The minor histocompatibility antigen 1 (HMHA1)/ArhGAP45 is a RacGAP and a novel regulator of endothelial integrity
The minor histocompatibility antigen 1 (HMHA1)/ArhGAP45 is a RacGAP and a novel regulator of endothelial integrity
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DOI：
10.1016/j.vph.2017.11.007
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发表时间：
2018-02-01
影响因子：
4
通讯作者：
Hordijk, P. L.
中科院分区：
文献类型：
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作者：
Amado-Azevedo, J.;Reinhard, N. R.;Hordijk, P. L.
内皮细胞排列在血管系统中，并作为守门人控制血浆、大分子和细胞从循环到间质空间的通道。内皮屏障功能障碍可导致不受控制的渗漏或水肿。血管渗漏是一系列疾病的标志，尽管其影响很大，但没有专门的治疗方法可用于预防或减少它。RhoGTP酶是已知的细胞行为的关键调节剂，直接参与内皮屏障的调节。我们最近进行了全面的分析，所有RhoGTP酶和它们的监管基础内皮完整性的影响。除了新的内皮屏障功能的正调节因子外，我们还鉴定了新的负调节因子，其中ArhGAP 45（也称为HMHA 1）是最重要的。我们现在证明ArhGAP 45在内皮细胞中作为Rac-GAP（GTP酶激活蛋白），这解释了其对内皮屏障功能的负面影响。沉默ArhGAP 45不仅促进基础内皮屏障功能，而且增加细胞表面积并诱导3D纤维蛋白基质中的芽形成。我们的数据进一步表明，ArhGAP 45的缺失促进了迁移和剪切应力适应。总之，我们确定ArhGAP 45（HMHA 1）作为一种新的调节剂，这有助于基础内皮完整性的调节微调。
Endothelial cells line the vasculature and act as gatekeepers that control the passage of plasma, macromolecules and cells from the circulation to the interstitial space. Dysfunction of the endothelial barrier can lead to uncontrolled leak or edema. Vascular leakage is a hallmark of a range of diseases and despite its large impact no specialized therapies are available to prevent or reduce it. RhoGTPases are known key regulators of cellular behavior that are directly involved in the regulation of the endothelial barrier. We recently performed a comprehensive analysis of the effect of all RhoGTPases and their regulators on basal endothelial integrity. In addition to novel positive regulators of endothelial barrier function, we also identified novel negative regulators, of which the ArhGAP45 (also known as HMHA1) was the most significant. We now demonstrate that ArhGAP45 acts as a Rac-GAP (GTPase-Activating Protein) in endothelial cells, which explains its negative effect on endothelial barrier function. Silencing ArhGAP45 not only promotes basal endothelial barrier function, but also increases cellular surface area and induces sprout formation in a 3D-fibrin matrix. Our data further shows that loss of ArhGAP45 promotes migration and shear stress adaptation. In conclusion, we identify ArhGAP45 (HMHA1) as a novel regulator, which contributes to the fine-tuning of the regulation of basal endothelial integrity.