Endothelial notch signaling is essential to prevent hepatic vascular malformations in mice.
Endothelial notch signaling is essential to prevent hepatic vascular malformations in mice.
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内皮缺口信号传导对于预防小鼠肝血管畸形至关重要。
DOI：
10.1002/hep.28713
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发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Wang RA
中科院分区：
文献类型：
--
作者：
Cuervo H;Nielsen CM;Simonetto DA;Ferrell L;Shah VH;Wang RA
肝脏的血管系统对维持正常的肝功能至关重要。小鼠Notch信号的全局缺失导致肝脏血管病变。然而，内皮中的Notch是否对肝血管的结构和功能至关重要尚不清楚。为了揭示肝脏内皮Notch的功能，我们从出生后小鼠的内皮中特异性地删除了Rbpj（一种介导所有典型Notch信号的转录因子）或Notch1。我们研究了这些突变体的肝血管缺陷。肝脏在出生后内皮细胞Rbpj缺失后两周内受到严重影响。两周大的突变小鼠肝脏表面血管扩张，血管结构异常，鼻窦炎扩张。血管铸型和荧光球传代实验表明存在门-系统分流。这些突变小鼠表现出严重坏死的肝实质和明显较大的缺氧区域，可能是由血管分流引起的。我们还发现VEGF受体3水平升高，同时ephrin-B2水平降低，这表明这些因素可能对肝血管异常的产生有贡献。成年后内皮细胞中Rbpj的缺失也会导致窦状动脉扩张、血管分流和坏死，尽管这种情况比出生时缺失的小鼠要轻。与Rbpj的缺失类似，出生时内皮细胞Notch1的缺失会在两周内导致类似的肝血管畸形。内皮Notch信号对于正常的肝血管结构和功能的发展和维持至关重要。我们的发现可能有助于了解肝血管畸形的分子发病机制和抑制Notch的治疗方法的安全性。
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, specifically from the endothelium of postnatal mice. We investigated the hepatic vascular defects in these mutants. The liver was severely affected within two weeks following 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 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 in mice with deletion from birth. Similar to deletion of Rbpj, loss of endothelial Notch1 from birth led to similar hepatic vascular malformations within two weeks. Endothelial Notch signaling is essential for the development and maintenance of proper hepatic vascular architecture and function. Our findings may help understand the molecular pathogenesis of hepatic vascular malformation and the safety of therapeutics inhibiting Notch.