[Frontiers in Bioscience 9, 3276-3285, September 1, 2004] 3276 MOLECULAR AND BIOLOGICAL EFFECTS OF HEMODYNAMICS ON VASCULAR CELLS Sanjeev Pradhan and Bauer Sumpio Department of Surgery, Yale University School of Medicine and VA Connecticut TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Localization of atherosclerosis 4. Hemodynamic forces 5. Effects on the extracellular matrix and vascular cells 6. Intracellular effects 7. Conclusion 8. References 1. ABSTRACT A variety of systemic risk factors, including smoking, hypertension, hyperlipidemia and diabetes have been found to promote atherosclerosis. Although these elements affect blood vessels equally, clinically significant lesions develop at predictable locations, i.e., major branch points and bifurcations. This suggests that the development of clinically significant atherosclerotic plaques involves a complex interplay between vascular anatomy, vascular biology and hemodynamic forces. Cyclic strain, circumferential pulsatile pressure exerted upon a vessel wall, has been found to cause changes in endothelial cells that tend to disfavor atherosclerosis formation. Cultured endothelial cells have been shown to migrate, proliferate and alter cytoskeletal alignment in response to cyclic strain. Levels of macromolecules such as prostacyclin, endothelin, nitric oxide and tissue plasminogen activator have been found to be altered by cyclic strain. Additionally, cyclic strain has been shown to stimulate expression of cellular adhesion molecules such as ICAM-1 and intracellular second messenger systems such as the adenylate cyclase- cAMP, diacylglycerol-IP 3 , and protein kinase C pathways. This article reviews the most current pertinent literature and summarizes the presently known effects of cyclic strain on endothelial cells. 2. INTRODUCTION Atherosclerosis is a chronic disease with systemic risk factors. Smoking, hypertension, hypercholesterolemia, and diabetes are processes that affect the vasculature as a whole. Atherosclerotic plaques are characterized by the accumulation of cholesterol, macrophages, smooth muscle cells (SMC), extracellular matrix (ECM) proteins and thrombus in the intimal layer of the vessel wall. As the plaque increases in size, the lumen of the vessel narrows until it is completely occluded by plaque and thrombus. The formation of atherosclerotic plaque involves multiple interrelated mechanisms. The initiating event is the activation of endothelial cells, which has several consequences (Figure 1). Exposure of subendothelial collagen facilitates platelet attachment, aggregation, and EC secretion of a variety of cytokines, including platelet derived growth factor (PDGF). PDGF acts directly on vascular SMC to cause them to proliferate and migrate to the intima, which is a key event of atherosclerosis. (1) Intimal SMC produce transforming growth factor-beta (TGF-β), which acts in an autocrine fashion to cause the secretion of collagen and other proteins into the extra- cellular matrix (ECM). (2) Concurrent damage to the endothelium impairs its barrier function, allowing for deposition of cholesterol and migration of macrophages and lymphocytes into the intima. Further endothelial damage by the growing plaque impairs the secretion of nitric oxide (NO), prostacyclin (PGI2) and tissue plasminogen activator (tPA) which results in the propagation of thrombus. (3) 3. LOCALIZATION OF ATHEROSCLEROSIS The lesions of atherosclerosis, interestingly, localize in distinct sites within the vasculature, especially affecting the coronary arteries, the major branches of the aortic arch, and the abdominal aorta and its visceral and major lower extremity branches (Figure 2). (4) The carotid bifurcation is a good example of this localizing process. Plaque formation occurs at the origin of the internal carotid artery, whereas, the distal internal carotid artery and the proximal common carotid artery do not demonstrate any plaque formation. (5) The configuration and branch angle of the internal carotid sinus produce an area of altered hemodynamics along the outer wall of the vessel, where atherosclerotic plaques tend to form. (6) In one study, human carotid bifurcations obtained at autopsy were used to construct glass and plexiglass models for flow visualization and velocity measurements with laser doppler anemometry. Using quantitative measurements, the authors were able to correlate the presence (or absence) of atherosclerosis in the cadaveric carotid bifurcation