Stretch-inducible Expression of the Angiogenic Factor CCN1 in Vascular Smooth Muscle Cells Is Mediated by Egr-1

Grote, Karsten; Bavendiek, Udo; Grothusen, Christina; Flach, Inna; Hilfiker‐Kleiner, Denise; Drexler, Helmut; Schieffer, Bernhard

doi:10.1074/jbc.m406532200

Cited by 45 publications

(50 citation statements)

References 34 publications

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“…The gene cyr61, encodes for a matrix-associated cysteine-rich secretory protein, CYR61, also known as CCN-1. CYR61/CCN1 is expressed by fibroblasts in response to TGF-␤ and other growth factors, and is transcriptionally regulated by egr-1 (46). CYR61/CCN1 is associated with fibroblast adhesion, migration, and proliferation; with extracellular matrix remodeling; and with cutaneous wound repair (29,30,(47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Essential Role of MMP-12 in Fas-Induced Lung Fibrosis

Matute-Bello

Wurfel

Lee

et al. 2007

Am J Respir Cell Mol Biol

113

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Acute lung injury (ALI) is characterized by an early inflammatory response followed by a late fibroproliferative phase, and by an increase in the bronchoalveolar lavage fluid (BALF) concentrations of bioactive soluble FasL (sFasL). Activation of Fas (CD95) has been associated with the development of lung fibrosis in mice. The goal of this study was to determine the mechanisms that link Fas activation with the development of fibrosis in the lungs. We treated mice with three daily intratracheal instillations of a Fas-activating monoclonal antibody (Jo2) or a control IgG, and studied the animals at sequential times. Mice treated with Jo2 had increased caspase-3 activation in alveolar wall cells on Days 2, 4, and 7; an inflammatory response peaking on Day 7, and increased total lung collagen on Day 21. Gene expression profiling performed on Days 2, 4, and 7 showed sequential activation of co-regulated profibrotic genes, including marked up-regulation of matrix metalloproteinase 12 (MMP-12). Targeted deletion of MMP-12 protected mice from Fasinduced pulmonary fibrosis, even though the inflammatory responses in the lungs were similar to those of wild-type mice. Compared with wild-type mice, the mmp12 Ϫ/؊ mice showed decreased expression of the profibrotic genes egr1 and cyr61. We conclude that Fas activation in the lungs induces a complex response that includes apoptosis, inflammation, and eventually fibrosis, and that MMP-12 is essential for the fibrotic phenotype. We speculate that MMP-12 activity is required for activation of the profibrotic genes egr1 and cyr61.Keywords: apoptosis; inflammation; MMP-12; Fas; CYR61/CCN1 Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are characterized by an early inflammatory response, which is maximal during the first three days of clinically defined ALI/ARDS, and a subsequent fibroproliferative response (1, 2). The fibroproliferative response is thought to occur late in the course of ALI/ARDS, but autopsy studies have shown histopathologic evidence of fibroproliferation as early as Day 5, and human studies have identified evidence of collagen production in the lungs even on the first day of ALI/ARDS (3, 4). However, the mechanisms linking the early events in acute lung injury with subsequent fibrosis are incompletely understood. Correspondence and requests for reprints should be addressed to Gustavo MatuteBello, UW Medicine/South Lake Union Campus, 815 Mercer Street, Seattle, WA 98109. E-mail: matuteb@u.washington.edu CLINICAL RELEVANCEThis study provides novel information suggesting that macrophage activation drives the lung fibrotic response to Fas activation, and that matrix metalloproteinase-12, a metalloelastase previously associated with emphysema, is essential for Fas-induced fibroproliferation.

