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Inhibition of smooth muscle cell migration and neointima formation in vein grafts by overexpression of matrix metalloproteinase-3  Klaus Kallenbach, MD,

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Presentation on theme: "Inhibition of smooth muscle cell migration and neointima formation in vein grafts by overexpression of matrix metalloproteinase-3  Klaus Kallenbach, MD,"— Presentation transcript:

1 Inhibition of smooth muscle cell migration and neointima formation in vein grafts by overexpression of matrix metalloproteinase-3  Klaus Kallenbach, MD, Rolf Salcher, MD, Albert Heim, MD, Matthias Karck, MD, Paolo Mignatti, MD, Axel Haverich, MD  Journal of Vascular Surgery  Volume 49, Issue 3, Pages (March 2009) DOI: /j.jvs Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

2 Fig 1 Characterization of hMMP-3 overexpression in HASMC transduced with hMMP-3. a, Northern blotting analysis of total ribonucleic acid (RNA) from non-transduced, ß-galactosidase (Ad.ßgal)- or human matrix metalloproteinases (hMMP)-3-transduced human aortic smooth muscle cells (HASMC). Only cells transduced with hMMP-3 express the 2.2 Kb MMP-3 mRNA (rec. hMMP-3). The 18 s rRNA is shown as a control. b, Western blotting. Expression of an immunoreactive 57 kDa band consistent with the Mr of pro-MMP-3 is present in hMMP-3-transduced HASMC or 293 cells. HASMC grown on the amniotic membrane (transfected/a) or in a culture dish (transfected) produced comparable levels of MMP-3. c, Casein zymography. Medium conditioned by hMMP-3-transduced 293 cells, or by non-transduced, Ad.ßgal- or hMMP-3-transduced HASMC was used. A lysis band of 57 kDa consistent with the Mr of pro-MMP-3 was present only in Ad.MMP-3 transduced cells. Transduced HASMC grown on the amniotic membrane (transfected/a) showed higher MMP-3 caseinolytic activity than cells grown on plastic. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

3 Fig 2 Migration of human aortic smooth muscle cells (HASMC) through the amniotic membrane mimicking the vascular extracellular matrix, stimulated with 10 ng/mL of PDGF. a, Untreated HASMC migrated from the surface into the stroma and were found in various depths of the matrix (arrows). b, HASMC were transduced with adenoviral vectors encoding ß-galactosidase (AVEßgal) before seeding. Cells migrated in comparable numbers into the stroma as untreated HASMC. c, When transduced with hMMP-3 before seeding, HASMC rarely invade the stroma and remain on the surface (arrows). d, Number of migrated HASMC was counted by 10 random microscopic high power fields (HPF) per histologic sections. Difference between MMP-3-overexpressing HASMC and controls was highly significant (** P < .001), but not between controls. Differences in thickness of the membrane (c) relate to natural variability of amnion membrane. Hematoxylin and eosin (H&E), magnification 400× for all photographs. Mean ± standard deviation is shown (d). Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

4 Fig 3 Immunocytochemical analysis of matrix metalloproteinase (MMP)-3 in cross-sections of vein grafts 7 days after implantation. a, Vein graft transduced with human matrix metalloproteinase (hMMP)-3. b, Non- transduced control. c, Vein graft transduced with hMMP-3 stained with secondary antibody alone. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

5 Fig 4 In situ casein zymography of vein grafts 7 days after implantation. a, Vein graft transduced with human matrix metalloproteinase (hMMP)-3. Dark areas in the intima (arrows) indicate digestion of red-labeled casein. b, Non-transduced control. c, Adenoviral vectors encoding ß-galactosidase (AVEßgal) transduced control. No caseinolytic activity is visible in the two controls. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

6 Fig 5 Development of intimal hyperplasia in vein grafts 28 after interposition into the carotid artery. Elastica van Gieson, magnification 20×. a, Graft incubated with PBS before implantation, showing severe neointima formation. Comparable amounts of intimal hyperplasia were found in vein grafts incubated with Poloxamer 407 (b) or transduced ex vivo with adenoviral vectors encoding ß-galactosidase (AVEßgal) (c) before implantation. Vein grafts transduced with human matrix metalloproteinase (hMMP)-3 showed almost no intimal hyperplasia 28 days after implantation (d). Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

7 Fig 6 Degree of intimal hyperplasia in vein grafts 28 day after implantation. N = 6 animals per group were investigated. Lesion thickening, intima/media ratio and stenosis degree were measured as detailed under Materials and Methods. Mean ± standard deviation is shown. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

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