Analysis of the role of angiogenesis and non-parenchymal cells during hepatic regeneration.

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We investigated the influence of anti-angiogenesis for hepatic regeneration using HGF antagonist (NK4) and suppressor of VEGF receptor (sFlt-1). NK4 expressing adenoviral vector (Ad.NK4) or sFlt-1 expressing adenoviral vector (Ad.sFlt-1) were infected mice liver. Seventy percent hepatectomy was performed 48 hours after infection. LacZ expressing adenoviral vector (Ad.LacZ) was used as control. Expression of Nk4 or sFlt-1 reached maximum level 48 hours after infection (NK4: 300ng/ml, sFlt-1:350ng/ml) and sustained for 2 weeks. Remnant liver was removed at 12, 24, 36, 48, 72 and 120 hrs after partial hepatectomy, and hepatic regeneration was assessed. As a result, increase of remnant hepatic weight was significantly delayed in Ad.NK4 or Ad.sFlt-1 infected mice. Results of mitotic cells and BrdU index showed significant delay of hepatic regeneration in Ad.NK4 or Ad.sFlt-1 infected mice at 48 or 36 hours after hepatectomy. Immnuhistochemical staining of CD31 showed suppression of sinusoidal endothelial cells growth in Ad.NK4 infected mice. Ang-1, Ang-2, Tie-1, and Tie-2 are considered to be crucial in the process of maturation of vessels. Real time PCR showed suppression of mRNA of Ang-1, Ang-2, Tie-1, and Tie-2 with significant difference. These results suggested that hepatic regeneration after hepatectomy closely correlates with angiogenesis.