Vascular endothelial growth factor-C derived from CD11b+ cells induces therapeutic improvements in a murine model of hind limb ischemia Go Kuwahara,

Slides:

Advertisements

Similar presentations

Recovery from hind limb ischemia is less effective in type 2 than in type 1 diabetic mice: Roles of endothelial nitric oxide synthase and endothelial.

Advertisements

Angiogenic properties of sustained release platelet-rich plasma: Characterization in-vitro and in the ischemic hind limb of the mouse Shyamal Chandra.

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

High mobility group box 1 promotes endothelial cell angiogenic behavior in vitro and improves muscle perfusion in vivo in response to ischemic injury

Adeno-associated virus serotype 9-mediated overexpression of extracellular superoxide dismutase improves recovery from surgical hind-limb ischemia in.

Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps Rahmi Oklu,

Ginkgo biloba extract inhibits oxidized low-density lipoprotein (oxLDL)-induced matrix metalloproteinase activation by the modulation of the lectin-like.

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

Ulka Sachdev, MD, Xiangdong Cui, MS, Edith Tzeng, MD

Elastic fibers reconstructed using adenovirus-mediated expression of tropoelastin and tested in the elastase model of abdominal aortic aneurysm in rats

Yi-kuan Chen, MD, Xue-mei Jiang, MSc, Jian-ping Gong, MD

Elevation of hemopexin-like fragment of matrix metalloproteinase-2 tissue levels inhibits ischemic wound healing and angiogenesis April E. Nedeau, MD,

Pharmacologic blockade and genetic deletion of androgen receptor attenuates aortic aneurysm formation John P. Davis, MD, Morgan Salmon, PhD, Nicolas.

The therapeutic effect of vascular endothelial growth factor gene- or heme oxygenase-1 gene-modified endothelial progenitor cells on neovascularization.

An engineered vascular endothelial growth factor-activating transcription factor induces therapeutic angiogenesis in ApoE knockout mice with hindlimb.

The bone marrow-derived endothelial progenitor cell response is impaired in delayed wound healing from ischemia Stephen M. Bauer, MD, Lee J. Goldstein,

Hyperphosphatemia induces protective autophagy in endothelial cells through the inhibition of Akt/mTOR signaling Yu-Juei Hsu, MD, PhD, Shih-Che Hsu,

Bertrand Poussier, MD, Alfredo C

Potential role of erythropoietin receptors and ligands in attenuating apoptosis and inflammation in critical limb ischemia Dhiraj Joshi, MD, MRCS, David.

Rapamycin is an effective inhibitor of human renal cancer metastasis1

Gale Tang, MD, David N. Charo, Rong Wang, PhD, Israel F

Angiogenic properties of human placenta-derived adherent cells and efficacy in hindlimb ischemia Aleksandar Francki, PhD, Kristen Labazzo, PhD, Shuyang.

Inflammation-related induction of absent in melanoma 2 (AIM2) in vascular cells and atherosclerotic lesions suggests a role in vascular pathogenesis

Volume 71, Issue 3, Pages (February 2007)

Volume 69, Issue 8, Pages (April 2006)

Intrathecal transplantation of bone marrow stromal cells attenuates blood-spinal cord barrier disruption induced by spinal cord ischemia-reperfusion injury.

Robert A. Brenes, MD, Caroline C

Polydeoxyribonucleotide restores blood flow in an experimental model of ischemic skin flaps Francesca Polito, PhD, Alessandra Bitto, MD, PhD, Mariarosaria.

Combination of stromal-derived factor-1α and vascular endothelial growth factor gene- modified endothelial progenitor cells is more effective for ischemic.

Ryan M. McEnaney, MD, Ankur Shukla, MD, Michael C

Shock wave treatment induces angiogenesis and mobilizes endogenous CD31/CD34- positive endothelial cells in a hindlimb ischemia model: Implications for.

Ulka Sachdev, MD, Xiangdong Cui, MS, Edith Tzeng, MD

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

The effect of gradual or acute arterial occlusion on skeletal muscle blood flow, arteriogenesis, and inflammation in rat hindlimb ischemia Gale L. Tang,

Increased connexin43 expression in human saphenous veins in culture is associated with intimal hyperplasia Sébastien Déglise, MD, David Martin, MS, Hervé.

