MMP-9 and -12 cause N-cadherin shedding and thereby β-catenin signalling and vascular smooth muscle cell proliferation

Dwivedi, Amrita; Slater, S. D.; George, Sarah J.

doi:10.1093/cvr/cvn278

Cited by 122 publications

(103 citation statements)

References 49 publications

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“…MMP-9 promotes cell proliferation in several cell types (Dwivedi et al 2009, Sans-Fons et al 2010, Ingraham et al 2011. The present study showed that MMP-9 inhibition suppressed proliferative activity of FS cells on laminin, which indicates that MMP-9 is necessary in FS cell division (Figs 3G and 4D).…”

Section: Discussionsupporting

confidence: 59%

Matrix metalloproteinase-9 expression in folliculostellate cells of rat anterior pituitary gland

Ilmiawati¹,

Horiguchi²,

Fujiwara³

et al. 2011

Journal of Endocrinology

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Folliculostellate (FS) cells of the anterior pituitary gland express a variety of regulatory molecules. Using transgenic rats that express green fluorescent protein specifically in FS cells, we recently demonstrated that FS cells in vitro showed marked changes in motility, proliferation, and that formation of cellular interconnections in the presence of laminin, a component of the extracellular matrix, closely resembled those observed in vivo. These findings suggested that FS cells express matrix metalloproteinase-9 (MMP-9), which assists their function on laminin. In the present study, we investigate MMP-9 expression in rat anterior pituitary gland and examine its role in motility and proliferation of FS cells on laminin. Immunohistochemistry, RT-PCR, immunoblotting, and gelatin zymography were performed to assess MMP-9 expression in the anterior pituitary gland and cultured FS cells. Real-time RT-PCR was used to quantify MMP-9 expression in cultured FS cells under different conditions and treatments. MMP-9 expression was inhibited by pharmacological inhibitor or downregulated by siRNA and time-lapse images were acquired. A 5-bromo-2 0 -deoxyuridine assay was performed to analyze the proliferation of FS cells. Our results showed that MMP-9 was expressed in FS cells, that this expression was upregulated by laminin, and that laminin induced MMP-9 secretion by FS cells. MMP-9 inhibition and downregulation did not impair FS motility; however, it did impair the capacity of FS cells to form interconnections and it significantly inhibited proliferation of FS cells on laminin. We conclude that MMP-9 is necessary in FS cell interconnection and proliferation in the presence of laminin.

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Section: Discussionsupporting

confidence: 59%

Matrix metalloproteinase-9 expression in folliculostellate cells of rat anterior pituitary gland

Ilmiawati¹,

Horiguchi²,

Fujiwara³

et al. 2011

Journal of Endocrinology

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“…Interestingly, a previous study showed that MMP9 and MMP12, but not MMP2 or MMP14, can cause N-cadherin shedding on VSMCs. 34 Thus, it seems that MMP9 and MMP12 can shed N-cadherin, whereas MMP8 can promote N-cadherin shedding by ADMA10.…”

Section: Discussionmentioning

confidence: 98%

“…It has been shown that VSMCs isolated from MMP9 knockout mice have a significantly lower proliferation rate than VSMCs from wild-type mice, 38 and that MMP9 and MMP12 promote VSMC proliferation by shedding N-cadherin and activating the β-catenin signaling pathway. 34 Meanwhile, MMP2 and MMP14 have been shown to play a role in oxidized low density lipoprotein-induced VSMC proliferation involving a sphingomyelin/ ceramide signaling pathway. 39 The difference in VSMC proliferation between MMP8 wild-type and knockout is not attributable to a change in the expression of those MMPs because we showed in our previous study that there is no difference in their expression between MMP8 wild-type and knockout.…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-8 Promotes Vascular Smooth Muscle Cell Proliferation and Neointima Formation

Xiao

Zhang

Grassia

et al. 2014

ATVB

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T he pathogenesis of postangioplasty restenosis involves migration and proliferation of vascular smooth muscle cells (VSMCs), which constitute a major component of postangioplasty neointimal lesions.1-4 VSMC migration and proliferation are regulated by growth factors, adhesion molecules, proteases, and intracellular proteins. Among them, the cadherin-β-catenin complex and its cognate intracellular pathway have been increasingly appreciated as important regulators of these processes. 5-8Matrix metalloproteinase-8 (MMP8) was once thought to be produced exclusively by polymorphonuclear leukocytes, but more recent studies have shown that various other cell types including stem/progenitor cells express this protease.9 Compared with some other members of the MMP family, MMP8 has been less investigated for its proteolytic substrates and biological roles. Herman et al 10 were the first to reveal that VSMCs, endothelial cells, and macrophages in atherosclerotic plaques express MMP8. Subsequently other investigators showed a correlation between increased MMP8 expression and rapid atherosclerotic lesion progression.11,12 A causal role of MMP8 in atherosclerosis development was demonstrated by our recent study, which showed that in apolipoprotein E (apoE)-deficient mice fed a Western diet for 12 weeks, MMP8 knockout resulted in a significant reduction of atherosclerotic lesions with decreased macrophage and VSMC contents. 13 The study also revealed a role of MMP8 in vascular recruitment of leukocytes, 13 providing a mechanistic explanation for the effect of MMP8 knockout on macrophage content in atherosclerotic lesions.In the present study, we sought to investigate whether MMP8 also plays a role in neointima formation after vessel © 2013 American Heart Association, Inc. Objective-We investigated the role of matrix metalloproteinase-8 (MMP8) in neointima formation and in vascular smooth muscle cell (VSMC) migration and proliferation. Approach and Results-After carotid artery wire injuring, MMP8-/-/apoE -/-mice had fewer proliferating cells in neointimal lesions and smaller lesion sizes. Ex vivo assays comparing VSMCs isolated from MMP8 knockout and wild-type mice showed that MMP8 knockout decreased proliferation and migration. Proteomics analysis revealed that a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) had lower concentrations in MMP8 knockout VSMC culture media than in MMP8 wild-type VSMC culture media. Western blot, flow cytometric, and immunocytochemical analyses showed that MMP8 knockout VSMCs contained more pro-ADAM10 but less mature ADAM10, more N-cadherin, and β-catenin in the plasma membrane but less β-catenin in the nucleus and less cyclin D1. Treatment of MMP8 wildtype VSMCs with an ADAM10 inhibitor, GI254023X, or siRNA knockdown of ADAM10 in MMP8 wild-type VSMCs inhibited proliferation and migration, increased N-cadherin and β-catenin in the plasma membrane, reduced β-catenin in the nucleus, and decreased cyclin D1 expression. Incubation of MMP8 knockout VSMCs with a recombinant ADAM...

