Arteriogenic therapy based on simultaneous delivery of VEGF-A and FGF4 genes improves the recovery from acute limb ischemia

Journal of Angiogenesis Research

Jozef Dulak²  Alicja Jozkowicz²  Costanza Emanueli¹  Seppo Yla-Herttuala⁴  Mauro Giacca³  Lorena Zentilin³  Mateusz Stoszko²  Elisa Hytonen⁴  Hevidar M Taha²  Mateusz Tomczyk²  Agnieszka Jazwa² 

[1] Laboratory of Vascular Pathology and Regeneration, School of Clinical Sciences, Regenerative Medicine Section, University of Bristol, Bristol, UK;Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland;Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy;Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

关键词: VEGF-A;    FGF4;    Arteriogenesis;    Angiogenesis;    AAV;   

Others  :  801553
DOI  :  10.1186/2045-824X-5-13

 received in 2012-11-08, accepted in 2013-06-14,  发布年份 2013

【 摘 要 】

Background

Gene therapy stimulating the growth of blood vessels is considered for the treatment of peripheral and myocardial ischemia. Here we aimed to achieve angiogenic synergism between vascular endothelial growth factor-A (VEGF-A, VEGF) and fibroblast growth factor 4 (FGF4) in murine normoperfused and ischemic limb muscles.

Methods

Adeno-associated viral vectors (AAVs) carrying β-galactosidase gene (AAV-LacZ), VEGF-A (AAV-VEGF-A) or two angiogenic genes (AAV-FGF4-IRES-VEGF-A) were injected into the normo-perfused adductor muscles of C57Bl/6 mice. Moreover, in a different experiment, mice were subjected to unilateral hindlimb ischemia by femoral artery ligation followed by intramuscular injections of AAV-LacZ, AAV-VEGF-A or AAV-FGF4-IRES-VEGF-A below the site of ligation. Post-ischemic blood flow recovery was assessed sequentially by color laser Doppler. Mice were monitored for 28 days.

Results

VEGF-A delivered alone (AAV-VEGF-A) or in combination with FGF4 (AAV-FGF4-IRES-VEGF-A) increased the number of capillaries in normo-perfused hindlimbs when compared to AAV-LacZ. Simultaneous overexpression of both agents (VEGF-A and FGF4) stimulated the capillary wall remodeling in the non-ischemic model. Moreover, AAV-FGF4-IRES-VEGF-A faster restored the post-ischemic foot blood flow and decreased the incidence of toe necrosis in comparison to AAV-LacZ.

Conclusions

Synergy between VEGF-A and FGF4 to produce stable and functional blood vessels may be considered a promising option in cardiovascular gene therapy.

【 授权许可】

   
2013 Jazwa et al.; licensee BioMed Central Ltd.

【 图 表 】

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