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Adventitial delivery of platelet-derived endothelial cell growth factor gene prevented intimal hyperplasia of vein graft  Mitsuteru Handa, MD, Wei Li,

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Presentation on theme: "Adventitial delivery of platelet-derived endothelial cell growth factor gene prevented intimal hyperplasia of vein graft  Mitsuteru Handa, MD, Wei Li,"— Presentation transcript:

1 Adventitial delivery of platelet-derived endothelial cell growth factor gene prevented intimal hyperplasia of vein graft  Mitsuteru Handa, MD, Wei Li, MD, PhD, Kouichi Morioka, MD, PhD, Atsushi Takamori, MD, Narihisa Yamada, MD, PhD, Akio Ihaya, MD, PhD  Journal of Vascular Surgery  Volume 48, Issue 6, Pages (December 2008) DOI: /j.jvs Copyright © 2008 The Society for Vascular Surgery Terms and Conditions

2 Fig 1 Determination of optimal gene transfer efficiency. A and B, Representative gross views are shown of X-gal staining of whole vein grafts. C and D, Photomicrographs of sections of vein grafts 7 days are shown after implantation and gene transfection (scale bars, 100 μm). Panels A and C were from grafts treated with poloxamer hydrogel containing LacZ alone; and B and D were from grafts treated with poloxamer hydrogel containing 0.25% trypsin and LacZ. E, The percentage of cells stained positive for LacZ is shown in the adventitia (A, black bars) and intima and media (IM, gray bars).*P < .01 vs 0% trypsin, and †P < .01 vs 0.1% trypsin. F, Intima thickness after 1 week of graft implantation is shown for different concentrations of trypsin. Error bars indicate the standard deviation. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2008 The Society for Vascular Surgery Terms and Conditions

3 Fig 2 Effects of platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) on the development of intimal hyperplasia of vein grafts at 2 (2W) and 8 weeks (8W) after implantation and gene transfection. A, Representative images show the middle portion of vein graphs from rabbits that received saline, 20% poloxamer F127 hydrogel containing 0.25% trypsin and plasmid encoding human PD-ECGF/TP (pCIhTP group), and rabbits receiving the hydrogel containing the LacZ gene (pCILacZ group). Elastica van Gieson staining; the scale bar equals 200 μm, and the dashed line indicates the border of intima (I) and media. Quantitative analysis of the (B) intimal thickness and (C) intimal areas of vein grafts in saline (dark gray bars), pCILacZ (light gray bars), and pCIhTP (white bars) groups indicated they were decreased in treated group. Error bars show the standard deviation; *P < .01, pCIhTP vs pCILacZ and saline. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2008 The Society for Vascular Surgery Terms and Conditions

4 Fig 3 Assessment of heme oxygenase-1 expression and vascular smooth muscle cell (VSMC) proliferation index in the vein grafts. A, Immunohistochemical staining for heme oxygenase-1 (brown) and (B) representative images of double immunohistochemical staining for proliferative cell nuclear antigen (PCNA; brown) and VSMCs (pink) at 2 weeks are shown. The arrowheads indicate the double positively stained VSMCs, and the dashed line indicates the border of the intima (I) and media. Scale bar equals 100 μm. C, Quantitative analysis of the ratio of PCNA-positive cells in the intimal areas of vein graphs at 2 and 8 weeks from rabbits that received saline, 20% poloxamer F127 hydrogel containing 0.25% trypsin and plasmid encoding human platelet-derived endothelial cell growth factor/thymidine phosphorylase (pCIhTP group), and rabbits receiving the hydrogel containing the LacZ gene (pCILacZ group). Error bars show the standard deviation; *P < .01, pCIhTP vs pCILacZ and saline. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2008 The Society for Vascular Surgery Terms and Conditions

5 Fig 4 Identification of transgene expression. Total RNA was extracted from vein graft or spleen and reverse transcriptase-polymerase chain reaction (RT-PCR) assay was performed for (A) human platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) in grafts at 2 and 8 weeks, or (B) the LacZ gene in grafts and spleen at 1, 2, and 8 weeks. RT-PCR assay for rabbit β-actin was examined as an RNA quality and loading control. C, Immunoblotting analysis of human PD-ECGF/TP protein 2 weeks after graft implantation. Actin was reblotted as a loading control in the same membrane. D and E, Immunohistochemical staining for human PD-ECGF/TP in the rabbits that received 20% poloxamer F127 hydrogel containing 0.25% trypsin and PD-ECGF (pCIhTP) group at (D) 2 weeks and (E) 8 weeks after operation (200× magnification). Cells stained positive for PD-ECGF/TP are brown, and arrowheads indicate representative staining. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2008 The Society for Vascular Surgery Terms and Conditions

6 Fig 5 Scheme of effect of platelet-derived endothelial cell growth factor/thymidine phosphorylase on vascular smooth muscle cells (VSMC) and the endothelium. The red arrows indicate promotive effect, and blue lines (⊥) indicates an inhibitory effect. 2-DDR-1, 2-deoxy-d-ribose 1-phosphate; HO-1, heme oxygenase-1; IL, interleukin; MMP, matrix metalloproteinase; TP, thymidine phosphorylase; VEGF, vascular endothelial growth factor, Cyto-c, Cytochrome C; Bcl-2 (anti-apoptosis) and Bax (pro-apoptosis), members of Bcl-2 gene family; VSMC, vascular smooth muscle cell. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2008 The Society for Vascular Surgery Terms and Conditions

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