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Sustained Vascular Endothelial Growth Factor Delivery Enhances Angiogenesis and Perfusion in Ischemic Hind Limb

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Purpose

We hypothesized that sustained delivery of vascular endothelial growth factor (VEGF) using a polymer [85:15 poly(lactide-co-glycolide) (PLG)] would enhance angiogenesis and improve perfusion of ischemic tissue.

Methods

C57BL/6J mice (n = 20/group) underwent unilateral hind limb ischemia surgery and were randomized to groups of no scaffold implantation (∅-Implant), unloaded scaffold implantation (Empty-PLG), or implantation of scaffolds incorporating 3 μg of VEGF165 (PLG-VEGF). Endpoints included laser Doppler perfusion imaging (LDPI, ischemic/nonischemic limb, %), local vessel counts, immunohistochemistry for CD31, and α-smooth muscle actin. In vitro release kinetics of VEGF from PLG was also measured.

Results

PLG-VEGF resulted in improved lower extremity perfusion vs. controls as measured by LDPI% at 7, 14, 21, and 28 days (p < 0.05). PLG-VEGF was associated with significantly greater percentage of vessels staining for CD31 and α-smooth muscle actin compared to the Empty-PLG or ∅-Implant (p < 0.05 for both).

Conclusions

The PLG-VEGF scaffolds resulted in sustained VEGF delivery, improved tissue perfusion, greater capillary density, and more mature vasculature compared to the controls. The sustained-release PLG polymer vehicle is a promising delivery system for therapeutic neovascularization applications.

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Abbreviations

Empty-PLG:

PLG polymer not loaded with growth factor

∅-Implant:

hind limb surgery performed with no PLG polymer implanted

PAD:

peripheral arterial disease

PLG:

poly(lactide-co-glycolide)

PLG-VEGF:

PLG polymer loaded with 3 μg of VEGF165

SMA:

smooth muscle actin

VEGF:

vascular endothelial growth factor

References

  1. J. M. Isnerand T. Asahara (1999) ArticleTitleAngiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization J. Clin. Invest. 103 1231–1236

    Google Scholar 

  2. M. Simons R. O. Bonow N. A. Chronos D. J. Cohen F. J. Giordano H. K. Hammond R. J. Laham W. Li M. Pike F. W. Sellke T. J. Stegmann J. E. Udelson T. K. Rosengart (2000) ArticleTitleClinical trials in coronary angiogenesis: issues, problems, consensus: an expert panel summary Circulation 102 E73–E86

    Google Scholar 

  3. S. Rafii S. Meeus S. Dias K. Hattori B. Heissig S. Shmelkov D. Rafii D. Lyden (2002) ArticleTitleContribution of marrow-derived progenitors to vascular and cardiac regeneration Semin. Cell Dev. Biol. 13 61–67

    Google Scholar 

  4. J. A. Nagy E. Vasile D. Feng C. Sundberg L. F. Brown M. J. Detmar J. A. Lawitts L. Benjamin X. Tan E. J. Manseau A. M. Dvorak H. F. Dvorak (2002) ArticleTitleVascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis J. Exp. Med. 196 1497–1506

    Google Scholar 

  5. H. K. Hammondand M. D. McKirnan (2001) ArticleTitleAngiogenic gene therapy for heart disease: a review of animal studies and clinical trials Cardiovasc. Res. 49 561–567

    Google Scholar 

  6. S. Rajagopalan E. R. Mohler SuffixIII R. J. Lederman F. O. Mendelsohn J. F. Saucedo C. K. Goldman J. Blebea J. Macko P. D. Kessler H. S. Rasmussen B. H. Annex (2003) ArticleTitleRegional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication Circulation 108 1933–1938

    Google Scholar 

  7. M. C. Peters P. J. Polverini D. J. Mooney (2002) ArticleTitleEngineering vascular networks in porous polymer matrices J. Biomed. Mater. Res. 60 668–678

    Google Scholar 

  8. M. Simonsand J. A. Ware (2003) ArticleTitleTherapeutic angiogenesis in cardiovascular disease Nat. Rev., Drug Discov. 2 863–871

    Google Scholar 

  9. M. C. Peters B. C. Isenberg J. A. Rowley D. J. Mooney (1998) ArticleTitleRelease from alginate enhances the biological activity of vascular endothelial growth factor J. Biomater. Sci., Polym. Ed. 9 1267–1278

