Therapeutic angiogenesis induced by human hepatocyte growth factor gene inrat and rabbit hindlimb ischemia models: preclinical study for treatment of peripheral arterial disease
Y. Taniyama et al., Therapeutic angiogenesis induced by human hepatocyte growth factor gene inrat and rabbit hindlimb ischemia models: preclinical study for treatment of peripheral arterial disease, GENE THER, 8(3), 2001, pp. 181-189
Hepalocyte growth factor (HGF) exclusively stimulates the growth of endothe
lial cells without replication of vascular smooth muscle cells, and acts as
a survival factor against endothelial cell death. Recently, a novel therap
eutic strategy for ischemic diseases using angiogenic growth factors to exp
edite and/or augment collateral artery development has been proposed. We ha
ve previously reported that intraarterial administration of recombinant HGF
induced angiogenesis in a rabbit hindlimb ischemia model. In this study, w
e examined the feasibility of gene therapy using HGF to treat peripheral ar
terial disease rather than recombinant therapy, due to its disadvantages. I
nitially, we examined the transfection of 'naked' human HGF plasmid into a
rat hindlimb ischemia model. Intramuscular injection of human HGF plasmid r
esulted in a significant increase in blood flow as assessed by laser Dopple
r imaging, accompanied by the detection of human HGF protein. A significant
increase in capillary density was found in rats transfected with human HGF
as compared with control vector, in a dose-dependent manner (P < 0.01). Im
portantly, at 5 weeks after transfection, the degree of angiogenesis induce
d by transfection of HGF plasmid was significantly greater than that caused
by a single injection of recombinant HGF. As an approach to human gene the
rapy, we also employed a rabbit hindlimb ischemia model as a preclinical st
udy. Naked HGF plasmid was intramuscularly injected in the ischemic hindlim
b of rabbits, to evaluate its angiogenic activity. Intramuscular injection
of HGF plasmid once on day 10 after surgery produced significant augmentati
on of collateral vessel development on day 30 in the ischemia model, as ass
essed by angiography (P < 0.01). Serial angiograms revealed progressive lin
ear extension of collateral arteries from the origin stem artery to the dis
tal point of the reconstituted parent vessel in HGF-transfected animals. In
addition, a significant increase in blood flow was assessed by a Doppler f
low wire and the ratio in blood pressure of the ischemic limb to the normal
limb was observed in rabbits transfected with HGF plasmid as compared with
rabbits transfected with control vector (P < 0.01). Overall, intramuscular
injection of naked human HGF plasmid induced therapeutic angiogenesis in r
at and rabbit ischemic hindlimb models, as potential therapy for peripheral
arterial disease.