The response-to-retention hypothesis of early atherogenesis.

Many processes have been implicated in early atherogenesis. These include endothelial denudation, injury, or activation, including shear stress–related events; local adherence of platelets; lipoprotein oxidation; lipoprotein aggregation; macrophage chemotaxis and foam cell formation; and smooth muscle cell alterations. Which process, if any, could be regarded as the key event in early atherogenesis, ie, absolutely required, yet also sufficient as the sole pathological stimulus in an otherwise normal artery to provoke a cascade of events leading to lesion formation? The work of many investigators, which we summarize here, strongly supports subendothelial retention of atherogenic lipoproteins as the central pathogenic process in atherogenesis (for prior reviews, see References 1 through 61 2 3 4 5 6 ). Our thesis is that other contributory processes are either not individually necessary or are not sufficient. Most often, they are merely normal, expected responses of otherwise-healthy tissue to the presence of retained lipoproteins. It is instructive to catalog other processes that have been argued to be central to the initiation of atherogenesis. The first is endothelial denudation,7 8 9 injury,10 or activation,11 12 as outlined in the “response-to-injury” hypothesis of Ross, Glomset, and coworkers. Although this important hypothesis has stimulated much of the work that we cite here, there is no definitive evidence in vivo that endothelial injury is either necessary or sufficient for lesion formation. The response-to-injury hypothesis originally presupposed endothelial desquamation as the key event in atherogenesis.7 8 9 It is now clear, however, that developing atheromata are covered by an intact endothelial layer throughout most stages of lesion progression: lipoprotein retention, fatty streak formation, and formation of advanced lesions.5 6 12 13 14 15 In humans, only the most complicated, ulcerated lesions lose their endothelial layer. Furthermore, in some experimental models, an intact endothelium is required …