    Google Scholar 

  10. R. Langer (1998) ArticleTitleDrug delivery and targeting Nature 392 5–10

    Google Scholar 

  11. K. Park (Eds) (1997) Controlled Drug Delivery: Challenges and Strategies American Chemical Society Washington, Dc

    Google Scholar 

  12. W. L. Murphy M. C. Peters D. H. Kohn D. J. Mooney (2000) ArticleTitleSustained release of vascular endothelial growth factor from mineralized poly(lactide-co-glycolide) scaffolds for tissue engineering Biomaterials 21 2521–2527

    Google Scholar 

  13. D. Gilding (1981) Biodegradable Polymers CRC Press Boca Raton, FL

    Google Scholar 

  14. M. H. Sheridan L. D. Shea M. C. Peters D. J. Mooney (2000) ArticleTitleBioabsorbable polymer scaffolds for tissue engineering capable of sustained growth factor delivery J. Control. Rel. 64 91–102

    Google Scholar 

  15. T. P. Richardson M. C. Peters A. B. Ennett D. J. Mooney (2001) ArticleTitlePolymeric system for dual growth factor delivery Nat. Biotechnol. 19 1029–1034

    Google Scholar 

  16. J. L. Cleland E. T. Duenas A. Park A. Daugherty J. Kahn J. Kowalski A. Cuthbertson (2001) ArticleTitleDevelopment of poly-(d,l-lactide-coglycolide) microsphere formulations containing recombinant human vascular endothelial growth factor to promote local angiogenesis J. Control Rel. 72 13–24

    Google Scholar 

  17. S. F. Schlossman (1995) Leucocyte Typing V: White Cell Differentiation Antigens: Proceedings of the Fifth International Workshop and Conference held in Boston, USA, 3–7 November, 1993 Oxford University Press Oxford, NY

    Google Scholar 

  18. O. Skalli P. Ropraz A. Trzeciak G. Benzonana D. Gillessen G. Gabbiani (1986) ArticleTitleA monoclonal antibody against alpha-smooth muscle actin: a new probe for smooth muscle differentiation J. Cell Biol. 103 2787–2796

    Google Scholar 

  19. L. D. Harris B. S. Kim D. J. Mooney (1998) ArticleTitleOpen pore biodegradable matrices formed with gas foaming J. Biomed. Mater. Res. 42 396–402

    Google Scholar 

  20. A. Rivard J. E. Fabre M. Silver D. Chen T. Murohara M. Kearney M. Magner T. Asahara J. M. Isner (1999) ArticleTitleAge-dependent impairment of angiogenesis Circulation 99 111–120

    Google Scholar 

  21. S. Takeshita L. P. Zheng E. Brogi M. Kearney L. Q. Pu S. Bunting N. Ferrara J. F. Symes J. M. Isner (1994) ArticleTitleTherapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model J. Clin. Invest. 93 662–670

    Google Scholar 

  22. S. Takeshita L. Q. Pu L. A. Stein A. D. Sniderman S. Bunting N. Ferrara J. M. Isner J. F. Symes (1994) ArticleTitleIntramuscular administration of vascular endothelial growth factor induces dose-dependent collateral artery augmentation in a rabbit model of chronic limb ischemia Circulation 90 II228–II234

    Google Scholar 

  23. B. Witzenbichler T. Asahara T. Murohara M. Silver I. Spyridopoulos M. Magner N. Principe M. Kearney J. S. Hu J. M. Isner (1998) ArticleTitleVascular endothelial growth factor-C (VEGF-C/VEGF-2) promotes angiogenesis in the setting of tissue ischemia Am. J. Pathol. 153 381–394

    Google Scholar 

  24. S. Rajagopalan M. Shah A. Luciano R. Crystal E. G. Nabel (2001) ArticleTitleAdenovirus-mediated gene transfer of VEGF(121) improves lower-extremity endothelial function and flow reserve Circulation 104 753–755

    Google Scholar 

  25. J. E. Nor J. Christensen D. J. Mooney P. J. Polverini (1999) ArticleTitleVascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression Am. J. Pathol. 154 375–384

