Atherosclerosis and its Devastating Clinical Complications
Atherosclerosis and its devastating clinical complications -- arterial thrombosis, ischemia and infarction of the heart, brain and other vital organs, ruptured aortic aneurysms and peripheral vascular insufficiency -- continue to account for the majority of the morbidity and mortality in the adult populations of industrialized nations. Atherosclerosis is a progressive multifactorial process characterized initially by the subendothelial intimal accumulation of lipid-rich macrophages and T lymphocytes ("fatty streaks"), followed by lesions composed of layers of foam cells and proliferating smooth muscle cells with deposition of extracellular matrix ("atheroma"). The disease focally affects the aorta, carotid, coronary, iliac and femoral arteries. Cardio-vascular risk factors include features related to life-style, such as cigarette smoking and obesity, as well as intrinsic factors such as hypertension, hypercholesterolemia and diabetes, which contribute to the pathological mechanisms that make the vascular endothelium dysfunctional, thereby inducing the early processes of atherosclerosis. However, since these factors affect the entire vascular system, they are unlikely to determine alone the focal nature of atherosclerosis. In contrast, the hemodynamic forces imposed on the vascular wall by pulsatile blood flow vary locally, depending on the arterial geometry and architecture and, therefore, are likely candidates for localized alterations. Indeed, evidence accumulates that the localization of atherosclerotic plaques correlates with areas of low and/or oscillating fluid wall shear stress. Moreover, differences in cellular composition between upstream and downstream parts of plaques have been observed, which might refer to a role for arterial flow in the distribution of different cell types. During the last decade, hemodynamics are increasingly recognized as another component playing an important role in the pathophysiology of atherosclerosis.
Although the presence and role of lymphocytes and macrophages during the atherosclerotic process is now well established, the mechanisms of recruitment and accumulation of these immunocompetent cells within the vascular wall lesions remain obscure and poorly understood. It is becoming increasingly clear that factors important for crosstalk between cells, such as chemokines, gap junctions and adhesion molecules show altered expression patterns in atherosclerotic plaques.
In some of our research projects, we propose to determine in a controlled ex vivo model of early stage atherosclerosis whether expression of chemokines, connexins and adhesion molecules may be implicated in the endothelial dysfunction and could contribute this way to the recruitment of T lymphocytes and monocytes/macrophages in the vessel wall, and examine how cardiovascular risk factors, e.g. hypertension, smoking, diabetes, hyperlipidemia, as well as their treatment, e.g. normal pressure, PPAR agonists (anti-diabetic drugs) and statins (lipid-lowering drugs) may influence the initial phase of atherosclerotic plaque development.
With the use of our unique ex-vivo artery perfusion system, which can combine both hemodynamic and extrinsic risk factors, we will be able to investigate in great detail the pathophysiology of atherosclerosis as well as better understand the beneficial mechanism of different treatments.