Thrombospondin-1 induces matrix metalloproteinase-2 activation in vascular smooth muscle cells1 1Competition of interest: none.

Lee, Taeseung; Esemuede, Nowokere; Sumpio, Bauer E.; Gahtan, Vivian

doi:10.1016/s0741-5214(02)75468-2

Cited by 38 publications

(33 citation statements)

References 33 publications

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“…2). In view of the recent literature on matricellular proteins (10,26,30,39), these findings are compatible with the working hypothesis outlined in Fig. 3.…”

Section: Differential Gene Expressionsupporting

confidence: 92%

Toward functional genomics of flow-induced outward remodeling of resistance arteries

Mey

Schiffers

Hilgers

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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.-In resistance-sized arteries, a chronic increase in blood flow leads to increases in arterial structural luminal diameter and arterial wall mass. In this review, we summarize recent evidence that outward remodeling of resistance arteries 1) can help maintain and restore tissue perfusion, 2) is not intimately related to flowinduced vasodilatation, 3) involves transient dedifferentiation and turnover of arterial smooth muscle cells, and 4) is preceded by increased expression of matricellular proteins, which have been shown to promote disassembly of focal adhesion sites. Studies of experimental and physiological resistance artery remodeling involving differential gene expression analyses and the use of knockout and transgenic mouse models can help unravel the mechanisms of outward remodeling.flow-induced vasodilatation; matricellular protein; gene expression microarray analysis IN ARTERIES, TRANSMURAL PRESSURE and blood flow influence wall thickness and structural luminal diameter (13,16,28,29,49). Mathematical modeling, cell and molecular biological approaches, and experiments in genetically modified animals are beginning to shed light on the mechanisms that underlie these arterial remodeling responses. Here, we summarize recent observations concerning flow-induced outward remodeling of resistance arteries. Exploration of this type of arterial structural response might lead to pharmacological treatments to 1) improve collateral perfusion and 2) reverse the inward arterial remodeling in essential hypertension. TERMINOLOGYRemodeling is frequently used to describe any alteration of arterial structure. In agreement with others (4, 38), we find it useful to note the differences among several types of arterial remodeling: 1) neointima formation, 2) alteration of the arterial structural luminal diameter (outward or inward), and 3) alteration of tunica media mass (hypertrophic, eutrophic, and hypotrophic). Although this classification is helpful, it also highlights gaps in current knowledge, such as the manner in which media, adventitia, and ultrastructural wall components, such as extracellular matrix, focal adhesion sites, and cytoskeleton, determine the diameter. Arterial structural diameter refers to the maximally dilated diameter and results from the elastic properties of the arterial wall. The diameter of an arterial segment in vivo obviously depends on this structural diameter and on the degree of vasomotor tone or smooth muscle contractile activity.Resistance arteries are small (300 -100 m diameter) muscular arteries that are situated between large elastic conduit arteries and arterioles. In contrast to the large arteries, resistance arteries 1) not only respond to, but also influence, local mean arterial pressure and blood flow, 2) rarely, if ever, develop a neointima, and 3) do not display hypertrophy but, rather, exhibit inward eutrophic remodeling during chronic hypertension (37). In resistance arteries, circumferential wall stress and wall shear stress are maintained at higher values than in arterioles (43)...

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“…2). In view of the recent literature on matricellular proteins (10,26,30,39), these findings are compatible with the working hypothesis outlined in Fig. 3.…”

Section: Differential Gene Expressionsupporting

confidence: 92%

Toward functional genomics of flow-induced outward remodeling of resistance arteries

Mey

Schiffers

Hilgers

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…The results concerning these matricellular proteins could also be interpreted in light of MMP-2 activity. Indeed, TSP-1 has been shown to stimulate MMP-2 activity, 35 and both proteins show concurrent kinetics in our study. In large elastic arteries, TN-C abundance appears to parallel that of MMP activity, 36 as it is the case in the present study.…”