    Google Scholar 

  26. S. I. Stiver X. Tan L. F. Brown E. T. Hedley-Whyte H. F. Dvorak (2004) ArticleTitleVEGF-A angiogenesis induces a stable neovasculature in adult murine brain J. Neuropathol. Exp. Neurol. 63 841–855

    Google Scholar 

  27. M. Therin P. Christel S. Li H. Garreau M. Vert (1992) ArticleTitleIn vivo degradation of massive poly(alpha-hydroxy acids): validation of in vitro findings Biomaterials 13 594–600

    Google Scholar 

  28. A. G. Mikos Y. Bao L. G. Cima D. E. Ingber J. P. Vacanti R. Langer (1993) ArticleTitlePreparation of poly(glycolic acid) bonded fiber structures for cell attachment and transplantation J. Biomed. Mater. Res. 27 183–189

    Google Scholar 

  29. D. J. Mooney P. M. Kaufmann K. Sano K. M. McNamara J. P. Vacanti R. Langer (1994) ArticleTitleTransplantation of hepatocytes using porous, biodegradable sponges Transplant. Proc. 26 3425–3426

    Google Scholar 

  30. S. L. Ishaug-Riley G. M. Crane A. Gurlek M. J. Miller A. W. Yasko M. J. Yaszemski A. G. Mikos (1997) ArticleTitleEctopic bone formation by marrow stromal osteoblast transplantation using poly(dl-lactic-co-glycolic acid) foams implanted into the rat mesentery J. Biomed. Mater. Res. 36 1–8

    Google Scholar 

  31. B. S. Kimand D. J. Mooney (1998) ArticleTitleDevelopment of biocompatible synthetic extracellular matrices for tissue engineering Trends Biotechnol. 16 224–230

    Google Scholar 

  32. K. Y. Lee M. C. Peters K. W. Anderson D. J. Mooney (2000) ArticleTitleControlled growth factor release from synthetic extracellular matrices Nature 408 998–1000

    Google Scholar 

  33. C. A. Vacanti R. Langer B. Schloo J. P. Vacanti (1991) ArticleTitleSynthetic polymers seeded with chondrocytes provide a template for new cartilage formation Plast. Reconstr. Surg. 88 753–759

    Google Scholar 

  34. F. D. Fortuin P. Vale D. W. Losordo J. Symes G. A. DeLaria J. J. Tyner G. L. Schaer R. March R. J. Snell T. D. Henry J. Camp ParticleVan J. J. Lopez W. Richenbacher J. M. Isner R. A. Schatz (2003) ArticleTitleOne-year follow-up of direct myocardial gene transfer of vascular endothelial growth factor-2 using naked plasmid deoxyribonucleic acid by way of thoracotomy in no-option patients Am. J. Cardiol. 92 436–439

    Google Scholar 

  35. E. R. Mohler SuffixIII S. Rajagopalan J. W. Olin J. D. Trachtenberg H. Rasmussen R. Pak R. G. Crystal (2003) ArticleTitleAdenoviral-mediated gene transfer of vascular endothelial growth factor in critical limb ischemia: safety results from a phase I trial Vasc. Med. 8 9–13

    Google Scholar 

  36. J. A. Nagy A. M. Dvorak H. F. Dvorak (2003) ArticleTitleVEGF-A(164/165) and PlGF: roles in angiogenesis and arteriogenesis Trends Cardiovasc. Med. 13 169–175

    Google Scholar 

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Acknowledgement

This work was financially supported by the National Heart, Lung and Blood Institute (R01 HL069957).

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Hospitals and Health System, Ann Arbor, Michigan, 48109-0311, USA

    Qinghua Sun, Yuechun Shen, Sanjay Rajagopalan & P. Michael Grossman

  2. Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan, 48109, USA

    Ruth R. Chen & David J. Mooney

Authors
  1. Qinghua Sun
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  2. Ruth R. Chen
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  3. Yuechun Shen
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  4. David J. Mooney
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  5. Sanjay Rajagopalan
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  6. P. Michael Grossman
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Correspondence to P. Michael Grossman.

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Sun, Q., Chen, R.R., Shen, Y. et al. Sustained Vascular Endothelial Growth Factor Delivery Enhances Angiogenesis and Perfusion in Ischemic Hind Limb. Pharm Res 22, 1110–1116 (2005). https://doi.org/10.1007/s11095-005-5644-2

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  • DOI: https://doi.org/10.1007/s11095-005-5644-2

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