Abstract
Matrix metalloproteinases play a crucial role in the remodelling of the extracellular matrix through direct degradation of its structural proteins and control of extracellular signalling. The most common cause of ischemic brain damage is an atherothrombotic lesion in the supplying arteries. The progress of the atherosclerotic plaque development and the related thrombotic complications are mediated in part by matrix metalloproteinases. In addition to their role in the underlying disease, various members of this protease family are upregulated in the acute phase of ischemic brain damage as well as in the post-ischemic brain recovery following stroke. This review summarizes the current understanding of the matrix metalloproteinase-related molecular events at three stages of the ischemic cerebrovascular disease (in the atherosclerotic plaque, in the neurovascular unit of the brain and in the regenerating brain tissue).
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Nagy Z., Blood-brain barrier and the cerebral endothelium, In: Johanson B.B., Owman C., Widner H., (Eds.), Pathophysiology of the bloodbrain barrier, Elsevier Science, Amsterdam — New York, 1990, 11–29
Rolfe D.F., Brown G.C., Cellular energy utilization and molecular origin of standard metabolic rate in mammals, Physiol. Rev., 1997, 77, 731–758
Webersinke G., Bauer H., Amberger A., Zach O., Bauer H.C., Comparison of gene expression of extracellular matrix molecules in brain microvascular endothelial cells and astrocytes, Biochem. Biophys. Res. Commun., 1992, 189, 877–884
Hornig C.R., Dorndorf W., Agnoli A.L., Haemorrhagic cerebral infarction — a prospective study, Stroke, 1986, 17, 179–185
Gross J., Lapière C.M., Collagenolytic activity in amphibian tissues: a tissue culture assay, Proc. Natl. Acad. Sci. USA, 1962, 48, 1014–1022
Sternlicht M.D., Werb Z., How matrix metalloproteinases regulate cell behavior, Annu. Rev. Cell Dev. Biol., 2001, 17, 463–516
Fisher G.J., Talwar H.S., Lin J., Lin P., McPhillips F., Wang Z., et al., Retinoic acid inhibits induction of c-Jun protein by ultraviolet radiation that occurs subsequent to activation of mitogen-activated protein kinase pathways in human skin in vivo, J. Clin. Invest., 1998, 101, 1432–1440
Sato H., Seiki M., Regulatory mechanism of 92 kDa type IV collagenase gene expression which is associated with invasiveness of tumor cells, Oncogene, 1993, 8, 395–405
Dong X., Song Y.N., Liu W.G., Guo X.L., MMP-9, a potential target for cerebral ischemic treatment, Curr. Neuropharmacol., 2009, 4, 269–275
Vogel W., Gish G.D., Alves F., Pawson T., The discoidin domain receptor tyrosine kinases are activated by collagen, Mol. Cell, 1997, 1, 13–23
Shrivastava A., Radziejewski C., Campbell E., Kovac L., McGlynn M., Ryan T.E., et al., An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors, Mol. Cell, 1997, 1, 25–34
Gu Z., Kaul M., Yan B., Kridel S.J., Cui J., Strongin A.Y., et al., S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death, Science, 2002, 297, 1186–1190
Wang X., Hou M., Tan L., Sun X., Zhang Y., Li P., et al., A hybrid protein of the amino-terminal fragment of urokinase and mutant plasminogen activator inhibitor-2 efficiently inhibits tumor cell invasion and metastasis, J. Cancer Res. Clin. Oncol., 2005, 131, 129–136
Nagase H., Woessner J.F., Matrix metalloproteinases, J. Biol. Chem., 1999, 274, 21491–21494
Sottrup-Jensen L., Birkedal-Hansen H., Human fibroblast collagenase-a-macroglobulin interactions. Localization of cleavage sites in the bait regions of five mammalian a-macroglobulins, J. Biol. Chem., 1989, 264, 393–401
