טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentHamed Saher
SubjectMechanisms for Impaired Endothelial Progenitor Cell
Migration in Type II Diabetes Mellitus
DepartmentDepartment of Medicine
Supervisors Professor Ariel Roguin
Professor Benjamin Brenner
Full Thesis textFull thesis text - English Version


Abstract

It is widely accepted that vascular repair results from migration and proliferation of adjacent vascular cells. Accumulating evidence suggests that bone marrow progenitor cells can give rise to endothelial-like cells that potentially contribute to vascular healing and remodeling under physiological and pathological conditions. However, a growing amount of evidence demonstrates that bone marrow-derived endothelial progenitor cells (EPCs) are involved in adult neovasculogenesis and maintenance of vascular integrity. EPC decrease and dysfunction are related to atherosclerosis and cardiovascular disease (CVD), and it has been proposed that the level of circulating EPCs may be used as a surrogate index of cumulative cardiovascular risk. The prevalence of CVD is low in populations which consume large amounts of red wine. This low prevalence has been attributed to the antioxidant properties of red wine, and increased NO bioavailability. Diabetes Mellitus (DM) is a clinical condition characterized by a high incidence of CVD and is indeed associated with alterations in EPC physiology. Type 2 DM patients with coronary artery disease (CAD) have elevated plasma oxidized-LDL (oxLDL) levels and impaired neovascularization. Hyperglycemia and hyperlipidemia impair EPC migration, and endothelial nitric oxide (NO) bioavailability and NO synthase (NOS) activity are essential for EPC migration. Stromal-derived factor-1α (SDF1α) contributes to EPC mobilization and homing by stimulating the CXC receptor-4 (CXCR4) on the EPC plasmalemma to activate the Pi3K/Akt/eNOS signaling pathway. In the present work, we studied the potential mechanism underlying the impaired EPC migration in DM both in-vitro and in-vivo. Initially we demonstrated that increased oxidative stress caused by hyperglycemia plays an important role in EPC dysfunction in DM. We also demonstrated that hyperglycemia and elevated circulating oxLDL in DM patients with CAD severely impair EPC migration. These results suggest that the underlying mechanism for this impaired EPC migration is linked to the CXCR4/Pi3K/Akt/eNOS signaling pathway. The results of this work suggest that (a) increased oxidative stress plays an important role in EPC dysfunction in DM, (b) the underlying mechanism for impaired EPC migration in DM is linked to the CXCR4/Pi3K/Akt/eNOS signaling pathway, and (c) red wine upregulates the expression levels of several members of the SDF1α/CXCR4/Pi3K/Akt/eNOS signaling pathway which results in increased EPC migration and reduces EPC senescence. These findings emphasize the important role of antioxidant therapy in DM, and we suggest that CXCR4/Pi3K/Akt/eNOS signaling pathway could be targeted therapeutically to rescue the impaired migration of EPCs and restore their neovascularization capacity in DM patients.