Travelling to Rome : inflammation, endoplasmic reticulum stress and angiogenesis during atherosclerotic plaque development

Cardiovascular diseases are the leading cause of death worldwide followed by cancer. Atherosclerosis, the major underlying cause of cardiovascular diseases, is a syndrome affecting medium-sized and large arteries. Progressive atherosclerotic disease and the development of acute lesion instability are linked with plaque angiogenesis. It is widely accepted as an inflammatory disease involving both innate and adaptive immune mechanisms. During the development of an atherosclerotic plaque, lesions are infiltrated by inflammatory cells and professional antigen presenting cells (APCs). Identifying the leukocyte populations and APCs involved during plaque maturation is of great interest for understanding the pathogenesis of the disease and providing targets for therapeutic interventions aimed at controlling the activation state of culprit cells.
Endothelial dysfunction (ED) is another key event in the initiation and progression of atherosclerosis and it serves as a risk factor for the development of cardiovascular events. Stimuli that cause oxidative stress, endoplasmic reticulum (ER) stress, metabolic stress and genotoxic stress may lead to ED through enhanced endothelial cell (EC) injury or death, conditions which are considered essential for plaque rupture. Unfolded protein response (UPR) is the front line of defense during ER stress, aiming to re-establish cellular homeostasis and rescue the cell from apoptosis. Although many steps of the ER stress signalling pathway have been elucidated, coordination between intracellular ER stress and cell-surface prompted survival signals has been poorly investigated.
Paraphrasing the modern version of the medieval sentiment “all roads lead to Rome” to “all cellular paths which lead to atherosclerosis”, my dissertation addresses the pathophysiology of atherosclerosis from two different perspectives.
iNKT cells, inflammation and angiogenesis
In the present dissertation we provide evidence for the first time for the involvement of CD1d-expressing APCs and invariant natural killer T (iNKT) cells in disease progression in patients suffering from atherosclerosis. CD1d-expressing APCs are present in advanced atherosclerotic plaques and are more abundant in plaques with ectopic neovascularization. Patients with active disease have reduced numbers of iNKT cells circulating in blood and the iNKTs present in plaques are more responsive to lipid antigens than the ones found in blood. The in vitro data demonstrate that lipid activation of plaque-derived iNKTs increases the migration capacity and angiogenic activity of EC in an IL-8 dependent manner. Further investigations revealed that the stimulatory effects of EC on migration, sprouting and actin reorganization from activated iNKT cells are driven through EGFR with selective downstream activation of focal adhesion kinase (FAK) and Src. These findings introduce iNKT cells as novel cellular candidates promoting plaque neovascularization and destabilization in human atherosclerosis. In addition the data demonstrate that EGFR inhibition may represents a novel therapeutic modality for the control of inflammation-associated neovascularization within developing atherosclerotic plaques.
ER stress and T-cadherin
T-cadherin is an unusual member of the cadherin superfamily of surface adhesion molecules. It is widely expressed in the cardiovascular system and is upregulated during proliferative vascular disorders such as atherosclerosis. This dissertation provides evidence for the importance of T-cadherin to influence UPR signalling and EC survival during ER stress. During UPR T-cadherin levels are significantly elevated. Overexpression or silencing of T-cadherin in EC respectively attenuated or amplified the ER stress-induced increase in phospho-eIF2alpha, Grp78, CHOP and active caspases. Upregulation of T-cadherin expression on EC during ER stress attenuates the activation of the proapoptotic PERK (PKR (double-stranded RNA-activated protein kinase)-like ER kinase) branch of the UPR cascade and thereby protects EC from ER stress-induced apoptosis.