Matrix sieving-enforced retrograde transcytosis regulates tissue accumulation of C-reactive protein
Matrix sieving-enforced retrograde transcytosis regulates tissue accumulation of C-reactive protein
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基质筛分强制逆行转胞吞作用调节 C 反应蛋白的组织积累
DOI：
10.1093/cvr/cvy181
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发表时间：
2019-02-01
影响因子：
10.8
通讯作者：
Wu, Yi
中科院分区：
文献类型：
--
作者：
Li, Hai-Yun;Liu, Xiao-Ling;Wu, Yi
目的 大于3纳米的循环蛋白可通过胞吞转运穿过血管的连续内皮屏障。然而，即使对于那些在循环中含量丰富的血清蛋白，其在血管壁内的过度积聚也并不常见。本研究的目的是探究胞吞转运如何调节典型急性期反应物C - 反应蛋白（CRP）及其他血清蛋白在组织中的积聚。
方法与结果 在体外和体内，CRP以及转铁蛋白和低密度脂蛋白穿过主动脉内皮细胞的胞吞转运是双向的，且从顶端（血液）到基底外侧（组织）方向具有优先性。然而，内皮细胞基底外侧表面下方的基底膜（BM）基质会逆转这种方向优先性。这是由于基底膜的筛分效应在物理上阻碍了胞吞转运的蛋白从顶端区室向下方组织的扩散，导致立即的逆向胞吞转运，从而限制了基底外侧的蛋白积聚。相反，血管壁病变内产生的CRP也可被转运到循环中。
结论 我们的研究结果确定了基质筛分强制的逆向胞吞转运是一种防止血源性蛋白在组织中过度积聚的通用机制，并表明病变来源的CRP可能也有助于血清CRP水平升高，而血清CRP水平升高与心血管疾病风险增加相关。
Aims Circulating proteins larger than 3nm can be transported across continuous endothelial barrier of blood vessels via transcytosis. However, excessive accumulation of serum proteins within the vessel walls is uncommon even for those abundant in the circulation. The aim of this study was to investigate how transcytosis regulates tissue accumulation of the prototypical acute-phase reactant C-reactive protein (CRP) and other serum proteins.Methods and results Transcytosis of CRP as well as of transferrin and low-density lipoprotein across aortic endothelial cells is bidirectional with directional preference from the apical (blood) to basolateral (tissue) direction both in vitro and in vivo. This directional preference is, however, reversed by the basement membrane (BM) matrix underlying the basolateral surface of endothelial cells. This is due to the sieving effect of the BM that physically hinders the diffusion of transcytosed proteins from the apical compartment towards underlying tissues, resulting in immediate retrograde transcytosis that limits basolateral protein accumulation. Conversely, CRP produced within vessel wall lesions can also be transported into the circulation.Conclusion Our findings identify matrix sieving-enforced retrograde transcytosis as a general mechanism that prevents excessive tissue accumulation of blood-borne proteins and suggest that lesion-derived CRP might also contribute to elevated serum CRP levels associated with increased risk for cardiovascular diseases.