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Regional variations in endothelin-1 and its receptor subtypes in human coronary vasculature: pathophysiological
M R Dashwood1, M Timm, J R Muddle
1Department of Physiology, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK. mickey@rfhsm.ac.uk
Insights
Endothelin-1 (ET-1) plays a role in coronary artery disease by influencing cell growth and blood vessel constriction. Its receptors show varied distribution in healthy and diseased human coronary vasculature.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Vascular Physiology
Background:
- Endothelin-1 (ET-1) is a potent vasoconstrictor and mitogen implicated in cardiovascular diseases like atherosclerosis.
- Elevated ET-1 levels are observed post-myocardial infarction and in atherosclerosis, suggesting a pathophysiological role.
Purpose of the Study:
- To investigate regional variations of ET-1 and its receptors (ET(A) and ET(B)) in human coronary vasculature.
- To correlate receptor distribution with atherosclerosis and potential roles in coronary syndromes.
Main Methods:
- Standard immunohistochemistry and in vitro autoradiography were employed.
- Analysis was performed on control and atherosclerotic human coronary vasculature.
Main Results:
- ET-1 immunoreactivity was found in endothelial and smooth muscle cells at atherosclerotic sites.
- ET(A) receptors were located on coronary artery smooth muscle cells and cardiac myocytes.
- ET(B) receptor binding increased distally in coronary arteries and was exclusively expressed on specific microvascular and endocardial endothelial cells.
Conclusions:
- Regional receptor variations support ET-1's association with vascular cell proliferation and neovascularization.
- Findings suggest ET-1 contributes to increased distal coronary artery reactivity and microvessel constriction in disease states.
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.