Strongin A.Y., Collier I., Bannikov G., Marmer B.L., Grant G.A., Goldberg G.I., Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease, J. Biol. Chem., 1995, 270, 5331–5338
Langton K.P., Barker M.D., McKie N., Localization of the functional domains of human tissue inhibitor of metalloproteinases-3 and the effects of a Sorsby’s fundus dystrophy mutation, J. Biol. Chem., 1998, 273, 16778–16781
Loftus I.M., Naylor A.R., Goodall S., Crowther M., Jones L., Bell P.R.F., et al., Increased matrix metalloproteinase-9 activity in unstable carotid plaques. A potential role in acute plaque disruption, Stroke, 2000, 31, 40–47
Nikkari S.T., O’Brien K.D., Ferguson M., Hatsukami T., Welgus H.G., Alpers C.E., et al., Interstitial collagenase (MMP-1) expression in human carotid atherosclerosis, Circulation, 1995, 92, 1393–1398
Sukhova G.K., Schönbeck U., Rabkin E., Schoen F.J., Poole A.R., Billinghurst R.C., et al., Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques, Circulation, 1999, 99, 2503–2509
Herman M.P., Sukhova G.K., Libby P., Gerdes N., Tang N., Horton D.B., et al., Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: a novel collagenolytic pathway suggested by transcriptional profiling, Circulation, 2001, 104, 1878–1880
Galis Z.S., Muszynski M., Sukhova G.K., Simon-Morrissey E., Unemori E.N., Lark M.W., et al., Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion, Circ. Res., 1994, 75, 181–189
Galis Z.S., Sukhova G.K., Kranzhöfer R., Clark S., Libby P., Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases, Proc. Natl. Acad. Sci. USA, 1995, 92, 402–406
Sarén P., Welgus H.G., Kovanen P.T., TNF-a and IL-1b selectively induce expression of 92-kDa gelatinase by human macrophages, J. Immunol., 1996, 157, 4159–4165
Rajagopalan S., Meng X.P., Ramasamy S., Harrison D.G., Galis Z.S., Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability, J. Clin. Invest., 1996, 98, 2572–2579
Amento E.P., Ehsani N., Palmer H., Libby P., Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells, Arterioscler. Thromb., 1991, 11, 1223–1230
Rekhter M.D., Zhang K., Narayanan A.S., Phan S., Schork M.A., Gordon D., Type I collagen gene expression in human atherosclerosis. Localization to specific plaque regions, Am. J. Pathol., 1993, 143, 1634–1648
Ang A.H., Tachas G., Campbell J.H., Bateman J.F., Campbell G.R., Collagen synthesis by cultured rabbit aortic smooth-muscle cells. Alteration with phenotype, Biochem. J., 1990, 265, 461–469
Luttun A., Lutgens E., Manderveld A., Maris K., Collen D., Carmeliet P., et al., Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth, Circulation, 2004, 109, 1408–1414
Godin D., Ivan E., Johnson C., Magid R., Galis Z.S., Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model, Circulation, 2000, 102, 2861–2866
Galis Z.S., Johnson C., Godin D., Magid R., Shipley J.M., Senior R.M., et al., Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling, Circ. Res., 2002, 91, 852–859
Galis Z.S., Sukhova G.K., Lark M.W., Libby P., Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques, J. Clin. Invest., 1994, 94, 2493–2503
Fabunmi R.P., Sukhova G.K., Sugiyama S., Libby P., Expression of tissue inhibitor of metalloproteinases-3 in human atheroma and regulation in lesion-associated cells: a potential protective mechanism in plaque stability, Circ. Res., 1998, 83, 270–278
Mun-Bryce S., Rosenberg G.A., Matrix metalloproteinases in cerebrovascular disease, J. Cerebr. Blood Flow Metab., 1998, 18, 1163–1172
Rosenberg G.A., Mun-Bryce S., Wesley M., Kornfeld M., Collagenase-induced intracerebral hemorrhage in rats, Stroke, 1990, 21, 801–807
Rosenberg G.A., Navratil M., Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat, Neurology, 1997, 48, 921–926.
