טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentKraizer Yehudit
SubjectThe Involvement of Angiogenic Factors during Liver
Regeneration
DepartmentDepartment of Medicine
Supervisor Professor Gad Spira


Abstract

Following partial hepatectomy (PHx) the liver regenerates to restore its mass and function. Rebuilding its unique, intricate network of blood vessels is an integral part of liver regeneration. This study examines the involvement of angiogenic factors, Vascular Endothelial Growth Factor (VEGF) and angiopoietin during regeneration. Following PHx the level of VEGF and angiopoietin mRNA gradually rises thereby returning to normal at the end of the recovery period. The expression of the angiopoietin receptors Tie1 and Tie2 fluctuates concomitantly. Using RT-PCR, we have shown that VEGF is differentially expressed in the liver. Of the five isoforms identified in man, three equivalents are expressed in rat: VEGF188, VEGF164 and VEGF120, VEGF188 being the dominant. Though the level of expression of the three rises following PHx the relative expression remains constant. We have shown that the level of expression of neuropilin1, a VEGF164 co-receptor rises during liver regeneration further pointing to the role of VEGF during this process. Administration of antibodies to VEGF causes a significant inhibition of liver cell proliferation. VEGF165 and VEGF121 administration stimulated liver cell proliferation. As hepatocytes do not express VEGF receptors it is likely that the effect of VEGF is indirect. Proliferating endothelial cells most probably supply hepatocytes with the essential growth factors, thus leading to regeneration. The involvement of VEGF in the process of cirrhotic liver regeneration was also noted. Preliminary experiments using halofuginone have shown a possible benefit for this agent in decreasing liver fibrosis. Combined treatment of VEGF and halofuginone may be effective in aiding liver regeneration following resection of the cirrhotic liver.