Effect of Fluid Shear Stress on the Permeability of the Arterial Endothelium OLAKUNLE OGUNRINADE,GERI T. KAMEYA, and GEORGE A. TRUSKEY Department of Biomedical Engineering, Duke University, Durham, NC (Received 11 July 2001; accepted 16 January 2002) Abstract—The localization of atherosclerotic lesions is due, in part, to regional variations in the permeability of arterial en- dothelium to macromolecules. In turn, endothelial permeability may be influenced by fluid shear stresses. The spatial variation in endothelial permeability is reviewed and evidence for shear stress dependence upon permeability is presented. These results are examined in light of various signaling mechanisms that increase permeability by increasing the transport of water and macromolecules through the junctions separating endothelial cells. Signaling pathways cause a change in the dense periph- eral band of actin and actin stress fibers or alter the phospho- rylation of junction proteins which affects their ability to local- ize in junctions. Future directions to clarify the effect of shear stress on permeability are considered. © 2002 Biomedical En- gineering Society. DOI: 10.1114/1.1467924 Keywords—Arterial fluid mechanics, Macromolecular trans- port, Atherosclerosis, Low density lipoprotein. INTRODUCTION A major function of vascular endothelium is the regu- lation of the transport of macromolecules into the arterial wall and surrounding tissue. All endothelium exhibit some permeability to macromolecules and alter perme- ability in response to a number of agents such as cytok- ines and vasoactive molecules e.g., thrombin, histamine, nitric oxide. Large arteries exhibit discrete sites of el- evated permeability that are associated with a small num- ber of endothelial cells. Differences in the frequency, area, and permeability of sites of elevated low density lipoprotein LDL permeability around arterial branches may influence the subsequent accumulation of LDL within the arterial wall. 59 Although the permeability of the endothelium to macromolecules is not altered during the early stages of atherosclerosis, 105 the localization of atherosclerosis in rabbits is correlated with sites of el- evated permeability. 87 In addition, the accumulation, modification, and residence time 105,117 of LDL within the vessel wall clearly influence lesion progression. 136 Macromolecular transport across endothelium occurs either through the intercellular junctions between endot- helial cells, across endothelial cells by vesicular trans- port, or the formation of transient channels resulting from vesicle fusion Fig. 1. Reorganization of the inter- cellular junctions is believed to be the primary mecha- nism by which endothelial permeability to water, small and large solutes is increased. 130,131 Such reorganization involves actin and myosin or direct dissolution of junc- tional contacts. 79 Elucidating the molecular events under- lying the control of the cytoskeleton and endothelial junctional integrity is important in understanding the regulation of endothelial permeability by a variety of agents, including shear stress. Evidence for a role for hemodynamics in atheroscle- rosis is based upon the distribution of atherosclerotic lesions and the effect of fluid shear stress on vascular endothelium. Atherosclerotic lesions occur preferentially at arterial branches and along curved arteries such as the aortic arch and coronary arteries. Several studies have demonstrated that intimal thickening and lesion size are inversely correlated with shear stress 50 or the extent of flow oscillation. 67 Spatial and temporal shear stress gra- dients during the cardiac cycle 23,42 as well as longer term variations in shear stress 51 have been implicated in the disease process. Competing shear stress dependent pro- cesses further complicate the elucidation of the effect of flow on atherosclerosis. 50 In this review we consider the effect of shear stress on endothelial permeability and the mechanism by which this might occur. The routes for transport across the endothelium are presented first. Next, evidence for an effect of shear stress upon permeability is examined. Signaling pathways that are believed to be involved in increased permeability due to agonists and shear stress are discussed. Finally, a brief discussion on the perti- nence of shear stress and increased permeability to ath- erosclerosis is presented. Address correspondence to George A. Truskey, PhD, Department of Biomedical Engineering, 136 Hudson Hall, Box 90281 Campus, Duke University, Durham, NC 27708-0281. Annals of Biomedical Engineering, Vol. 30, pp. 430–446, 2002 0090-6964/2002/304/430/17/$15.00 Printed in the USA. All rights reserved. Copyright © 2002 Biomedical Engineering Society 430