Many of the inflammatory responses and pathways that are initiated in the microvasculature by hypercholes-terolemia have also been implicated in the development of atherosclerotic plaques. Whether the early inflammatory responses seen in venules influence the development of lesions in large vessels remains unclear. Since the inflammatory responses to hypercholesterolemia appear to be experienced by all tissues in the body, it appears tenable that the large endothelial surface area (> 500 m2) within the microvasculature may serve as a motor that drives the systemic immune response, ultimately leading to lesion development in large arteries. It is clear, however, that this risk factor, while rendering tissue more likely to experience an ischemic episode through the development of atherosclerosis, also predisposes organs to greater microvascular dysfunction and more tissue injury following a given ischemic insult. Hence, an improved understanding of the mechanisms that underlie the inflammatory phenotype that is assumed by the microvasculature during hypercholes-terolemia may reduce the morbidity and mortality associated with cardiovascular diseases.
Adhesion molecules: Molecules expressed on the endothelial cells, leukocytes, and platelets, which bind their ligands on other cells, thereby mediating the interactions between the circulating cells and the vessel wall.
Blood cell recruitment: The adhesion of blood cells (leukocytes and platelets) to the vascular endothelium at sites of inflammation.
I/R: Ischemia/reperfusion, or the cessation and restoration of blood flow to an organ or tissue.
Oxidant stress: This usually occurs as a result of an imbalance between nitric oxide and oxidant-generating systems, resulting in an overall increase in the oxidative capacity of the tissue.
OxLDL: Low-density lipoprotein (normally responsible for carrying cholesterol to tissues) that is oxidatively modified, thereby attaining proinflammatory properties.
Supported by a grant from the National Heart, Lung and Blood Institute (HL26441).
Granger, D. N. (2003). Risk factors for cardiovascular disease amplify reperfusion-induced inflammation and microvascular dysfunction. In Molecular Basis for Microcirculatory Disorders, G. W. SchmidtSchonbein and D. N. Granger, eds., pp. 333-342. Paris: Springer-Verlag France.
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Laroia, S. T., Ganti, A. K., Laroia, A. T., and Tendulkar, K. K. (2003). Endothelium and the lipid metabolism: The current understanding. Int. J. Cardiol. 88, 1-9. Napoli, C., and Lerman, L. O. (2001). Involvement of oxidation-sensitive mechanisms in the cardiovascular effects of hypercholesterolemia. Mayo Clin. Proc. 76, 619-631. This article focuses on the pathways involved in the oxidant-mediated events that are associated with hyper cholesterolemia and examines potential therapeutic strategies in this context.
Ross, R. (1999). Atherosclerosis—an inflammatory disease. N. Engl. J. Med. 340, 115-126. This is a comprehensive review of the mechanisms involved in the development of atherosclerosis, many of which are now being addressed in the microvascular responses to hypercholesterolemia. Scalia, R., Appel 3rd , J. Z. and Lefer, A. M. (1998). Leukocyte-endothe-lium interaction during the early stages of hypercholesterolemia in the rabbit: Role of P-selectin, ICAM-1, and VCAM-1. Arterioscler. Thromb. Vasc. Biol. 18, 1093-1100. Stokes, K. Y., Clanton, E. C., Clements, K. P., and Granger, D. N. (2003). Role of interferon-gamma in hypercholesterolemia-induced leukocyte-endothelial cell adhesion. Circulation 107, 2140-2145. Stokes, K. Y., Cooper, D., Tailor, A., and Granger, D. N. (2002). Hyper-cholesterolemia promotes inflammation and microvascular dysfunction: Role of nitric oxide and superoxide. Free Radic. Biol. Med. 33, 1026-1036. This provides a more in-depth review of the topic discussed here, with particular reference to the role of oxidative stress in the responses to hypercholesterolemia.
Karen Stokes earned her Ph.D. in physiology from Trinity College, Dublin. She is currently an instructor in the Department of Molecular and Cellular Physiology at Louisiana State University Health Sciences Center in Shreveport. Her research interests include the microvascular responses to ischemia-reperfusion and to hypercholesterolemia.
D. Neil Granger, Ph.D., is Boyd Professor and Head of the Department of Molecular and Cellular Physiology at Louisiana State University Health Sciences Center in Shreveport. He has served as President of the Micro-circulatory Society, President of the American Physiological Societ, and Editor-in-Chief of Microcirculation.
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