Pathological Importance of the Endothelin-1/ETBReceptor System on Vascular Diseases

Kento Kitada,Yasuo Matsumura,Mamoru Ohkita

doi:10.1155/2012/731970

Abstract

Activation of the endothelin (ET)-1/ET receptor system is involved in the development of vascular diseases such as atherosclerosis, vascular hypertrophy, and restenosis. Some issues still remain unresolved including whether ET receptor antagonists are expected to become the new therapeutic tools for the treatment of vascular diseases. One of the unresolved critical points is the functional role of ET receptor subtypes on each vascular disease, in particular the pathophysiological roles of the ETB receptor. We recently demonstrated that selective inhibition of the ETB receptor system showed harmful effects in the development of neointimal formation after vascular injury. However, there was no apparent difference in the therapeutic effects between a nonselective ETA/ETB receptor antagonist and selective ETA receptor antagonist. These findings indicate that antagonism of the ETA receptor system is essential for suppressing vascular remodeling, irrespective of the presence of ETB-receptor-mediated actions, although the selective ETB receptor antagonist worsens vascular remodeling. In addition, we found that ET receptor systems contribute to sex differences in the severity of vascular disease, thereby suggesting that the efficacy of ET receptor antagonists for vascular diseases may differ between sexes. In this paper, we outline the roles of the ET-1/ETB receptor system on vascular diseases and its sex differences.

Highlights

Endothelin (ET)-1 was discovered as a potent and longlasting vasoconstrictive peptide derived from endothelial cells [1]
These findings indicate that antagonism of the ETA receptor system is essential for suppressing vascular remodeling, irrespective of the presence of ETB-receptor-mediated actions, the selective ETB receptor antagonist worsens vascular remodeling
We found that ET receptor systems contribute to sex differences in the severity of vascular disease, thereby suggesting that the efficacy of ET receptor antagonists for vascular diseases may differ between sexes

Summary

Introduction

Endothelin (ET)-1 was discovered as a potent and longlasting vasoconstrictive peptide derived from endothelial cells [1]. Clinical and basic studies have indicated that proliferation of VSMCs and neointimal formation in response to ET-1 stimulation play a key role in several vascular lesions such as atherosclerosis, restenosis, and arterial hypertrophy by hypertension or diabetes [10, 11]. Shirai et al [17] reported that neointimal VSMCs after PTCA exhibited enhanced expressions of ECE, ET-1, and ET receptors This basic and clinical evidence suggests that the ET-1/ET receptor system contributes to the pathogenesis of neointimal formation after vascular injury. There is general agreement that the ET-1/ETA receptor system plays an important role in the development of vascular disease because ETA receptor-mediated ET-1 actions induce VSMCs proliferation and both selective ETA receptor and ETA/ETB dual receptor antagonists showed vasoprotective effects. It is still difficult to answer which type of ET antagonist is more effective for the treatment of vascular disease

Pathophysiological Roles of the ETB Receptor in Vascular Diseases

Roles of the ETB Receptor in the Sex Differences of Vascular Diseases