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Cardiovascular Research 2001 52(3):468-476; doi:10.1016/S0008-6363(01)00431-X
© 2001 by European Society of Cardiology
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Copyright © 2001, European Society of Cardiology

Administration of exogenous endothelin-1 following vascular balloon injury: early and late effects on intimal hyperplasia

Alan W Barolet1, Saeid Babaei1, Ranga Robinson, Pierre Picard, Winston Tsui, Nafiseh Nili, Farida Mohamed, Olga Ornatsky, John D Sparkes, Duncan J Stewart and Bradley H Strauss*

Division of Cardiology, Terrence Donnelly Heart Center, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada M5B 1W8

straussb{at}smh.toronto.on.ca

* Corresponding author. Tel.: +1-416-864-5913; fax: +1-416-864-5978

Administration of exogenous endothelin-1 (ET-1) has been shown to stimulate neointimal hyperplasia following arterial balloon angioplasty (BA). However, the specific effects of ET-1 on the cellular and extracellular matrix response of the vessel wall after balloon injury and the persistence of these ET-1 effects have not been studied. The objectives of this study were to determine the acute (1 week) and long term (10 weeks) effects of administering exogenous ET-1 after arterial BA on neointimal hyperplasia, collagen synthesis and content, cellular proliferation, and ETA and ETB receptor expression. Thirty-one rabbits were randomized to receive subcutaneous ET-1 (500 pmol/kg/day for 1 week) or placebo time-release pellets and sacrificed at either 1 or 10 weeks after BA. At 1 week, there was a significant two-fold increase in intimal cross-sectional area (CSA) in ET-1 treated animals compared with placebo. ET-1 treated animals showed significant increases in collagen synthesis (ten-fold) and collagen content (three-fold) compared to placebo treated animals. ET-1 treated animals also had a significant increase (two-fold) in proliferation rates. In addition, ETA and ETB receptor expression were significantly upregulated in ET-1 treated animals. By 10 weeks these stimulatory effects on intimal CSA and collagen content were no longer evident with a ‘catch up’ phenomenon observed in the placebo treated animals. Similarly, ETA and ETB mRNA levels had declined significantly in both groups. Therefore, exogenous ET-1 acutely stimulates extracellular and cellular processes including increased expression of ETA and ETB receptors contributing to intimal hyperplasia. However, these effects are transient and not maintained long term after withdrawal of exogenous ET-1 stimulation.

KEYWORDS Angioplasty; Arteries; Connective tissue; Endothelins; Extracellular matrix; Remodeling; Restenosis


1 Contributed equally to this work.


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