Therapeutic Angiogenesis Induced by Human Recombinant Hepatocyte Growth Factor in Rabbit Hind Limb Ischemia Model as Cytokine Supplement Therapy

Abstract

Abstract-Hepatocyte growth factor (HGF) exclusively stimulates the growth of endothelial cells without replication of vascular smooth muscle cells and acts as a survival factor against endothelial cell death. Therefore we hypothesized that a decrease in local vascular HGF might be related to the pathogenesis of peripheral arterial disease. We initially evaluated vascular HGF concentration in the vessels of patients with arteriosclerosis obliterans. Consistent with in vitro findings that hypoxia downregulated vascular HGF production, vascular HGF concentration in the diseased segments of vessels from patients with arteriosclerosis obliterans was significantly decreased as compared with disease-free segments from the same patients (PϽ0.05), accompanied by a marked reduction in HGF mRNA. On the other hand, a novel therapeutic strategy for ischemic diseases that uses angiogenic growth factors to expedite and/or augment collateral artery development has recently been proposed. Thus in view of the decreased endogenous vascular HGF, rhHGF (500 g/animal) was intra-arterially administered through the internal iliac artery of rabbits in which the femoral artery was excised to induce unilateral hind limb ischemia, to evaluate the angiogenic activity of HGF, which could potentially have a beneficial effect in hypoxia. Administration of rhHGF twice on days 10 and 12 after surgery produced significant augmentation of collateral vessel development on day 30 in the ischemic model as assessed by angiography (PϽ0.01). Serial angiograms revealed progressive linear extension of collateral arteries from the origin stem artery to the distal point of the reconstituted parent vessel in HGF-treated animals. In addition, we examined the feasibility of intravenous administration of rhHGF in a moderate ischemia model. Importantly, intravenous administration of rhHGF also resulted in a significant increase in angiographic score as compared with vehicle (PϽ0.01). Overall, a decrease in vascular HGF might be related to the pathogenesis of peripheral arterial disease. In the presence of decreased endogenous HGF, administration of rhHGF induced therapeutic angiogenesis in the rabbit ischemic hind limb model, as potential cytokine supplement therapy for peripheral arterial disease. (Hypertension. 1999;33:1379-1384.)

Hepatocyte growth factor secreted by cultured adipocytes promotes tube formation of vascular endothelial cells in vitro

“…27 Several recent studies have reported that HGF exhibits angiogenetic actions. Morishita et al 28 reported that treatment with human recombinant HGF improved hindlimb ischemia in rabbits. Human recombinant HGF has been applied in therapeutic angiogenesis, as a cytokine supplement for patients with arteriosclerosis obliterans.…”

NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells

“…Since previous (Paciucci et al, 1998) and our present results showed that production of HGF in pancreatic cancer cell lines is either undetectable or is low and that HGF mediated fibroblast-dependent invasion of pancreatic cancer cells, HGF is likely to be a stromal mediator which affects invasion and probably subsequent metastasis and dissemination of pancreatic cancer cells. Taken together with the notion that HGF is a potent inducer of angiogenesis (Bussolino et al, 1992;Van Belle et al, 1998;Morishita et al, 1999), the abrogation of functional association between HGF and the Met/HGF receptor would be considerable to suppress malignant behaviour of human pancreatic cancer cells.…”

Development of safe and efficient novel nonviral gene transfer using ultrasound: enhancement of transfection efficiency of naked plasmid DNA in skeletal muscle

“…12,42,43 Briefly, male New Zealand White rabbits (3.5 to 4.0 kg) (Kitayama Rabes, Kyoto, Japan) were used. Four separate injections of 250 g human HGF vector (total 1 mg) locally (intramuscularly into the pretibial muscle of ischemic limb) were performed approximately 2-4 cm below the skin.…”

“…12,42,43 Briefly, morphometric analysis of collateral vessel development in the ischemic limb was performed in 4-s angiograms recorded after injection of contrast medium into the internal iliac artery. A grid with 20-mm spaces was placed over the angiogram in the region of the medial thigh.…”

“…12,41,42 The wire was advanced via a 3-F infusion catheter positioned at the origin of the common iliac artery to the proximal segment of the iliac artery supplying the ischemic limb. Maximum APV (average peak velocity) was recorded at rest.…”