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Platelet-derived growth factor C promotes revascularization in ischemic limbs of diabetic mice  Junji Moriya, MD, PhD, Xiumin Wu, PhD, Jose Zavala-Solorio,

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Presentation on theme: "Platelet-derived growth factor C promotes revascularization in ischemic limbs of diabetic mice  Junji Moriya, MD, PhD, Xiumin Wu, PhD, Jose Zavala-Solorio,"— Presentation transcript:

1 Platelet-derived growth factor C promotes revascularization in ischemic limbs of diabetic mice 
Junji Moriya, MD, PhD, Xiumin Wu, PhD, Jose Zavala-Solorio, PhD, Jed Ross, MS, Xiao Huan Liang, MS, Napoleone Ferrara, MD  Journal of Vascular Surgery  Volume 59, Issue 5, Pages e4 (May 2014) DOI: /j.jvs Copyright © 2014 Society for Vascular Surgery Terms and Conditions

2 Fig 1 Platelet-derived growth factor (PDGF)-C contributes to revascularization in a murine model of hind limb ischemia. a, Mice were treated with anti-Ragweed antibody (control), antivascular endothelial growth factor (VEGF) antibody (anti-VEGF), or anti-PDGF-C antibody (anti-PDGFC) at the dose of 10 mg/kg body weight immediately and 5 days after ischemia. Blood flow recovery was analyzed by laser Doppler perfusion imaging as described in the Methods section. *P < .05, **P < .01 vs control (n = 5-8 for each group). Data represent means ± standard error of the mean. b, The messenger RNA (mRNA) levels of PDGF-C, PDGF receptor α (PDGFRα), and VEGF in ischemic limbs at several time points were assessed by real-time reverse transcription polymerase chain reaction analysis. *P < .05, **P < .01 vs pre (n = 3-5 for each group). Data represent means ± standard error of the mean. Journal of Vascular Surgery  , e4DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

3 Fig 2 Platelet-derived growth factor (PDGF)-C positively regulates revascularization after ischemia. a, Ischemic limbs of mice were intramuscularly injected with empty vector (control), vascular endothelial growth factor expression vector (VEGF), or PDGF-C expression vector (PDGF-C). Blood flow recovery was analyzed. *P < .05 vs control (n = 5-11 for each group). Data represent means ± standard error of the mean. b, Ischemic limbs of wild-type (WT) mice and PDGF-C knock-out (KO) mice were analyzed for blood flow recovery. *P < .05, **P < .01 vs WT (n = 9-10 for each group). Data represent means ± standard error of the mean. Journal of Vascular Surgery  , e4DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

4 Fig 3 Platelet-derived growth factor (PDGF)-C expression is downregulated in diabetic mice. a, The baseline messenger RNA (mRNA) levels of PDGF-A, PDGF-B, PDGF-C, PDGF-D, PDGF receptor α (PDGFRα), and vascular endothelial growth factor (VEGF) in limb tissues of nondiabetic (Control) or streptozotocin (STZ)-treated diabetic mice were assessed by real-time reverse transcription-polymerase chain reaction analysis. *P < .05, **P < .01 vs control (n = 4-8 for each group). Data represent means ± standard error of the mean. b, Time course of relative PDGF-C, PDGFRα, and VEGF mRNA expression in ischemic limbs of nondiabetic (Control) or diabetic (STZ) mice. *P < .05, **P < .01 vs control; #P < .05, ##P < .01 vs precontrol; †P < .05, ††P < .01 vs pre-STZ (n = 4-8 for each group). Data represent means ± standard error of the mean. Journal of Vascular Surgery  , e4DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

5 Fig 4 Platelet-derived growth factor (PDGF)-C introduction improves revascularization after ischemia in diabetic mice. a, Blood flow recovery in ischemic limbs of nondiabetic mice after treatment with empty vector (Control) or of diabetic mice after treatment with vascular endothelial growth factor (VEGF) vector (streptozotocin [STZ] + VEGF) or empty vector (STZ only). Blood flow was assessed as described in the Methods section. *P < .05 vs control (n = 4-9 for each group). Data represent means ± standard error of the mean. b, Blood flow recovery in ischemic limbs of diabetic mice treated with an empty vector (STZ only), VEGF expression vector (STZ + VEGF), PDGF-C expression vector (STZ + PDGFC), or VEGF expression vector plus PDGF-C expression vector (STZ + VEGF + PDGFC) was analyzed. *P < .05 vs STZ only (n = 5-7 for each group). Data represent means ± standard error of the mean. Journal of Vascular Surgery  , e4DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

