VE-Cadherin and Vesicles Differentially Regulate Lymphatic Vascular Permeability to Solutes of Various Sizes.
VE-Cadherin and Vesicles Differentially Regulate Lymphatic Vascular Permeability to Solutes of Various Sizes.
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DOI：
10.3389/fphys.2021.687563
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发表时间：
2021
影响因子：
4
通讯作者：
Scallan JP
中科院分区：
文献类型：
--
作者：
Jannaway M;Scallan JP
淋巴管通透性可防止淋巴渗漏，淋巴渗漏与淋巴水肿、淋巴管畸形、肥胖和炎症有关。然而，淋巴通透性的分子控制仍然知之甚少。最近的研究表明，黏附连接和囊泡运输可能参与调节淋巴管的通透性。为了确定每条运输途径的贡献，我们利用体外通透性测试来直接测量在完整的小鼠收集淋巴管中不同分子量溶质在一定压力范围内的溶质通量。药理学和生物学工具被用来探索小泡和连接蛋白在淋巴管系统中的相对作用。我们发现收集淋巴管的通透性与溶质分子量成反比。此外，作为囊泡形成的抑制剂，囊泡选择性转运牛血清白蛋白显著降低了对牛血清白蛋白的通透性(∼降低60%，n=8，P=0.02)，但对3 kDa葡聚糖(n=7，P=0.41)、α-乳清蛋白(n=5，P=0.26)和70 kDa葡聚糖(n=8，P=0.13)的通透性无明显影响。相反，VE-钙粘附素与功能阻断抗体结合的破坏显著增加淋巴管对3 kDa葡聚糖(5.7倍，P=5，0.0001)和牛血清白蛋白(5.8倍，n=5，P<；0.0001)的通透性。因此，在淋巴管系统中，黏附连接对这里测试的任何溶质都没有显示出选择性，而小泡专门运输BSA。总体而言，研究结果表明，扰乱VE-钙粘附素定位或表达的疾病状态将导致大量溶质和液体从淋巴管系统泄漏。
Lymphatic vascular permeability prevents lymph leakage that is associated with lymphedema, lymphatic malformations, obesity, and inflammation. However, the molecular control of lymphatic permeability remains poorly understood. Recent studies have suggested that adherens junctions and vesicle transport may be involved in regulating lymphatic vessel permeability. To determine the contribution of each transport pathway, we utilized an ex vivo permeability assay to directly measure the solute flux of various molecular weight solutes across a range of pressures in intact murine collecting lymphatic vessels. Pharmacological and biological tools were used to probe the relative contributions of vesicles and junction proteins in the lymphatic vasculature. We show that the permeability of collecting lymphatic vessels is inversely related to the solute molecular weight. Further, our data reveal that vesicles selectively transport BSA, as an inhibitor of vesicle formation significantly decreased the permeability to BSA (∼60% decrease, n = 8, P = 0.02), but not to 3 kDa dextran (n = 7, P = 0.41), α-lactalbumin (n = 5, P = 0.26) or 70 kDa dextran (n = 8, P = 0.13). In contrast, disruption of VE-cadherin binding with a function blocking antibody significantly increased lymphatic vessel permeability to both 3 kDa dextran (5.7-fold increase, n = 5, P < 0.0001) and BSA (5.8-fold increase, n = 5, P < 0.0001). Thus, in the lymphatic vasculature, adherens junctions did not exhibit selectivity for any of the solutes tested here, whereas vesicles specifically transport BSA. Overall, the findings suggest that disease states that disrupt VE-cadherin localization or expression will cause significant leakage of solutes and fluid from the lymphatic vasculature.
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影响因子：
4
作者：
Dejana, Elisabetta;Orsenigo, Fabrizio;Lampugnani, Maria Grazia
通讯作者：
Lampugnani, Maria Grazia
影响因子：
--
作者：
HUXLEY, VH;CURRY, FE;THIPAKORN, B
通讯作者：
THIPAKORN, B
影响因子：
--
作者：
HUXLEY, VH;CURRY, FE;ADAMSON, RH
通讯作者：
ADAMSON, RH
影响因子：
--
作者：
ADAMSON, RH;HUXLEY, VH;CURRY, FE
通讯作者：
CURRY, FE
影响因子：
--
作者：
CURRY, FE;RUTLEDGE, JC;LENZ, JF
通讯作者：
LENZ, JF