Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 22, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp026
Vascular endothelial cell-derived endothelin-1 mediates vascular inflammation and neointima formation following blood flow cessation
1 Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, 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, Michigan
5 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas
* Correspondence address: Noriaki Emoto, M.D., Ph.D., Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, 650-0017 Kobe, Japan, Email: emoto{at}med.kobe-u.ac.jp, Phone: +81-78-382-5846, FAX: +81-78-382-5859
Aims: Although endothelin-1 (ET-1) has been suggested to contribute in 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 signaling in vascular endothelial cells.
Time for primary review: 22 Days