Bone Morphogenetic Protein-Modulator BMPER Regulates Endothelial Barrier Function
Bone Morphogenetic Protein-Modulator BMPER Regulates Endothelial Barrier Function
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DOI：
10.1007/s10753-016-0490-4
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发表时间：
2017-04-01
期刊：
影响因子：
5.1
通讯作者：
Moser, Martin
中科院分区：
文献类型：
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作者：
Helbing, Thomas;Wiltgen, Gwendoline;Moser, Martin
内皮细胞作为一种选择性屏障，控制血液和组织之间营养物质、激素和白细胞的交换。导致内皮屏障功能障碍的分子机制仍不完全清楚。越来越多的证据表明骨形态发生蛋白（BMP）-调节剂BMPER是内皮生物学的关键调节剂。在此，我们分析了BMPER在控制内皮屏障功能中的影响。为了评估BMPER在小鼠血管屏障功能中的作用，我们测量了伊文思蓝染料从血液到间质肺组织的渗漏。与野生型同胞相比，BMPER+/-小鼠表现出显著更高程度的血管渗漏。根据我们的体内观察，在人脐内皮细胞中基于siRNA的BMPER敲低增加了通过transwell测定中的FITC-葡聚糖通道测量的内皮渗透性。从机制上讲，BMPER敲低降低了VE-钙粘蛋白的表达，VE-钙粘蛋白是内皮粘附连接的关键组分。相反，重组人BMPER蛋白上调VE-钙粘蛋白的蛋白水平，并改善transwell试验中的内皮屏障功能。BMPER敲低对VE-钙粘蛋白表达和内皮通透性的影响由增强的BMP活性诱导。支持这一观点，BMP 4-Smad-Id 1信号的激活降低了VE-钙粘蛋白水平，并在体外损害了内皮屏障功能。在体内，与对照相比，BMP 4处理的C57 BL/6小鼠的肺中伊文思蓝染料积累更高，表明BMP 4增加了血管通透性。高水平的BMPER拮抗BMP 4-Smad 5-Id 1信号传导，并阻止BMP 4诱导的VE-钙粘蛋白下调和内皮渗漏，表明BMPER发挥抗BMP作用并恢复内皮屏障功能。总之，这些数据表明，BMPER调节的BMP通路活性调节VE-钙粘蛋白表达和血管屏障功能。
The endothelium serves as a selective barrier and controls the exchange of nutrients, hormones, and leukocytes between blood and tissues. Molecular mechanisms contributing to the pathogenesis of endothelial barrier dysfunction remain incompletely understood. Accumulating evidence implicates bone morphogenetic protein (BMP)-modulator BMPER as a key regulator in endothelial biology. Herein, we analyze the impact of BMPER in the control of endothelial barrier function. To assess the role of BMPER in vascular barrier function in mice, we measured the leakage of Evans blue dye from blood into interstitial lung tissue. BMPER+/- mice exhibited a significantly higher degree of vascular leak compared with wild-type siblings. In accordance with our in vivo observation, siRNA-based BMPER knockdown in human umbilical endothelial cells increased endothelial permeability measured by FITC-dextran passage in transwell assays. Mechanistically, BMPER knockdown reduced the expression of VE-cadherin, a pivotal component of endothelial adherens junctions. Conversely, recombinant human BMPER protein upregulated VE-cadherin protein levels and improved endothelial barrier function in transwell assays. The effects of BMPER knockdown on VE-cadherin expression and endothelial permeability were induced by enhanced BMP activity. Supporting this notion, activation of BMP4-Smad-Id1 signaling reduced VE-cadherin levels and impaired endothelial barrier function in vitro. In vivo, Evans blue dye accumulation was higher in the lungs of BMP4-treated C57BL/6 mice compared to controls indicating that BMP4 increased vascular permeability. High levels of BMPER antagonized BMP4-Smad5-Id1 signaling and prevented BMP4-induced downregulation of VE-cadherin and endothelial leakage, suggesting that BMPER exerts anti-BMP effects and restores endothelial barrier function. Taken together, this data demonstrates that BMPER-modulated BMP pathway activity regulates VE-cadherin expression and vascular barrier function.