Localization and smooth muscle cell composition of atherosclerotic lesions in Watanabe heritable hyperlipidemic rabbits.

Abstract

Morphological techniques (histology and electron microscopy), as well as immunofluorescence assays, were applied to the study of the localization and smooth muscle cell (SMC) composition of atherosclerotic lesions in Watanabe heritable hyperlipidemic (WHHL) rabbits during a 4.5-month period. Vascular segments from different arteries (carotid, coronary, and iliac arteries) or from the same vessel at different levels (aorta) of animals at days 7,15, 30, 40, 60, 90, and 135 showed that the atherosclerotic lesion first became visible at the level of the aortic arch in 60-day-old WHHL animals. Histological examination of serial cryosections from this vascular region indicated that the vascular lesion arose from a cavity in the media layer, located anatomically at the level of the juncture of the ligamentum arteriosum with the aortic arch. This aortic arch cavity is formed during the postnatal closure of the ductus arteriosus and is characterized by the presence of a thickened intima, which was absent in the other vascular regions examined. Immunofluorescence comparison of normal and atherosclerotic tissues from the aortic arch cavity wall with the use of monoclonal antibodies specific for smooth muscle and nonmuscle myosin isoforms revealed the existence of distinct SMC populations. SMCs in the thickened intima showed a myosin isoform pattern peculiar to cells with a degree of maturation intermediate between the fully differentiated and the developing (fetal) aortic SMCs. By contrast, SMCs present in atherosclerotic lesions displayed a predominant fetal-type pattern of myosin isoform expression. The achievement of this myosin isoform content seems to be correlated with the accumulation of lipids in the intima. In the media subjacent to the intimal thickening or atherosclerotic lesion, SMCs primarily displayed an intermediate degree of maturation. In older WHHL animals and at this aortic level, the SMC composition of the atherosclerotic lesion did not change, whereas in the subjacent media, the cells of intermediate type almost disappeared. In the vascular regions in which the atherosclerotic lesion appeared at later stages, such as near the aortic bifurcation, the distribution of fetal and intermediate cell types in the atherosclerotic wall was similar to that taken at the aortic arch level. These results indicate that there is 1) a preferential anatomic site from which atherogenesis initiates in WHHL rabbits; 2) a time correlation between the accumulation of lipids in the wall and the phenotypic change of SMCs toward a poorly differentiated cell type; and 3) the tendency for SMCs to follow the same differentiation pattern in early atherosclerotic lesions, irrespective of the site and time at which they develop. (

Fish Oil Supplementation Prevents Neointima Formation in Nonhypercholesterolemic Balloon-Injured Rabbit Carotid Artery by Reducing Medial and Adventitial Cell Activation

“…We purposely selected a segment of the rabbit common carotid artery that is histologically unable to develop an atherosclerotic plaque when subjected to the diet regimen used in this study. 49 In addition, this vessel is relatively enriched with postnatal-type SMCs 35,37 and thus is potentially at risk for developing SMC growth and migration. 35,37 Twenty-one days after injury, in the FO-treated group, there was a slight increase in the differentiation pattern of both neointimal and medial SMCs, although a complete maturation was not achieved (high signal for fetal fibronectin 59 and scarce presence of SM22 60 ; see Figure 4).…”

“…32 We have also sought to compare the potential efficacy of FO treatment on injured carotid arteries in the presence of high or low serum CT levels. Because lipid accumulation in the vascular wall is preceded by intimal SMC proliferation 37,38 and LDL-CT can alter the in vitro phenotypic 39 and the proliferative 40 level of SMCs, the possibility exists that this atherogenic risk factor may interfere with the putative antineointima action of FO. 27 Using a combined morphometric and immunocytochemical approach, we determined that the efficacy of FO in preventing neointima formation is restricted to the normocholesterolemic rabbit.…”

Expression of α 2 -Adrenergic Receptors in Normal and Atherosclerotic Rabbit Aorta

“…Macrophages accumulate early in the atherogenic process and may promote vascular damage through the release of cytokines that stimulate SMC chemotaxis and proliferation, as well as migration of other monocyte/macrophage cells. 10,11 Furthermore, in vitro studies suggest that catecholamines act through the ␣ 2 -AR to activate macrophage function and augment the lipopolysaccharide-induced cytokine production. 31,32 The presence of ␣ 2A -AR mRNA within macrophages suggests the need for further study of the role of ␣ 2A -AR stimulation on macrophage function.…”

“…9,10 Later lesions include macrophages as well as proliferating SMCs that are phenotypically distinct from the SMCs in the media. 11 In this report, we analyze the expression of ␣ 2 -AR mRNA in aortas from NZW rabbits and WHHL rabbits, a model of atherosclerosis, by in situ hybridization with ␣ 2 -AR probes.…”

Glycosaminoglycan fractions from human arteries presenting diverse susceptibilities to atherosclerosis have different binding affinities to plasma LDL.

“…43 ' 44 In different experiments, an in vitro-elicited change of rabbit aortic smooth muscle cells from a contractile to a less-contractile phenotype was accompanied by an increase in the synthesis of sulfated GAGs, 45 and subsets of arterial smooth muscle cells expressing different cytoskeletal phenotypes were indeed demonstrated in atherosclerotic plaques and adjacent areas. 46 ' 47 Of the complex array of mediators taking part in atherogenesis, growth factors have a salient role, 48 being present in lesions since their earliest phases. 49 Moreover, growth factors are capable not only of inducing phenotypic changes in arterial smooth muscle cells 50 but also of increasing the synthesis of chondroitin sulfate proteoglycan by these cells.…”