Abstract
BackgroundGene 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.MethodsAdeno-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.ResultsVEGF-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.ConclusionsSynergy between VEGF-A and FGF4 to produce stable and functional blood vessels may be considered a promising option in cardiovascular gene therapy.
Highlights
Cardiovascular diseases constitute the major cause of morbidity and mortality
Synergy between Vascular endothelial growth factor-A (VEGF-A) and fibroblast growth factor 4 (FGF4) to produce stable and functional blood vessels may be considered a promising option in cardiovascular gene therapy
In this paper we described the effects of intramuscular injections of VEGF-A gene, delivered either separately or in combination with FGF4 coding sequence in adeno-associated viral vectors (AAV), on endothelial cells (ECs) proliferation, mural cell recruitment and post-ischemic blood flow recovery
Summary
Vascular endothelial growth factor-A (VEGF-A, VEGF) is a critical regulator of angiogenesis that stimulates proliferation, migration, and proteolytic activity of endothelial cells (ECs) and is one of the well-studied factors for therapeutic angiogenesis for post-ischemic vascular repair [ 2]. The lack of expected benefits of VEGF-A therapy in humans suggests that the stimulation of therapeutic angiogenesis for the treatment of cardiac or limb ischemia with only one growth factor may be insufficient [ 8]. Gene therapy stimulating the growth of blood vessels is considered for the treatment of peripheral and myocardial ischemia. 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
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