Fenestral diaphragms and PLVAP associations in liver sinusoidal endothelial cells are developmentally regulated
Fenestral diaphragms and PLVAP associations in liver sinusoidal endothelial cells are developmentally regulated
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DOI：
10.1038/s41598-019-52068-x
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发表时间：
2019-10-30
影响因子：
4.6
通讯作者：
Salmi, Marko
中科院分区：
文献类型：
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作者：
Auvinen, Kaisa;Lokka, Emmi;Salmi, Marko
内皮细胞包含几个纳米结构域，如小泡、开孔和跨内皮通道，它们调节信号传导和跨内皮通透性。这些结构可以由类似过滤器的隔膜覆盖。一个跨膜的PLVAP（质膜囊泡相关蛋白）蛋白已被证明是隔膜形成所必需的。PLVAP在肝窦内皮细胞（LSEC）中的表达、亚细胞定位和成孔作用一直存在争议。本研究显示，LSEC的开孔在胎儿血管生成期间含有plvap -膈，但在出生时膈消失。尽管人们认为PLVAP仅定位于膈肌，但我们通过多种成像技术发现成人LSEC中PLVAP的管腔定位。PLVAP缺陷小鼠发现，缺乏PLVAP和膈肌并不影响肝窦的形态、开窗数量或整体血管结构。然而，PLVAP在胎儿LSEC（有膈开孔）中与LYVE-1（淋巴管内皮透明质酸受体1）、neuropilin-1和VEGFR2（血管内皮生长因子受体2）相关，而在成人LSEC（无膈开孔）中这些复合物消失。总的来说，我们的数据表明，PLVAP可以在没有膈的内皮细胞上表达，这与普遍认为的窗窗生物发生依赖PLVAP的观点相矛盾，并揭示了血管生成过程中LSEC中先前未知的PLVAP依赖分子复合物。
Endothelial cells contain several nanoscale domains such as caveolae, fenestrations and transendothelial channels, which regulate signaling and transendothelial permeability. These structures can be covered by filter-like diaphragms. A transmembrane PLVAP (plasmalemma vesicle associated protein) protein has been shown to be necessary for the formation of diaphragms. The expression, subcellular localization and fenestra-forming role of PLVAP in liver sinusoidal endothelial cells (LSEC) have remained controversial. Here we show that fenestrations in LSEC contain PLVAP-diaphragms during the fetal angiogenesis, but they lose the diaphragms at birth. Although it is thought that PLVAP only localizes to diaphragms, we found luminal localization of PLVAP in adult LSEC using several imaging techniques. Plvap-deficient mice revealed that the absence of PLVAP and diaphragms did not affect the morphology, the number of fenestrations or the overall vascular architecture in the liver sinusoids. Nevertheless, PLVAP in fetal LSEC (fenestrations with diaphragms) associated with LYVE-1 (lymphatic vessel endothelial hyaluronan receptor 1), neuropilin-1 and VEGFR2 (vascular endothelial growth factor receptor 2), whereas in the adult LSEC (fenestrations without diaphragms) these complexes disappeared. Collectively, our data show that PLVAP can be expressed on endothelial cells without diaphragms, contradict the prevailing concept that biogenesis of fenestrae would be PLVAP-dependent, and reveal previously unknown PLVAP-dependent molecular complexes in LSEC during angiogenesis.