Koch Philipp-Sebastian, Sandorski Kajetan, Heil Joschka, Schmid Christian D, Kürschner Sina W, Hoffmann Johannes, Winkler Manuel, Staniczek Theresa, de la Torre Carolina, Sticht Carsten, Schledzewski Kai, Taketo Makoto Mark, Trogisch Felix A, Heineke Joerg, Géraud Cyrill, Goerdt Sergij, Olsavszky Victor
Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.
European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Front Physiol. 2021 Sep 29;12:722394. doi: 10.3389/fphys.2021.722394. eCollection 2021.
Endothelial wingless-related integration site (Wnt)-/β-catenin signaling is a key regulator of the tightly sealed blood-brain barrier. In the hepatic vascular niche angiokine-mediated Wnt signaling was recently identified as an important regulator of hepatocyte function, including the determination of final adult liver size, liver regeneration, and metabolic liver zonation. Within the hepatic vasculature, the liver sinusoidal endothelial cells (LSECs) are morphologically unique and functionally specialized microvascular endothelial cells (ECs). Pathological changes of LSECs are involved in chronic liver diseases, hepatocarcinogenesis, and liver metastasis. To comprehensively analyze the effects of endothelial Wnt-/β-catenin signaling in the liver, we used endothelial subtype-specific mice to generate hepatic ECs with overexpression of Ctnnb1. In the resultant ( ) mice, activation of endothelial Wnt-/β-catenin signaling resulted in sinusoidal transdifferentiation with disturbed endothelial zonation, that is, loss of midzonal LSEC marker lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve1) and enrichment of continuous EC genes, such as cluster of differentiation and . Notably, gene set enrichment analysis revealed overrepresentation of brain endothelial transcripts. Activation of endothelial Wnt-/β-catenin signaling did not induce liver fibrosis or alter metabolic liver zonation, but mice exhibited significantly increased plasma triglyceride concentrations, while liver lipid content was slightly reduced. Ctnnb1 overexpression in arterial ECs of the heart has been reported previously to cause cardiomyopathy. As is active in a subset of cardiac ECs, it was not unexpected that mice showed reduced overall survival and cardiac dysfunction. Altogether, balanced endothelial Wnt-/β-catenin signaling in the liver is required for normal LSEC differentiation and for maintenance of normal plasma triglyceride levels.
内皮无翅相关整合位点（Wnt）/β-连环蛋白信号通路是紧密密封的血脑屏障的关键调节因子。最近发现，在肝血管微环境中，血管生成素介导的Wnt信号通路是肝细胞功能的重要调节因子，包括决定成年肝脏的最终大小、肝脏再生和肝脏代谢分区。在肝血管系统中，肝窦内皮细胞（LSEC）是形态独特且功能特殊的微血管内皮细胞（EC）。LSEC的病理变化与慢性肝病、肝癌发生和肝转移有关。为了全面分析内皮Wnt/β-连环蛋白信号通路在肝脏中的作用，我们使用内皮亚型特异性小鼠来生成过表达Ctnnb1的肝EC。在所得的（ ）小鼠中，内皮Wnt/β-连环蛋白信号通路的激活导致肝窦转分化，内皮分区紊乱，即中区LSEC标志物淋巴管内皮透明质酸受体1（Lyve1）丢失，连续EC基因如分化簇和（此处原文缺失具体基因名称）富集。值得注意的是，基因集富集分析显示脑内皮转录本过度表达。内皮Wnt/β-连环蛋白信号通路的激活未诱导肝纤维化或改变肝脏代谢分区，但（此处原文缺失具体小鼠模型名称）小鼠血浆甘油三酯浓度显著升高，而肝脏脂质含量略有降低。先前报道心脏动脉EC中Ctnnb1过表达会导致心肌病。由于（此处原文缺失具体蛋白名称）在一部分心脏EC中活跃，因此（此处原文缺失具体小鼠模型名称）小鼠显示总体生存率降低和心脏功能障碍并不意外。总之，肝脏中平衡的内皮Wnt/β-连环蛋白信号通路对于正常LSEC分化和维持正常血浆甘油三酯水平是必需的。
