Focal smooth muscle proliferation in the aortic intima produced by an initiation-promotion sequence.

Abstract

Human atherosclerotic fibrous plaques display a clonal character similar to many benign neoplasms. We report here that chickens treated with an initiation-promotion sequence developed focal intimal smooth muscle lesions in the thoracic aorta that resemble early forms of atherosclerosis. Scanning electron microscopy revealed small mound-like lesions protruding from an intact endothelium in birds treated with an initiating dose of 7,12-dimethylbenz[alanthracene (Me2BA) followed by twice weekly injections of the a,-selective adrenergic agonist methoxamine for 20 weeks. Intimal lesion foci were composed of densely packed modified smooth muscle cells, abundant extracellular matrix, and occasional mononuclear cells (possibly monocytes). There was no ultrastructural evidence of lipid accumulation or alteration of the underlying media. These intimal lesions appeared in aortic segments of treated chickens in a pattern similar to that observed in classical experiments of multistage tumorigenesis in epidermis and other tissues. The treatment with Me2BA followed by methoxamine produced more focal lesions per thoracic segment and more segments per group with lesions than did treatment with either Me2BA or methoxamine alone. Thoracic intimal foci were absent from untreated and vehicle-treated groups. In contrast, the growth of a spontaneously arising atheroma in the distal abdominal aorta was not demonstrably affected by the initiation-promotion regimen. Likewise, weekly injections of Me2BA for 23 weeks, while greatly enhancing abdominal atheroma growth, produced no thoracic lesions. These results provide evidence that focal proliferation of intimal smooth muscle cells, a critical early event in atherogenesis, can be produced by an initiation-promotion treatment sequence.Atherosclerosis has been described as a multifactorial disease in which various influences, acting together or in sequence, appear to govern the formation and progression of atheromatous fibrous plaque lesions. Intimal smooth muscle cell (SMC) proliferation is regarded as a key early event in the pathogenesis of atherosclerosis (1-3). Cell lineage analysis of human atheromata, using X-linked glucose-6-phosphate dehydrogenase isozymes as markers, revealed that the cell population of many lesions consisted of a single phenotype, in sharp contrast to the normal artery wall and diffusely thickened intima (4-6). These results are indicative of an unusual proliferative response and are similar to data obtained from analyses of cell origins of benign smooth muscle tumors of the uterus (7, 8). These findings suggest that at least some atheromata have the properties of benign neoplasms (9, 10). As such they may develop in response to combinations of stimuli similar to those that provoke the formation of benign neoplasms in animals. In the experiments reported here we have explored the possibility that an initiation-promotion sequence, modeled after the classic regimens of chemical carcinogenesis used to elicit epidermal papillomas in rabbits and mice (11-13), ...

Transforming gene in human atherosclerotic plaque DNA.

“…Additionally, dimethylbenz [a]anthracene and methoxamine administered to cockerels in an initiation-promotion protocol elicited the appearance (via scanning EM) of small focal mounds of cells in the thoracic aortas, which were absent from aortas of controls (10). While these results suggest that gross phenomenological similarities may exist during the development of tumors and plaques, they do not provide direct evidence for mechanistic similarities between the origins of plaques and tumors.…”

Pharmacology of smooth muscle cell replication.

“…Administration of the a r adrenergic receptor agonist methoxamine to chickens results in the formation of thoracic aortic intimal accumulations of smooth muscle cells. 95 Another a r adrenergic receptor agonist, phenylephrine, does not stimulate DNA synthesis in the thoracic aorta of normal rats. 96 These disparate results may be related to differences in aortic morphology between chickens and rats; in chickens, there are occasional smooth muscle cells in the subendothelial intima, 95 but these are not found in normal rats.…”

“…95 Another a r adrenergic receptor agonist, phenylephrine, does not stimulate DNA synthesis in the thoracic aorta of normal rats. 96 These disparate results may be related to differences in aortic morphology between chickens and rats; in chickens, there are occasional smooth muscle cells in the subendothelial intima, 95 but these are not found in normal rats. 97 Perhaps in the uninjured vessel increased aj-adrenergic receptor stimulation by exogenous agonist provokes the prolifer-ation of intimal but not of medial smooth muscle cells.…”

Identification and Cloning of a New Gene (2A3-2), Homologous to Human Translational Elongation Factor, Upregulated in a Proliferating Rat Smooth Muscle Cell Line and in Carotid Hyperplasia

“…19,20 Indeed, certain genes have been shown to be implicated in the pathobiology of atherosclerosis and cancer. 21,22 This hypothesis has been supported by experimental data demonstrating the appearance of SMCs in aortas of animals injected with carcinogens alone, 23 in combination with methoxamine, 24 or with oncogenic Marek's herpes virus. 25 Moreover, DNA from human plaques was shown to completely transform transfected NIH 3T3 cells.…”