD;Valent ET;Nawaz K;van Bezu J;Eringa EC;Hoevenaars FPM;De Cuyper IM;Hordijk PL;van Hinsbergh VWM;van Nieuw Amerongen GP;Aman J;Margadant C
内皮屏障破坏和血管渗漏在脓毒症和急性呼吸窘迫综合征等炎症性疾病期间会导致器官功能障碍和死亡。我们确定激酶 Arg/Abl2 是内皮屏障破坏的介质，但 Arg 在内皮单层调节中的作用及其体内相关性仍知之甚少。在这里，我们发现内皮细胞中精氨酸的消耗会导致 RhoA 和 Rac1 的激活，增加细胞的铺展和伸长，整合素依赖性细胞基质粘附到细胞周围的重新分布，并改善与细胞外基质的粘附。我们进一步表明，在炎症过程中，精氨酸在暴露于屏障破坏剂的小鼠肺部和脓毒症患者的肺微血管中的内皮细胞中被激活。重要的是，精氨酸耗尽的内皮细胞对屏障破坏剂不太敏感。尽管形成了F-肌动蛋白应力纤维和肌球蛋白轻链磷酸化，但精氨酸耗尽通过减少细胞-基质粘附的分解和细胞回缩来减少粘附连接破坏和细胞间间隙形成。在体内，在存在正常免疫反应的情况下，精氨酸的基因缺失减少了皮肤和肺部的血管渗漏。总之，我们的数据表明，Arg 是内皮屏障完整性的核心和非冗余调节剂，它通过以 Rho GTPase 依赖性方式增加粘附连接和细胞基质粘附的动态，有助于细胞回缩和间隙形成。 Arg 的治疗性抑制可为治疗以血管渗漏为特征的多种临床病症提供合适的策略。在线版本包含可在 10.1007/s10456-021-09781-x 获取的补充材料。
Endothelial barrier disruption and vascular leak importantly contribute to organ dysfunction and mortality during inflammatory conditions like sepsis and acute respiratory distress syndrome. We identified the kinase Arg/Abl2 as a mediator of endothelial barrier disruption, but the role of Arg in endothelial monolayer regulation and its relevance in vivo remain poorly understood. Here we show that depletion of Arg in endothelial cells results in the activation of both RhoA and Rac1, increased cell spreading and elongation, redistribution of integrin-dependent cell-matrix adhesions to the cell periphery, and improved adhesion to the extracellular matrix. We further show that Arg is activated in the endothelium during inflammation, both in murine lungs exposed to barrier-disruptive agents, and in pulmonary microvessels of septic patients. Importantly, Arg-depleted endothelial cells were less sensitive to barrier-disruptive agents. Despite the formation of F-actin stress fibers and myosin light chain phosphorylation, Arg depletion diminished adherens junction disruption and intercellular gap formation, by reducing the disassembly of cell-matrix adhesions and cell retraction. In vivo, genetic deletion of Arg diminished vascular leak in the skin and lungs, in the presence of a normal immune response. Together, our data indicate that Arg is a central and non-redundant regulator of endothelial barrier integrity, which contributes to cell retraction and gap formation by increasing the dynamics of adherens junctions and cell-matrix adhesions in a Rho GTPase-dependent fashion. Therapeutic inhibition of Arg may provide a suitable strategy for the treatment of a variety of clinical conditions characterized by vascular leak. The online version contains supplementary material available at 10.1007/s10456-021-09781-x.
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DOI：
10.1161/atvbaha.118.311705
发表时间：
2018-11
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Al-Yafeai Z;Yurdagul A Jr;Peretik JM;Alfaidi M;Murphy PA;Orr AW
通讯作者：
Orr AW
影响因子：
16.6
作者：
Jonker CTH;Galmes R;Veenendaal T;Ten Brink C;van der Welle REN;Liv N;de Rooij J;Peden AA;van der Sluijs P;Margadant C;Klumperman J
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Klumperman J
影响因子：
4
作者：
Fong, Lai Yen;Ng, Chin Theng;Ahmad, Zuraini
通讯作者：
Ahmad, Zuraini
DOI：
10.1164/rccm.201905-1011cp
发表时间：
2019-12-15
影响因子：
24.7
作者：
Filewod, Niall C.;Lee, Warren L.
通讯作者：
Lee, Warren L.
影响因子：
16.6
作者：
Heemskerk N;Schimmel L;Oort C;van Rijssel J;Yin T;Ma B;van Unen J;Pitter B;Huveneers S;Goedhart J;Wu Y;Montanez E;Woodfin A;van Buul JD
通讯作者：
van Buul JD