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Journal ArticleDOI

Expression of Extracellular Matrix Proteins Accompanies Lesion Growth in a Model of Intimal Reinjury

01 May 1998-Circulation Research (Lippincott Williams & Wilkins)-Vol. 82, Iss: 9, pp 988-995
TL;DR: It is demonstrated that the accumulation of extracellular matrix is important in the increase in lesion size after reinjury and that a balance of matrix synthesis and degradation may explain why no change in matrix volume was detected until 28 days after the reinjury.
Abstract: —Reinjury of rat arterial lesions induces an increase in lesion size that is not associated with an increase in cell number. In this study, matrix volume was examined after reinjury to preexisting lesions, and the kinetics of matrix gene expression and activity of proteolytic enzymes in the lesion were evaluated. Volume densitometry in intima showed a significant increase in matrix volume 28 days after the reinjury, although no change was observed at 14 days. Three common vascular matrix molecules, α1(I)procollagen, tropoelastin, and fibronectin, were expressed highly at 7 days after the reinjury. Expression of tropoelastin remained upregulated for the entire 28 days after the reinjury, whereas α1(I)procollagen and fibronectin returned to the control level by 28 days. Protease activity was also increased after reinjury. Within days, a marked increase in urokinase plasminogen activator activity was observed in intima, and this activity decreased to control level by 14 days. The activity of tissue p...
Citations
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Journal ArticleDOI
Mark D. Rekhter1
TL;DR: This review discusses cellular sources of collagen synthesis in atherosclerosis, local and systemic factors modulating collagen gene expression, as well as temporal and spatial patterns of collagen production in human and experimental atherosclerotic lesions.
Abstract: Fibrillar collagen is a critical component of atherosclerotic lesions. Uncontrolled collagen accumulation leads to arterial stenosis, while excessive collagen breakdown combined with inadequate synthesis weakens plaques thereby making them prone to rupture. This review discusses cellular sources of collagen synthesis in atherosclerosis, local and systemic factors modulating collagen gene expression, as well as temporal and spatial patterns of collagen production in human and experimental atherosclerotic lesions.

261 citations

Journal ArticleDOI
TL;DR: Effects as summarized in this short review, are not always, at first sight, consistent and should be kept in mind, though, when considering the response of a cell to collagen.

145 citations

Journal ArticleDOI
TL;DR: It is indicated that inhibition of endothelial miR-92a attenuates neointimal lesion formation by accelerating re-endothelialization and thus represents a putative novel mechanism to enhance the functional recovery following vascular injury.
Abstract: Aims MicroRNA (miR)-92a is an important regulator of endothelial proliferation and angiogenesis after ischaemia, but the effects of miR-92a on re-endothelialization and neointimal lesion formation after vascular injury remain elusive. We tested the effects of lowering miR-92a levels using specific locked nucleic acid (LNA)-based antimiRs as well as endothelial-specific knock out of miR-92a on re-endothelialization and neointimal formation after wire-induced injury of the femoral artery in mice. Methods and results MiR-92a was significantly up-regulated in neointimal lesions following wire-induced injury. Pre-miR-92a overexpression resulted in repression of the direct miR-92a target genes integrin α5 and sirtuin1, and reduced eNOS expression in vitro . MiR-92a impaired proliferation and migration of endothelial cells but not smooth muscle cells. In vivo , systemic inhibition of miR-92a expression with LNA-modified antisense molecules resulted in a significant acceleration of re-endothelialization of the denuded vessel area. Genetic deletion of miR-92a in Tie2-expressing cells, representing mainly endothelial cells, enhanced re-endothelialization, whereas no phenotype was observed in mice lacking miR-92a expression in haematopoietic cells. The enhanced endothelial recovery was associated with reduced accumulation of leucocytes and inhibition of neointimal formation 21 days after injury and led to the de-repression of the miR-92a targets integrin α5 and sirtuin1. Conclusion Our data indicate that inhibition of endothelial miR-92a attenuates neointimal lesion formation by accelerating re-endothelialization and thus represents a putative novel mechanism to enhance the functional recovery following vascular injury.

127 citations


Cites background from "Expression of Extracellular Matrix ..."

  • ...The expression of Itga5 in EC is essential for the regenerative capacity of the cells following vascular injury, mainly due to its interaction with fibronectin, which represents an abundant component of the extracellular matrix (ECM) following vascular injury.(22) Indeed, the concerted interaction of integrins with ECM components is a prerequisite for the adhesion, proliferation, and migration of EC in the process of re-endothelialization....