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“…Cadherins help to maintain blood vessel integrity (5). MMP-9 has been reported to downregulate cadherins through proteolytic shedding, which would increase vascular permeability (9,32). The absence of a similar increase of Cdh1 in the Null mice suggests that the increase in the WT may be a compensatory mechanism to improve impaired vascular permeability.…”

Section: Discussionmentioning

confidence: 99%

Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction

Yabluchanskiy

Chiao

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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. Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction. Am J Physiol Heart Circ Physiol 306: H1398 -H1407, 2014. First published March 21, 2014; doi:10.1152/ajpheart.00090.2014Aging is linked to increased matrix metalloproteinase-9 (MMP-9) expression and extracellular matrix turnover, as well as a decline in function of the left ventricle (LV). Previously, we demonstrated that C57BL/6J wild-type (WT) mice Ͼ 18 mo of age show impaired diastolic function, which was attenuated by MMP-9 deletion. To evaluate mechanisms that initiate the development of cardiac dysfunction, we compared the LVs of 6 -9-and 15-18-mo-old WT and MMP-9 null (Null) mice. All groups showed similar LV function by echocardiography, indicating that dysfunction had not yet developed in the older group. Myocyte nuclei numbers and cross-sectional areas increased in both WT and Null 15-18-mo mice compared with young controls, indicating myocyte hypertrophy. Myocyte hypertrophy leads to an increased oxygen demand, and both WT and Null 15-18-mo mice showed an increase in angiogenic signaling. Plasma proteomic profiling and LV analysis revealed a threefold increase in von Willebrand factor and fivefold increase in vascular endothelial growth factor in WT 15-18-mo mice, which were further elevated in Null mice. In contrast to the upregulation of angiogenic stimulating factors, actual LV vessel numbers increased only in the 15-18-mo Null LV. The 15-18-mo WT showed amplified expression of inflammatory genes related to angiogenesis, including C-C chemokine receptor (CCR)7, CCR10, interleukin (IL)-1f8, IL-13, and IL-20 (all, P Ͻ 0.05), and these increases were blunted by MMP-9 deletion (all, P Ͻ 0.05). To measure vascular permeability as an index of endothelial function, we injected mice with FITC-labeled dextran. The 15-18-mo WT LV showed increased vascular permeability compared with young WT controls and 15-18-mo Null mice. Combined, our findings revealed that MMP-9 deletion improves angiogenesis, attenuates inflammation, and prevents vascular leakiness in the setting of cardiac aging.aging; inflammation; angiogenesis; MMP-9; proteomics; extracellular matrix AGING IS A MAJOR RISK FACTOR for cardiac mortality and morbidity (11, 30). Elderly patients with acute cardiovascular disease have poor clinical outcomes. Aging is associated with alterations in homeostatic mechanisms that make the vasculature more susceptible to damaging effects of pathophysiological conditions (35). Aging impairs diastolic function in humans, independent of existing comorbidities such as hypertension (18). In mice, aging associates with a subtle but significant decline in function of the left ventricle (LV) (21). Altered LV function is characterized by the development of diastolic dysfunction, as systolic function remains relatively unchanged (7). The cardiac extracellular matrix (ECM) regulates LV diastolic properties, provides structural support for the myocardium, and incorporates homeostatic elements such as growth factors (16). Matrix metal...

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MMP-9 and -12 cause N-cadherin shedding and thereby β-catenin signalling and vascular smooth muscle cell proliferation

Abstract: In conclusion, we propose that MMP-9 and -12 promote intimal thickening by independent cleavage of N-cadherin, which elevates VSMC proliferation via beta-catenin signalling.

Cited by 122 publications

References 49 publications

Matrix metalloproteinase-9 expression in folliculostellate cells of rat anterior pituitary gland

Matrix metalloproteinase-9 expression in folliculostellate cells of rat anterior pituitary gland

Matrix Metalloproteinase-8 Promotes Vascular Smooth Muscle Cell Proliferation and Neointima Formation

Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction

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