Mechanism of sinusoidal endothelial cell proliferation and maturation during hepatic regeneration

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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.