Adhesion of circulating monocytes (white blood cells that become particle-ingesting macrophages once they enter another tissue) to the surface of intact endothelial cells appears to be an early event in the development of atherosclerotic lesions [Hajjar DP and Nicholson AC, 1995]. Investigators have determined that monocyte binding to the endothelium of animals fed a high-cholesterol diet is preceded by expression of the vascular cell adhesion molecule (VCAM) and that a lipid is ultimately responsible for activating the gene for VCAM [Gimbrone MA, Jr. Cybulsky MI, et al. Anne New York Acad Sci. 1995:748:122].
The expression of VCAM on the endothelium can be altered by abrupt changes in the direction and force of local blood flow at atherosclerotic lesion-prone sites in the circulatory system [Gimbrone MA and Cybulsky MI, 1995]. Specifically, a shear-stress responsive element, identified in the regulatory region of several genes, has been show to promote the expression of adhesion molecules as well as other molecular factors that participate in atherogenesis. One mechanism by which abnormal shear forces on the surface of an endothelial cell can induce the expression of genes that contribute to the development of atherosclerosis may involve certain transcription factors (proteins that bind to regulatory regions of genes) that are produced in response to shear stress [Davies PF, Tripathi SC. Circulation Research. 1993;72:239. Hajjar DP and Nicholson AC, 1995].
After adhesion, monocytes insinuate themselves between the tight junctions of the endothelial cells and enter the subendothelial space [Hajjar DP and Nicholson AC, 1995].
Immune mechanisms also appear to play a role in atherogenesis [Ip JH, et al, 1994. Hajjar DP and Nicholson AC, 1995]. In particular, T-lymphocytes (cells responsible for the cell-mediated immune response) have been found to be present, albeit in small numbers, in both early fatty lesions and in advanced fibrous lesions in humans. It has been suggested that activation of T-lymphocytes during atherogenesis may be similar to other immune responses in which T-cells help to mobilize macrophages.
After monocytes have migrated beneath the endothelial layer into the intima, they are transformed into a phagocytic state (macrophages) in which they ingest modified lipids (primarily oxidized lipids) [Hajjar DP and Nicholson AC, 1995]. As atherogenesis progresses, these macrophages take on a “foamy” appearance (thus their designation as “foam cells”) and become one of the primary components of the fatty streak.
The mechanisms by which macrophages accumulate lipids within the intima and the possible role of T-lymphocytes in this process are major areas of research.
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