Section: Bouvet Et Al Matrix Changes During Eutrophic Remodelingsupporting

confidence: 67%

Different Involvement of Extracellular Matrix Components in Small and Large Arteries During Chronic NO Synthase Inhibition

et al. 2005

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Abstract-In essential hypertension, conduit arteries present hypertrophic remodeling (increased cross-sectional area), whereas small arteries undergo eutrophic remodeling. The involvement of matrix metalloproteinases (MMPs) and de-adhesion proteins, such as tenascin-C and thrombospondin, has been relatively well characterized in large artery remodeling, but their contribution is not known in small artery remodeling. Rats received N -nitro-L-arginine methyl ester (L-NAME; 50 mg/kg per day) in their drinking water on days 1, 3, 7, 14, and 28. Arterial MMP-2 activity was measured by ELISA, whereas levels of tenascin-C and thrombospondin were assessed by Western blotting. To determine the involvement of MMPs, additional L-NAME rats received the nonselective MMP inhibitor doxycycline (30 mg/kg per day) on days 7, 14, and 28. Already, at day 1, pressure was elevated. Media/lumen ratio of mesenteric arteries and the aorta increased gradually to reach significance at 28 days. However, the cross-sectional area increased only in the aorta, confirming the heterogeneous remodeling process. In small arteries, MMP-2 activity increased after 7 and 14 days of treatment and returned to baseline at 28 days, whereas the elevation was more progressive but sustained in the aorta. The level of thrombospondin paralleled that of MMP-2 in small arteries, whereas tenascin-C levels declined rapidly and stayed below control values. Doxycycline blunted large artery remodeling but had no influence on the development of eutrophic remodeling despite elevation of MMP-2 activity in the process. Thus, in contrast to large artery hypertrophic remodeling, in which the contributions of cellular de-adhesion and matrix breakdown is manifest, the contribution of MMPs in eutrophic remodeling appears less crucial. Key Words: nitric oxide synthase Ⅲ arteries V ascular remodeling is considered an adaptive response to elevation of arterial pressure to normalize the wall tension. In essential hypertension, large artery remodeling is characterized by an increase in media thickness-lumen diameter (M/L) ratio and cross-sectional area (CSA). This augmentation of media mass, or hypertrophic remodeling, is explained by changes in size or number of vascular smooth muscle cells (VSMCs) and matrix collagen deposition. 1 In resistance arteries (diameter Ͻ300 m), essential hypertension is associated with a reduced lumen and increased M/L ratio but without CSA increase, producing a type of remodeling designated as inward eutrophic remodeling. 2 To explain this different response between large and small arteries, it is suggested that small arteries are not submitted to an augmented wall stress because they are initially constricted. 3-5 Thus, we hypothesized that inward eutrophic remodeling, which appears as a fixed form of vasoconstriction, could proceed through specific modifications of VSMC-matrix interactions.As in essential hypertension, chronic inhibition of NO synthesis with the L-arginine analogue N -nitro-L-arginine methyl ester (L-NAME) produces hypertrophic re...

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Section: Discussionmentioning

confidence: 60%

“…37 Furthermore, in vitro, TSP1 upregulates MMP2 by transcriptional and nontranscriptional mechanisms, and MMP2 activation is relevant for TSP1-induced vascular SMC migration. 28 Our findings therefore indicate that vascular TSP1 participates in early SMC activation after vessel occlusion, affecting morphological features of medial SMC and triggering SMC proliferation and migration.In WT mice, the early proliferation and migration of medial SMCs after carotid artery ligation are followed by a reduction of SMC numbers in the media and the development of a neointima, as SMCs migrate into the lumen. 33 In contrast, in Tsp1 Ϫ/Ϫ mice, as SMC numbers in the media did not change beyond day 3, Tsp1 Ϫ/Ϫ vessels persisted with a thick media and a 2-fold smaller neointima at day 28.…”

mentioning

confidence: 60%

“…27 The TSP1-induced SMC migration on gelatin appears to rely on metalloproteinase (MMP)-2 activation. 28 Indeed, endogenous TSP1 increases MMP2 levels and limits collagen production in the vascular outgrowth of muscle explants. 29 In vivo, TSP1 neutralization by antibodies resulted in less neointima development, after carotid artery denudation, 30 but it remains unclear to which extent this was attributable to accelerated reendothelialization or decreased vascular SMC function.…”

mentioning

confidence: 99%

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Thrombospondin-1 Activates Medial Smooth Muscle Cells and Triggers Neointima Formation Upon Mouse Carotid Artery Ligation

