Cuervo Henar, Nielsen Corinne M, Simonetto Douglas A, Ferrell Linda, Shah Vijay H, Wang Rong A
Laboratory for Accelerated Vascular Research, Department of Surgery, University of California, San Francisco, San Francisco, CA.
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
Hepatology. 2016 Oct;64(4):1302-1316. doi: 10.1002/hep.28713. Epub 2016 Aug 4.
Liver vasculature is crucial for adequate hepatic functions. Global deletion of Notch signaling in mice results in liver vascular pathologies. However, whether Notch in endothelium is essential for hepatic vascular structure and function remains unknown. To uncover the function of endothelial Notch in the liver, we deleted Rbpj, a transcription factor mediating all canonical Notch signaling, or Notch1 from the endothelium of postnatal mice. We investigated the hepatic vascular defects in these mutants. The liver was severely affected within 2 weeks of endothelial deletion of Rbpj from birth. Two-week old mutant mice had enlarged vessels on the liver surface, abnormal vascular architecture, and dilated sinusoids. Vascular casting and fluorosphere passage experiments indicated the presence of porto-systemic shunts. These mutant mice presented with severely necrotic liver parenchyma and significantly larger hypoxic areas, likely resulting from vascular shunts. We also found elevated levels of VEGF receptor 3 together with reduced levels of ephrin-B2, suggesting a possible contribution of these factors to the generation of hepatic vascular abnormalities. Deletion of Rbpj from the adult endothelium also led to dilated sinusoids, vascular shunts, and necrosis, albeit milder than that observed in mice with deletion from birth. Similar to deletion of Rbpj, loss of endothelial Notch1 from birth led to similar hepatic vascular malformations within 2 weeks.
Endothelial Notch signaling is essential for the development and maintenance of proper hepatic vascular architecture and function. These findings may elucidate the molecular pathogenesis of hepatic vascular malformation and the safety of therapeutics inhibiting Notch. (Hepatology 2016;64:1302-1316).
肝脏血管系统对于肝脏正常功能至关重要。在小鼠中全局删除Notch信号会导致肝脏血管病变。然而，内皮细胞中的Notch对于肝脏血管结构和功能是否必不可少仍不清楚。为了揭示肝脏中内皮细胞Notch的功能，我们从出生后的小鼠内皮细胞中删除了介导所有经典Notch信号的转录因子Rbpj或Notch1。我们研究了这些突变体中的肝脏血管缺陷。从出生起在内皮细胞中删除Rbpj后2周内，肝脏受到严重影响。两周大的突变小鼠肝脏表面血管扩张、血管结构异常且肝血窦扩张。血管铸型和荧光球通过实验表明存在门体分流。这些突变小鼠出现严重坏死的肝实质和明显更大的缺氧区域，可能是由血管分流导致的。我们还发现血管内皮生长因子受体3水平升高，同时ephrin-B2水平降低，提示这些因子可能对肝脏血管异常的发生有作用。从成年内皮细胞中删除Rbpj也会导致肝血窦扩张、血管分流和坏死，尽管比出生时就删除的小鼠中观察到的情况要轻。与删除Rbpj类似，出生时内皮细胞Notch1缺失在2周内会导致类似的肝脏血管畸形。
内皮细胞Notch信号对于正常肝脏血管结构和功能的发育及维持至关重要。这些发现可能阐明肝脏血管畸形的分子发病机制以及抑制Notch治疗的安全性。（《肝脏病学》2016年；64卷：1302 - 1316页）
