טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentBerger Yaroslav
SubjectEndothelial Progenitor Cells in Acute Myocardial Infarction
and Sleep Disordered Breathing, and Identification
of Monocyte-Derived Immature Dendritic
Cells...end of subject missing
DepartmentDepartment of Medicine
Supervisor Dr. Lena Lavie
Full Thesis textFull thesis text - English Version


Abstract

The aims of the present study were first to determine the numbers and angiogenic functions of endothelial progenitor cells (EPCs) in patients with acute myocardial infarction (AMI) and coexistent sleep disordered breathing (SDB) and second to identify additional mononuclear derived cells with endothelial-like and angiogenic properties, which may contribute to vascular repair and homeostasis.

Part 1. Blood samples were taken from nineteen male AMI patients with SDB (AMI-SDB), with oxygen desaturation index (ODI) ≥5 events/hour and 21 male AMI patients without SDB ((AMI-only), with ODI <5 events/hour). Circulating EPCs, angiogenic T cells and vascular endothelial growth factor (VEGF) in monocytes were significantly higher in AMI-SDB patients while plasma stromal cell-derived factor (SDF)-1α levels were significantly lower. Also, endothelial cell colony-forming-units (EC-CFUs) numbers and EC-CFUs paracrine effects on endothelial tube formation were significantly higher in AMI-SDB patients as compared to AMI-only patients. Similarly, in cell cultures from healthy subjects, exposure to intermittent hypoxia (IH) in vitro increased EC-CFU numbers and their paracrine effects on endothelial tube formation, as compared to normoxia.

Part 2. In addition, we investigated endothelial-like properties in monocyte-derived immature dendritic cells DCs (Mo-iDCs) by analyzing the changes in morphology and function after a short-term fibronectin (FN) treatment. Within 90 min of re-plating onto FN a swift morphologic transformation of round (Mo-iDCs) into spindle-shaped iDCs (sp-iDCs) was also characterized by redistribution of mitochondria into dendritic spindles, decreased dendritic cell-associated marker CD1c, and increased endothelial cell-associated marker CD141 expression. Functionally, sp-iDCs acquired Ulex-europaeus-agglutinin-1 lectin binding and phagocytosis was decreased. Intracellular VEGF was increased in FN-treated cells. Furthermore, FN-treatment of Mo-iDCs induced a paracrine angiogenic effect on endothelial tube formation, which was abolished by inhibiting ERK1/2 or VEGF. Inhibiting p38MAPK had no effect on endothelial tube formation.

Conclusions: Co-existent SDB in AMI patients increased the mobilization, proliferative and angiogenic capacities of EPCs, angiogenic T cells numbers and VEGF expression in monocytes, compared to AMI patients without SDB. Moreover these changes were attributed to IH as attested by the in vitro experiments.

In additional sets of experiments a population of monocyte-derived cells was identified as sp-iDCs and expressed endothelial-like and angiogenic markers. This may act as an immediate protective mechanism to maintain vascular homeostasis. Moreover, inducing sp-iDCs by short term FN-treatment or ERK1/2 modulation might be considered as new approaches for regulating angiogenesis through the production/inhibition of pro-angiogenic mediators, thus supporting a role for FN and Mo-iDCs in vascular function and angiogenesis.