A New Strategy Of Vascular-Targeted Therapy For Liver Fbrosis

No effective treatments are available for liver fibrosis.Angiogenesis is deeply involved in liver fibrogenesis,but controversial results make it difficult to treat liver fibrosis through vascular targeting.There are three different microvessels in liver:portal vessels,liver sinusoids and central vessels.The changes and roles of the three different vessels during liver fibrogenesis are unclear.We propose that the three different vessels play different roles during liver fibrogenesis,and a single vascular endothelial cell(EC)regulator is not enough to fully regulate these three different vessels to treat liver fibrosis.Therefore,the combined regulation of multiple different EC regulatory signaling will provide new strategies for liver fibrosis therapy.Herein,we perform a proof of concept by combining LECT2/Tie1 signaling regulation with VEGF/VEGFR signaling regulation.During fibrogenesis,vascular changes occurred at very early stage,different liver vessels showed different changes and played different roles:decreased portal vessels,increased sinusoid capillarization and the increased central vessels;the increase of portal vessels alleviates liver fibrosis,the increase of central vessels aggravates liver fibrosis,and the increase of sinusoid capillarization aggravates liver fibrosis.The combination treatment of AAV9-LECT2-shRNA and rVEGF shows improved therapeutic effects,but it leads to body weight loss and liver function decline,indicating serious side effects.The combination of AAV9-LECT2-shRNA and bevacizumab shows both improved therapeutic effects and decreased side effects.The combination treatment of AAV9-LECT2-shRNA and bevacizumab significantly improved the therapeutic effects on liver fibrosis.The strategy of exploring the specific regulatory pathways of the different changes and functions of the three hepatic microvessels in the liver,and organically combining multiple different vascular regulatory signal pathways to achieve precise regulation of blood vessels at different locations in the liver to treat liver fibrosis is worthy of further research.