(262c) Lipoprotein Entry into the Arterial Wall: Lipoprotein Interactions with Monocytes/Macrophages in Atherosclerosis

Important early events in atherosclerotic lesion development include accumulation of two lesion components that cross the endothelium from the blood ? low-density lipoprotein (LDL) and monocytes. These are both dramatically altered from the state in which they existed in blood, and they interact with each other. As this is a symposium honoring Professor Clark K. Colton, Ph.D., I would like to highlight findings emanating from when I was his postdoctoral fellow and refer to outgrowths of this research on which I have worked since my time with Dr. Colton. I had the great fortune to work with Dr. Robert Bratzler, Clark's then graduate student, under the co-supervision of Professors Colton, Ken A. Smith and Robert S. Lees, MD, on a project to understand rates at which lipoproteins get from blood into arteries in normal rabbit arteries as a basis to look at what features of this process change under pathological circumstances. Dr. Bratzler developed a technique for quantifying concentration profiles for radiolabeled LDL and other proteins across the rabbit aorta wall after in vivo circulation. From these profiles, mass transfer and reaction kinetic parameters governing accumulation were calculated. The articles published by our group highlighted these data, mathematical models predicting the data and transport parameters predicted from the models. These papers revealed then rates at which LDL, although over two million in molecular weight, passed both the endothelium and the internal elastic lamina, the two barriers bounding the inner intimal layer of the arterial wall where the early accumulations of LDL and monocyte-derived macrophages occur. Later, my graduate student at Case Western Reserve University, Marc Penn, developed a novel technique to obtain such concentration profiles with a resolution of 1-2 microns (instead of around ~10 microns) by injecting the protein horseradish peroxidase in vivo and quantifying images of its reaction product in the excised artery wall. Thus, concentration profiles could be discerned in the arterial walls of rats and mice instead of rabbits. The resulting articles answered questions related to altered transport during vascular injury and infection. The enhanced resolution also allowed Dr. Penn to develop and apply hybrid distributed and compartmental models to predict changes in transport parameters at the internal elastic lamina. Recently, Dr. Penn and his Ph.D. student, Kwangdeok Lee, have published their first articles using this technique to study altered transport into mouse vessels during atherogenesis They have found, for example, that the internal elastic lamina significantly changes its transport properties as the disease progresses. In parallel with these transport studies, my laboratory began in the late 70s and early 80s to explore whether LDL may be atherogenic not because of the effects of native LDL on cells, but because the LDL is first altered, and in its altered state, changes cell functions and causes cell injury. The discoveries reported in our early articles on the injurious effects of LDL after it becomes altered by oxidation contributed to the formulation of the ?lipoprotein oxidation theory of atherosclerosis.? More recently, we are exploring the interactions of these oxidized lipoproteins with monocyte/macrophages and the intercellular signaling processes by which these interactions convert monocytes to ?foam cells?, the lipid-engorged macrophages that are the hallmark of an early atherosclerotic lesion. These findings, too, are to the credit of the early studies with Colton, Bratzler, Smith, Lees, et al, showing the transport of LDL into the vessel wall. They focus on questions related to what happens in interactions between oxidized LDL and monocyte-derived macrophages that accumulate in an expanded intima. [REFERENCES] Bratzler RL, Chisolm GM, Colton CK, Smith KA, Zilversmit DB, Lees RS. The distribution of labeled albumin across the rabbit thoracic aorta in vivo. Circ Res. 1977;40(2):182-90. Bratzler RL, Chisolm GM, Colton CK, Smith KA, Lees RS. The distribution of labeled low-density lipoproteins across the rabbit thoracic aorta in vivo. Atherosclerosis. 1977;28(3):289-307. Massaro TA, Glatz CE, Peppas NA, Chisolm GM, Colton CK. Distribution of glycosaminoglycans in consecutive layers of the rabbit aorta. Artery. 1979;5(1):1-13. Chisolm GM 3rd, Bohrer MP, Colton CK, Smith KA, Lees RS. Transmural [125I]albumin concentration in the rabbit aorta during acute hypoxia. Atherosclerosis. 1983;46(2):195-202. Penn MS, Koelle MR, Schwartz SM, Chisolm GM. Visualization and quantification of transmural concentration profiles of macromolecules across the arterial wall. Circ Res. 1990;67(1):11-22. Penn MS, Chisolm GM. Relation between lipopolysaccharide-induced endothelial cell injury and entry of macromolecules into the rat aorta in vivo. Circ Res. 1991;68(5):1259-69. Penn MS, Saidel GM, Chisolm GM. Vascular injury by endotoxin: changes in macromolecular transport parameters in rat aortas in vivo. Am J Physiol. 1992;262(5 Pt 2):H1563-71. Penn MS, Saidel GM, Chisolm GM. Relative significance of endothelium and internal elastic lamina in regulating the entry of macromolecules into arteries in vivo. Circ Res. 1994;74(1):74-82. Penn MS, Chisolm GM. Oxidized lipoproteins, altered cell function and atherosclerosis. Atherosclerosis. 1994;108 Suppl:S21-9. Rangaswamy S, Penn MS, Saidel GM, Chisolm GM. Exogenous oxidized low-density lipoprotein injures and alters the barrier function of endothelium in rats in vivo. Circ Res. 1997;80(1):37-44. Penn MS, Rangaswamy S, Saidel GM, Chisolm GM. Macromolecular transport in the arterial intima: comparison of chronic and acute injuries. Am J Physiol. 1997 Apr272(4 Pt 2):H1560-70. Chisolm GM, Steinberg D. The oxidative modification hypothesis of atherogenesis: an overview. Free Radic Biol Med. 2000 15;28(12):1815-26. Lee K, Saidel GM, Penn MS. Macromolecular transport in the arterial wall: alternative models forestimating barriers. Ann Biomed Eng. 2005;33(11):1491-503. Lee K, Forudi F, Saidel GM, Penn MS. Alterations in internal elastic lamina permeability as a function of age and anatomical site precede lesion development in apolipoprotein E-null mice. Circ Res. 2005;97(5):450-6.