INTRODUCTION Atherosclerosis is an arterial disease charac- terized by the accumulation of lipids and fatty tissue within the vascular wall. The pathologi- cal complications of atherosclerosis, namely heart attacks and strokes, remain the leading cause of mortality in the Western world. It has long been known that early atherosclerosis is focal in nature — early lesions localize prefer- entially in regions of arterial branching and curvature where blood flow patterns are multi- directional and highly disturbed (1–3). This has motivated the notion that disturbed flow acts as a localizing factor for atherosclerosis. Atherogenesis likely involves dysfunction of the vascular endothelium, the monolayer of cells lining the inner surfaces of all blood ves- sels (2,4,5); however, how disturbed flow initi- ates and modulates endothelial dysfunction remains unknown. Over the past two decades, our understand- ing of the role of endothelium in overall vascu- lar homeostasis has evolved considerably. The Differential Responsiveness of Vascular Endothelial Cells to Different Types of Fluid Mechanical Shear Stress Abdul I. Barakat * and Deborah K. Lieu Department of Mechanical and Aeronautical Engineering, University of California, Davis, CA Abstract Early atherosclerotic lesions localize preferentially in arterial regions exposed to low flow, oscil- latory flow, or both; however, the cellular basis of this observation remains to be determined. Atherogenesis involves dysfunction of the vascular endothelium, the cellular monolayer lining the inner surfaces of blood vessels. How low flow, oscillatory flow, or both may lead to endothelial dysfunction remains unknown. Over the past two decades, fluid mechanical shear (or frictional) stress has been shown to intricately regulate the structure and function of vascular endothelial cells (ECs). Furthermore, recent data indicate that beyond being merely responsive to shear stress, ECs are able to distinguish among and respond differently to different types of shear stress. This review focuses on EC differential responses to different types of steady and unsteady shear stress and discusses the implications of these responses for the localization of early atherosclerotic lesions. The mechanisms by which endothelial differential responsiveness to different types of flow may occur are also discussed. Index Entries: Shear stress; endothelium; mechanotransduction; atherosclerosis; hemodynamics. *Author to whom all correspondence and reprint requests should be addressed. E-mail: abarakat@ ucdavis.edu REVIEW ARTICLE © Copyright 2003 by Humana Press Inc. All rights of any nature whatsoever reserved. 1085-9195/03/38/323–343/$20.00 Cell Biochemistry and Biophysics 323 Volume 38, 2003 323-344/Barakat 7/17/03 1:13 PM Page 323