ABSTRACT
Cholesterol is one of the major lipid components of the plasma membrane in all mammalian cells where cholesterol:phospholipids molar ratio may be as high as 1:1 (Yeagle 1985). It is well known that maintaining normal levels of cholesterol is essential for cell function and growth but that the excess of cholesterol above the physiological level is cytotoxic (Kellner-Weibel et al. 1999, Simons and Ikonen 2000, Yeagle 1985, Yeagle 1991). Numerous studies have shown that one of the major properties of cholesterol is its ability to alter the physical properties of the lipid membrane bilayer including ordering of the phospholipids (e.g., Demel et al. 1972, Demel and De Kruyff 1976, Stockton and Smith 1976), membrane fl uidity
1Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612. 2College of Medicine, Department of Cardiology, UCSD, Dan Diego, CA 92093. 3Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210. 4Department of Physics and Astronomy, University of Missouri, Columbia, MO 65211. *Corresponding author: levitan@uic.edu
(e.g., Brulet and McConnell 1976, Cooper 1978, Xu and London 2000), and membrane elastic modulus (Evans and Needham 1987, Needham and Nunn 1990). However, it is much less clear how changes in the level of membrane cholesterol affect the physical properties of the cellular envelope, a bi-component system composed of the membrane lipid bilayer and the underlying cortical cytoskeleton. Our studies focus on the impact of cholesterol on the stiffness, contractility and membrane-cytoskeleton adhesion of vascular endothelial cells. Our fi rst unexpected and surprising observation was that it is cholesterol depletion rather than cholesterol enrichment that increases endothelial stiffness, enhances contractility and strengthens membrane-cytoskeleton adhesion. As described in more detail below, this was unexpected because an increase in membrane cholesterol typically results in increased stiffness of the lipid bilayer, contrary to our observations in endothelial cells. It was a further surprise that exposing endothelial cells to oxidized modifi cations of low density lipoproteins (oxLDL) had the same effect on endothelial biomechanics as cholesterol depletion. In this chapter, we will discuss these fi ndings in the context of endothelial function in health and disease.
