Smooth muscle cell signal transduction: Implications of vascular biology for vascular surgeons  Akihito Muto, MD, PhD, Tamara N. Fitzgerald, MD, PhD, Jose M. Pimiento, MD, Stephen P. Maloney, MD, Desarom Teso, MD, Jacek J. Paszkowiak, MD, Tormod S. Westvik, MD, Fabio A. Kudo, MD, PhD, Toshiya Nishibe, MD, PhD, Alan Dardik, MD, PhD  Journal of Vascular Surgery  Volume 45, Issue 6, Pages A15-A24 (June 2007) DOI: 10.1016/j.jvs.2007.02.061 Copyright © 2007 The Society for Vascular Surgery Terms and Conditions

Fig 1 Signaling during smooth muscle cell (SMC) phenotype switching. The left side of the figure denotes pathways involved in signaling during SMC differentiation to the contractile phenotype. Insulin growth factor-I (IGF-1) causes expression of genes associated with the contractile, differentiated phenotype through the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) pathway, while at the same time blocks the Ras-mitogen-activated protein kinase (MAPK) pathway with the insulin receptor substrate-I (IRS-I)/Scr homology protein 2 (SHP2) complex. The right side of the figure denotes pathways involved in signaling during SMC phenotype switching to the synthetic phenotype. Several growth factors stimulate SMC phenotype switching by stimulating MAPK directly as well as by cleaving the IRS-I/SHP2 complex. MAPK transposition to the nucleus inhibits transcription of genes associated with the contractile phenotype and stimulates expression of genes associated with growth. Signals from each cascade inhibit the opposite cascade. PDGF, Platelet derived growth factor; EGF, epidermal growth factor; FGF, fibroblast growth factor 2; p, phosphorylation. Journal of Vascular Surgery 2007 45, A15-A24DOI: (10.1016/j.jvs.2007.02.061) Copyright © 2007 The Society for Vascular Surgery Terms and Conditions

Fig 2 Proliferative signaling during smooth muscle cell (SMC) response to injury. The figure shows convergent signaling pathways resulting in protein synthesis and cell proliferation, leading to restenosis and neointimal hyperplasia. Implications of vascular intervention may include inducing growth factors that are SMC mitogens and chemoattractants. These factors stimulate SMC signal transduction pathways including the Ras-mitogen-activated protein kinase (MAPK) and the PI3K-Akt-mammalian target of rapamycin (mTOR) pathways for growth gene transcription. PDGF-BB, Platelet-derived growth factor-BB; bFGF, basic fibroblast growth factor; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PIP2, phosphatidylinositol bisphosphate; Grb2, growth factor receptor-bound protein 2; PI3K, phosphatidylinositol 3-kinase; PDK1, 3-phosphoinositide-dependent kinase 1; MEK, MAPK/ERK kinase 1/2; Sos, son of sevenless. Journal of Vascular Surgery 2007 45, A15-A24DOI: (10.1016/j.jvs.2007.02.061) Copyright © 2007 The Society for Vascular Surgery Terms and Conditions

Fig 3 Apoptotic signaling during smooth muscle cell (SMC) response to injury. The figure shows divergent pathways resulting in control of apoptosis, leading to different outcomes. The extrinsic apoptosis pathway is stimulated by signals external to the SMC, whereas the intrinsic apoptosis pathway is stimulated by signals internal to the SMC nucleus or mitochondria, or both. In the extrinsic pathway, apoptosis ligands activate caspase-8 and caspase-10 or c-Jun N-terminal kinase (JNK). The intrinsic pathway is activated by DNA damage or genetic programs and induces the apoptosis activating factor 1 (Apaf1)-caspase-9 complex directly or through the release of cytochrome c. Both the internal and external pathways activate caspase-3, caspase-5, and caspase-7 to effect apoptosis. TNFα, Tumor necrosis factor-α; PKA, protein kinase A; PI3K, phosphatidylinositol 3-kinase; ERK, extracellular signal-regulated kinase; Cyto c, cytochrome c; UV, ultraviolet radiation. Journal of Vascular Surgery 2007 45, A15-A24DOI: (10.1016/j.jvs.2007.02.061) Copyright © 2007 The Society for Vascular Surgery Terms and Conditions

Fig 4 Relevance of the mammalian target of rapamycin (mTOR) signal transduction pathway in the response to vascular injury. The right carotid artery of New Zealand White rabbits was subjected to sham operation (control), balloon injury (B), outflow branch ligation to reduce flow (LF), or both balloon injury and reduction in flow (B+LF), and harvested after 21 days. Either rapamycin (5 mg/kg) or saline was orally administered daily from 48 hours before the procedure until harvest. In animals given rapamycin, serum levels (day 7) were therapeutic (mean, 10.9 ± 0.5 ng/mL; therapeutic range, 4 to 12 ng/mL; n = 21). Animals treated with rapamycin demonstrated significant inhibition of neointimal thickening in balloon-injured arteries (B), including arteries treated with low flow (B+LF; P < .0001). Negative remodeling was evident in all vessels in both low flow groups (LF, B+LF), and rapamycin did not affect this reduction in vessel size due to low flow. A, Low-power magnification. B, High-power magnification. Reprinted from Paszkowiak JJ, Maloney SP, Kudo FA, et al. Evidence supporting changes in Nogo-B levels as a marker of neointimal expansion but not adaptive arterial remodeling. Vasc Pharmacol 2007;46:293-301. Copyright 2007, with permission from Elsevier. Journal of Vascular Surgery 2007 45, A15-A24DOI: (10.1016/j.jvs.2007.02.061) Copyright © 2007 The Society for Vascular Surgery Terms and Conditions