title: Expression of heparin-binding epidermal growth factor-like growth factor in neointimal cells induced by balloon injury in rat carotid arteries.
abstract: Balloon catheter injury of rat carotid arteries induces migration and proliferation of smooth muscle cells (SMCs), with subsequent neointimal formation. Several growth factors, such as platelet-derived growth factor and basic fibroblast growth factor, have been shown to be involved in this process, but the mechanisms that modulate the growth and/or migratory properties of SMCs remain unclear. In this study, we investigated whether heparin-binding epidermal growth factor-like growth factor (HB-EGF), which is known to be a potent SMC stimulator from in vitro study, is associated with the proliferative response of SMCs to arterial injury. Northern blot analysis showed that the transcript levels of HB-EGF increased rapidly approximately 12-fold within 2 hours after injury and declined by 2 days but remained 3-fold at 14 days. In situ hybridization analysis demonstrated that the transcript of HB-EGF remained strongly expressed in the neointima, especially near the luminal surface, at 14 days after injury. Immunohistochemical staining showed that HB-EGF protein was positive in the endothelium and only faintly visible in medial SMCs in uninjured vessels. In contrast, 2 days after injury, positive HB-EGF immunostaining was detected in the medial SMCs along the luminal surface. At 7 days, the neointimal SMCs exhibited strong immunostaining for HB-EGF, and at 14 days, they exhibited a gradient of HB-EGF expression with strong immunoreactivity in the most luminal cells. SMCs labeled with 5-bromo-2'-deoxyuridine in their nuclei showed strong immunostaining for HB-EGF protein. Furthermore, the epidermal growth factor receptor to which HB-EGF can bind was also immunostained positively in neointimal SMCs. These data suggest that HB-EGF may play an important role of the proliferation and migration of SMCs in the process of neointimal accumulation induced by arterial injury, probably in an autocrine, paracrine, and/or juxtacrine manner.
authors.affiliation: Second Department of Internal Medicine, Osaka University Medical School, Japan. ikura@imed2.med.osaka-u.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Igura
authors.forename: S
authors.initials: S
authors.lastname: Kawata
authors.forename: J
authors.initials: J
authors.lastname: Miyagawa
authors.forename: Y
authors.initials: Y
authors.lastname: Inui
authors.forename: S
authors.initials: S
authors.lastname: Tamura
authors.forename: K
authors.initials: K
authors.lastname: Fukuda
authors.forename: K
authors.initials: K
authors.lastname: Isozaki
authors.forename: K
authors.initials: K
authors.lastname: Yamamori
authors.forename: N
authors.initials: N
authors.lastname: Taniguchi
authors.forename: S
authors.initials: S
authors.lastname: Higashiyama
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuzawa
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology*; D002404:Catheterization; D002455:Cell Division; D002465:Cell Movement; D004815:Epidermal Growth Factor / Q000096:biosynthesis*; D066257:Heparin-binding EGF-like Growth Factor; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar
chemical_list: C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D004815:Epidermal Growth Factor