Cellular and molecular mechanism regulating blood flow recovery in acute versus gradual femoral artery occlusion are distinct in the mouse Yagai Yang,

Metformin stimulates ischemia-induced revascularization through an eNOS dependent pathway in the ischemic hindlimb mice model Noriko Takahashi, MD, Rei.

Potential role of erythropoietin receptors and ligands in attenuating apoptosis and inflammation in critical limb ischemia Dhiraj Joshi, MD, MRCS, David.

Combining the Multitargeted Tyrosine Kinase Inhibitor Vandetanib with the Antiestrogen Fulvestrant Enhances Its Antitumor Effect in Non-small Cell Lung.

Simvastatin pretreatment enhances ischemia-induced neovascularization and blood flow recovery in streptozotocin-treated mice Po-Hsun Huang, MD, PhD,

Nanoparticle-mediated endothelial cell-selective delivery of pitavastatin induces functional collateral arteries (therapeutic arteriogenesis) in a rabbit.

Aging impairs the angiogenic response to ischemic injury and the activity of implanted cells: Combined consequences for cell therapy in older recipients

Galit Ankri-Eliahoo, PhD, Kevin Weitz, BS, Timothy C. Cox, PhD, Gale L

Volume 64, Issue 5, Pages (November 2003)

Polydeoxyribonucleotide (PDRN) restores blood flow in an experimental model of peripheral artery occlusive disease Alessandra Bitto, MD, Francesca Polito,

Endothelial nitric oxide synthase affects both early and late collateral arterial adaptation and blood flow recovery after induction of hind limb ischemia.

Antisense to transforming growth factor-β1 messenger RNA reduces vein graft intimal hyperplasia and monocyte chemotactic protein 1 Randal A. Wolff, PhD,

Midkine is expressed by infiltrating macrophages in in-stent restenosis in hypercholesterolemic rabbits Hiroshi Narita, MD, Sen Chen, PhD, Kimihiro Komori,

Simultaneous application of basic fibroblast growth factor and hepatocyte growth factor to enhance the blood vessels formation Akira Marui, MD, Akihiro.

Therapeutic Potential of Human Umbilical Cord Derived Stem Cells in a Rat Myocardial Infarction Model Kai Hong Wu, MD, PhD, Bin Zhou, PhD, Cun Tao Yu,

Leptin receptor is elevated in carotid plaques from neurologically symptomatic patients and positively correlated with augmented macrophage density Jacob.

Therapeutic site selection is important for the successful development of collateral vessels Ayako Nishiyama, MD, PhD, Hiroyuki Koyama, MD, PhD, Tetsuro.

International Journal of Cardiology

Biochemically engineered stromal cell-derived factor 1-alpha analog increases perfusion in the ischemic hind limb Bryan B. Edwards, BE, Alexander S.

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

Volume 22, Issue 4, Pages (April 2014)

Tormod S. Westvik, MD, Tamara N

Recovery from hind limb ischemia is less effective in type 2 than in type 1 diabetic mice: Roles of endothelial nitric oxide synthase and endothelial.

Extracorporeal shock wave therapy ameliorates secondary lymphedema by promoting lymphangiogenesis Masayuki Kubo, PhD, Tao-Sheng Li, MD, PhD, Takahiro.

Subacute limb ischemia induces skeletal muscle injury in genetically susceptible mice independent of vascular density Joseph M. McClung, PhD, Timothy.

Volume 12, Issue 2, Pages (August 2005)

Ex vivo gene delivery of ephrin-B2 induces development of functional collateral vessels in a rabbit model of hind limb ischemia Masatake Katsu, MD, Hiroyuki.

Volume 16, Issue 12, Pages (December 2008)

Controlled delivery of vascular endothelial growth factor promotes neovascularization and maintains limb function in a rabbit model of ischemia Steven.

Volume 19, Issue 4, Pages (April 2011)

Macrophage depletion reduces monocyte chemotactic protein-1 and transforming growth factor-β1 in healing rat vein grafts Randal A Wolff, PhD, Jeffrey.

Overexpression of endothelial nitric oxide synthase increases skeletal muscle blood flow and oxygenation in severe rat hind limb ischemia Lucy S Brevetti,

Recovery from hind limb ischemia is less effective in type 2 than in type 1 diabetic mice: Roles of endothelial nitric oxide synthase and endothelial.

