טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentGuetta Julia
SubjectThe Regulation of Angiogenic Receptors by Shear Stress in
Vascular Endothelium - The Multiple Levels of Tie1
Regulation
DepartmentDepartment of Medicine
Supervisor Ms. Nitzan Resnick


Abstract

Blood vessel growth and remodeling requires coordination of signaling pathways

As blood flows through arteries, it imparts physical forces to the vascular wall that regulate a number of important physiological responses in blood vessels, and also in the development of arterial wall pathologies. We hypothesize that shear stress mediated vascular remodeling occurs through the regulation of the expression of angiogenic ligands and receptors.

  The present study aims at documenting the regulation of Tie1 (the receptor tyrosine kinases Tie1 and Tie2 are essential for angiogenesis.) by laminar shear stress in vascular endothelial cells and decipher the mechanism of this regulation.

The response of the endothelium to shear stress could be divided into two groups. Laminar shear stress induces Tie1 cleavage, and the increase in the cleavage product, overlaps the rapid decrease in levels of the full size receptor. We have found that shear stress mediated cleavage of Tie1 is inhibited by the MMP - non - specific inhibitor phenantrolene. 

Also we have demonstrated that Tie1 promoter activity is restricted to endothelial cells and affected by several stimuli : is repressed by TNFα and, induced by hypoxia. Furthermore, we have found that exposure of endothelial cells to shear stress also repressed the activity of Tie1 promoter.

We have demonstrated that the responsiveness to shear stress is retained within a fragment of 250bp of the Tie1 promoter. Our studies point at a novel negative SSRE.

The present study demonstrated that shear stress regulates Tie1 in endothelial cells, both transcriptionally and post-translationally.