Beldi Guido, Wu Yan, Sun Xiaofeng, Imai Masato, Enjyoji Keiichi, Csizmadia Eva, Candinas Daniel, Erb Laurie, Robson Simon C
Transplant and Liver Centers, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts 02215, USA.
Gastroenterology. 2008 Nov;135(5):1751-60. doi: 10.1053/j.gastro.2008.07.025. Epub 2008 Jul 31.
BACKGROUND & AIMS: Little is known about how endothelial cells respond to injury, regulate hepatocyte turnover and reconstitute the hepatic vasculature. We aimed to determine the effects of the vascular ectonucleotidase CD39 on sinusoidal endothelial cell responses following partial hepatectomy and to dissect purinergic and growth factor interactions in this model.
Parameters of liver injury and regeneration, as well as the kinetics of hepatocellular and sinusoidal endothelial cell proliferation, were assessed following partial hepatectomy in mice that do not express CD39, that do not express ATP/UTP receptor P2Y2, and in controls. The effects of extracellular ATP on vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and interleukin-6 responses were determined in vivo and in vitro. Phosphorylation of the endothelial VEGF receptor in response to extracellular nucleotides and growth factors was assessed in vitro.
After partial hepatectomy, expression of the vascular ectonucleotidase CD39 increased on sinusoidal endothelial cells. Targeted disruption of CD39 impaired hepatocellular regeneration, reduced angiogenesis, and increased hepatic injury, resulting in pronounced vascular endothelial apoptosis, and decreased survival. Decreased HGF release by sinusoidal endothelial cells, despite high levels of VEGF, reduced paracrine stimulation of hepatocytes. Failure of VEGF receptor-2/KDR transactivation by extracellular nucleotides on CD39-null endothelial cells was associated with P2Y2 receptor desensitization.
Regulated phosphohydrolysis of extracellular nucleotides by CD39 coordinates both hepatocyte and endothelial cell proliferation following partial hepatectomy. Lack of CD39 activity is associated with decreased hepatic regeneration and failure of vascular reconstitution.
关于内皮细胞如何应对损伤、调节肝细胞更新以及重建肝血管系统，我们了解得还很少。我们旨在确定血管外核苷酸酶CD39对部分肝切除术后肝血窦内皮细胞反应的影响，并剖析该模型中嘌呤能与生长因子之间的相互作用。
在不表达CD39、不表达ATP/UTP受体P2Y2的小鼠以及对照小鼠中，评估部分肝切除术后的肝损伤与再生参数，以及肝细胞和肝血窦内皮细胞增殖的动力学。在体内和体外确定细胞外ATP对血管内皮生长因子（VEGF）、肝细胞生长因子（HGF）和白细胞介素-6反应的影响。在体外评估内皮VEGF受体对细胞外核苷酸和生长因子的磷酸化反应。
部分肝切除术后，肝血窦内皮细胞上血管外核苷酸酶CD39的表达增加。靶向破坏CD39会损害肝细胞再生、减少血管生成并增加肝损伤，导致明显的血管内皮细胞凋亡，并降低生存率。尽管VEGF水平很高，但肝血窦内皮细胞释放的HGF减少，降低了对肝细胞的旁分泌刺激。在CD39基因敲除的内皮细胞上，细胞外核苷酸未能激活VEGF受体-2/KDR，这与P2Y2受体脱敏有关。
CD39对细胞外核苷酸的调节性磷酸水解作用在部分肝切除术后协调肝细胞和内皮细胞的增殖。缺乏CD39活性与肝再生减少和血管重建失败有关。