Rosenberg G.A., Estrada E.Y., Dencoff J.E., Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain, Stroke, 1998, 29, 2189–2195
Gasche Y., Fujimura M., Morita-Fujimura Y., Copin J.C., Kawase M., Massengale J., et al., Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood-brain barrier dysfunction, J. Cerebr. Blood Flow Metab., 1999, 19, 1020–1028
Romanic A.M., White R.F., Arleth A.J., Ohlstein E.H., Barone F.C., Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size, Stroke, 1998, 29, 1020–1030
Lapchak P.A., Chapman D.F., Zivin J.A., Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke, Stroke, 2000, 31, 3034–3040
Heo J.H., Lucero J., Abumiya T., Koziol J.A., Copeland B.R., del Zoppo G.J., Matrix metalloproteinases increase very early during experimental focal cerebral ischemia, J. Cerebr. Blood Flow Metab., 1999, 19, 624–633
Ramos-Fernandez M., Bellolio M.F., Stead L.G., Matrix metalloproteinase-9 as a marker for acute ischemic stroke: a systematic review, J. Stroke Cerebrovasc. Dis., 2011, 20, 47–54
Rosell A., Alvarez-SabÃn J., Arenillas J.F., Rovira A., Delgado P., Fernández-Cadenas I., et al., A matrix metalloproteinase protein array reveals a strong relation between MMP-9 and MMP-13 with diffusion-weighted image lesion increase in human stroke, Stroke, 2005, 36, 1415–1420
Montaner J., Alvarez-SabÃn J., Molina C.A., Anglés A., Abilleira S., Arenillas J., et al., Matrix metalloproteinase expression is related to hemorrhagic transformation after cardioembolic stroke, Stroke, 2001, 32, 2762–2767
Montaner J., Molina C.A., Monasterio J., Abilleira S., Arenillas J.F., Ribó M., et al., Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke, Circulation, 2003, 107, 598–603
Asahi M., Wang X., Mori T., Sumii T., Jung J.C., Moskowitz M.A., et al., Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia, J. Neurosci., 2001, 21, 7724–7732
Svedin P., Hagberg H., Savman K., Zhu C., Mallard C., Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxiaischemia, J. Neurosci., 2007, 27, 1511–1518
Asahi M., Sumii T., Fini M.E., Itohara S., Lo E.H., Matrix metalloproteinase 2 gene knock-out has no effect on acute brain injury after focal ischemia, Neuroreport, 2001, 12, 3003–3007
Lucivero V., Prontera M., Mezzapesa D.M., Petruzellis M., Sancilio M., Tinelli A., et al., Different roles of matrix metalloproteinases-2 and -9 after human ischaemic stroke, Neurol. Sci., 2007, 28, 165–170
Yang Y., Estrada E.Y., Thompson J.F., Liu W., Rosenberg G.A., Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat, J. Cereb. Blood Flow Metab., 2007, 27, 697–709
Rosenberg G.A., Cunningham L.A., Wallace J., Alexander S., Estrada E.Y., Grossetete M., et al., Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures, Brain Res., 2001, 893, 104–112
Kolev K., Skopál J., Simon L., Csonka É., Machovich R., Nagy Z., Matrix metalloproteinase-9 expression in post-hypoxic human brain capillary endothelial cells: H2O2 as a trigger and NF-κB as a signal transducer, Thromb. Haemost., 2003, 90, 528–537
Harkness K.A., Adamson P., Sussman J.D., Davies-Jones G.A., Greenwood J., Woodroofe M.N., Dexamethasone regulation of matrix metalloproteinase expression in CNS vascular endothelium, Brain, 2000, 123, 698–709
Gidday J.M., Gasche Y.G., Copin J.C., Shah A.R., Perez R.S., Shapiro S.D., et al., Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia, Am. J. Physiol. Heart Circ. Physiol., 2005, 289, 558–568
Wang G., Guo Q., Hossain M., Fazio V., Zeynalov E., Janigro D., et al., Bone marrow-derived cells are the major source of MMP-9 contributing to blood-brain barrier dysfunction and infarct formation after ischemic stroke in mice, Brain Res., 2009, 1294, 183–192
Haas T.L., Davis S.J., Madri J.A., Three-dimensional type I collagen lattices induce coordinate expression of matrix metalloproteinases MT1-MMP and MMP-2 in microvascular endothelial cells, J. Biol. Chem., 1998, 273, 3604–3610
Cao W., Carney J.M., Duchon A., Floyd R.A., Chevion M., Oxygen free radical involvement in ischemia and reperfusion injury to brain, Neurosci. Lett., 1988, 88, 233–238
Halliwell B., Reactive oxygen species and the central nervous system, J. Neurochem., 1992, 59, 1609–1623
Chinopoulos C., Tretter L., Rozsa A., Adam-Vizi V., Exacerbated responses to oxidative stress by an Na+ load in isolated nerve terminals: the role of ATP depletion and rise of [Ca2+]i, J. Neurosci., 2000, 20, 2094–2103
Hyslop P.A., Zhang Z., Pearson D.V., Phebus L.A., Measurement of striatal H2O2 by microdialysis following global forebrain ischemia and reperfusion in the rat: correlation with the cytotoxic potential of H2O2 in vitro, Brain Res., 1995, 671, 181–186
Ying W., Han S.H., Miller J.W., Swanson R.A., Acidosis potentiates oxidative neuronal death by multiple mechanisms, J. Neurochem., 1999, 73, 1549–1556.
