The phenotype of smooth muscle cells (SMCs) plays an important role in vascular function in health and disease. We investigated the mechanism of modulation of SMC phenotype (from contractile to synthetic) induced by the synergistic action of a growth factor (platelet-derived growth factor, PDGF-BB) and a cytokine (interleukin, IL-1β). Human aortic SMCs grown on polymerized collagen showed high expression levels of contractile markers (smooth muscle α-actin, myosin heavy chain, and calponin). These levels were not significantly affected by PDGF-BB and IL-1β individually, but decreased markedly after the combined usage of PDGF-BB and IL-1β. PDGF/IL-1β costimulation also induced a sustained phosphorylation of Akt and p70 ribosomal 56 kinase (p70S6K). The effects of PDGF/IL-1β costimulation on contractile marker expression and Akt and p70S6K phosphorylation were blocked by the phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 and by adenovirus expressing a dominant-negative Akt, and they were mimicked by constitutively active Akt. PDGF-BB/ IL-1β induced a sustained phosphorylation of PDGF receptor (PDGFR)-β and its association with IL-1 receptor (IL-1R1). Such activation and association of receptors were blocked by a PDGFR-β neutralizing antibody (AF385), an IL-1R1 antagonist (IL-1ra), as well as a specific inhibitor of PDGFR-β phosphorylation (AG1295); these agents also eliminated the PDGF-BB/IL-1β-induced signaling and phenotypic modulation. PDGF-BB/IL-1β inhibited the polymerized collagen-induced serum response factor DNA binding activity in the nucleus, and this effect was mediated by the PDGFR-β/IL-1R1 association and phosphatidylinositol 3-kinase Akt p70S6K pathway. Our findings provide insights into the mechanism of SMC phenotypic modulation from contractile to synthetic, e.g., in atherosclerosis.
|頁（從 - 到）||2665-2670|
|期刊||Proceedings of the National Academy of Sciences of the United States of America|
|出版狀態||已發佈 - 二月 21 2006|
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