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Section: Discussionmentioning

confidence: 99%

Essential Role of MMP-12 in Fas-Induced Lung Fibrosis

Matute-Bello

Wurfel

Lee

et al. 2007

Am J Respir Cell Mol Biol

113

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“…Vascular cells such as endothelial cells and smooth muscle cells themselves express CCN1 10 and react to different cardiovascular pathophysiologic settings with augmented CCN1 expression, [18][19][20]26,27 allowing autocrine cell stimulation in terms of tissue regeneration. In contrast, peripheral blood CD34 ϩ cells do not show endogenous CCN1 expression, excluding a mechanism of auto stimulation.…”

Section: Org Frommentioning

confidence: 99%

“…However, the underlying mechanism of cardiovascular regeneration through neovascularization and probably the interaction of different proangiogenic factors remain poorly understood. Upregulated expression of CCN1 accompanies diverse cardiovascular pathophysiologic conditions [18][19][20]27 and percutaneous transluminal coronary angioplasty (PTCA). 28 In particular, smooth muscle cells and cardiomyocytes are a major source of CCN1, suggesting that CCN1 may be a part of an important self-renewal program specifically promoting cardiovascular tissue regeneration.…”

Section: Org Frommentioning

confidence: 99%

“…15 In addition, it has been shown recently that CCN1 is critically involved in cardiac development. 16 Besides its ability to promote tumor growth, 17 we recently reported that enhanced CCN1 expression is associated with several cardiovascular pathophysiologic settings, such as atherosclerotic plaque formation, 18 enhanced vascular mechanical stretch, 19 cardiac pressure overload, and ischemic cardiomyopathy. 20 Recent evidence suggested that CCN1 expression is induced in various cardiovascular disorders, suggesting a role for CCN1 in cellular and tissue self-renewal, potentially involving circulating progenitor cells.…”

Section: Introductionmentioning

confidence: 99%

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The angiogenic factor CCN1 promotes adhesion and migration of circulating CD34+ progenitor cells: potential role in angiogenesis and endothelial regeneration

Grote¹,

Salguero²,

Ballmaier³

et al. 2007

Blood

Self Cite

103

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IntroductionBone marrow-derived and circulating hematopoietic progenitor cells have been shown to contribute to cardiovascular tissue regeneration. 1,2 CD34 ϩ hematopoietic progenitor cells were widely and successfully used in different transplantation models, including myocardial regeneration. 3 A subset of circulating CD34 ϩ cellsexpressing markers such as CD133 and vascular endothelial growth factor (VEGF) receptor-2 (flk1)-are endothelial progenitor cells (EPCs) with the ability to differentiate into mature endothelial cells, thus contributing to re-endothelialization and neovascularization. 4 In contrast, the ability of hematopoietic cells to transdifferentiate into functional cardiomyocytes is controversial. [5][6][7][8] Moreover, enhanced angiogenesis in response to progenitor cells may be influenced mainly by the release of growth factors rather than by cellular differentiation. 9 CCN1 (formerly known as CYR61) is a cysteine-rich heparinbinding protein that is encoded by an immediate early gene and belongs to the novel CCN gene family (connective tissue growth factor [CTGF], cysteine-rich angiogenic protein 61 [CYR61], and nephroblastoma overexpressed [Nov]). 10 The expression of CCN1 is rapidly induced in response to growth factors. 11 CCN1 is expressed by all types of vascular cells, is associated with the extracellular matrix (ECM) and mediates cell adhesion, migration, proliferation and neovascularization through cell type-specific binding mainly to ␣ 6 ␤ 1 , ␣ M ␤ 2 , and ␣ V ␤ 3 integrins. 10,[12][13][14] It is noteworthy that CCN1-deficient mice suffer embryonic death as a result of placental vascular insufficiency and compromised vessel integrity because of impaired vessel bifurcations and impaired VEGF-C expression, establishing CCN1 as a novel and essential regulator of vascular development. 15 In addition, it has been shown recently that CCN1 is critically involved in cardiac development. 16 Besides its ability to promote tumor growth, 17 we recently reported that enhanced CCN1 expression is associated with several cardiovascular pathophysiologic settings, such as atherosclerotic plaque formation, 18 enhanced vascular mechanical stretch, 19 cardiac pressure overload, and ischemic cardiomyopathy. 20 Recent evidence suggested that CCN1 expression is induced in various cardiovascular disorders, suggesting a role for CCN1 in cellular and tissue self-renewal, potentially involving circulating progenitor cells. Because the impact of CCN1 on progenitor cells is largely unknown, we used circulating human bone marrow-derived CD34 ϩ cells to study CCN1 effects on migration, release of growth factors, endothelial proliferation and neovascularization, which are important for cardiovascular regeneration. Materials and methods ReagentsAll chemicals were obtained from Sigma (Taufkirchen, Germany) unless otherwise specified. All cell culture plates were from TTP (Trasadingen, Switzerland). RGD peptides (Arg-Gly-Asp) and GRGDSP peptides (GlyArg-Gly-Asp-Ser-Pro) were from Bachem (Weil am Rhein, Germany). Human ...

