טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentSnir Ayelet
SubjectShear Stress Changes as a Primary Stimulus in
Liver Regeneration
DepartmentDepartment of Medicine
Supervisors Ms. Nitzan Resnick
Professor Gad Spira


Abstract

Liver regeneration involves changes in the expression of many genes among them angiogenic genes. Nevertheless, the stimuli initiating liver regeneration are poorly understood. Following hepatectomy (PHx), rapid changes in blood flow to the injured liver occur, where flow returns to basal levels when the liver reaches its original mass.

Thus, we hypothesize that these rapid changes in shear stress act as a primary stimulus for liver regeneration by modulating the expression of angiogenic genes and their receptors.

 To test this hypothesis Sprague- Dawley rats underwent 70% PHx and minutes to hours post operation the rats were sacrificed and liver samples were tested for the expression of VEGF and its receptors VEGFR1 (flt1) and VEGFR2 (flk1), and the angiopoietin receptors Tie1 and Tie2. VEGFR2 expression was dramatically increased as early as 15min. post operation. Changes in VEGFR1 Tie1 and Tie2 expression resembled those of VEGFR2, although more moderately.

 Ligation of the portal vein modulated the expression of the angiogenic receptors, in a similar fashion to the hepatectomized group. A very rapid (15’) increase was observed in VE- cadherin and β-catenin expression following both PHx and PL, which occurred concomitantly with VEGFR2 induction. The orchestrated increased expression of VEGFR2 and the A/J proteins following either PHx or PL was accompanied by a rapid binding of these molecules to each other as revealed by Co-immunoprecipitation.

Thus our data suggest, that rapid changes in blood flow sensed by the VEGFR2/VE-cadherin/b-catenin, may serve as a primary stimulus for liver regeneration by altering liver endothelial cells structure and function.