Zhang Z.G., Zhang L., Tsang W., Goussev A., Powers C., Ho K.L., et al., Dynamic platelet accumulation at the site of the occluded middle cerebral artery and in downstream microvessels is associated with loss of microvascular integrity after embolic middle cerebral artery occlusion, Brain Res., 2001, 912, 181–194
Pagenstecher A., Stalder A.K., Kincaid C.L., Shapiro S.D., Campbell I.L., Differential expression of matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase genes in the mouse central nervous system in normal and inflammatory states, Am. J. Pathol., 1998, 152, 729–741
Itoh Y., Nagase H., Preferential inactivation of tissue inhibitor of metalloproteinases-1 that is bound to the precursor of matrix metalloproteinase 9 (progelatinase B) by human neutrophil elastase, J. Biol. Chem., 1995, 270, 16518–16521
Haddad J.J., Olver R.E., Land S.C., Antioxidant/pro-oxidant equilibrium regulates HIF-1a and NF-kB redox sensitivity. Evidence for inhibition by glutathione oxidation in alveolar epithelial cells, J. Biol. Chem., 2000, 275, 21130–21139
Nagy Z., Kolev K., Csonka É., Pék M., Machovich R., Contraction of human brain endothelial cells induced by thrombogenic and fibrinolytic factors. An in vitro cell culture model, Stroke, 1995, 26, 265–270
Nagy Z., Kolev K., Csonka É., Vastag M., Machovich R., Perturbation of the integrity of the blood-brain barrier by fibrinolytic enzymes, Blood Coagul. Fibrinolysis, 1998, 9, 471–478
Turner J.S., Redpath G.T., Humphries J.E., Gonias S.L., Vandenberg S.R. Plasmin modulates the thrombin-evoked calcium response in C6 glioma cells, Biochem. J., 1994, 297, 175–179
Siao C.J., Fernandez S.R., Tsirka S.E., Cell typespecific roles for tissue plasminogen activator released by neurons or microglia after excitotoxic injury, J. Neurosci., 2003, 23, 3234–3242
Tsuji K., Aoki T., Tejima E., Arai K., Lee S.R., Atochin D.N., et al., Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia, Stroke, 2005, 36, 1954–1959
Zhang C., An J., Haile W.B., Echeverry R., Strickland D.K., Yepes, M., Microglial low-density lipoprotein receptor-related protein 1 mediates the effect of tissue-type plasminogen activator on matrix metalloproteinase-9 activity in the ischemic brain, J. Cereb. Blood Flow Metab., 2009, 12, 1946–1954
Suzuki Y., Nagai N., Umemura K., Collen D., Lijnen H.R., Stromelysin-1 (MMP-3) is critical for intracranial bleeding after t-PA treatment of stroke in mice, J. Thromb. Haemost., 2007, 5, 1732–1739
Suzuki Y., Nagai N., Yamakawa K, Kawakami J., Lijnen H.R., Umemura K., Tissue-type plasminogen activator (t-PA) induces stromelysin-1 (MMP-3) in endothelial cells through activation of lipoprotein receptor-related protein, Blood, 2009, 114, 3352–3358
Yepes M., Sandkvist M., Moore E.G., Bugge T.H., Strickland D.K., Lawrence D.A., Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein, J. Clin. Invest., 2003, 112, 1533–1540
Bini A., Wu D., Schnuer J., Kudryk B.J., Characterization of stromelysin 1 (MMP-3), matrilysin (MMP-7), and membrane type 1 matrix metalloproteinase (MT1-MMP) derived fibrin(ogen) fragments D-dimer and D-like monomer: NH2-terminal sequences of late-stage digest fragments, Biochemistry, 1999, 38, 13928–13936
Lelongt B., Bengatta S., Delauche M., Lund L.R., Werb Z., Ronco P.M., Matrix metalloproteinase 9 protects mice from anti-glomerular basement membrane nephritis through its fibrinolytic activity, J. Exp. Med., 2001, 193, 793–802
Kumura E., Yoshimine T., Iwatsuki K.I., Yamanaka K., Tanaka S., Hayakawa T., et al., Generation of nitric oxide and superoxide during reperfusion after focal cerebral ischemia in rats, Am. J. Physiol., 1996, 270, C748–C752
Cardone M.H., Salvesen G.S., Widmann C., Johnson G., Frisch S.M., The regulation of anoikis: MEKK-1 activation requires cleavage by caspases, Cell, 1997, 90, 315–323
Cunningham L.A., Wetzel M., Rosenberg G.A., Multiple roles for MMPs and TIMPs in cerebral ischemia, Glia, 2005, 50, 329–339
