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Objective-To elucidate processes by which the antioxidant probucol increases lesion size at the aortic sinus and decreases atherosclerosis at more distal sites in apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice. Methods and Results-Male apoEϪ/Ϫ mice were fed high-fat chow with 1% (w/w) probucol or without (controls) for 6 months, before aortic sinus, arch, and descending aorta were analyzed separately for lesion size and composition. Compared with control, probucol significantly increased lesion size by 33% at the sinus, but it inhibited atherosclerosis at the descending aorta by 94%. Sites where atherosclerosis was inhibited contained substantially fewer macrophages, less lipids (cholesterol and cholesteryl esters), and endogenous antioxidant (␣-tocopherol), but not oxidized lipids, and the extent to which probucol metabolism occurred was increased. Compared with control, aortic sinus lesions of probucol mice contained a substantially increased content of extracellular matrix, but decreased total cell and macrophage density, comparable levels of lipids and ␣-tocopherol, and decreased concentrations of oxidized lipids (cholesteryl ester hydroperoxides, F 2 -isoprostanes, and 7-ketocholesterol). Conclusions-Probucol affects atherosclerosis in apoEϪ/Ϫ mice independent of the accumulation of arterial lipid oxidation products, thereby dissociating the 2 processes. Rather, probucol exerts antiinflammatory activity by decreasing accumulation of macrophages in lesions, and it promotes a more stable lesion composition at the aortic sinus. Key Words: antioxidants Ⅲ atherosclerosis Ⅲ collagen Ⅲ free radicals Ⅲ inflammation A therosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. 1 The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in and that oxidized LDL contributes to atherogenesis. 2 Oxidized LDL supports foam cell formation in vitro and other potentially pro-atherogenic activities, the lipid in human lesions is oxidized and contains oxidized LDL, and several different antioxidants inhibit atherosclerosis in animals. 1 In addition to LDL oxidation, other relevant oxidative events include the production of reactive oxygen and nitrogen species by vascular cells, 3 and oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. 1 However, despite abundant data, fundamental problems remain with implicating oxidative modification as a requisite cause for atherosclerosis. 1 These include the poor performance of antioxidants in limiting atherosclerosis or cardiovascular events from it, 4 and observations in animals that suggest dissociation between atherosclerosis and lipoprotein lipid oxidation. [5][6][7][8][9] To reconcile these discrepancies, the "oxidative response to inflammation" model of atherosclerosis 1 considers inflammation as a primary process of atherosclerosis, an...

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Transmission electron microscopy was used to investigate morphological changes in surface ultrastructure of rat uterine luminal epithelial cells and to determine how quickly and to what extent microvilli return to the apical surface after the period of uterine receptivity for blastocyst attachment. Major, observable, differences in the surface morphology of uterine epithelial cells from six groups of pregnant rats were found. On the afternoon of day 6 of pregnancy, the apical surface is typically flattened and consists mostly of irregular projections, but by the morning of day 7, short, irregular microvilli are already evident among the remaining irregular projections giving the cell surface a 'taller' profile. By the afternoon of day 7, the microvilli have increased in height and frequency. This trend continues until by day 9 of pregnancy, the apical surface bears microvilli that are long, thin, and comparatively regularly distributed. These ultrastructural alterations demonstrate that the plasma membrane transformation of early pregnancy which is essential for uterine receptivity for blastocyst attachment, is transient and is followed by the return of regular microvilli.

Ultrastructural changes in the plasma membrane of uterine epithelial cells in the pseudopregnant rat were examined to determine if these changes resemble those found during normal pregnancy and also to examine if the well-known membrane alterations of early pregnancy are intrinsic to uterine epithelial cells. Changes in the surface contours of uterine epithelial cells from the afternoon of day 6 to the morning of day 9 of pseudopregnancy were similar to those present after attachment in normal pregnancy although somewhat delayed. The presence of short, irregular microvilli was seen from as early as day 7 of pseudopregnancy, with regular microvilli returning to the epithelial surface by days 8-9 of pseudopregnancy but to a slightly lesser extent as compared to normal pregnancy. Furthermore, observations made on the afternoon of day 6 to the morning of day 7 of pseudopregnancy showed that the uterine lumen was closed down and that complete membrane flattening between opposing uterine epithelial cells was seen all along the uterus in the absence of a blastocyst. These observations establish that the "plasma membrane transformation" does not depend on blastocyst implantation.

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