Published Online
on October 27, 2003

A more recent version of this article appeared on November 18, 2003

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Submitted on December 31, 2002
Revised on July 18, 2003
Accepted on July 21, 2003

Epiregulin as a Major Autocrine/Paracrine Factor Released From ERK- and p38MAPK-Activated Vascular Smooth Muscle Cells

Masanori Takahashi MD, Ken’ichiro Hayashi PhD, Kenji Yoshida MD, Yasuyuki Ohkawa PhD, Toshi Komurasaki PhD, Akira Kitabatake MD, PhD, Akira Ogawa MD, PhD, Wataru Nishida MD, PhD, Masahiko Yano MD, PhD, Morito Monden MD, PhD, and Kenji Sobue MD, PhD^*

From the Department of Neuroscience (K.H., Y.O., W.N., K.S.) and the Department of Surgery and Clinical Oncology (M.Y., M.M.), Osaka University Graduate School of Medicine, Osaka, Japan; the Department of Cardiovascular Medicine, Hokkaido University, Graduate School of Medicine (M.T., A.K.), Sapporo, Japan; the Department of Neurosurgery, Iwate Medical University School of Medicine (K.Y., A.O.), Morioka, Japan; and the Molecular Biology Laboratory, Medical Research Laboratories, Taisho Pharmaceutical Co, Ltd (T.K.), Saitama, Japan.

^* To whom correspondence should be addressed. E-mail: sobue{at}nbiochem.med.osaka-u.ac.jp.

Background--The coordinated activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) is critical for the induction of vascular and visceral smooth muscle cell (SMC) dedifferentiation. We previously reported that on the forced activation of both MAPKs, visceral SMCs secrete a non-heparin-binding protein factor(s) that is involved in the dedifferentiation of neighboring SMCs. In this study, we sought to identify the dedifferentiation factor(s) derived from vascular SMCs (VSMCs).

Methods and Results--We fractionated the VSMC dedifferentiation factor(s) in the conditioned medium obtained from differentiated VSMCs in which both ERK and p38MAPK were forcedly activated and identified epiregulin as a major autocrine/paracrine factor for VSMC dedifferentiation. The epiregulin-induced VSMC dedifferentiation was mediated through the coordinated activation of ERK and p38MAPK. Unsaturated lysophosphatidic acid and platelet-derived growth factor-BB, which are potent VSMC dedifferentiation factors, rapidly upregulated epiregulin mRNA expression in an ERK- and p38MAPK-dependent manner. Reverse transcriptase-polymerase chain reaction and/or immunohistological analyses revealed the restricted expression of epiregulin in human atherosclerotic and balloon-injured rat arteries, in which the phenotypic modulation of medial VSMCs occurred in vivo.

Conclusions--Epiregulin is released from VSMCs primed by atherogenic factors and acts as a major autocrine/paracrine factor for VSMC dedifferentiation. It may be involved in the progression of vascular remodeling such as atherosclerosis.

Key words: vasculature • remodeling • muscle, smooth • atherosclerosis

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