title: Regional variations in endothelin-1 and its receptor subtypes in human coronary vasculature: pathophysiological implications in coronary disease.
abstract: Endothelin-1 is a potent vasoconstrictor peptide and mitogen for vascular smooth muscle cells. Increased plasma or tissue levels of endothelin-1 have been described after myocardial infarction and in atherosclerosis, suggesting that this peptide may play a pathophysiological role in various coronary syndromes. Here, we have studied regional variations in ET-1 and its receptors in control and atherosclerotic human coronary vasculature using standard immunohistochemistry and in vitro autoradiography. ET-1 immunoreactivity was associated with luminal endothelial cells and smooth muscle cells at regions of atherosclerosis. ET(A) receptors were present on smooth muscle cells of coronary arteries and on cardiac myocytes. Medial ET(B) receptor binding at the proximal region of coronary arteries was weak, but increased significantly towards distal regions of this vessel (p<0.005 in control and p<0.0005 in ischaemic heart disease). Microvascular endothelial cells in the adventitia of coronary arteries, myocardial microvessels and the endocardial endothelium expressed the ET(B) receptor exclusively. The receptor variations revealed in this study provide supporting evidence that ET-1 is associated with (1) vascular smooth muscle and endothelial cell proliferation, including areas of intimal hyperplasia and regions of neovascularization (2) increased ET-1-induced reactivity of distal portions of the human coronary artery, (3) ET-1-mediated constriction of myocardial microvessels. These results provide new insights into different potential roles for this peptide in healthy and diseased human coronary vasculature.
authors.affiliation: Department of Physiology, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK. mickey@rfhsm.ac.uk
authors.forename: M R
authors.initials: MR
authors.lastname: Dashwood
authors.forename: M
authors.initials: M
authors.lastname: Timm
authors.forename: J R
authors.initials: JR
authors.lastname: Muddle
authors.forename: A C
authors.initials: AC
authors.lastname: Ong
authors.forename: J R
authors.initials: JR
authors.lastname: Tippins
authors.forename: R
authors.initials: R
authors.lastname: Parker
authors.forename: D
authors.initials: D
authors.lastname: McManus
authors.forename: A J
authors.initials: AJ
authors.lastname: Murday
authors.forename: B P
authors.initials: BP
authors.lastname: Madden
authors.forename: J C
authors.initials: JC
authors.lastname: Kaski
mesh_terms: D001345:Autoradiography; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology; D019332:Endothelin-1 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin