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Cardiovascular Research Advance Access first published online on January 22, 2009
This version [Corrected Proof] published online on February 13, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp026
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Vascular endothelial cell-derived endothelin-1 mediates vascular inflammation and neointima formation following blood flow cessation

Dyah W. Anggrahini1, Noriaki Emoto1,3,*, Kazuhiko Nakayama1, Bambang Widyantoro1, Suko Adiarto1, Naoko Iwasa1, Hidemi Nonaka1, Yoshiyuki Rikitake2, Yaz Y. Kisanuki4, Masashi Yanagisawa5 and Ken-ichi Hirata1

1 Division of Cardiovascular Medicine, Department of Internal Medicine, 7-5-1 Kusunoki, Chuo, Kobe 650-0017, Japan
2 Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
3 Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, Japan
4 Department of Neurology, The University of Michigan, Ann Arbor, MI, USA
5 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA

* Corresponding author. Tel: +81 78 382 5846; fax: +81 78 382 5859; E-mail address: emoto{at}med.kobe-u.ac.jp

Aims: Although endothelin-1 (ET-1) has been suggested to contribute to the pathogenesis of neointima formation and atherosclerosis, the individual roles of ET-1 derived from certain cell types in this disease remain unclear. In this study, we determined the role of vascular endothelial ET-1 on vascular inflammation and neointima formation using vascular endothelial ET-1-knockout [ET-1f/f; Tie2-Cre (+)] mice.

Methods and results: Intimal hyperplasia was induced by complete ligation of the left carotid artery in 12-week-old male ET-1f/f;Tie2-Cre (+) mice (n = 35) and the wild-type (WT) littermates (n = 34). Following this intervention, neointima formation was reduced in ET-1f/f;Tie2-Cre (+) mice compared with the WT mice, independent of the difference in blood pressure. This reduction was associated with a decrease in inflammatory cell recruitment to the vessel wall, which was accompanied by reduced expression levels of endothelial adhesion molecules as well as chemokines and a decrease in vascular smooth muscle cell proliferation.

Conclusion: The results of our study provide direct evidence for the role of vascular endothelial ET-1 in mediating vascular inflammation and neointima formation following vascular injury in addition to promoting vasoconstriction and cell proliferation. Furthermore, this study suggests a strategy for the efficient design of ET receptor antagonists with targeted inhibition of ET-1 signalling in vascular endothelial cells.

KEYWORDS Endothelin-1; Atherosclerosis; Neointima formation; Inflammation; Carotid ligation

Time for primary review: 22 days


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