Arsenic stimulates sinusoidal endothelial cell capillarization and vessel remodeling in mouse liver
Arsenic stimulates sinusoidal endothelial cell capillarization and vessel remodeling in mouse liver
复制标题
DOI：
10.1002/hep.21444
复制
发表时间：
2007-01-01
期刊：
影响因子：
13.5
通讯作者：
Barchowsky, Aaron
中科院分区：
文献类型：
--
作者：
Straub, Adam C.;Stolz, Donna B.;Barchowsky, Aaron
三价砷[As(Ill)]是一种众所周知的环境毒物，可导致多种器官特有的疾病和癌症。在人的肝脏中，As(III)促进血管重塑、门脉纤维化和高血压，但这些As(III)诱导的血管变化的机制尚不清楚。目的：探讨As(III)作用于肝内皮细胞的假设。为了启动病原学变化，小鼠暴露在饮用水中0或250 ppb的As(III)中5周。砷(III)暴露不会影响动物的整体健康、肝脏的一般结构或肝细胞的形态。组织总砷水平没有变化，表明在这种暴露水平下，砷不会在肝脏中积累。然而，AS(Ill)暴露的小鼠可见明显的血管重塑，表现为肝窦内皮细胞(SEC)毛细血管增多，胆管周围血管丛(PBVP)血管化，肝小动脉收缩。除了超微结构的SEC开窗和毛细血管形成外，定量免疫荧光分析显示PECAM-I和LN-1蛋白表达增加，提示黏附连接和基底膜的增加。在细胞水平上证实了SEC转化为毛细血管、去分化的内皮细胞，表现为小窝蛋白-1表达增加和SEC小窝，以及膜结合的rac1-GTP酶增加。结论：这些数据表明，暴露于As(III)可引起肝窦毛细血管形成的SEC信号的功能改变，这可能是肝脏病原性改变的初始事件。
Trivalent arsenic [As(Ill)] is a well-known environmental toxicant that causes a wide range of organ-specific diseases and cancers. In the human liver, As(III) promotes vascular remodeling, portal fibrosis, and hypertension, but the pathogenesis of these As(Ill)-induced vascular changes is unknown. To investigate the hypothesis that As(III) targets the hepatic endothelium. to initiate pathogenic change, mice were exposed to 0 or 250 parts per billion (ppb) of As(III) in their drinking water for 5 weeks. Arsenic(III) exposure did not affect the overall health of the animals, the general structure of the liver, or hepatocyte morphology. There was no change in the total tissue arsenic levels, indicating that arsenic does not accumulate in the liver at this level of exposure. However, there was significant vascular remodeling with increased sinusoidal endothelial cell (SEC) capillarization, vascularization of the peribiliary vascular plexus (PBVP), and constriction of hepatic arterioles in As(Ill)exposed mice. In addition to ultrastructural demonstration of SEC defenestration and capillarization, quantitative immunofluorescence analysis revealed increased sinusoidal PECAM-I and laminin-1 protein expression, suggesting gain of adherens junctions and a basement membrane. Conversion of SECs to a capillarized, dedifferentiated endothelium was confirmed at the cellular level with demonstration of increased caveolin-1 expression and SEC caveolae, as well as increased membrane-bound Rac1-GTPase. Conclusion: These data demonstrate that exposure to As(III) causes functional changes in SEC signaling for sinusoidal capillarization that may be initial events in pathogenic changes in the liver.