טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentChen-Konak Limor
SubjectRemodeling of the Cardiovascular System by Biomechanical
Forces - Interaction of Vascular Endothelial Cells
and Stressed Cardiac Myocytes and its
Effect on Angiogenesis
DepartmentDepartment of Biotechnology
Supervisors Ms. Nitzan Resnick
Professor Emeritus Ofer Binah


Abstract

Hemodynamic forces acting through the endothelium play a crucial role in chronic restructuring of blood vessels. In this study we hypothesized that collateral formation in the heart is augmented by biomechanical and biochemical stimuli: by shear stress changes that directly regulate VEGF and Angiopoietin receptors (VEGFR1, VEGFR2, Tie1 and Tie2) expression in vascular endothelial cells (VECs) and by paracrine stimuli secreted from stressed cardiac myocytes (cardiac myocytes - VECs communication). To test this hypothesis VECs were subjected to laminar shear stress using a unique cone-plate apparatus and the endothelial receptors expression was tested. While the expression of VEGFR2 was rapidly increased, that of VEGFR1 and of Tie1 was acutely suppressed by the flow, thus suggesting that hemodynamic forces play a direct role in the formation and maturation of blood vessels. Investigation of the mechanisms of Tie1 regulation by shear stress revealed a transcriptional and post-translation regulation of Tie1 by shear stress changes mediated by a novel defined negative shear stress response element. To study the cross talk between cardiac myocytes and VECs, conditioned media (CM) from neonatal rat ventricular myocytes exposed to hypoxia were incubated with VECs grown under static or shear stress conditions. Our results suggest that cardiac myocytes exposed to hypoxia secret factors, which affect the four angiogenic receptors expression in VECs, an effect which varies under shear stress conditions. Thus, we propose that biomechanical and biochemical stress conditions in the heart may lead to the secretion of factors by cardiac myocytes, affecting angiogenic receptors expression of VECs. The overall result of this communication together with the direct regulation of angiogenic receptors by shear stress is the formation of new blood vessels or collaterals in the heart.