Published Online
on September 23, 2002

A more recent version of this article appeared on October 8, 2002

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Submitted on April 2, 2002
Revised on July 10, 2002
Accepted on July 11, 2002

Vascular Endothelin-B Receptor System In Vivo Plays a Favorable Inhibitory Role in Vascular Remodeling After Injury Revealed by Endothelin-B Receptor-Knockout Mice

Nobuyuki Murakoshi MD, Takashi Miyauchi MD, PhD^*, Yoshihiko Kakinuma MD, PhD, Takashi Ohuchi MD, PhD, Katsutoshi Goto PhD, Masashi Yanagisawa MD, PhD, and Iwao Yamaguchi MD, PhD

From the Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine (N.M., T.M., Y.K., I.Y.), and the Department of Pharmacology, Institute of Basic Medical Sciences (K.G.), University of Tsukuba, Ibaraki, Japan, and the University of Texas Southwestern Medical Center (T.O., M.Y.), Dallas, Tex.

^* To whom correspondence should be addressed. E-mail: t-miyauc{at}md.tsukuba.ac.jp.

Background—Two subtypes of endothelin (ET) receptors, ET_A and ET_B, are distributed in vascular smooth muscle cells to cause contraction and proliferation. Vascular endothelial cells express only ET_B receptors, which cause NO release. Although ET_A receptor blockade is reported to be effective in ameliorating vascular remodeling, there is no report on the long-term effect of ET_B receptor blockade on vascular remodeling after injury.

Methods and Results—ET_B receptor-knockout (KO) mice, which were genetically rescued from lethal intestinal aganglionosis, and wild-type (WT) mice underwent complete ligation of the right common carotid artery, ie, a blood flow cessation model of vascular remodeling. Fourteen days after ligation, the intimal area, the ratio of intimal to medial areas, and the stenotic ratio in the ligated artery of KO mice were significantly increased compared with those of WT mice. The expression level of ET-1 mRNA in the ligated artery of KO mice was increased similarly to that of WT mice, whereas tissue NO_x levels in lesions of KO mice were significantly lower than those of WT mice. Long-term treatment with the ET_A receptor antagonist TA-0201 (0.5 mg · kg^-1 · d^-1) significantly ameliorated vascular stenosis in both groups. Long-term treatment with the ET_B receptor antagonist A-192621 (30 mg · kg^-1 · d^-1) worsened vascular remodeling in WT mice.

Conclusions—We demonstrated that inhibition of the ET_B receptor system is harmful for vascular remodeling after injury, the mechanism of which is partly attributed to decreased NO release, in KO mice. These results suggest that the overall effect of vascular ET_B receptors is antiproliferative in the injured artery.

Key words: endothelin • receptors • genes • remodeling

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