Fibroblast growth factor‐4 induces vascular permeability, angiogenesis, and arteriogenesis in a rabbit hind limb ischemia model

Abstract

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.

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

“…Analysis of mammary glands from fgf4 transgenic mice confirmed preliminary in vitro data about the angiogenic properties of FGF4 mediated through VEGF-A upregulation [93]. The pro-angiogenic activity of FGF4 is confirmed by the angiogenic effect exerted by FGF4-encoding adenovirus in a rabbit hind limb ischemia model [94] and by FGF4-transfected endothelial cells in the CAM assay [11]. Intracoronary gene transfer of FGF5 increases blood flow and contractile function in ischemic heart possibly related to an increased vascularization [95].…”

“…The angiogenic potency of FGF4 and FGF5 was evaluated by gene therapy using an adenoviral vector in the rabbit hindlimb [94,245] and in the pig myocardium [246]. Adenovirus-delivered FGF4 was tested in two phase I clinical trials (AGENT and AGENT 2), involving patients with chronic stable angina.…”

A novel way of therapeutic angiogenesis using an adeno-associated virus-mediated angiogenin gene transfer

“…The purpose of this study was to establish a safe and effective gene therapeutic angiogenesis using the seldom-investigated AAV-mediated angiogenin (ANG1) gene transfer system, rAAV-ANG1 (Kastrup, 2003;Rissanen et al, 2003;Kim et al, 2004;Lee et al, 2005). We selected ANG1 as a potential therapeutic gene and AAV as a safer and effective gene delivery vector because of the following characteristics.…”

“…Since 1994, when the VEGF was first applied as a treatment for patients with peripheral vascular disease, VEGF and FGF have been most commonly applied to develop angiogenic gene therapy using various delivery vehicles. These studies showed positive effects for the promotion of neo-vascularisation (Kastrup, 2003;Rissanen et al, 2003;Kim et al, 2004;Lee et al, 2005). However, VEGF has mostly been either associated with stimulated angiogenesis in tumors, production of nonfunctional leaky vessels or used for enhancement of atherosclerotic plaque development through an increase in focal macrophage levels.…”

Cardiovascular gene delivery: The good road is awaiting☆

“…Many of the genes of the following proteins have been investigated as neovascularization therapies, including vascular endothelial growth factor (VEGF) [170], fibroblast growth factor-1 (FGF-1, or acidic FGF) [171], FGF-2 (also known as basic FGF) [172], FGF-4 [173], placental growth factor (PlGF) [174], angiotensin-1 (Ang-1) [175], and hepatic growth factor (HGF) [176]. Direct intramuscular or intravascular injection of genes for these proteins is able to restore blood flow in animal models of limb ischemia.…”