VEGF-C alters barrier function of cultured lymphatic endothelial cells through a VEGFR-3-dependent mechanism
VEGF-C alters barrier function of cultured lymphatic endothelial cells through a VEGFR-3-dependent mechanism
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DOI：
10.1089/lrb.2007.1004
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发表时间：
2007-01-01
影响因子：
1.4
通讯作者：
Wu, Mack H.
中科院分区：
文献类型：
--
作者：
Breslin, Jerome W.;Yuan, Sarah Y.;Wu, Mack H.
背景：淋巴管内皮细胞是分隔淋巴液和组织间隙的重要半渗透屏障。然而，目前对淋巴管内皮屏障和淋巴形成机制的了解有限。本研究的目的是探讨淋巴管内皮细胞在屏障调节中的潜在积极作用，并测试内皮细胞激动剂VEGF-A和VEGF-C是否可以改变淋巴管内皮屏障功能。方法和结果：以培养的成人真皮微淋巴管内皮细胞（HMLEC-d）和人脐静脉内皮细胞（HUVEC）分别作为淋巴管和血管内皮细胞模型。内皮细胞单层的跨内皮电阻（TER）作为屏障功能的指标。用VEGF-A、VEGF-C或VEGFR-3选择性突变体VEGF-C156 S处理细胞。MAZ 51用于抑制VEGFR-3信号传导。结果显示，虽然VEGF-A导致HUVEC中TER的时间依赖性降低，但在HMLEC-d中没有响应。相比之下，VEGF-C和VEGF-C156 S在HMLEC-d中引起相似的TER降低，而在HUVEC中未观察到。这些结果对应于通过蛋白质印迹法测定的这些细胞类型中VEGFR-2和VEGFR-3的蛋白质表达。此外，MAZ 51抑制VEGF-C和VEGF-C156 S诱导的TER变化。结论：结果表明淋巴管和血管内皮屏障对VEGF-A和VEGF-C的反应不同。此外，我们的数据表明，VEGF-C通过涉及VEGFR-3的机制改变淋巴管内皮功能。
Background: The lymphatic endothelium is an important semi-permeable barrier separating lymph from the interstitial space. However, there is currently a limited understanding of the lymphatic endothelial barrier and the mechanisms of lymph formation. The objectives of this study were to investigate the potential active role of lymphatic endothelial cells in barrier regulation, and to test whether the endothelial cell agonists VEGF-A and VEGF-C can alter lymphatic endothelial barrier function. Methods and Results: Cultured adult human dermal microlymphatic endothelial cells (HMLEC-d) and human umbilical vein endothelial cells (HUVEC) were respectively used as models of lymphatic and vascular endothelium. Transendothelial electrical resistance (TER) of endothelial monolayers served as an index of barrier function. Cells were treated with VEGF-A, VEGF-C, or the VEGFR-3 selective mutant VEGF-C156S. MAZ51 was used to inhibit VEGFR-3 signaling. The results show that while VEGF-A causes a time-dependent decrease in TER in HUVEC, there is no response in HMLEC-d. In contrast, VEGF-C and VEGF-C156S cause a similar decrease in TER in HMLEC-d that is not observed in HUVEC. These results corresponded to the protein expression of VEGFR-2 and VEGFR-3 in these cell types, determined by Western blotting. In addition, the VEGF-C- and VEGF-C156S-induced TER changes were inhibited by MAZ51. Conclusions: The results indicate differential responses of the lymphatic and vascular endothelial barriers to VEGF-A and VEGF-C. Furthermore, our data suggest that VEGF-C alters lymphatic endothelial function through a mechanism involving VEGFR-3.