Denker B.M., Nigam S.K., Molecular structure and assembly of the tight junction, Am. J. Physiol., 1998, 274, F1–F9
Hamann G.F., Okada Y., Fitridge R., del Zoppo G.J., Microvascular basal lamina antigens disappear during cerebral ischemia and reperfusion, Stroke, 1995, 26, 2120–2126
Sole S., Petegnief V., Gorina R., Chamorro A., Planas A.M., Activation of matrix metalloproteinase-3 and agrin cleavage in cerebral ischemia/reperfusion, J. Neuropathol. Exp. Neurol., 2004, 63, 338–349
Gurney K.J., Estrada E.Y., Rosenberg G.A., Bloodbrain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation, Neurobiol. Dis., 2006, 23, 87–96
Gu Z., Cui J., Brown S., Fridman R., Mobashery S., Strongin A.Y., et al., A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia, J. Neurosci., 2005, 25, 6401–6408
Frisch S.M., Francis H., Disruption of epithelial cell-matrix interactions induces apoptosis, J. Cell Biol., 1994, 124, 619–626
Meredith J.E., Fazeli, B., Schwartz, M.A., The extracellular matrix as a cell survival factor, Mol. Biol. Cell, 1993, 4, 953–961
Van den Steen P.E., Proost P., Wuyts A., Van Damme J., Opdenakker G., Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-a and leaves RANTES and MCP-2 intact, Blood, 2000, 96, 2673–2681
McQuibban G.A., Butler G.S., Gong J.H., Bendall L., Power C., Clark-Lewis I., et al., Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1, J. Biol. Chem., 2001, 276, 43503–43508
Zhang K., McQuibban G.A., Silva C., Butler G.S., Johnston J.B., Holden J., et al., HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration, Nature Neurosci., 2003, 6, 1064–1071
Lee S.R., Kim H.Y., Rogowska J., Zhao B.Q., Bhide P., Parent J.M., et al., Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke, J. Neurosci., 2006, 26, 3491–3495
Barkho B.Z., Munoz A.E., Li X., Endogenous matrix metalloproteinase (MMP)-3 and MMP-9 promote the differentiation and migration of adult neural progenitor cells in response to chemokines, Stem Cells, 2008, 26, 3139–3149
Nagel S., Sandy J.D., Meyding-Lamade U., Schwark C., Bartsch J.W., Wagner S., Focal cerebral ischemia induces changes in both MMP-13 and aggrecan around individual neurons, Brain Res., 2005, 1056, 43–50
Zhao B.Q., Wang S., Kim H.Y., Storrie H., Rosen B.R., Mooney D.J., et al., Role of matrix metalloproteinases in delayed cortical responses after stroke, Nature Med., 2006, 12, 441–445
Oh L.Y., Larsen P.H., Krekoski C.A., Edwards D.R., Donovan F., Werb Z., et al., Matrix metalloproteinase-9/gelatinase B is required for process outgrowth by oligodendrocytes, J. Neurosci., 1999, 19, 8464–8475
Larsen P.H., Wells J.E., Stallcup W.B., Opdenakker G., Yong V.W., Matrix metalloproteinase-9 facilitates remyelination in part by processing the inhibitory NG2 proteoglycan, J. Neurosci., 2003, 23, 11127–11135
Shubayev V.I., Myers R.R., Matrix metalloproteinase-9 promotes nerve growth factor-induced neurite elongation but not new sprout formation in vitro, J. Neurosci. Res., 2004, 77, 229–239
Bergers G., Brekken R., McMahon G., Vu T.H., Itoh T., Tamaki K., et al., Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis, Nature Cell Biol., 2000, 2, 737–744
Zhang Z.G., Zhang L., Jiang Q., Zhang R., Davies K., Powers C., et al., VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain, J. Clin. Invest., 2000, 106, 829–838
Seo D.W., Li H., Guedez L., Wingfield P.T., Diaz T., Salloum R., et al., TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism, Cell, 2003, 114, 171–180
Qi J. H., Ebrahem Q., Moore N., Murphy G., Claesson-Welsh L., Bond M., et al., A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2, Nat. Med., 2003, 9, 407–415
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Rottenberger, Z., Kolev, K. Matrix metalloproteinases at key junctions in the pathomechanism of stroke. cent.eur.j.biol. 6, 471–485 (2011). https://doi.org/10.2478/s11535-011-0030-z
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DOI: https://doi.org/10.2478/s11535-011-0030-z