(i) Shear stress………..……….XXIII

(1)

ABBREVIATIONS………....I

INTRODUCTION………...III The endothelium………..………..IV Arterial remodeling………..………..VI Endothelial cell dysfunction……….………...X Impact of atherosclerosis and cardiovascular disease………..………...XIII Treatment options………...………...XI In vivo models of atherosclerosis……….XV The mechanism behind atherogenesis………XVI Lipoproteins and LDL………...…………...……..XIX LDL particles and their role in atherosclerosis………..…………..XX MPO and its action on LDL………..………..XXI Atherosclerosis contributing factors………...……….XXIII

(i) Shear stress………..……….XXIII

(ii) EC permeability, scavenger receptors and inflammatory state………….…………...XXIV

(iii)Haemostasis………...………XXV

Angiogenesis………...…...…XXVII

Cell motility in angiogenesis……….…XXX

MicroRNAs………..…………..XXXV

Role of microRNAs in atherosclerosis………...………XXXVIII

(2)

Role of microRNAs in angiogenesis……….XXXIX

MicroRNA 22……….……….XLI

AIM OF THE STUDY………..XLIII

RESULTS PART 1: THE EFFECT OF MYELOPEROXIDASE OXIDIZED LDL ON

PERICELLULAR FIBRINOLYSIS IN ENDOTHELIAL CELLS………...XLV

Fibrinolytic process on the cell surface………...2

Effects of TNF-ɑ on the fibinolytic process at the surface of EA.hy 926………...2

Effect of native LDL and Mox-LDL on the fibrinolytic processes at the surface of EA.hy 926 endothelial cells………...2

RESULTS PART 2: MYELOPEROXIDASE OXIDIZED LDL AND ITS EFFECT ON ENDOTHELIAL CELL MOTILITY………..…...XLVII MPO-oxidized LDL (Mox-LDL) interferes with cell behavior in HUVECs………..v

Mox-LDL decreases tubulogenesis in HUVECs……….v

Mox-LDL inhibits in vitro wound healing of endothelial cell monolayers………vi

MPO-modified LDL inhibits cell migration in HUVECs………..vi

Mox-LDL does not interfere with HUVEC proliferation or viability………...vii

The effect of Mox-LDL on markers of adhesion foci………...vii

microRNA signature of Mox-LDL HUVECs treatment………..viii

Angiogenesis-related gene expression profiling in Mox-LDL treated HUVECs……….viii

(3)

miR-22 knock-down prevents HO-1 expression and induction by Mox-LDL in HUVECs……..ix miR-22 knockdown reverses MPO-modified LDL effect on tubulogenesis………..ix

(i) Shear stress………..……….XXIII

TABLE OF CONTENTS

ABBREVIATIONS………....I

(i) Shear stress………..……….XXIII

(ii) EC permeability, scavenger receptors and inflammatory state………….…………...XXIV

(iii)Haemostasis………...………XXV

Angiogenesis………...…...…XXVII

Cell motility in angiogenesis……….…XXX

MicroRNAs………..…………..XXXV

Role of microRNAs in atherosclerosis………...………XXXVIII

Role of microRNAs in angiogenesis……….XXXIX

MicroRNA 22……….……….XLI

AIM OF THE STUDY………..XLIII

RESULTS PART 1: THE EFFECT OF MYELOPEROXIDASE OXIDIZED LDL ON

PERICELLULAR FIBRINOLYSIS IN ENDOTHELIAL CELLS………...XLV

Fibrinolytic process on the cell surface………...2

Effects of TNF-ɑ on the fibinolytic process at the surface of EA.hy 926………...2

Effect of native LDL and Mox-LDL on the fibrinolytic processes at the surface of EA.hy 926 endothelial cells………...2

RESULTS PART 2: MYELOPEROXIDASE OXIDIZED LDL AND ITS EFFECT ON ENDOTHELIAL CELL MOTILITY………..…...XLVII MPO-oxidized LDL (Mox-LDL) interferes with cell behavior in HUVECs………..v

Mox-LDL decreases tubulogenesis in HUVECs……….v

Mox-LDL inhibits in vitro wound healing of endothelial cell monolayers………vi

MPO-modified LDL inhibits cell migration in HUVECs………..vi

Mox-LDL does not interfere with HUVEC proliferation or viability………...vii

The effect of Mox-LDL on markers of adhesion foci………...vii

microRNA signature of Mox-LDL HUVECs treatment………..viii

Angiogenesis-related gene expression profiling in Mox-LDL treated HUVECs……….viii

miR-22 knock-down prevents HO-1 expression and induction by Mox-LDL in HUVECs……..ix miR-22 knockdown reverses MPO-modified LDL effect on tubulogenesis………..ix

HO-1 overexpression inhibits tubulogenesis………..ix

SUPPLEMENTARY DATA………...XLIX

DISCUSSION………...…….LIX

GENERAL CONTEXT AND PERSPECTIVES……….……..………..LXXIX

REFERENCES……….…………...LXXXIII