Expression of Extracellular Matrix Proteins Accompanies Lesion Growth in a Model of Intimal Reinjury
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...
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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
190 citations
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
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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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
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TL;DR: In the intact pulmonary artery, stretch, but not pressure, can stimulate hypertrophy and hyperplasia in smooth muscle cells and hyperPlasia in fibroblasts and matrix protein synthesis and accumulation are also increased by stretch.
Abstract: The effect of mechanical stimuli on pulmonary artery growth and matrix tissue synthesis (and how individual cell types in the vessel wall respond to such stimuli) is incompletely characterized. Rabbit pulmonary arteries were placed in tissue culture medium and subjected to varying magnitudes of stretch or hydrostatic pressure (separately) for 4 days. The rate of protein synthesis in smooth muscle cells (by quantitative autoradiography) was positively related to the magnitude of stretch, as were the percentage of procollagen type I-positive cells and the rate of cell replication. In adventitial fibroblasts, stretch increased the rate of replication but not of protein synthesis. Hydrostatic pressure had little or no effect on the variables measured in either smooth muscle cells or fibroblasts. Stretch also increased the rate of elastin and collagen synthesis in the whole pulmonary artery segment, and after 4 days of stretch, the contents of actin and elastin were increased. Removal of the endothelium did not affect stretch-induced protein, collagen, or elastin synthesis but augmented stretch-induced smooth muscle replication. These data suggest that in the intact pulmonary artery, stretch, but not pressure, can stimulate hypertrophy and hyperplasia in smooth muscle cells and hyperplasia in fibroblasts. Matrix protein synthesis and accumulation are also increased by stretch. Neither stretch-mediated growth nor matrix protein synthesis required endothelium in this model.
122 citations
TL;DR: The results suggest that plasminogen activator and inhibitor expression correlates with the migration of both SMCs and endothelial cells into an arterial wound.
Abstract: The expression of plasminogen activators and inhibitors was examined in denuded arteries. Within 5 days, smooth muscle cells (SMCs) on the luminal surface expressed the mRNA for tissue-type plasminogen activator (TPA), urokinase-type plasminogen activator (UPA), the receptor for UPA (UPAR), and plasminogen activator inhibitor type-1 (PAI-1). Similar results were seen after 8 days. Six weeks later, only TPA mRNA was still expressed by SMCs on the luminal surface. En face casein zymograms revealed a net fibrinolytic activity in areas covered with luminal SMCs. Reverse zymography showed no antifibrinolytic activity in these zones. Quiescent endothelial cells did not express TPA, UPA, UPAR, or PAI-1 mRNA. Regenerating endothelium at the wound edge strongly expressed TPA, UPA, and UPAR, as well as PAI-1. UPA and UPAR expression was highly restricted to cells at the wound edge and was not present elsewhere. En face zymography showed no plasmin activity in endothelialized areas, and reverse zymography s...
122 citations
TL;DR: In this paper, the in vivo effect of transforming growth factor β1 (TGF-β1) was studied in a model system in which arterial intimal thickening was induced by injury of rabbit arteries with a balloon cath...
Abstract: The in vivo effect of transforming growth factor–β1 (TGF-β1) was studied in a model system in which arterial intimal thickening was induced by injury of rabbit arteries with a balloon cath...
119 citations
Journal Article•
TL;DR: It is demonstrated that total regrowth of endothelium can occur over large denuded areas despite the presence of transforming growth factor-beta and fibronectin on these surfaces.
113 citations
TL;DR: A randomized, double-blind placebo controlled trial was conducted to assess the effect of angiopeptin in restenosis prevention after percutaneous transluminal coronary angioplasty (PTCA) as mentioned in this paper.
Abstract: Background Angiopeptin is a cyclic octapeptide analogue of somatostatin that has been shown to limit myointimal thickening of arteries in balloon injury models and to restore the vasodilating response to acetylcholine. A randomized, double-blind placebo controlled trial was conducted to assess the effect of angiopeptin in restenosis prevention after percutaneous transluminal coronary angioplasty (PTCA). Methods and Results Patients received a continuous infusion of either placebo or angiopeptin subcutaneously 6 to 24 hours before PTCA and for 4 days after PTCA (3 mg per 24 hours before PTCA followed by 6 mg per 24 hours after PTCA and for the remaining period). A 1.5-mg bolus dose of placebo or angiopeptin was given at PTCA. Aspirin (acetylsalicylic acid, 150 mg/d) was administered throughout the study period. Coronary angiograms obtained before and after PTCA and at 6-month follow-up were subjected to computerized quantification. Clinical follow-up was performed after 12 months. Primary clinical end poin...
108 citations