Delivery of nerve growth factor (NGF) gene via recombinant plasmid vector induces angiogenesis in murine ischemic hind limb



Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

The development of therapeutic angiogenesis that can stimulate the formation of mature vessels is a valuable prospect for treatment of ischemic disease, and the combination of well-known angiogenic factors with other growth factors is now beginning to show promise in therapy. In our efforts to identify possible targets for therapeutic intervention using combinations of growth factors, nerve growth factor (NGF) seems to be a possible candidate. In this study we analyzed the possibility to stimulate angiogenesis via local delivery of a plasmid encoding human nerve growth factor (hNGF). We used a murine hind-limb ischemia model to assess plasmid angiogenic potential in vivo. Plasmid DNA was diluted in saline and injected into ischemic m. tibialis anterior. Blood flow restoration was analyzed by laser Doppler imaging every 7 days after surgery, and throughout the experiment we assessed total hind-limb necrosis. After animals were sacrificed, muscle samples were frozen for histological analysis. Tissue sections were stained with antibodies against endothelium marker CD31 to assess vascular density. Blood perfusion by day 7 was higher in the NGF-treated group compared to control (p = 0.01), and by day 14 animals in the NGF-treated group had perfusion 2.8 fold higher than control animals (NGF 44.62±7.68; control 16.74±5.85; р = 0.005). Vascular density in tissue samples by day 14 in NGF-treated animals was about 2-fold higher than in the control group (р<0.05).

