טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentSilberman Michal
SubjectThe Role Of Biomechanical Forces in New Blood Vessel
Formation in the Failing Heart
DepartmentDepartment of Medicine
Supervisors Professor Emeritus Ofer Binah
Ms. Nitzan Resnick


Abstract

Our hypothesis suggests that blood vessel formation in the diseased heart is promoted directly by endothelial cells undergoing shear stress changes, and indirectly by stressed cardiac myocytes expressing factors that further modulate the endothelium angiogenic phenotype.

In endothelial cells exposed to shear stress, VEGFR-2 was increased, VEGFR-1 and Tie1 decreased and Tie2 increased 2 hours after the flow onset .Tie1 transcriptional suppression was mediated by a new 250bp negative shear stress response element in its promoter that contains an AP1-like site which is similar to the VCAM-1 negative SSRE. We pointed at JDP-2 protein as a potential suppressor of Tie1 promoter activity through an interaction with the AP1 site.

Hybrid promoters were designed with the goal to create a tool to drive a transgene expression in a specific time and location. NR1/2 was most responsive to shear stress, and was combined with a U region from Tie2 promoter to render the expression endothelial specific. Our constructs were preferentially expressed in endothelial cells but were unaffected by shear stress.

Exposure of cardiac myocytes to mechanical overload, using glass microspheres, lead to increased VEGF, Ang-2 and TGF-β expression and to β-FGF non-specific induction. Cyclic stretch resulted in a modest increase in Ang-2, TGF-β and β-FGF mRNA levels. Conditioned medium from cardiac myocytes loaded with microspheres significantly affected the migration rate and the ability to form tubes of endothelial cells.

Taken together the present study may point to new approaches in our attempts to enhance new blood vessels formation in ischemic patients.