Volume 69, Issue 11, Pages (June 2006)

Galit Ankri-Eliahoo, PhD, Kevin Weitz, BS, Timothy C. Cox, PhD, Gale L

Presentation transcript:

Vascular endothelial growth factor-C derived from CD11b+ cells induces therapeutic improvements in a murine model of hind limb ischemia Go Kuwahara, MD, Hitomi Nishinakamura, PhD, Daibo Kojima, MD, PhD, Tadashi Tashiro, MD, PhD, Shohta Kodama, MD, PhD Journal of Vascular Surgery Volume 57, Issue 4, Pages 1090-1099 (April 2013) DOI: 10.1016/j.jvs.2012.08.121 Copyright © 2013 Society for Vascular Surgery Terms and Conditions

Fig 1 Recovery of blood flow in ischemic limbs treated with bone marrow cells (BMCs) and CD11b+ cells derived from BMCs. A and C, Representative laser Doppler perfusion images taken at indicated intervals for the phosphate-buffered saline (PBS) control group, unselected BMCs group, CD11b− group, and CD11b+ group. Blood perfusion in the ischemic hind limbs was markedly increased in the unselected BMCs and CD11b+ groups compared with the control and CD11b− groups, respectively. Quantitative analysis of hind limb blood perfusion demonstrated an increase in the ischemic/nonischemic ratio, which was significantly higher in the BMCs group compared with the control group at postoperative days 7 and 14 (day 7: 38.9% ± 9.0% vs 14.8 ± 6.7%; P < .01; day 14: 72.2% ± 7.4% vs 31.1 ± 12.0%; P < .05; n = 5-7). The increase in the ischemic/nonischemic ratio was significantly higher in the CD11b+ group compared with the CD11b− group at postoperative days 1, 3, 7, and 14 ( day 1: 17.1% ± 4.0% vs 12.3 ±1.7%; P < .05; day 3: 26.4% ± 3.1% vs 12.3% ± 7.2%; P < .05; day 7: 48.4% ± 16.0% vs 20.7% ± 8.6%; P < .01; day 14: 85.7% ± 23.3% vs 45.7% ± 4.8%; P < .01; n = 5-7). Data are given as mean ± SEM, n = 5-7 per group. *P < .05; **P < .01; ***P < .001. B, Flow cytometric analysis of CD11b+ macrophages from BMCs. The purity of subpopulations of the enriched CD11b+ macrophages was approximately 95% according to the FACS analysis. Journal of Vascular Surgery 2013 57, 1090-1099DOI: (10.1016/j.jvs.2012.08.121) Copyright © 2013 Society for Vascular Surgery Terms and Conditions

Fig 2 Expression of vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGFR-1, VEGFR-2, and VEGFR-3 in CD11b− and CD11b+ cells. A, Concentration of VEGF-A and VEGF-C secreted by CD11b− or CD11b+ cells. After magnetic cell sorting (MACS), 1 × 105 CD11b− or CD11b+ cells were incubated for 7 days and the supernatant analyzed by enzyme-linked immunosorbent assay (n = 3; mean [standard deviation]; ***P < . 001). B, Representative messenger ribonucleic acid (mRNA) of VEGFR-1, VEGFR-2, and VEGFR-3 from CD11b− and CD11b+ cells. Glyceraldehyde-3-phosphate dehydrogenase (G3PDH) was used as an internal control. Reverse transcription-polymerase chain reaction is representative of three separate experiments. C, Representative immunoblotting images for VEGFR-1, VEGFR-2, and VEGFR-3 from CD11b− and CD11b+ cells. After MACS sorting, 5 × 106 CD11b− and CD11b+ cells were lysed and examined by immunoblotting analysis. The staining of β-actin was used as an internal control. Blots are representative of three separate experiments. E11 and E13 used for positive control means embryonic day 11 and 13. Journal of Vascular Surgery 2013 57, 1090-1099DOI: (10.1016/j.jvs.2012.08.121) Copyright © 2013 Society for Vascular Surgery Terms and Conditions

