Regulation of Endothelial Matrix Metalloproteinase-2 by Hypoxia/Reoxygenation

Ben-Yosef, Yaara; Lahat, Nitza; Shapiro, Sarah; Bitterman, Haim; Miller, David H.

doi:10.1161/01.res.0000015588.70132.dc

Cited by 157 publications

(107 citation statements)

References 35 publications

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“…In particular, cells were found to constitutively release only the 496 latent 72 kDa form of MMP-2, whereas its 62 kDa activated form was not detected. These 497 results are in line with previous reports on endothelial cells from both micro-and macro-498 vascular vessels [Hanemaaijer et al, 1993;Ben-Yosef et al, 2002;Ben-Yosef et al, 2005; 499 Bertl et al, 2006]. Exposure of endothelial cells to prolonged hypoxia led to enhanced MMP-500 2 and diminished TIMP-2 protein levels in cell supernatants, whereas TIMP-1 production 501…”

Section: Effects Of Hypoxia and Olns On Abilities Of Human Dermal Micsupporting

confidence: 82%

“…Consistently, in another in 527 vitro model, tube-like formation in human microvascular endothelial cells was shown to 528 depend directly on membrane-bound MT1-MMP and not on secreted MMPs such as MMP-2 529 [Koike et al, 2002]. Therefore, the compromised migration and invasion abilities of HMEC-1 530 highlighted here might be secondary to hypoxia-induced reduction of MT1-MMP, previously 531 reported for endothelial cells [Ben-Yosef et al, 2002]. On the other hand, in chronic wounds, 532 reduced protein levels compared to acute wounds have been described for several growth 533 factors including FGF, EGF, PDGF, VEGF, and TGF-β, secondary to trapping by ECM 534 molecules or excessive degradation by MMPs [Greaves et al, 2013].…”

Section: Effects Of Hypoxia and Olns On Abilities Of Human Dermal Micsupporting

confidence: 70%

“…Additionally, low levels of TIMP-2, the main MMP-2 inhibitor, 505 participate in MT1-MMP-mediated activation of MMP-2, while high levels of TIMP-2 can 506 block MMP-2 activation [Brew & Nagase, 2010]. Interestingly, hypoxia-dependent down-507 regulation of MT1-MMP expression was previously reported for human endothelial cells 508 [Ben-Yosef et al, 2002]. This might justify the absence of the active 62 kDa form of MMP-2 509 in the present hypoxic model.…”

Section: Effects Of Hypoxia and Olns On Abilities Of Human Dermal Micmentioning

confidence: 89%

See 2 more Smart Citations

Dextran-shelled oxygen-loaded nanodroplets reestablish a normoxia-like pro-angiogenic phenotype and behavior in hypoxic human dermal microvascular endothelium

Basilico

Magnetto

D’Alessandro

et al. 2015

Toxicology and Applied Pharmacology

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When citing, please refer to the published version. MMP-9 and increases TIMP-1 without affecting TIMP-2 secretion, whereas in human 60 keratinocytes it reduces MMP-2, MMP-9, and TIMP-2, without affecting TIMP-1 release. 61Provided that the phenotype of the cellular environment is better understood, chronic wounds 62 might be targeted by new oxygenating compounds such as chitosan-or dextran-shelled and 63 2H,3H-decafluoropentane-cored oxygen-loaded nanodroplets (OLNs). Here, we investigated 64 the effects of hypoxia and dextran-shelled OLNs on the pro-angiogenic phenotype and 65 behavior of human dermal microvascular endothelium (HMEC-1 cell line), another cell 66 population playing key roles during wound healing. Normoxic HMEC-1 constitutively 67 released MMP-2, TIMP-1 and TIMP-2 proteins, but not MMP-9. Hypoxia enhanced MMP-2 68 and reduced TIMP-1 secretion, without affecting TIMP-2 levels, and compromised cell 69 ability to migrate and invade the extracellular matrix. When taken up by HMEC-1, nontoxic 70OLNs abrogated the effects of hypoxia, restoring normoxic MMP/TIMP levels and 71 promoting cell migration, matrix invasion, and formation of microvessels. These effects were 72 specifically dependent on time-sustained oxygen diffusion from OLN core, since they were 73 not achieved by oxygen-free nanodroplets or oxygen-saturated solution. Collectively, these 74 data provide new information on the effects of hypoxia on dermal endothelium and support 75 the hypothesis that OLNs might be used as effective adjuvant tools to promote chronic wound 76 healing processes. 77 78Keywords: oxygen; nanodroplet; matrix metalloproteinase (MMP); tissue inhibitor of 79 metalloproteinase (TIMP); human microvascular endothelial cell (HMEC); skin. 80 5 Introduction 81 82After injury, skin integrity must be restored promptly to reestablish the homeostatic 83 mechanisms, minimize fluid loss, and prevent infection [Greaves et al., 2013]. This is 84 achieved through wound healing, a complex biological process where multiple pathways are 85 simultaneously activated to induce tissue repair and regeneration. Traditionally, acute wound 86 healing is defined as a complex multi-step and multi-cellular process, distinguished in four 87 phases involving different cell types: i) hemostasis, involving platelets; ii) inflammation, 88 involving neutrophils, monocytes, and macrophages; iii) proliferation, involving 89 keratinocytes, endothelial cells, and fibroblasts; and iv) matrix remodeling, involving 90 keratinocytes, myofibroblasts, and endothelial cells. [Diegelmann et al., 2004]. In particular, 91 during the third and fourth phases, the endothelium plays a pivotal role, since wound 92 microvasculature is rebuilt through angiogenesis to restore the supply of oxygen, blood 93 constituents and nutrients to the regenerating tissue, helping to promote fibroplasia and 94 prevent sustained tissue hypoxia [Eming et al., 2014]. Notably, oxygen represents a key 95 regulator of normal wound healing since it is required for collagen deposition, 96 epith...

