Clonal markers in the study of the origin and growth of human atherosclerotic lesions.

Abstract

The X-linked enzyme, glucose-6-phosphate dehydrogenase (G-6-PD) was used as a cellular marker to study the clonal characteristics of human atherosclerotic lesions from females heterozygous for G-6-PD isoenzymes. Portions of uninvolved aortic wall contained both isoenzyme types (A and B), and their isoenzyme patterns were used to establish criteria for polyclonal lesions. Portions of uterine leiomyomas contained predominantly one isoenzyme type (either all A or all B) and their isoenzyme patterns were used to establish criteria for monoclonal lesions. These techniques were used to address three questions concerning atherogenesis. First, evidence for the monoclonal origin of fibrous-capped plaques was provided by the findings that small plaques had G-6-PD isoenzyme distributions similar to those of leimyomas; that in large plaques with multiple portions assayed for G-6-PD, a large proportion (25 of 26, 96%) of plaques had monoclonal characteristics; and that multiple monoclonal portions were present in the same plaque. Second, the role of the fatty streak as a precursor of fibrous plaques was supported by the demonstration that a proportion (11 of 66, 16.7%) of fatty streaks contained isoenzyme patterns intermediate between those of polyclonal uninvolved aortic wall and monoclonal leiomyomas. Increased cellularity of fatty streaks correlated with increased deviation of isoenzyme pattern toward monoclonality. Third, the assay of portions of both small and large plaques provided no evidence for clonal selection as plaques increase in size.

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

“…Previous observations that a single phenotype for SMC made up a significant proportion of atherosclerotic fibrous plaques suggested the possibility that they are a form of benign neoplasm in the arterial intima (4)(5)(6)10). This view has been disputed largely on the basis of experimental animal models of atherosclerosis.…”

“…Intimal smooth muscle cell (SMC) proliferation is regarded as a key early event in the pathogenesis of atherosclerosis (1)(2)(3). Cell lineage analysis of human atheromata, using X-linked glucose-6-phosphate de-hydrogenase 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)(5)(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).…”

Clonal heterogeneity in the fibroblast response to mononuclear cell derived mediators

“…It has been suggested that such monoclonal populations could arise consequent to endothelial cell injury (25), perhaps secondary to differential growth responses to platelet or mononuclear cell derived growth mediators.…”

Arterial Smooth Muscle Cell Heterogeneity

“…This possibility has been raised on the basis of original work by Benditt and Benditt,4 who reported that human atheromatous plaques have the features of a monoclonal lesion, an observation that has been confirmed by several laboratories. [5][6][7] More recently, with use of in situ microdissection techniques, it has been demonstrated that human plaques are at least oligoclonal. 8 These findings support the suggestion that SMCs of the arterial wall are biologically heterogeneous, and thus, attempts have been made to isolate distinct SMC phenotypes from arterial vessels.…”