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“…It has been shown to play a principal role in osteogenesis by stimulating the migration and differentiation of MSCs into osteoblasts (41,42), and by stimulating proliferation and differentiation of osteoblasts in an integrin and BMP dependent manner (43). The expression of Cyr61/CCN1 is known to be activated in response to mechanical stress at the transcriptional level (6) in several kinds of cells, such as fibroblasts (40), smooth muscle cells (13) in vitro, and skeletal muscle in vivo (20). With regard to bone cells and MSCs, only in vitro studies with shear stress have reported the upregulation of Cyr61/CCN1 (19,21,48).…”

Section: Discussionmentioning

confidence: 99%

<b>Tensile stress stimulates the expression of osteogenic cytokines/growth factors and matricellular proteins in the mouse cranial suture at the site of osteoblast differ</b><b>entiation </b>

et al. 2016

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Mechanical stress promotes osteoblast proliferation and differentiation from mesenchymal stem cells (MSCs). Although numerous growth factors and cytokines are known to regulate this process, information regarding the differentiation of mechanically stimulated osteoblasts from MSCs in in vivo microenvironment is limited. To determine the significant factors involved in this process, we performed a global analysis of differentially expressed genes, in response to tensile stress, in the mouse cranial suture wherein osteoblasts differentiate from MSCs. We found that the gene expression levels of several components involved in bone morphogenetic protein, Wnt, and epithelial growth factor signalings were elevated with tensile stress. Moreover gene expression of some extracellular matrices (ECMs), such as cysteine rich protein 61 (Cyr61)/CCN1 and galectin-9, were upregulated. These ECMs have the ability to modulate the activities of cytokines and are known as matricellular proteins. Cyr61/CCN1 expression was prominently increased in the fibroblastic cells and preosteoblasts in the suture. Thus, for the first time we demonstrated the mechanical stimulation of Cyr61/CCN1 expression in osteogenic cells in an ex vivo system. These results suggest the importance of matricellular proteins along with the cytokine-mediated signaling for the mechanical regulation of MSC proliferation and differentiation into osteoblastic cell lineage in vivo.Mechanical stress controls bone mass by affecting recruitment of osteoprogenitors as well as osteoblast differentiation from mesenchymal stem cells (MSCs) in the bone tissue (7,8). Elucidation of the precise mechanisms involved in the osteoblastogenesis stimulated by mechanical stress, especially the mechanism for osteogenic differentiation of MSCs, will contribute to the progress of regenerative medicine for effective production of bone tissue from MSC sources. Increasing evidence has revealed that the process of mechanical stress-stimulated osteoblastogenesis is controlled by many cytokines/growth factors (9,32,34,36). Especially bone morphogenetic protein (BMP) signaling and Wnt signaling play important roles in the development of osteoblasts from MSCs (5), but the more relevant factors among these or

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Stretch-inducible Expression of the Angiogenic Factor CCN1 in Vascular Smooth Muscle Cells Is Mediated by Egr-1

Cited by 45 publications

References 34 publications

Essential Role of MMP-12 in Fas-Induced Lung Fibrosis

Essential Role of MMP-12 in Fas-Induced Lung Fibrosis

The angiogenic factor CCN1 promotes adhesion and migration of circulating CD34+ progenitor cells: potential role in angiogenesis and endothelial regeneration

<b>Tensile stress stimulates the expression of osteogenic cytokines/growth factors and matricellular proteins in the mouse cranial suture at the site of osteoblast differ</b><b>entiation </b>

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