Lung endothelial barrier disruption in Lyl1-deficient mice
Lung endothelial barrier disruption in Lyl1-deficient mice
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DOI：
10.1152/ajplung.00200.2013
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发表时间：
2014-04-01
影响因子：
4.9
通讯作者：
Pinet, Valerie
中科院分区：
文献类型：
--
作者：
Pirot, Nelly;Delpech, Helene;Pinet, Valerie
新生血管的成熟是一个多步骤的现象，在此过程中建立了功能性内皮屏障。血管完整性的破坏是许多生理和病理过程中的重要特征。我们以前报道过，淋巴母细胞白血病衍生序列1（LYL1）是出生后血管生成的晚期阶段所需的，以限制新血管的形成，特别是通过调节小GTdR Rap1的活性。在这项研究中，我们表明，LYL1也需要在成熟的内皮屏障在成年小鼠的肺形成。具体而言，LYL1敲低人内皮细胞下调ARHGAP 21和ARHGAP 24的表达，ARHGAP 21和ARHGAP 24编码两种Rho GTP酶激活蛋白，这与RhoA活性增加和肌动蛋白细胞骨架重组成应力纤维相关。重要的是，在Lyl1缺陷小鼠的肺中，血管内皮（VE）-钙粘蛋白和p120-连环蛋白都很难招募到内皮粘附连接，表明细胞-细胞连接缺陷。与此一致，Lyl1-/-小鼠肺实质中伊文思蓝染料外渗、水肿和白细胞浸润高于野生型同窝小鼠，证实Lyl1-/-成年小鼠的肺血管通透性组成性升高。我们的数据表明，LYL1作为一个稳定的信号粘附连接形成的VE-钙粘蛋白和两个GTP酶Rap1和RhoA的上游操作。由于血管通透性增加是急性呼吸窘迫综合征的关键特征和主要机制，因此调节LYL 1活性的分子可能是改变内皮屏障通透性的额外工具。
Maturation of newly formed vessels is a multistep phenomenon during which functional endothelial barriers are established. Disruption of vessel integrity is an important feature in many physiological and pathological processes. We previously reported that lymphoblastic leukemia-derived sequence 1 (LYL1) is required for the late stages of postnatal angiogenesis to limit the formation of new blood vessels, notably by regulating the activity of the small GTPase Rap1. In this study, we show that LYL1 is also required during the formation of the mature endothelial barrier in the lungs of adult mice. Specifically, LYL1 knockdown in human endothelial cells downregulated the expression of ARHGAP21 and ARHGAP24, which encode two Rho GTPase-activating proteins, and this was correlated with increased RhoA activity and reorganization of the actin cytoskeleton into stress fibers. Importantly, in lungs of Lyl1-deficient mice, both vascular endothelial (VE)-cadherin and p120-catenin were poorly recruited to endothelial adherens junctions, indicative of defective cell-cell junctions. Consistent with this, higher Evans blue dye extravasation, edema, and leukocyte infiltration in the lung parenchyma of Lyl1-/- mice than in wild-type littermates confirmed that lung vascular permeability is constitutively elevated in Lyl1-/- adult mice. Our data show that LYL1 acts as a stabilizing signal for adherens junction formation by operating upstream of VE-cadherin and of the two GTPases Rap1 and RhoA. As increased vascular permeability is a key feature and a major mechanism of acute respiratory distress syndrome, molecules that regulate LYL1 activity could represent additional tools to modify the endothelial barrier permeability.