Effects of cyclic mechanical stretch on extracellular matrix synthesis by human scleral fibroblasts

Shelton, Lindsey B.; Rada, Jody Summers

doi:10.1016/j.exer.2006.10.004

Cited by 78 publications

(79 citation statements)

References 43 publications

(58 reference statements)

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“…This could directly induce MMP activation, as has been shown in isolated fibroblasts (58). Endocrine changes, particularly the elevations in relaxin and estrogen characteristic of mammalian pregnancy, may exert a synergistic effect, as both hormones have been implicated in MMP regulation and activation in the pregnant state (30,35).…”

Section: Discussionmentioning

confidence: 98%

Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition

Hale

Weger

Mandalà

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Hale SA, Weger L, Mandala M, Osol G. Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition. Am J Physiol Heart Circ Physiol 301: H1266 -H1275, 2011. First published August 19, 2011 doi:10.1152/ajpheart.00519.2011.-Recent findings indicate that endothelial nitric oxide (NO) plays a key role in uterine artery outward circumferential remodeling during pregnancy. Although the underlying mechanisms are not known, they likely involve matrix metalloproteinases (MMPs). The goal of this study was to examine the linkage among NO inhibition, expansive remodeling, and MMP expression within the uterine vascular wall. Adult female rats were treated with N G -nitro-L-arginine methyl ester [L-NAME (LPLN)] beginning on day 10 of pregnancy and until death at day 20 and compared with age-matched controls [late pregnant (LP)]. Mean arterial pressure of LPLN rats was significantly higher than controls. LPLN fetal and placental weights were significantly reduced compared with controls. Main uterine arteries (mUA) were collected to determine dimensional properties (lumen area and wall thickness), collagen and elastin content, and levels of endothelial nitric oxide synthase (eNOS) and MMP expression. Circumferential remodeling was attenuated, as evidenced by significantly smaller lumen diameters. eNOS RNA and protein were significantly (Ͼ90%) decreased in the LPLN mUA compared with LP. Collagen and elastin contents were significantly increased in LPLN rats by ϳ10 and 25%, respectively, compared with LP (P Ͻ 0.05). Both MMP-2 and tissue inhibitors of metalloproteinase-2 as assessed by immunofluorescence were lower in the endothelium (reduction of 60%) and adventitia (reduction of 50%) of LPLN compared with LP mUA. Membrane bound MMP-1 (MT1-MMP) as assessed by immunoblot was significantly decreased in LPLN. These data suggest a novel contribution of MMPs to gestational uterine vascular remodeling and substantiate the linkage between NO signaling and gestational remodeling of the uterine circulation via altered MMP, TIMP-2, and MT1-MMP expression and activity. matrix metalloproteinase; extracellular matrix; hypertension; pregnancy; nitric oxide DURING PREGNANCY, THE UTERINE vasculature undergoes significant expansive remodeling to accommodate the dramatic increase in uteroplacental blood flow that is requisite for normal pregnancy outcome. Studies from our and other laboratories (40,41,44,46,50,61) have established that nitric oxide (NO) is a key molecule involved in vascular remodeling during pregnancy and that expression of endothelial nitric oxide synthase (eNOS) is increased during pregnancy, leading to increased synthesis and release of NO from the endothelium.The importance of NO and NO signaling during pregnancy is underscored by the vascular and reproductive implications evident in mouse knockouts for endothelial NO synthase and in rats treated with the NO inhibitor N G -nitro-L-arginine methyl ester (L-NAME) during pregnancy (50, 64). Tre...

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Section: Discussionmentioning

confidence: 98%

Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition

Hale

Weger

Mandalà

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Although a recent gene array study (30) has highlighted the large number of genes in the sclera that are under the control of mechanical factors, other studies have concentrated on stress-induced scleral ECM remodeling, specifically reporting decreased collagen synthesis and increased matrix metalloproteinase-2 activity (29,31). Thus, it is likely that the intrinsic contractile capacity of scleral cells is important in providing resistance to the expansile forces in the eye generated by the intraocular pressure.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Scleral Cell Contraction by Transforming Growth Factor-β and Stress

