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In vivo electroporation of constitutively expressed HIF-1α plasmid DNA improves neovascularization in a mouse model of limb ischemia  Geoffrey O. Ouma,

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Presentation on theme: "In vivo electroporation of constitutively expressed HIF-1α plasmid DNA improves neovascularization in a mouse model of limb ischemia  Geoffrey O. Ouma,"— Presentation transcript:

1 In vivo electroporation of constitutively expressed HIF-1α plasmid DNA improves neovascularization in a mouse model of limb ischemia  Geoffrey O. Ouma, DO, Eduardo Rodriguez, MD, Karuppiah Muthumani, PhD, David B. Weiner, PhD, Robert L. Wilensky, MD, Emile R. Mohler, MD  Journal of Vascular Surgery  Volume 59, Issue 3, Pages (March 2014) DOI: /j.jvs Copyright © 2014 Society for Vascular Surgery Terms and Conditions

2 Fig 1 A summary of experimental study design. EP, Electroporation; HIF-1α, hypoxia-inducible factor 1 alpha; IM, intramuscular injection; LDPI, laser Doppler perfusion imager; pVAX, empty backbone plasmid DNA. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

3 Fig 2 A, Time course of hindlimb blood flow after femoral artery ligation followed by either electroporation (EP) of injected plasmid (hypoxia-inducible factor-EP [HIF-EP] and empty backbone plasmid DNA-EP [pVAX-EP]) or injected plasmid alone (hypoxia-inducible factor-intramuscular injection [HIF-IM]). The representative laser Doppler perfusion imager (LDPI) are recorded on the days indicated. Acute reduction in blood flow was apparent in the left limb (ligated, white arrows) as indicated in blue, on day 0 after femoral artery ligation. Sustained blood flow recovery was observed in the group treated with HIF-EP as compared with the other two groups (HIF-IM and pVAX-EP). The perfusion signal is displayed in color codes. Poor perfusion is blue (0) and good perfusion ranges from red to white (1000). B, Treatment with hypoxia-inducible factor 1 alpha (HIF-1α) DNA followed by EP improves limb perfusion recovery postfemoral artery ligation in mice. Limb perfusion recovery was performed serially from the preoperative day through postoperative day 21 using LDPI. Mean perfusion ratios (ligated/nonligated limb) were calculated for each mouse at each time point and for each treatment group. The data are expressed as mean ± standard error of the mean (error bars across each animal) for statistical significance through day 21 (P < .05). *HIF-EP vs pVAX-EP; P < .001; **HIF-IM vs pVAX-EP; P < .01; and aHIF-EP vs HIF-IM; P < .05. C, Clinical foot movement was improved postfemoral artery ligation in mice treated with HIF-1α DNA followed by EP. Foot movement was determined and scored 0 to 4 as a functional readout parameter to assess functional deficit after ischemia induction. Active foot movement was significantly impaired in pVAX-EP mice but significantly improved in the HIF-EP mice on day 21. The data are mean ± standard error of the mean (error bars across each mice) for statistical significance (P < .05). *HIF-EP vs pVAX-EP; P < .001; **HIF-IM vs pVAX-EP; P < .01; and aHIF-EP vs HIF-IM; P < .05. D, Clinical limb necrosis score was improved over 21 days in mice treated with HIF-1α followed by EP. A clinical scoring system from 0 to 4 was used to determine the rate of limb necrosis postfemoral artery ligation, and mice with scores ≥3 were deemed to have severe necrosis and were euthanized. More pVAX-EP mice were likely to have limb necrosis >3 requiring euthanasia when compared with HIF-EP and HIF-IM mice. Data are summarized as mean ± standard error of the mean (error bars) for the 39 mice through day 21, (HIF-EP, n = 13; HIF-IM, n = 14; pVAX-EP, n = 12), statistical significance at P < .05. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

4 Fig 3 A, Representative photomicrographs (original magnification, ×200) of adductor muscle tissue sections stained with hematoxylin and eosin (H&E) on day 21 revealing that there were more necrotic tissue areas (dark blue) in the ligated muscles in the negative control group (empty backbone plasmid DNA-electroporation [pVAX-EP]), compared with the positive control group (hypoxia-inducible factor-intramuscular injection [HIF-IM]). There was less necrotic infiltrating inflammatory cells in the active treatment group (HIF-EP). B, Summarized quantitative data revealed significantly fewer percent areas of necrotic tissues in the active treatment group (HIF-EP) as compared with the positive control group (HIF-IM) and the negative control group (pVAX-EP). Data presented as mean ± standard error of the mean (error bars) at statistical significance set at P < .05. *P < .001 (HIF-EP vs HIF-IM); **P < .01 (HIF-IM vs pVAX-EP); and #P < (HIF-EP vs pVAX-EP). C, Representative photomicrograph (original magnification, ×200) of adductor muscle tissue stained for CD31+ capillaries on day 21 to quantify capillary density. The number of CD31+ capillaries (bright red) was more in the ligated limb muscles that received HIF-EP treatment as compared with those that received negative control therapy (pVAX-EP) and positive control (HIF-IM). D, Quantitative data summary demonstrated that CD31+ capillaries were significantly higher in the active treatment group (HIF-EP) compared with the negative control group (pVAX-EP) and the positive control group (HIF-IM). Data presented as mean ± standard error of the mean, statistical significance at P < .05. *P < .001 (HIF-EP vs HIF-IM); **P < .001 (HIF-IM vs pVAX-EP); and #P < (HIF-EP vs pVAX-EP). Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

5 Fig 4 A, Summarized quantitative data showed that smooth muscle actin (SMA)+ vessels (vascular remodeling/collaterals) were significantly higher in the active treatment group (hypoxia-inducible factor-electroporation [HIF-EP]) compared with the negative control group (empty backbone plasmid DNA-EP [pVAX-EP]) and the positive control group (hypoxia-inducible factor-intramuscular injection [HIF-IM]). Data presented as mean ± standard error of the mean, statistical significance at P < .05. *P < (HIF-EP vs HIF-IM); **P < (HIF-IM vs pVAX-EP); and #P < .001 (HIF-EP vs pVAX-EP). B, Quantitative data summary demonstrated that the SMA+ vessels were significantly larger in total area (μm2) in the active treatment group (HIF-EP) compared with the negative control group (pVAX-EP) and the positive control group (HIF-IM). Statistical significance was set at P < .05. *P < .001 (HIF-EP vs HIF-IM); **P < .05 (HIF-IM vs pVAX-EP); and #P < (HIF-EP vs pVAX-EP). Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

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