No abstract

Initial description of apolipoprotein (apo) E-deficient transgenic mice demonstrated the development of severe hypercholesterolemia due to probable delayed clearance of large atherogenic particles from the circulation. Examination of these mice demonstrated foam cell accumulation in the aortic root and pulmonary arteries by 10 weeks of age. In the present study, the animals were fed either chow or a high-fat, Western-type diet and examined at ages ranging from 6 to 40 weeks. Gross examination by dissection microscopy revealed a predilection for development of lesions in the aortic root, at the lesser curvature of the aortic arch, the principal branches of the aorta, and in the pulmonary and carotid arteries. Monocyte attachment to endothelial cells was observed by light and electron microscopic examination at 6 weeks, the earliest time point examined. Foam cell lesions developed as early as 8 weeks, and after 15 weeks advanced lesions (fibrous plaques) were observed. The latter consisted of a fibrous cap containing smooth muscle cells surrounded by connective tissue matrix that covered a necrotic core with numerous foamy macrophages. Mice fed the Western-type diet generally had more advanced lesions than those fed a chow diet. The apoE-deficient mouse contains the entire spectrum of lesions observed during atherogenesis and is the first mouse model to develop lesions similar to those in humans. This model should provide numerous opportunities to study the pathogenesis and therapy of atherosclerosis in a small, genetically defined animal. ( Correspondence to Russell Ross, PhD, Department of Pathology, SM30, University of Washington, Seattle, WA 98195.The principal purpose of the present study was to analyze in detail the genesis of these lesions, including the nature of the cells involved, the sequence of cellular events, and the anatomic location of specific lesion types with increasing age and time on both a chow diet and a Western-type diet (0.15% by weight cholesterol). This study demonstrates that these animals develop a full range of lesions of atherosclerosis from fatty streaks to fibrous plaques; that the lesions are distributed throughout the arterial tree; and that in their development they contain many features of the specialized, chronic, inflammatory-fibroproliferative response characteristic of atherosclerosis seen in other species. Methods MiceControl and apoE-deficient male mice were second-or third-generation hybrid 129olaxC57BL/6 or 129olaxBALB/c mice derived from brother-sister matings using only apoEdeficient animals that were initially created by homologous recombination in embryonic stem cells.18 Both control and apoE-deficient mice were weaned at 4 weeks of age and maintained on chow for 1 week, at which time they were either maintained on chow (PicoLab Rodent Chow 20), which contained 4.5% fat by weight (0.02% cholesterol), or a Westerntype diet (Teklad Adjusted Calories Western-type diet), which contained 21% fat by weight (0.15% by weight cholesterol and 19.5% by weight casein w...

Abstract-Focal recruitment of monocytes and lymphocytes is one of the earliest detectable cellular responses in the formation of lesions of atherosclerosis. This localized accumulation of leukocytes is a multistep process in which the endothelium remains intact and may regulate leukocyte recruitment by expressing specific adhesion molecules. To examine the relationship of adhesion molecule expression to initiation factors and the sites of lesion formation, we analyzed the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and platelet-endothelial cell adhesion molecule-1 (PECAM-1) en face on the aortic endothelium of control mice and homozygous apolipoprotein E-deficient (ApoE Ϫ/Ϫ) mice that develop complex lesions of atherosclerosis similar to those in humans. In control mice, VCAM-1 staining was weak and limited to sites of altered blood flow. In contrast, in the ApoE Ϫ/Ϫ mice, VCAM-1 appeared to be localized over the surface of groups of endothelial cells in lesion-prone sites. Expression of VCAM-1 preceded lesion formation, and increased expression above control levels appeared to be correlated with the extent of exposure to plasma cholesterol. Although ICAM-1 was the most prominent adhesion molecule in lesion-prone sites, its expression appeared to be independent of plasma cholesterol levels and was upregulated in both ApoE Ϫ/Ϫ and control mice. At lesion-prone sites associated with altered blood flow, ICAM-1 was located over the surface of each endothelial cell and on microvilli, whereas VCAM-1 was confined to the cell periphery in non-lesion-prone sites. PECAM-1 was localized at the cell periphery throughout the aorta, and its expression did not appear to be regulated. Thus, the levels, localization, and characteristics of expression of VCAM-1, ICAM-1, and PECAM-1 appear to be differentially regulated. Upregulation of VCAM-1 and ICAM-1 is associated with sites of lesion formation. (Arterioscler Thromb Vasc Biol. 1998;18:842-851.)

In Drosophila, Slit at the midline activates Robo receptors on commissural axons, thereby repelling them out of the midline into distinct longitudinal tracts on the contralateral side of the central nervous system. In the vertebrate spinal cord, Robo1 and Robo2 are expressed by commissural neurons, whereas all three Slit homologs are expressed at the ventral midline. Previous analysis of Slit1;Slit2 double mutant spinal cords failed to reveal a defect in commissural axon guidance. We report here that when all six Slit alleles are removed, many commissural axons fail to leave the midline, while others recross it. In addition, Robo1 and Robo2 single mutants show guidance defects that reveal a role for these two receptors in guiding commissural axons to different positions within the ventral and lateral funiculi. These results demonstrate a key role for Slit/Robo signaling in midline commissural axon guidance in vertebrates.