Jobling

Gentle

Metlapally

et al. 2009

Journal of Biological Chemistry

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Reduced extracellular matrix accumulation in the sclera of myopic eyes leads to increased ocular extensibility and is related to reduced levels of scleral transforming growth factor-␤ (TGF-␤). The current study investigated the impact of this extracellular environment on scleral cell phenotype and cellular biomechanical characteristics. Scleral cell phenotype was investigated in vivo in a mammalian model of myopia using the myofibroblast marker, ␣-smooth muscle actin (␣-SMA). In eyes developing myopia ␣-SMA levels were increased, suggesting increased numbers of contractile myofibroblasts, and decreased in eyes recovering from myopia. To understand the factors regulating this change in scleral phenotype, the competing roles of TGF-␤ and mechanical stress were investigated in scleral cells cultured in three-dimensional collagen gels. All three mammalian isoforms of TGF-␤ altered scleral cell phenotype to produce highly contractile, ␣-SMA-expressing myofibroblasts (TGF-␤3 > TGF-␤2 > TGF-␤1). Exposure of cells to the reduced levels of TGF-␤ found in the sclera in myopia produced decreased cellmediated contraction and reduced ␣-SMA expression. These findings are contrary to the in vivo gene expression data. However, when cells were exposed to both the increased stress and the reduced levels of TGF-␤ found in myopia, increased ␣-SMA expression was observed, replicating in vivo findings. These results show that although reduced scleral TGF-␤ is a major contributor to the extracellular matrix remodeling in the myopic eye, it is the resulting increase in scleral stress that dominates the competing TGF-␤ effect, inducing increased ␣-SMA expression and, hence, producing a larger population of contractile cells in the myopic eye.

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“…Large studies have revealed a relationship between mechanical stretch and MMPs and TIMPs in many kinds of eye cells. For example, Shelton et al (28) reported that mechanical strain increased levels of MMP-2 and reduced levels of TIMP-2 by human scleral fibroblasts. Kirwan et al (30) reported that cyclical stretch induced MMP-2 expression in human lamina cribrosa cells.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have suggested that many diseases have been associated with an imbalance of ECM synthesis and degradation and mechanical factors have been found involved in the pathogenesis of these diseases (26,27). Mechanical stimulation is involved in the regulation of MMPs in some ocular tissues, such as sclera (28), trabecular meshwork (29) and lamina cribrosa cells (30). The cornea is a dynamic tissue, capable of altering its ECM composition and biomechanical properties in response to changes in the visual environment (31,32).…”

Section: Introductionmentioning

confidence: 99%

Induction of MMP-1 and −3 by cyclical mechanical stretch is mediated by IL-6 in cultured fibroblasts of keratoconus

Du¹,

Chen²,

Li³

et al. 2017

Molecular Medicine Reports

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Abstract. In order to understand the effect of mechanical stretch on corneal extracellular matrix remodeling, human keratoconus fibroblasts (HKCFBs) were subjected to cyclic stretch in vitro and the expression of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs), and inflammatory cytokines were evaluated. HKCFBs were seeded into a flexible membrane base and subjected to a cyclic stretch regimen of 10% equibiaxial stretch at a stretching frequency of 1 Hz for 6 h using a Flexcell tension unit. An antibody directed against interleukin-6 (IL-6 Ab) was used to investigate the roles of IL-6 on mechanical stretch mediated regulation of MMP in HKCFBs. Culture supernatants were assayed using an enzyme-linked immunosorbent assay for MMP-1 and -3, TIMP-1 and -2, and IL-6. Total RNA from the cells was extracted, and quantitative polymerase chain reaction was used to determine mRNA for MMP-1 and -3, TIMP-1 and -2, and IL-6. In stretched cells, levels of MMP-1 and -3 demonstrated an increase compared with unstretched cells, but levels of TIMP-1, and -2 revealed a decrease. Mechanical stretch significantly increased the mRNA expression and protein synthesis of IL-6 compared with unstretched cells. IL-6 induced MMP-1 and -3 expression, whereas no significant effects were observed in levels of TIMP-1 and -2 compared with the untreated control groups. Additionally, the IL-6 Ab markedly inhibited the stretch-induced increase in MMP-1 and -3 in culture supernatants in a dose-dependent manner. No significant differences in TIMP-1 and -2 protein levels were detected between stretched cells treated with IL-6 Ab and stretched cells without IL-6 Ab treatment. These results indicate that cyclical mechanical stretch augments IL-6 production and MMP expression, and reduces levels of TIMP in HKCFBs. Thus, it is suggested that IL-6 mediates the stretch-induced MMP expression.

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Effects of cyclic mechanical stretch on extracellular matrix synthesis by human scleral fibroblasts

Cited by 78 publications

References 43 publications

Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition

Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition

Regulation of Scleral Cell Contraction by Transforming Growth Factor-β and Stress

Induction of MMP-1 and −3 by cyclical mechanical stretch is mediated by IL-6 in cultured fibroblasts of keratoconus

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