Enhanced angiogenesis and growth of collaterals by in vivo administration of recombinant basic fibroblast growth factor in a rabbit model of acute lower limb ischemia: Dose-response effect of basic fibroblast growth factor

Abstract

The purpose of this study was to evaluate the effects of exogenous recombinant basic fibroblast growth factor (bFGF) on angiogenesis in severely ischemic tissue beds. We used a two-stage procedure to produce severe ischemia of the hindlimb of 34 New Zealand rabbits. The ischemic hindlimb received intramuscular injection of saline (group A), 1 microgram bFGF (group B), or 3 micrograms bFGF (group C), daily for 2 weeks. Tissue perfusion, skeletal muscle infarction, angiogenesis, and collateral growth were assessed by angiography, transcutaneous oximetry (TcPO2), quantitative spectrophotometric assay of triphenyltetrazolium chloride reduction in muscle, capillary density (capillaries per square millimeter), and capillary per muscle fiber ratio. There were no significant differences in baseline TcPO2 among the three groups for both thigh and calf measurements. Angiography revealed extensive perfusion of the left hindlimb in all the assessed bFGF treated animals. Both thigh and calf TcPO2 values showed a significant increase in all groups over the 14 days ischemia was induced (p less than 0.0001), but the two treatment groups exhibited a much more rapid rise in TcPO2 than the control group (p less than 0.0001). The capillaries per square millimeter and capillaries per muscle fiber ratios were significantly increased in all posttreatment measurements for all animals that received bFGF. The treatment groups with bFGF had a significant (p = 0.025) increase in thigh muscle viability compared with controls based on triphenyltetrazolium chloride reduction. Whereas there was evidence of muscle infarction in both the thighs of groups A and B, there was none in group C.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiogenesis induced in muscle by a recombinant adenovirus expressing functional isoforms of basic fibroblast growth factor

“…24,25 Basic FGF treatment of acute ischemic hindlimbs in rabbit or rat models using arterial ligation enhances angiogenesis, collateral vessel development, and muscle function. 26 The first clinical treatment with the bFGF protein resulted in myocardial revascularization in ischemic myocardium of patients with coronary disease. 9 In this report, we demonstrated by Western blot analysis and ELISA that at least three of the different isoforms of human bFGF (18K, 22.5K and 24-25K) are correctly expressed in different cell lines of various tissue origins after adenovirus-mediated gene transfer.…”

Efficacy of intracoronary versus intravenous FGF-2 in a pig model of chronic myocardial ischemia

“…FGF-2 stimulates endothelial cell proliferation, migration, and vascular tube formation in three-dimensional cultures in collagen [9] as well as angiogenesis in an in vivo Matrigel pellet assay [10]. The angiogenic efficacy of FGF-2 was confirmed in numerous animal models [11,12]. Although the first phase I clinical trial has shown the safety of intracoronary FGF-2 over a wide range of dosages [3], the optimal dose regimen and delivery strategy for efficacy with respect to cardiac angiogenesis have not been established yet.…”

Delivery of FGF-2 but not VEGF by encapsulated genetically engineered myoblasts improves survival and vascularization in a model of acute skin flap ischemia

“…Gene Therapy (2001) 8, 523-533. dial and limb ischemia. [4][5][6][7][8] In light of these results, clinicians have begun evaluating the therapeutic potential of various angiogenic factors in patients. 9 The recent failure of a clinical trial targeting the ischemic heart, where recombinant VEGF 165 protein was administered by a combination of intercoronary and intravenous injections, 10 has highlighted the need for alternative methods of delivering angiogenic factors in a chronic and sitespecific manner.…”