6 Supplementary Fig 1 (online only)
Neuropilin (Nrp)1 and Nrp2, along with platelet-derived growth factor (PDGF)-C, contribute to revascularization after ischemia. a, Mice were treated with anti-ragweed antibody (control), anti-Nrp1 antibody (anti-Nrp1), or anti-Nrp2 antibody (anti-Nrp2) at the dose of 10 mg/kg body weight immediately and 5 days after induction of ischemia. Blood flow recovery was analyzed by laser Doppler perfusion imaging. *P < .05 vs control (n = 5 for each group). Data represent means ± standard error of the mean (SEM). b, Mice were treated with anti-ragweed antibody (control), or anti-PDGF-A antibody (anti-PDGFA) at the dose of 10 mg/kg body weight immediately and 5 days after ischemia induction, and blood flow recovery was analyzed. Data represent means ± SEM (n = 5 for each group). c, Mice were treated with anti-ragweed antibody (control), anti-PDGF-C antibody at the dose of 5 mg/kg body weight (anti-PDGFC low) or 10 mg/kg body weight (anti-PDGFC high) immediately and 5 days after ischemia, and blood flow recovery was analyzed as above described. *P < .05, **P < .01 vs control (n = 3-8 for each group). Data represent means ± SEM. Journal of Vascular Surgery  , e4DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

7 Supplementary Fig 2 (online only)
Expression levels of neuropilin 1 (Nrp1), Nrp2, and platelet-derived growth factor (PDGF) family members after ischemia. a, The messenger RNA (mRNA) levels of Nrp1, Nrp2, platelet-derived growth factor receptor β (PDGFRβ), PDGF-A, PDGF-B, and PDGF-D in ischemic limbs at several time courses were assessed by real-time reverse transcription polymerase chain reaction analysis. *P < .05, **P < .01 vs pre (n = 4-8 for each group). Data represent means ± standard error of the mean. b, The PDGF-C mRNA levels in ischemic limbs of mice treated with an anti-ragweed antibody (control Ab) or anti-PDGF-C antibody (anti-PDGFC Ab) were assessed as described above. *P < .05, **P < .01 vs pre (n = 4-6 for each group). Data represent means ± standard error of the mean. Journal of Vascular Surgery  , e4DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

8 Supplementary Fig 3 (online only)
Effect of combined introduction of the platelet-derived growth factor C (PDGFC) and the vascular endothelial growth factor (VEGF) expression vectors into ischemic limbs on blood flow recovery after ischemia. a, Ischemic limbs of mice were injected with empty vector (control), VEGF expression vector (VEGF), or VEGF expression vector plus PDGF-C expression vector (VEGF + PDGFC) as described in the Methods section. Blood flow recovery was analyzed. *P < .05, **P < .01 vs control (n = 6-13 for each group). Data represent means ± standard error of the mean. Journal of Vascular Surgery  , e4DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

9 Supplementary Fig 4 (online only)
Expressions of neuropilin 1 (Nrp1) and Nrp2 are downregulated in diabetic mice. a, Mice treated with an intraperitoneal injection of sodium citrate buffer (control) or streptozotocin (STZ) were weighed. The black arrows indicate the timing of injection. *P < .05, **P < .01 vs control (n = 5 for each group). Data represent means ± standard error of the mean (SEM). b, Blood glucose levels of mice injected with sodium citrate buffer (control) or STZ were measured. **P < .01 vs control (n = 5 for each group). Data represent means ± SEM. c, Time course of relative Nrp1 and Nrp2 messenger RNA (mRNA) expression in ischemic limbs of nondiabetic (control) or diabetic (STZ) mice. *P < .05, **P < .01 vs control; ##P < .01 vs precontrol; ††P < .01 vs pre-STZ (n = 4-8 for each group). Data represent means ± SEM. Journal of Vascular Surgery  , e4DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

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