Endothelial to Mesenchymal Transition Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension
Endothelial to Mesenchymal Transition Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension
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DOI：
10.1016/j.ajpath.2015.03.019
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发表时间：
2015-07-01
影响因子：
6
通讯作者：
Holmes, Alan M.
中科院分区：
文献类型：
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作者：
Good, Robert B.;Gilbane, Adrian J.;Holmes, Alan M.
肺动脉高压(PAH)是以肺内皮细胞功能障碍和血管重构为特征的进展性疾病。正常情况下，内皮细胞形成一个完整的细胞屏障来调节血管的动态平衡。在胚胎发育过程中，内皮细胞表现出良好的可塑性，通过内皮细胞向间充质细胞的转化(EndoMT)促进心脏发育。我们在体内检测了EndoMT在肺血管中的存在，以及在体外EndoMT对肺动脉内皮细胞(PAECs)的功能影响。对系统性硬化性PAH患者和低氧/SU5416小鼠模型的组织学评估发现，高达5%的肺血管内皮细胞存在von Willebrand因子/α-平滑肌肌动蛋白阳性。炎性细胞因子IL-1β、肿瘤坏死因子α和转化生长因子β诱导的血管内皮细胞内MT导致肌动蛋白细胞骨架重组和间质形态的发展。诱导内皮细胞表达间质标志物，包括I型胶原和α-平滑肌肌动蛋白，减少内皮细胞和连接蛋白，包括von Willebrand因子、CD31、occludin和血管内皮-钙粘素。诱导的EndoMT单层不能形成可行的生物屏障，并在与血管内皮细胞共培养时导致渗漏。与PAEC相比，诱导的EndoMT细胞分泌明显升高的促炎细胞因子，包括IL-6、IL-8和肿瘤坏死因子α，并支持更高的免疫跨内皮迁移。提示内源性MT可能参与了PAH的发生发展。
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by lung endothelial cell dysfunction and vascular remodeling. Normally, the endothelium forms an integral cellular barrier to regulate vascular homeostasis. During embryogenesis endothelial cells exhibit substantial plasticity that contribute to cardiac development by undergoing endothelial-to-mesenchymal transition (EndoMT). We determined the presence of EndoMT in the pulmonary vasculature in vivo and the functional effects on pulmonary artery endothelial cells (PAECs) undergoing EndoMT in vitro. Histologic assessment of patients with systemic sclerosis-associated PAH and the hypoxia/SU5416 mouse model identified the presence von Willebrand factor/alpha-smooth muscle actin-positive endothelial cells in up to 5% of pulmonary vessels. Induced EndoMT in PAECs by inflammatory cytokines IL-1 beta, tumor necrosis factor alpha, and transforming growth factor beta led to actin cytoskeleton reorganization and the development of a mesenchymal morphology. Induced EndoMT cells exhibited up-regulation of mesenchymal markers, including collagen type I and alpha-smooth muscle actin, and a reduction in endothelial cell and junctional proteins, including von Willebrand factor, CD31, occludin, and vascular endothelial-cadherin. Induced EndoMT monolayers failed to form viable biological barriers and induced enhanced leak in co-culture with PAECs. Induced EndoMT cells secreted significantly elevated proinflammatory cytokines, including IL-6, IL-8, and tumor necrosis factor alpha, and supported higher immune transendothelial migration compared with PAECs. These findings suggest that EndoMT may contribute to the development of PAH.