Full Text

Restricted Access

About the authors

MA. A Boldyreva

Russian Cardiology Research and Production Complex

Moscow, Russia

P. I Makarevich

Russian Cardiology Research and Production Complex

Moscow, Russia

L. M Rafieva

Institute of Molecular Genetics of RAS

Moscow, Russia

I. B Beloglazova

Russian Cardiology Research and Production Complex

Moscow, Russia

K. V Dergilev

Russian Cardiology Research and Production Complex

Moscow, Russia

S. V Kostrov

Institute of Molecular Genetics of RAS

Moscow, Russia

Ye. V Parfyonova

Russian Cardiology Research and Production Complex

Moscow, Russia

References

  1. Roger V.L., Go A.S., Lloyd-Jones D.M. et al. Executive summary: heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation 2012; 125(1): 188-97.
  2. Gupta R., Tongers J., Losordo D.W. Human studies of angiogenic gene therapy. Circ. Res. 2009; 105(8): 724-36.
  3. Парфенова Е.В., Ткачук В.А. Перспективы генной терапии сердечно-сосудистых заболеваний. Вопросы медицинской химии 2000; 46(3): 293-310.
  4. Парфенова Е.В., Ткачук В.А. Терапевтический ангиогенез: достижения, проблемы, перспективы. Кардиологический вестник 2007; 2(2): 4-12.
  5. Шевченко Е.К., Талицкий К.А., Парфенова Е.В. Перспективы повышения эффективности генной и клеточной терапии сердечнососудистых заболеваний: генетически модифицированные клетки. Клеточная трансплантология и тканевая инженерия 2010; V(2): 19-28.
  6. Korpisalo P., Yla-Herttuala S. Stimulation of functional vessel growth by gene therapy. Integr. Biol. (Camb.). 2010; 2(2-3): 102-12.
  7. Robich M.P., Chu L.M., Oyamada S. et al. Myocardial therapeutic angiogenesis: a review of the state of development and future obstacles. Expert. Rev. Cardiovasc. Ther. 2011; 9(11): 1469-79.
  8. Giacca M., Zacchigna S. VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond. Gene Therapy 2012; 19: 622-9.
  9. Mughal N.A., Russell D.A., Ponnambalam S. et al. Gene therapy in the treatment of peripheral arterial disease. Br. J Surg. 2012; 99(1): 6-15.
  10. Madonna R., Rokosh G. Insights into gene therapy for critical limb ischemia: the devil is in the details. Vascul. Pharmacol. 2012; 57(1): 10-4.
  11. Forsythe R.O., Hinchliffe R.J. Management of peripheral arterial disease and the diabetic foot. J. Cardiovasc. Surg. (Torino). 2014; 55(2 Suppl 1): 195-206.
  12. El-Helou V., Proulx C., Gosselin H. et al. Dexamethasone treatment of post-MI rats attenuates sympathetic innervation of the infarct region. J. Appl. Physiol. (1985) 2008; 104(1):150-6.
  13. Gupta S.C., Kim J.H., Prasad S. et al. Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metastasis Rev. 2010; 29(3): 405-34.
  14. Ouma G.O., Zafrir B., Mohler E.R. 3rd et al. Therapeutic Angiogenesis in Critical Limb Ischemia. Angiology 2013; 64(6): 466-80.
  15. Powell R.J. Update on clinical trials evaluating the effect of biologic therapy in patients with critical limb ischemia. J. Vasc. Surg. 2012; 56(1): 264-6.
  16. Zachary I. Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function, and therapeutic potential. Neurosignals 2005; 14(5): 207-21.
  17. Kundi S., Bicknell R., Ahmed Z. The role of angiogenic and wound-healing factors after spinal cord injury in mammals. Neurosci. Res. 2013; 76(1-2): 1-9.
  18. Efimenko A. Yu., Kochegura T. N., Akopyan Zh. A. et al. Autologous stem cell therapy: how aging andcChronic diseases affect stem and progenitor cells. 2015. BioResearch Open Access Vol. 4.1. doi: 10.1089/biores.2014.0042.
  19. Levi-Montalcini R., Hamburger V. Selective growth stimulating effects of mouse sarcoma on the sensory and sympathetic nervous system of the chick embryo. J. Exp. Zool. 1951; 116(2): 321-61.
  20. Moser K.V., Reindl M., Blasig I. et al. Brain capillary endothelial cells proliferate in response to NGF, express NGF receptors and secrete NGF after inflammation. Brain Res. 2004; 1017: 53-60.
  21. Rahbek U.L., Dissing S., Thomassen C. et al. Nerve growth factor activates aorta endothelial cells causing PI3K/Akt- and ERK-dependent migration. Pflugers Arch. 2005; 450: 355-61.
  22. Ribatti D., Nico B., Vacca A. et al. The gelatin sponge-chorioallantoic membrane assay. Nat. Protoc. 2006; 1(1): 85-91.
  23. Caroleo M.C., Costa N., Bracci-Laudiero L. et al. Human monocyte/macrophages activate by exposure to LPS overexpress NGF and NGF receptors. J. Neuroimmunol. 2001; 113(2): 193-201.
  24. Calza L., Giardino L., Giuliani A. et al. Nerve growth factor control of neuronal expression of angiogenetic and vasoactive factors. PNAS USA 2001; 98: 4160-5.
  25. Tuveri M., Generini S., Matucci-Cerinic M. et al. NGF, a useful tool in the treatment of chronic vasculitic ulcers in rheumatoid arthritis. Lancet 2000; 356(9243): 1739-40.
  26. Сафина Д. Р., Рафиева Л. М., Коваль А. В. и соавт. Олигомерная организация рекомбинантных нейротрофинов человека, экспрессированных в клетках Escherichia coli. Биоорг. Химия 2008; 34(3): 327-32.
  27. Takeshita S., Isshiki T., Ochiai M. et al. Endothelium-dependent relaxation of collateral microvessels after intramuscular gene transfer of vascular endothelial growth factor in a rat model of hindlimb ischemia. Circulation 1998; 98(13): 1261-3.
  28. Traktuev D.O., Tsokolaeva Z.I., Shevelev A.A. et al. Urokinase gene transfer augments angiogenesis in ischemic skeletal and myocardial muscle. Mol. Ther. 2007; 15(11): 1939-46.
  29. Макаревич П.И., Шевелев А.Я., Рыбалкин И.Н. и соавт. Новые плазмидные конструкции, предназначенные для терапевтического ангиогенеза и несущие гены ангиогенных факторов роста - VEGF, HGF и ангиопоэтина-1. Клеточная трансплантология и тканевая инженерия 2010; V(1): 47-52.
  30. Makarevich P., Tsokolaeva Z., Shevelev A. et al. Combined transfer of human VEGF165 and HGF genes renders potent angiogenic effect in ischemic skeletal muscle. PLoS One 2012; 7(6): e38776.
  31. Boyce V.S., Mendell L.M. Neurotrophins and spinal circuit function. Front. Neural Circuits 2014; 8: 59.
  32. Bothwell M. NGF, BDNF, NT3, and NT4. Handb. Exp. Pharmacol. 2014; 220: 3-15.
  33. Allen S.J., Watson J.J., Shoemark D.K. et al. GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol. Ther. 2013; 138(2): 155-75.
  34. Ieda M., Kimura K., Kanazawa H. et al. Regulation of cardiac nerves: a new paradigm in the management of sudden cardiac death? Curr. Med. Chem. 2008; 15(17): 1731-6.
  35. Tonchev A.B. Brain ischemia, neurogenesis, and neurotrophic receptor expression in primates. Arch. Ital. Biol. 2011; 149(2): 225-31.
  36. Lazarovici P., Gazit A., Staniszewska I. et al. Nerve growth factor (NGF) promotes angiogenesis in the quail chorioallantoic membrane. Endothelium 2006; 13(1): 51-9.
  37. Varon S., Conner J.M. Nerve growth factor in CNS repair. J. Neurotrauma 1994; 11(5): 473-86.
  38. Emanueli C., Salis M.B., Pinna A. et al. Nerve growth factor promotes angiogenesis and arteriogenesis in ischemic hindlimbs. Circulation 2002; 106(17): 2257-62.
  39. Orike N., Middleton G., Borthwick E. et al. Role of PI 3-kinase, Akt and Bcl-2-related proteins in sustaining the survival of neurotrophic factor-independent adult sympathetic neurons. J. Cell Biol. 2001; 154(5): 995-1005.
  40. Zubkova E., Semenkova L., Dudich E. et al. Alpha-fetoprotein contributes to THP-1 cell invasion and chemotaxis via protein kinase and Gi-protein-dependent pathways. Mol. Cell. Biochem. 2013; 379(1-2): 283-93.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2014 Eco-Vector


СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: 

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies