MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi'an Jiaotong University, West Yanta Road, Xi'an, Shaanxi, PR China.
MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, South Tianshui Road, Lanzhou, PR China.
Cardiovasc Res. 2019 Feb 1;115(2):440-452. doi: 10.1093/cvr/cvy181.
Circulating proteins larger than 3 nm 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.
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.
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.
大于 3nm 的循环蛋白可以通过胞吞作用穿过血管连续内皮屏障进行转运。然而，即使是在血液中丰富的蛋白质，其在血管壁内的过度积累也不常见。本研究旨在探讨胞吞作用如何调节典型急性期反应物 C 反应蛋白（CRP）和其他血清蛋白在组织中的积累。
CRP 以及转铁蛋白和低密度脂蛋白在体外和体内均能双向穿过主动脉内皮细胞的胞吞作用，并有从顶端（血液）到基底外侧（组织）方向的定向偏好。然而，这种定向偏好被内皮细胞基底外侧表面下方的基底膜（BM）基质所逆转。这是由于 BM 的筛网效应，它物理上阻碍了从顶端隔室向下面组织扩散的转胞吞蛋白，导致立即逆行转胞吞作用，限制了基底外侧蛋白的积累。相反，血管壁损伤内产生的 CRP 也可以被转运到血液循环中。
我们的发现确定了基质筛网强制逆行转胞吞作用是一种防止血液来源蛋白过度组织积累的一般机制，并表明病变衍生的 CRP 也可能导致与心血管疾病风险增加相关的血清 CRP 水平升高。
