Journal
BIOMATERIALS
Volume 33, Issue 28, Pages 6728-6738Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2012.06.030
Keywords
Cell cycle; Fibrillar collagen; P66Shc; Signal transduction; Smooth muscle cell
Funding
- [NSC-100-2321-B-400-001/NSC-101-2325-B-400-009]
- [NHRI-ME-100-PP06]
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Arterial smooth muscle cell (SMC) phenotype and proliferation is regulated by their surrounding collagens, which transform from fibrillar to monomeric type in atherogenesis, and platelet-derived growth factor (PDGF)-BB/interleukin (IL)-1 beta. This study aims at elucidating the mechanisms by which physical (monomeric vs. fibrillar collagens) and chemical (PDGF-BB/IL-1 beta vs. vehicle controls) stimuli modulate SMC cycle and proliferation. SMCs were cultured on monomeric vs. fibrillar type 1 collagens. In parallel experiments, SMCs on fibrillar collagen were co-stimulated with PDGF-BB/IL-1 beta. These physical and chemical factors induced common SMC cycle signaling events, including up-regulations of cyclin-dependent kinase-4/6 and cyclins A/D1, phosphorylation of retinoblastoma (Rb) and its dissociations with E2F2/3. The physical and chemical inductions of SMC cycle signaling and progression were oppositely regulated by phosphatidylinositol 3-kinase (PI3K)-mediated Akt and p38 mitogen-activated protein kinase (MAPK). Fibrillar collagen degraded p66Shc, whose Ser36-phosphorylation plays important roles in the modulation of SMC cycle. Monomeric collagen and PDGF-BB/IL-1 beta co-stimulation induced p66Shc expression and Ser36-phosphorylation through beta(1) integrin and PDGF receptor-beta, respectively. In conclusion, our results demonstrate that fibrillar collagen-regulated p66Shc converges the physical and chemical stimuli to modulate SMC cycle and proliferation through PI3K-mediated Akt and p38 MAPK and their opposite regulation in downstream common cell cycle signaling cascades. (C) 2012 Elsevier Ltd. All rights reserved.
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