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Section: Effects Of Hypoxia and Olns On Abilities Of Human Dermal Micsupporting

confidence: 82%

Section: Effects Of Hypoxia and Olns On Abilities Of Human Dermal Micsupporting

confidence: 70%

Section: Effects Of Hypoxia and Olns On Abilities Of Human Dermal Micmentioning

confidence: 89%

See 1 more Smart Citation

Dextran-shelled oxygen-loaded nanodroplets reestablish a normoxia-like pro-angiogenic phenotype and behavior in hypoxic human dermal microvascular endothelium

Basilico

Magnetto

D’Alessandro

et al. 2015

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

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“…The mitogen-activated protein kinase signaling pathway may play an important role in hyperoxia-induced cell death (14), whereas the subfamily member c-jun N-terminal kinase (JNK1/2) appears to be involved in reactive oxygen species -induced cell death (15). The mechanisms behind the detrimental effects of hypoxia-reoxygenation injury in the lungs are not completely understood, but experimental evidence indicates a worsening of hypoxic injury by reoxygenation with high FiO 2 (12,16).…”

mentioning

confidence: 99%

Transcriptome profiling of the newborn mouse lung after hypoxia and reoxygenation: hyperoxic reoxygenation affects mTOR signaling pathway, DNA repair, and JNK-pathway regulation

et al. 2013

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“…These genes can be induced by growth factors, cytokines, and cell-cell or cell-matrix interactions in several cell types, including mononuclear cells and ECs (8 -16). The proteolytic activity of MMPs is repressed by nonspecific protease inhibitors, such as ␣1-antiprotease and ␣2-macroglobulin, and by the specific tissue inhibitors of the metalloproteinases (TIMPs) that form noncovalent stoichiometric complexes with the active zinc binding site (15,17,18). TIMP-2 is generally constitutively expressed, while TIMP-1 is produced when cells are challenged with growth factors, hormones, and cytokines (15,17,18).…”

Section: Il-12 Regulates An Endothelialmentioning

confidence: 99%

IL-12 Regulates an Endothelial Cell-Lymphocyte Network: Effect on Metalloproteinase-9 Production

Mitola¹,

Strasly²,

Prato³

et al. 2003

The Journal of Immunology

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IL-12 is key cytokine in innate immunity and participates in tumor rejection by stimulating an IFN-γ-mediated response characterized by CD8+ mediated-cytotoxicity, inhibition of angiogenesis, and vascular injury. We previously demonstrated that activated lymphocytes stimulated with IL-12 induced an angiostatic program in cocultured vascular endothelial cells. In this study, we have extended this observation showing that a reciprocal modulation of cellular responses occurs. Actually, the presence of endothelial cells enhanced the inhibitory effect of IL-12 on metalloproteinase-9 expression in activated PBMC as well as their ability to transmigrate across an extracellular matrix. IL-12 triggered intracellular signaling, as indicated by STAT-1 activation, appeared to mainly operative in activated CD4 + cells challenged with IL-12, but it was also initiated in CD8+ lymphocytes in the presence of endothelial cells. On the other hand, stimulated PBMC reduced the expression and the activity of metalloproteinase-9, up-regulated that of tissue inhibitor metalloproteinase-1, and stimulated the STAT-1 pathway in cocultured endothelial cells. We used neutralizing Abs to show that the IFN-inducible protein 10 (CXCL10) and monokine-induced by IFN-γ (CXCL9) chemokines produced by both PBMC and endothelial cells are pivotal in inducing these effects. Altogether these results suggest the existence of an IL-12-regulated circuit between endothelium and lymphocytes resulting in a shift of proteolytic homeostasis at site of tissue injury.

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Regulation of Endothelial Matrix Metalloproteinase-2 by Hypoxia/Reoxygenation

Cited by 157 publications

References 35 publications

Dextran-shelled oxygen-loaded nanodroplets reestablish a normoxia-like pro-angiogenic phenotype and behavior in hypoxic human dermal microvascular endothelium

Dextran-shelled oxygen-loaded nanodroplets reestablish a normoxia-like pro-angiogenic phenotype and behavior in hypoxic human dermal microvascular endothelium

Transcriptome profiling of the newborn mouse lung after hypoxia and reoxygenation: hyperoxic reoxygenation affects mTOR signaling pathway, DNA repair, and JNK-pathway regulation

IL-12 Regulates an Endothelial Cell-Lymphocyte Network: Effect on Metalloproteinase-9 Production

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