Ds. Taylor et al., Epiregulin is a potent vascular smooth muscle cell-derived mitogen inducedby angiotensin II, endothelin-1, and thrombin, P NAS US, 96(4), 1999, pp. 1633-1638
Citations number
31
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Vasoactive GTP-binding protein-coupled receptor agonists such as angiotensi
n II (AII), endothelin-1 (ET-1), and alpha-thrombin (alpha-Thr) have been r
eported to indirectly stimulate vascular smooth muscle cell (VSMC) prolifer
ation by regulating the expression of one or more autocrine growth factors.
Using ion-exchange, gel-filtration, and reverse-phase chromatographic puri
fication methods, we isolated a major mitogenic protein present in AII-stim
ulated rat aortic smooth muscle (RASM) cell conditioned medium. Twenty N-te
rminal amino acids of the purified peptide were identified, and they had 75
% amino acid sequence identity with mouse epiregulin, an epidermal growth f
actor (EGF)related growth factor. We cloned the cDNA for rat epiregulin to
determine its pattern of expression in G-protein-coupled receptor agonist-s
timulated cells and confirm its activity as a mitogen, After treatment of R
ASM cells with AII, ET-1, or alpha-Thr for 1 h, induction of two epiregulin
transcripts was observed, including a 4.8-kb transcript and a novel transc
ript of approximately 1.2 kb. Recombinant rat epiregulin arts strongly mito
genic for RASM cells, stimulating DNA synthesis to levels similar to those
induced by serum or platelet-derived growth factor and approximately 3-fold
above that observed with saturating concentrations of EGF. In addition, ep
iregulin caused rapid EGF receptor activation in RASM cells, However, relat
ive levels of EGF receptor tyrosine phosphorylation stimulated by epireguli
n were less than those induced by EGF or betacellulin. Taken together, thes
e results indicate that epiregulin is a potent VSMC-secreted mitogen, induc
ed in common by AII, ET-1, and alpha-Thr, that may contribute to VSMC proli
feration and vascular remodeling stimulated by vasoactive agonists.