Mechanism of sinusoidal endothelial cell proliferation and maturation during hepatic regeneration

目标：部分肝切除术后的调控机制仍然知之甚少。方法：我们研究了血管生成素（Ang）-1，Ang- 2，Tie-2和血管内皮生长因子（VEGF）在再生肝组织和分离的肝细胞70%肝切除术后大鼠的表达。结果：VEGF mRNA表达在肝切除后72 h达高峰，此后逐渐下降，肝窦内皮细胞（SECs）的增殖和凋亡情况在肝切除后72 h达高峰，肝窦内皮细胞（SECs）的增殖和凋亡情况在肝切除后72 h达高峰。Ang-1 mRNA在肝切除前即有表达，但表达缓慢增加，96 h达高峰。Ang-2 mRNA在肝切除前几乎不表达，而在120 h和144 h表达明显增加。在分离的细胞中，VEGF mRNA的表达被发现主要在肝细胞部分。同时，Ang-1和Ang-2的mRNA在SEC和肝星状细胞（HSC）组分中被发现，但在后者中更为突出。SEC的PCNA标记指数缓慢增加，在72 h达到峰值，而凋亡的SEC之间检测到120和144 h。结论：VEGF的肝细胞分泌可能在SEC增殖中发挥关键作用，其次是增加Ang-1，推测促进窦成熟。此后，在缺乏VEGF的情况下，主要从HSC释放的Ang-2可能有助于过量SEC的凋亡，从而停止再生过程。Ang-Tie系统与VEGF一起在肝切除术后肝窦再生过程中调节SEC增殖与凋亡之间的平衡中起关键作用。

AIMS : The regulatory mechanisms of sinusoidal regeneration after partial hepatectomy remain poorly understood.METHODS : We investigated the expression of angiopoietin (Ang)-1, Ang- 2, Tie-2, and vascular endothelial growth factor (VEGF) in both regenerating liver tissue and isolated liver cells after 70% hepatectomy in rats. Proliferation and apoptosis of sinusoidal endothelial cells (SECs) were also evaluated with proliferating cell nuclear antigen (PCNA) and TUNEL staining, respectively.Results : VEGF mRNA expression was increased with a peak at 72 h after hepatectomy, decreasing thereafter. The expression of Ang-1 mRNA was present at detectable levels before hepatectomy and was increased slowly with a peak at 96 h. Meanwhile, Ang-2 mRNA was hardly detected before hepatectomy, but was remarkably induced at 120 h and 144 h. In isolated cells, VEGF mRNA expression was found mainly in the hepatocyte fraction. Meanwhile, mRNA for Ang-1 and Ang-2 was found in the SEC and hepatic stellate cell (HSC) fractions, but was more prominent in the latter. The PCNA labeling index of SECs increased slowly, reaching a peak at 72 h, whereas apoptotic SECs were detected between 120 h and 144 h.Conclusions : VEGF secreted by hepatocytes may play a key role in SEC proliferation, followed by increased Ang-1, presumably promoting sinusoidal maturation. Thereafter, Ang-2 mainly released from HSCs in the absence of VEGF may contribute to apoptosis of superfluous SECs for cessation of the regenerative process. Ang-Tie system, together with VEGF, plays a critical role in regulating balance between SEC proliferation and apoptosis during sinusoidal regeneration after hepatectomy.