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Journal ArticleDOI
TL;DR: In this article, the expression of proteases and collagen involved in early vein wall remodeling was investigated in early venous thrombosis in the mouse, and the results showed that wound healing after DVT is similar to wound healing and is associated with increased procollagen gene expression and total collagen.

112 citations

References
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Journal ArticleDOI
TL;DR: Results are consistent with the hypothesis that TGF-beta is a cell-type-specific regulator of proteoglycan synthesis in human blood vessels and may contribute to the myo-intimal accumulation of proteglycan in atherosclerotic lesions.
Abstract: Myo-intimal proteoglycan metabolism is thought to be important in blood vessel homeostasis, blood clotting, atherogenesis, and atherosclerosis. Human platelet-derived transforming growth factor type beta (TGF-beta) specifically stimulated synthesis of at least two types of chondroitin sulfate proteoglycans in nonproliferating human adult arterial smooth muscle cells in culture. Stimulation of smooth muscle cell proteoglycan synthesis by smooth muscle cell growth promoters (epidermal growth factor, platelet-derived growth factor, and heparin-binding growth factors) was less than 20% of that elicited by TGF-beta. TGF-beta neither significantly stimulated proliferation of quiescent smooth muscle cells nor inhibited proliferating cells. The extent of TGF-beta stimulation of smooth muscle cell proteoglycan synthesis was similar in both nonproliferating and growth-stimulated cells. TGF-beta, which is a reversible inhibitor of endothelial cell proliferation, had no comparable effect on endothelial cell proteoglycan synthesis. These results are consistent with the hypothesis that TGF-beta is a cell-type-specific regulator of proteoglycan synthesis in human blood vessels and may contribute to the myo-intimal accumulation of proteoglycan in atherosclerotic lesions.

188 citations

Journal ArticleDOI
TL;DR: Enoxaparin (40 mg/d SC for 1 month) following successful angioplasty did not reduce the incidence of angiographic restenosis or the occurrence of clinical events over 6 months, although the treatment was well tolerated, although in-hospital minor bleeding was more common with active treatment.
Abstract: BACKGROUNDHeparin, an anticoagulant, possesses antiproliferative effects and has been shown to reduce neointimal proliferation and restenosis following vascular injury in experimental studies.METHODS AND RESULTSThe primary aim of this double-blind multicenter study was to determine if 40 mg Enoxaparin, a low molecular weight heparin, administered subcutaneously once daily for 1 month after successful angioplasty would reduce the incidence of restenosis. Four hundred fifty-eight patients were randomized at nine clinical centers (231 to placebo and 227 to Enoxaparin). The primary end point was angiographic or clinical restenosis. Angiographic restenosis was defined as a loss of 50% of the initial gain as measured by quantitative coronary angiography (QCA) at a core laboratory. In the absence of QCA, clinical evidence of restenosis was defined as death, myocardial infarction, repeat revascularization, or worsening angina. Using the intention-to-treat analysis for all patients, restenosis occurred in 51% of t...

178 citations

Journal Article
TL;DR: It is demonstrated that endothelial regeneration will stop before cellular regrowth is complete and that cell senescence is not responsible.

178 citations


"Expression of Extracellular Matrix ..." refers background in this paper

  • ...The fact that these lesions do not possess an intact endothelium would render the arterial wall permeable to plasma proteins, which would include TPA.35,36 The presence of increased PA activity at early times (1 to 7 days) after reinjury may explain why no increase in matrix accumulation was detected at the early times after reinjury but does not provide an answer as to why an increase in ECM was detected 28 days after reinjury....

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  • ...The fact that these lesions do not possess an intact endothelium would render the arterial wall permeable to plasma proteins, which would include TPA.(35,36) The presence of increased PA activity at early times (1 to 7 days) after reinjury may explain why no increase in matrix accumulation was detected at the early times after reinjury but does not provide an answer as to why an increase in ECM was detected 28 days after reinjury....

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  • ...The lack of concordance between activity and expression may be due to plasma-derived TPA....

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Journal ArticleDOI
TL;DR: Increase in shear stress likely induces expansive remodeling in relation to flow-dependent vasodilation, whereas increase in tensile stress is responsible for medial hypertrophy and fibrosis.
Abstract: The effects of chronic increase in aortic blood flow on arterial wall remodeling were investigated in vivo with the use of an aortocaval fistula (ACF) model in rats. Phasic hemodynamics and aortic ...

170 citations

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These findings demonstrate that the accumulation of extracellular matrix is important in the increase in lesion size after reinjury and that a balance of matrix synthesis and degradation may explain why no change in matrix volume was detected until 28 days after the reinjury.