Fibroblast growth factor 4 induces vascular permeability, angiogenesis and arteriogenesis in a rabbit hindlimb ischemia model.
Previous studies have shown that fibroblast growth factor (FGF)-1, FGF-2, and FGF-5 induce therapeutic angiogenesis. Here, we investigated the potential of FGF-4 for therapeutic neovascularization in comparison to vascular endothelial growth factor (VEGF), using adenoviral gene transfer in a novel rabbit hind limb ischemia model, with ischemia restricted to the calf. Magnetic resonance imaging and a modified Miles assay showed that both AdFGF-4 and AdVEGF given intramuscularly (i.m.) resulted in increases in vascular permeability and edema in transduced muscles 6 days after the gene transfer. In contrast, recombinant FGF-4 protein injected in the rabbit skin did not induce acute vascular permeability. Injections (i.m.) of AdFGF-4 and AdVEGF, but not intra-arterially administered AdVEGF, increased collateral growth, popliteal blood flow, and muscle perfusion compared with controls. The angiogenesis response consisted mainly of the enlargement of pre-existing vessels rather than an increase in capillary density. Adenoviral FGF-4 overexpression up-regulated endogenous VEGF, which may explain many of the effects thought to be specific for VEGF such as the increase in vascular permeability. This study demonstrates for the first time that FGF-4 induces vascular permeability, therapeutic angiogenesis, and arteriogenesis comparable to that of VEGF and could be useful for the treatment of peripheral vascular disease.
Rissanen
Tuomas T
TT
Department of Molecular Medicine, A.I. Virtanen Institute, Kuopio University, Finland.
Markkanen
Johanna E
JE
Arve
Katja
K
Rutanen
Juha
J
Kettunen
Mikko I
MI
Vajanto
Ismo
I
Jauhiainen
Suvi
S
Cashion
Linda
L
Gruchala
Marcin
M
Närvänen
Outi
O
Taipale
Pekka
P
Kauppinen
Risto A
RA
Rubanyi
Gabor M
GM
Ylä-Herttuala
Seppo
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001158:Arteries / Q000254:growth & development*; D002196:Capillaries / Q000166:cytology / Q000254:growth & development; D002199:Capillary Permeability; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003097:Collateral Circulation; D004487:Edema / Q000209:etiology / Q000473:pathology; D016228:Endothelial Growth Factors / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000494:pharmacology; D005822:Genetic Vectors; D006614:Hindlimb / Q000098:blood supply; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007511:Ischemia / Q000473:pathology / Q000628:therapy*; D008222:Lymphokines / Q000235:genetics; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000494:pharmacology; D011817:Rabbits; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D051519:Fibroblast Growth Factor 4; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D005346:Fibroblast Growth Factors