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
References
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01 Jan 1992
TL;DR: Long-term angiotensin converting enzyme inhibition with cilazapril in a dose of 5 mg b.i.l.d. does not prevent restenosis and does not favorably influence the overall clinical outcome after PTCA.
Abstract: BACKGROUND. Cilazapril is a novel angiotensin converting enzyme inhibitor with antiproliferative effects in the rat model after balloon injury. METHODS AND RESULTS. We conducted a randomized, double-blind placebo-controlled trial to assess the effect of cilazapril in angiographic restenosis prevention after percutaneous transluminal coronary angioplasty (PTCA). Patients received cilazapril 2.5 mg in the evening after successful PTCA and 5 mg b.i.d. for 6 months or matched placebo. In addition, all patients received aspirin for 6 months. Coronary angiograms before PTCA, after PTCA, and at 6-month follow-up were quantitatively analyzed. In 94% of 735 recruited patients, PTCA was successful and all inclusion and exclusion criteria were met. For the per-protocol analysis, quantitative angiography after PTCA and at follow-up was available in 595 patients who complied with the treatment regimen (309 control, 286 cilazapril). The mean difference in minimal coronary lumen diameter between post-PTCA and follow-up angiogram (primary end point) was -0.29 +/- 0.49 mm in the control group and - 0.27 +/- 0.51 mm in the cilazapril group. Clinical events during 6- month follow-up, analyzed on an intention-to-treat basis, were ranked according to the most serious clinical event ranging from death (control, two; cilazapril, three), nonfatal myocardial infarction (control, eight; cilazapril, 5), coronary revascularization (control, 51; cilazapril, 53), or recurrent angina requiring medical therapy (control, 67; cilazapril, 68) to none of the above (control, 224; cilazapril, 212). There were no significant differences in ranking. CONCLUSIONS. Long-term angiotensin converting enzyme inhibition with cilazapril in a dose of 5 mg b.i.d. does not prevent restenosis and does not favorably influence the overall clinical outcome after PTCA.
231 citations
Journal Article•
TL;DR: The results support the conclusion that ECM gene expression is a relatively late event in the response of the carotid artery, and that some of the genes are expressed only in the intima whereas others are expressed in both the Intima and media.
Abstract: Accumulation of extracellular matrix (ECM) after arterial injury is an important event in the development of intimal thickening and is modulated by heparin. To investigate the regulation of matrix protein expression, we have analyzed messenger RNA levels by Northern blotting for various ECM proteins in the rat carotid artery balloon injury model. RNA was extracted from normal arteries and from intima-medial preparations at 2 days, 1 week, 2 weeks, and 4 weeks after balloon injury of arteries in animals receiving either saline or heparin infusion. Transcripts for the heparan sulfate proteoglycans perlecan, syndecan, and ryudocan; the chondroitin sulfate proteoglycan versican; the dermatan sulfate proteoglycan biglycan; type I procollagen; and tropoelastin all were increased on Northern blots beginning at 1 week after injury. By in situ hybridization, the transcripts for elastin nd biglycan were primarily localized to smooth muscle cells in the intima and were diminished by heparin in proportion to the decrease in intimal mass. Other matrix genes (perlecan, ryudocan) were expressed in the intima and media and were not affected by heparin. The results support the conclusion that ECM gene expression is a relatively late event in the response of the carotid artery, and that some of the genes are expressed only in the intima whereas others are expressed in both the intima and media.
207 citations
Journal Article•
TL;DR: In rabbits, it cannot be assumed that platelet survival provides an estimate of endothelial injury in all circumstances, and by injecting 51Cr-labeled platelets into rabbits at different times after injury, the reactivity of the exposed surface to newly injected platelets was estimated.
203 citations
TL;DR: It is reported here that genes encoding PDGF A- and B-chain precursors are expressed at similar low levels in intact aortas from newborn and adult rats, and evidence for age-related change in the control of PDGF B- chain gene expression in aortic SMC is provided.
Abstract: Cultured arterial smooth muscle cells (SMC) can produce platelet-derived growth factor (PDGF)-like molecules. This property raises the possibility that SMC-derived PDGFs function as autocrine/paracrine regulators in the formation and maintenance of the artery wall. In this study we have asked if levels of mRNAs directing synthesis of PDGF are modulated in aortic SMC during postnatal development. We report here that genes encoding PDGF A- and B-chain precursors are expressed at similar low levels in intact aortas from newborn and adult rats. Marked differences in regulation of transcript abundance of these genes were revealed when aortic SMC were grown in cell culture. PDGF B-chain transcripts accumulated in passaged newborn rat SMC but not adult rat SMC, whereas PDGF A-chain RNA was found in comparable amounts in SMC from both age groups. Similarly, SMC from newborn rats secreted at least 60-fold more PDGF-like activity into conditioned medium than did adult rat SMC. PDGF B-chain transcripts in newborn rat aortic SMC are short-lived and increased 5-fold by 3 hr after treatment with cycloheximide. In contrast, PDGF A-chain transcripts are more stable, and their constitutive levels were generally unaffected by cycloheximide. These results show that PDGF A- and B-chain genes are transcribed in the normal rat aorta and provide evidence for age-related change in the control of PDGF B-chain gene expression in aortic SMC. Independent regulation of transcript levels in cultured SMC leaves open the possibility that PDGFs of different composition (AA, AB, BB) play different roles in normal function of the artery wall.
197 citations
Journal Article•
TL;DR: It is shown that heparin administered in vivo can alter the accumulation and distribution of each of the major vascular ECM components in a specific and differential manner.
Abstract: Heparin and related molecules influence vascular wall structure by their ability to inhibit smooth muscle cell (smc) proliferation and migration. However, little is known as to whether heparin has an effect on the extracellular matrix. In the present study, the effect of heparin on the content and regional distribution of elastin, collagen, and proteoglycans (PGs) in blood vessels following experimental injury was determined. Two groups of rats were subjected to left common carotid balloon injury and were infused with either 0.9% saline or heparin in a saline solution, for 2 weeks. Using a new morphometric method of analysis, the authors determined changes in volumes of elastin, collagen, and PGs contained within an 'extracellular matrix domain (ECM domain),' the average envelope of connective tissue surrounding each smc. Heparin treatment inhibited intimal thickening and decreased the elastin content in the ECM domain in the upper and lower arterial intima. Collagen also was found to be significantly decreased 5.0-fold and 7.6-fold in the ECM domains of upper and lower intima, respectively, of heparin-treated animals. The decrease in both elastin and collagen was balanced by a significant increase in amorphous and filamentous electron-dense material. Heparin also caused a significant 1.8-fold and 1.9-fold increase in the PG content in the ECM domain in the upper and lower intima, respectively. Immunohistochemical analysis, using antibodies to elastin and PG subclasses, supported the morphometric observations. This study has shown that heparin administered in vivo can alter the accumulation and distribution of each of the major vascular ECM components in a specific and differential manner.
191 citations