(Circulation. 1999;99:1147-1155.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Endothelin-1 and Its mRNA in the Wall Layers of Human Arteries Ex Vivo
From the Departments of Clinical and Experimental Medicine (G.P.R., S.C., E.P., G.A., F.D.R., P.P., A.C.P.), Cardiac Surgery (G.G., D.C.), and Biomedical Sciences and CNR Unit for Muscle Biology and Physiopathology (S.S.), University of Padova, Italy.
Correspondence to Gian Paolo Rossi, MD, FACC, Department of Clinical and Experimental Medicine, Clinica Medica 4, University Hospital, via Giustiniani, 2, 35126 Padova, Italy. E-mail gprossi{at}ux1.unipd.it
Background—The participation of endothelin-1 (ET-1) in the control of vascular tone in humans has been questioned, on the basis of the finding of subthreshold immunoreactive (ir) ET-1 plasma levels. However, because most ET-1 is secreted abluminally, it might attain a higher concentration in the tunica media than in plasma. Furthermore, evidence indicates that vascular smooth muscle cells (VSMCs) can synthesize ET-1 on stimulation in vitro. We therefore looked for irET-1 in the different layers of the wall of human arteries, including renal, gastric, and internal thoracic artery wall, obtained ex vivo from consenting patients with coronary artery disease and/or high blood pressure undergoing surgery, as well as from young organ donors.
Methods and Results—We performed immunohistochemistry with specific anti–ET-1 and anti-vWF antibodies followed by detection with an avidin-biotin complex ultrasensitive kit. The presence of preproET-1 and human endothelin-converting enzyme-1 (hECE-1) mRNA was also investigated by reverse transcription–polymerase chain reaction in homogenates of vessel wall, including preparations deprived of both endothelium and adventitia, and in isolated VSMCs. We detected irET-1 in the endothelium of all arteries and in the tunica media of internal thoracic artery from most patients with coronary artery disease. PreproET-1 and hECE-1 mRNA was also detected in VSMCs isolated from these vessels. irET-1 and irvWF staining in endothelium and tunica media was measured by use of microscope-coupled computer-assisted technology. Significant correlations between the amount of irET-1 in the tunica media and mean blood pressure (P<0.05), total serum cholesterol (P<0.05), and number of atherosclerotic sites (P<0.001) were found. Thus, in organ donors, irET-1 was detectable almost exclusively in endothelial cells, whereas in patients with coronary artery disease and/or arterial hypertension, sizable amounts of irET-1 were detectable in the tunica media of different types of arteries. In addition, VSMCs isolated from these vessels coexpressed the preproET-1 and hECE-1 genes.
Conclusions—Collectively, these findings are consistent with the contention that endothelial damage occurs in most patients with atherosclerosis and/or hypertension and that ET-1 is synthesized in VSMCs of these patients.
Key Words: arteries • endothelin • antibodies • RNA
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