Moura

Tjwa

Vandervoort

et al. 2007

ATVB

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Objective-Thrombospondin-1 (TSP1) is described as a positive regulator of vascular smooth muscle growth in cell culture. However, insight into the in vivo effects of TSP1 on smooth muscle cell (SMC) function is lacking. Methods and Results-We analyzed wild-type (WT) and TSP1-deficient (Tsp1 Ϫ/Ϫ ) mice in a carotid artery ligation model, in which neointimal lesions form without overt mechanical damage to the endothelium. On ligation, the expression of TSP1 increased strongly in the matrix of neointima and adventitia. In the early phase after ligation (day 3 to 7), activation, proliferation, and migration of medial SMCs were delayed and impaired in Tsp1 Ϫ/Ϫ mice, in parallel with defective upregulation of metalloproteinase (MMP)-2 activity. As a result, Tsp1 Ϫ/Ϫ arteries developed smaller neointimal lesions, a thicker media but comparably attenuated patency as in WT arteries, 28 days after ligation. Furthermore, medial and neointimal SMCs in Tsp1 Ϫ/Ϫ mice produced more collagen, more osteopontin, and displayed weaker smooth muscle actin staining than WT SMCs, indicative of a modified SMC phenotype in Tsp1 Ϫ/Ϫ mice. Key Words: carotid artery Ⅲ matricellular proteins Ⅲ neointima Ⅲ smooth muscle cells T hrombospondin-1 (TSP1) is a matricellular protein, with a complex multidomain structure which can interact with a great variety of receptors, ligands, and matrix components (reviewed in 1,2 ). It is highly expressed during development, but present at a low level in adult tissues and upregulated in response to injury. [3][4][5] TSP1 is present in several cell types, including vascular cells, from which it is secreted on cell activation to participate in fine modulation of cell-cell and cell-matrix interactions and regulation of cell function. 6 -8 TSP1 gene-deficient (Tsp1 Ϫ/Ϫ ) mice are viable, and apparently normal, but challenge of these mice in various models has shown that TSP1 inhibits angiogenesis, 9,10 promotes wound healing in an excisional wound healing model, 11 and contributes to pulmonary homeostasis. 12 We have recently shown an in vivo role for TSP1 in platelet and thrombus adhesion to the injured vessel wall. 13 Percutaneous coronary interventions often result in the occurrence of intimal hyperplasia and restenosis. 14 They are triggered by endothelial injury, and involve proliferation and migration of smooth muscle cells (SMCs) from the media into the intima. A role for TSP1 in vascular injury has been suggested by the strong TSP1 upregulation in rat carotid arteries after balloon-angioplasty 15 and at sites of hyperplasia, in hypercholesterolemic lesions, and in the adventitia of diabetic rats. 5,16,17 Although TSP1 is not essential for SMC growth in vitro, the treatment of SMCs with growth factors results in strong TSP1 expression, which further amplifies SMC proliferation. 18 -21 The inhibition of TSP1 by specific antibodies reduced SMC proliferation. 21 TSP1 also acts as a chemoattractant for SMCs via interactions between its carboxyl terminus and CD47, and hence integrins. [22][23][24][25][26] ...

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Thrombospondin-1 induces matrix metalloproteinase-2 activation in vascular smooth muscle cells1 1Competition of interest: none.

Abstract: TSP-1 induced MMP2 activation through transcriptional and posttranslational mechanisms. These findings imply that MMP2 activation is relevant to the mechanism of TSP-1-induced VSMC migration.

Cited by 38 publications

References 33 publications

Toward functional genomics of flow-induced outward remodeling of resistance arteries

Toward functional genomics of flow-induced outward remodeling of resistance arteries

Different Involvement of Extracellular Matrix Components in Small and Large Arteries During Chronic NO Synthase Inhibition

Thrombospondin-1 Activates Medial Smooth Muscle Cells and Triggers Neointima Formation Upon Mouse Carotid Artery Ligation

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