Dunworth William P, Fritz-Six Kimberly L, Caron Kathleen M
Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Peptides. 2008 Dec;29(12):2243-9. doi: 10.1016/j.peptides.2008.09.009. Epub 2008 Sep 24.
The lymphatic vascular system functions to maintain fluid homeostasis by removing fluid from the interstitial space and returning it to venous circulation. This process is dependent upon the maintenance and modulation of a semi-permeable barrier between lymphatic endothelial cells of the lymphatic capillaries. However, our understanding of the lymphatic endothelial barrier and the molecular mechanisms that govern its function remains limited. Adrenomedullin (AM) is a 52 amino acid secreted peptide which has a wide range of effects on cardiovascular physiology and is required for the normal development of the lymphatic vascular system. Here, we report that AM can also modulate lymphatic permeability in cultured dermal microlymphatic endothelial cells (HMVEC-dLy). AM stimulation caused a reorganization of the tight junction protein ZO-1 and the adherens protein VE-cadherin at the plasma membrane, effectively tightening the endothelial barrier. Stabilization of the lymphatic endothelial barrier by AM occurred independently of changes in junctional protein gene expression and AM(-/-) endothelial cells showed no differences in the gene expression of junctional proteins compared to wildtype endothelial cells. Nevertheless, local administration of AM in the mouse tail decreased the rate of lymph uptake from the interstitial space into the lymphatic capillaries. Together, these data reveal a previously unrecognized role for AM in controlling lymphatic endothelial permeability and lymphatic flow through reorganization of junctional proteins.
淋巴血管系统通过从组织间隙中移除液体并将其返回静脉循环来维持液体平衡。这一过程依赖于淋巴毛细血管的淋巴内皮细胞之间半透性屏障的维持和调节。然而，我们对淋巴内皮屏障及其功能调控的分子机制的理解仍然有限。肾上腺髓质素（AM）是一种由52个氨基酸组成的分泌型肽，对心血管生理有广泛影响，是淋巴血管系统正常发育所必需的。在此，我们报告AM还可以调节培养的真皮微淋巴管内皮细胞（HMVEC-dLy）的淋巴通透性。AM刺激导致紧密连接蛋白ZO-1和黏附蛋白VE-钙黏蛋白在质膜上重新组织，有效地收紧了内皮屏障。AM对淋巴内皮屏障的稳定作用独立于连接蛋白基因表达的变化，与野生型内皮细胞相比，AM（-/-）内皮细胞在连接蛋白的基因表达上没有差异。尽管如此，在小鼠尾巴局部给予AM可降低液体从组织间隙进入淋巴毛细血管的摄取率。这些数据共同揭示了AM在通过连接蛋白的重新组织控制淋巴内皮通透性和淋巴流动方面以前未被认识的作用。
