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      Different Migration of Vascular Smooth Muscle Cells from Human Coronary Artery Bypass Vessels


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          Background: We examined whether vascular smooth muscle (VSMC) or endothelial cell (EC) migration from internal mammary artery (MA) differed from VSMC or EC migration from saphenous vein (SV). Methods and Results: Migration to PDGF-BB (1–10 ng/ml) was lower in VSMC from MA than SV; however, attachment, movement without chemokine, and chemokinesis were identical. Unlike VSMC, migration of EC was similar in response to several mediators. Expression of PDGF receptor-β was lower in VSMC from MA than SV, while α-receptor expression was higher. PDGF-BB-induced RhoA activity was lower in MA than SV, while basal activity was identical. Rosuvastatin and hydroxyfasudil impaired PDGF-BB-induced migration of VSMC from MA and SV. Mevalonate and geranylgeranylpyrophosphate rescued inhibition by rosuvastatin. PDGF-BB induced less stress fiber formation in VSMC from MA than SV. A dominant negative RhoA mutant inhibited stress fiber formation to PDGF-BB, while a constitutively active mutant resulted in maximal stress fiber formation in MA and SV. Rosuvastatin and hydroxyfasudil impaired PDGF-BB-induced stress fiber formation in MA and SV. Conclusions: VSMC migration to PDGF-BB is lower in MA than SV, which is at least in part related to lower activity of the Rho/ROCK pathway.

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          Most cited references 18

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          The High Mobility Group (Hmg) Boxes of the Nuclear Protein Hmg1 Induce Chemotaxis and Cytoskeleton Reorganization in Rat Smooth Muscle Cells

          HMG1 (high mobility group 1) is a ubiquitous and abundant chromatin component. However, HMG1 can be secreted by activated macrophages and monocytes, and can act as a mediator of inflammation and endotoxic lethality. Here we document a role of extracellular HMG1 in cell migration. HMG1 (and its individual DNA-binding domains) stimulated migration of rat smooth muscle cells in chemotaxis, chemokinesis, and wound healing assays. HMG1 induced rapid and transient changes of cell shape, and actin cytoskeleton reorganization leading to an elongated polarized morphology typical of motile cells. These effects were inhibited by antibodies directed against the receptor of advanced glycation endproducts, indicating that the receptor of advanced glycation endproducts is the receptor mediating the HMG1-dependent migratory responses. Pertussis toxin and the mitogen-activated protein kinase kinase inhibitor PD98059 also blocked HMG1-induced rat smooth muscle cell migration, suggesting that a Gi/o protein and mitogen-activated protein kinases are required for the HMG1 signaling pathway. We also show that HMG1 can be released by damage or necrosis of a variety of cell types, including endothelial cells. Thus, HMG1 has all the hallmarks of a molecule that can promote atherosclerosis and restenosis after vascular damage.
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            Coronary bypass surgery with internal-thoracic-artery grafts--effects on survival over a 15-year period.

            Aortocoronary bypass surgery has been performed most often with the patient's saphenous vein as the conduit. The internal-thoracic-artery graft, which has superior patency rates, has been shown to have clinical advantages, but it is not known how long these advantages persist. We identified all the patients in the registry of the Coronary Artery Surgery Study who had undergone first-time coronary-artery bypass grafting. Those with internal-thoracic-artery bypass grafts (749 patients) were compared with those with saphenous-vein bypass grafts only (4888 patients) with respect to survival over a 15-year follow-up period. In a multivariate analysis to account for differences between the two groups, the presence of an internal-thoracic-artery graft was an independent predictor of improved survival and was associated with a relative risk of dying of 0.73 (95 percent confidence interval, 0.64 to 0.83). This improved survival was also observed in subgroups including patients 65 years of age or older, both men and women, and patients with impaired ventricular function. The survival curves of the two groups showed further separation over the years of follow-up, with a more marked downsloping after eight years in the curve for the group with saphenous-vein grafts only than in that for the group with internal-thoracic-artery grafts. As compared with saphenous-vein coronary bypass grafts, internal-thoracic-artery grafts conferred a survival advantage throughout a 15-year follow-up period. The survival advantage increased with time, suggesting that the initial selection of the conduit was a more important factor in survival than problems appearing long after surgery, such as the progression of coronary disease.
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              Smooth muscle differentiation marker gene expression is regulated by RhoA-mediated actin polymerization.

              Smooth muscle cell (SMC) differentiation is regulated by a complex array of local environmental cues, but the intracellular signaling pathways and the transcription mechanisms that regulate this process are largely unknown. We and others have shown that serum response factor (SRF) contributes to SMC-specific gene transcription, and because the small GTPase RhoA has been shown to regulate SRF, the goal of the present study was to test the hypothesis that RhoA signaling is a critical mechanism for regulating SMC differentiation. Coexpression of constitutively active RhoA in rat aortic SMC cultures significantly increased the activity of the SMC-specific promoters, SM22 and SM alpha-actin, whereas coexpression of C3 transferase abolished the activity of these promoters. Inhibition of either stress fiber formation with the Rho kinase inhibitor Y-27632 (10 microm) or actin polymerization with latrunculin B (0.5 microm) significantly decreased the activity of SM22 and SM alpha-actin promoters. In contrast, increasing actin polymerization with jasplakinolide (0.5 microm) increased SM22 and SM alpha-actin promoter activity by 22-fold and 13-fold, respectively. The above interventions had little or no effect on the transcription of an SRF-dependent c-fos promoter or on a minimal thymidine kinase promoter that is not SRF-dependent. Taken together, the results of these studies indicate that in SMC, RhoA-dependent regulation of the actin cytoskeleton selectively regulates SMC differentiation marker gene expression by modulating SRF-dependent transcription. The results also suggest that RhoA signaling may serve as a convergence point for the multiple signaling pathways that regulate SMC differentiation.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                February 2007
                29 January 2007
                : 44
                : 2
                : 149-156
                aCardiovascular Research, Physiology Institute, bCenter for Integrative Human Physiology, University of Zürich, cCardiology, Cardiovascular Center, University Hospital Zürich, Zürich, and dCardiovascular Research, Department of Clinical Research, University of Bern and Clinic for Cardiovascular Surgery, University Hospital, Bern, Switzerland
                99141 J Vasc Res 2007;44:149–156
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 4, Tables: 1, References: 34, Pages: 8
                Research Paper


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