Molecular mechanisms in angiogenic reconstruction of sinusoidal endothelium in regenerating and developing liver

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Recently, several reports have experimentally shown that sinusoidal endothelial cell proliferation is essential for liver regeneration after major hepatic tissue loss. Several angiogenic growth factors including vascular endothelial growth factor (VEGF) and its receptors are expressed by the proliferating hepatocytes to induce angiogenesis during liver regeneration. It has been well established that hypoxia inducible factor-1α (HIF-1α) transcribes several angiogenic growth factors including VEGF for sensing hypoxia. However, the expression profile of HIF-1α during liver regeneration is not known. In the present study, expression of HIF-1α was evaluated in the regenerating liver following 70% partial hepatectomy in rats. Expressions of nuclear HIF-1α VEGF and fms-like tyrosine kinase-1 (flt-1) were measured by Western blot, liver blood flow by using a laser Doppler and sinusoidal endothelial cell area and HIF-1a localization were studied by immunohistochemistry. Liver blood flow peaked at 24h (P=0.002 compared with control) and was lowest at 36h after hepatectomy (P=0.006). Endothelial cell area was lowest at 72h after hepatectomy (P<0.001). Nuclear HIF-1α and VEGF peaks were recognized at 24h and 120h after hepatectomy, respectively. However, flt-1 level was continuously elevated after hepatectomy. HIF-1α mRNA increased at 24h, 36h and 72h after hepatectomy (P<0.05). In conclusions, the peak expression of nuclear HIF-1α was observed before VEGF expression in the regenerating rat liver. The elevated level of HIF-1α might be the result of transient hypoxia induced by exponential growth of hepatocytes following hepatectomy.