Human FGF-1 gene transfer promotes the formation of collateral vessels and arterioles in ischemic muscles of hypercholesterolemic hamsters.
BACKGROUND
Acidic fibroblast growth factor (FGF-1) has been identified as a potent mitogen for vascular cells, inducing formation of mature blood vessels in vitro and in vivo and represents one of the most promising approaches for the treatment of ischemic cardiovascular diseases by gene therapy. Nevertheless, and most probably due to the few experimental models able to address the issue, no study has described the therapeutic effects of FGF-1 gene transfer in subjects with peripheral arterial disease (PAD) exhibiting a clinically relevant cardiovascular pathology.


METHODS
In order to assess the potency of FGF-1 gene transfer for therapeutic angiogenesis in ischemic skeletal muscles displaying decreased gene expression levels and sustained impaired formation of collateral vessels and arterioles, we developed a model of PAD in hamsters with a background of hypercholesterolemia. Hamsters fed a cholesterol-rich diet and subjected to hindlimb ischemia exhibit a sustained impaired angiogenic response, as evidenced by decreased angiographic score and histological quantification of arterioles in the ischemic muscles.


RESULTS
In this model, we demonstrate that NV1FGF (a human FGF-1 expression plasmid), given intramuscularly 14 days after induction of hindlimb ischemia, promoted the formation of both collateral vessels and arterioles 14 days after treatment (i.e. 28 days post-ischemia).


CONCLUSIONS
Our data provide evidence that NV1FGF can reverse the cholesterol-induced impairment of revascularization in a hamster model of hindlimb ischemia by promoting the growth of both collateral vessels and arterioles in ischemic muscles exhibiting significantly decreased levels of gene expression compared with control muscles. Therefore, this study underscores the relevance of NV1FGF gene therapy to overcome perfusion defects in patients with PAD.
Caron
Alexis
A
Gencell S.A.S., Vitry-sur-Seine, France. Alexis.Caron@gencell.com
Michelet
Sandrine
S
Caron
Anne
A
Sordello
Sylvie
S
Ivanov
Marie-Agnès
MA
Delaère
Pia
P
Branellec
Didier
D
Schwartz
Bertrand
B
Emmanuel
Florence
F
D000818:Animals; D001160:Arterioles / Q000254:growth & development; D003097:Collateral Circulation / Q000502:physiology; D006224:Cricetinae; D004195:Disease Models, Animal; D016220:Fibroblast Growth Factor 1 / Q000235:genetics* / Q000627:therapeutic use; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D006937:Hypercholesterolemia / Q000150:complications; D007511:Ischemia / Q000628:therapy*; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D016491:Peripheral Vascular Diseases / Q000150:complications / Q000628:therapy*; D010957:Plasmids / Q000235:genetics / Q000627:therapeutic use
D016220:Fibroblast Growth Factor 1