Fig 3 Vascular endothelial growth factor (VEGF)-C promotes neovascularization and functional recovery following hind limb ischemia. A, Representative laser Doppler perfusion images taken at the indicated intervals for the phosphate-buffered saline (PBS) control group and the VEGF-C group. Blood perfusion in the ischemic hind limbs was markedly increased in the VEGF-C group compared with the control group. Quantitative analysis of hind limb blood perfusion demonstrated an increase in the ischemic/nonischemic ratio, which was significantly higher in the VEGF-C group compared with control group at postoperative days 7 and 14 (day 7: 39.8% ± 12.0% vs 14.8 ± 6.7%; P < .01; day 14: 65.5% ± 11.6% vs 31.1 ± 12.0%; P < .05; n = 5-7). Data are expressed as mean ± SEM, n = 5-7 per group. B, The Tarlov score was significantly higher in the VEGF-C group compared with the control group at postoperative days 7 and 14 (day 7: 5.25 ± 0.5 vs 1.0 ± 0.81; P < .05; day 14: 5.75 ± 0.5 vs 3.42 ± 2.37; P < .05; n = 5). Ischemic scores show that the tissue grade was significantly higher in the VEGF-C group compared with the control group at day 7 postoperation (4.75 ± 0.5 vs 2.85 ± 1.06; P < .01; n = 5). C, Video analysis of mice traversing an illuminated glass walkway. The period of time during which each of the paws was in contact with the glass is illustrated as a contact duration map. The mean paw contact time and paw intensity per step for each limb, based on five separate experiments each with three replicates, are quantified in the graph below the map. *P < .05; **P < .01; ***P < .001. Journal of Vascular Surgery 2013 57, 1090-1099DOI: (10.1016/j.jvs.2012.08.121) Copyright © 2013 Society for Vascular Surgery Terms and Conditions

Fig 4 Protein levels of vascular endothelial growth factor (VEGF)-A and VEGF-C in thigh muscle at postoperative days 7 and 14. A, There was no statistically significant difference in the level of VEGF-A expression between all groups (n = 3; mean [standard deviation]). B, The amount of VEGF-C from the thigh muscle after limb ischemia, 7 days after the intramuscular injection, revealed that CD11b+ cell-treated mice had significantly increased levels of VEGF-C compared with the other groups (n = 3; mean [standard deviation]; *P < .05). Journal of Vascular Surgery 2013 57, 1090-1099DOI: (10.1016/j.jvs.2012.08.121) Copyright © 2013 Society for Vascular Surgery Terms and Conditions

Fig 5 Effect of CD11b+ cell and vascular endothelial growth factor (VEGF)-C treatment on capillary density 14 days after the induction of ischemia (n = 5 animals in each group). A, In these representative photomicrographs (original magnification ×400), von Willebrand factor positive and LYVE-1 positive cells are stained green and red, respectively. B, During angiogenesis, capillary density was significantly higher in the CD11b+ and VEGF-C groups than in the control group (1.88 ± 0.34 vs 0.36 ± 0.09; P < .001; 0.88 ± 0.29 vs 0.36 ± 0.09; P < .001). Furthermore, in lymphangiogenesis, capillary density was significantly upregulated in the CD11b+ and VEGF-C groups compared with control group (1.89 ± 0.26 vs 0.22 ± 0.12; P < .001; 1.19 ± 0.37 vs 0.22 ± 0.12; P < .001). *P < .05; **P < .01; ***P < .001. C, Reverse transcription-polymerase chain reaction demonstrates VEGFR-1, VEGFR-2, and VEGFR-3 messenger ribonucleic acid (mRNA) expression in thigh muscle at postoperative days 7 and 14. Glyceraldehyde-3-phosphate dehydrogenase (G3PDH) was used as the internal control. Representative images are shown (n = 3). Photomicrographs (original magnification ×400) show representative diaminobenzidine staining for VEGFR-1, VEGFR-2, and VEGFR-3. The thigh muscle of each group was isolated 14 days after induction of ischemia. Photomicrographs are representative of observations made in three animals from each group. D and E, Recovery of blood flow in the ischemic hind limb of the CD11b+ and VEGF-C groups was suppressed by administration of anti-VEGFR-2 antibody (DC101). The recovery of blood flow in ischemic limbs in the CD11b+ group treated with VEGFR-2-neutralizing antibody was significantly suppressed compared with the CD11b+-treated group at postoperative days 3 and 7. In the VEGF-C group treated with VEGFR-2-neutralizing antibody, blood flow recovery was significantly suppressed compared with the VEGF-C group at postoperative day 7. †P < .05; ‡P < .01. Journal of Vascular Surgery 2013 57, 1090-1099DOI: (10.1016/j.jvs.2012.08.121) Copyright © 2013 Society for Vascular Surgery Terms and Conditions