© 1996 American Heart Association, Inc.
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Endothelin Peptide and Receptors in Human Atherosclerotic Coronary Artery and Aorta
the Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital (C.R.B., A.P.D.) and Papworth Hospital (N.R.B.C.), Cambridge, UK.
Correspondence to Dr A.P. Davenport, Clinical Pharmacology Unit, Box 110, Level 2, F&G Block, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK.
The aim of this study was to determine whether there is an alteration in the distribution or quantity of endothelin (ET) peptide or receptor subtypes in human atherosclerotic arteries. Levels of endogenous ET and big ET-1 detectable by radioimmunoassay in human aorta containing raised atherosclerotic plaques were significantly higher than those in histologically normal tissue (Student's t test, P<.01). Immunohistochemistry revealed ET-like immunoreactivity in endothelial cells lining the vessel lumen, neovascularization, recanalization of organized thrombus, and regions rich in macrophages. Little immunoreactivity was associated with vascular smooth muscle cells (VSMCs). Saturation binding assays with [125I]ET-1 indicated comparable affinities and maximal densities of receptors in the media of diseased and normal coronary arteries. Quantitative autoradiography with subtype-selective radioligands revealed similar small proportions of ETB receptors in the diseased and normal arterial media. In arteries with early and late disease, ETA receptors were localized to medial smooth muscle but were lacking in the VSMCs of the intimal layer, where ETB receptors were absent. ETB receptors were detected on perivascular nerves and lymphoid aggregates. In atherosclerotic arteries, microautoradiography localized ETB receptors to neovascularization and, interestingly, to macrophages. The results of this study indicate that there is an increase in ET and big ET-1 associated with fully developed atherosclerotic plaques. It is likely that this is derived from endothelial cells and macrophages but not VSMCs. ETA receptors predominate in the media of both normal and diseased arteries. ET receptors are deficient in intimal smooth muscle, and ETB receptors, where present, are found on endothelial cells and macrophages.
Key Words: atherosclerosis • endothelin • endothelin A • endothelin B • human artery
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