Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model.

Abstract

Vascular endothelial growth factor (VEGF) is a heparin-binding, endothelial cell-specific mitogen. Previous studies have suggested that VEGF is a regulator ofnaturally occurring physiologic and pathologic angiogenesis. In this study we investigated the hypothesis that the angiogenic potential of VEGF is sufficient to constitute a therapeutic effect. The soluble 165-amino acid isoform ofVEGF was administered as a single intraarterial bolus to the internal iliac artery of rabbits in which the ipsilateral femoral artery was excised to induce severe, unilateral hind limb ischemia. Doses of 500-1,090 0,g of VEGF produced statistically significant augmentation of collateral vessel development by angiography as well as the number of capillaries by histology; consequent amelioration of the hemodynamic deficit in the ischemic limb was significantly greater in animals receiving VEGF than in nontreated controls (calf blood pressure ratio, 0.75±0.14 vs. 0.48±0.19, P < 0.05). Serial angiograms disclosed progressive linear extension of the collateral artery of origin (stem artery) to the distal point of parent vessel (reentry artery) reconstitution in seven of nine VEGF-treated animals. These findings establish proof of principle for the concept that the angiogenic activity of VEGF is sufficiently potent to achieve therapeutic benefit. Such a strategy might ultimately be applicable to patients with severe limb ischemia secondary to arterial occlusive disease. (J. Clin. Invest. 1994. 93:662-670.)

Adenovirus-mediated ex vivo gene transfer of basic fibroblast growth factor promotes collateral development in a rabbit model of hind limb ischemia

“…In the direct application method for recombinant growth factor protein, an intra-arterial catheter was the major delivery device. 4,5,8 In contrast, it is complicated to apply naked DNA to the myocardium by intramuscular injection. Losordo et al 14 injected naked DNA of VEGF into the ventricular wall via mini-thoracotomy.…”

“…5 Many recent studies, however, selected VEGF as an angiogenic growth factor to induce collateral vessels in ischemic tissue. Isner and colleagues 4,7,8,17 presented several studies using VEGF in a rabbit model of hind limb ischemia and also in clinical trial, and showed favorable effects in improvement of the ischemic state. One reason for using VEGF is that VEGF receptors are upregulated on endothelial cells of newly formed blood vessels in vivo.…”

“…3,4 Vasculogenesis, angiogenesis and arteriogenesis are known to be promoted by some growth factors, such as bFGF and vascular endothelial growth factor (VEGF). 2 In order to develop a therapy to enhance collateral development, these growth factors have been tested in vivo with several delivery techniques.…”

“…2 In order to develop a therapy to enhance collateral development, these growth factors have been tested in vivo with several delivery techniques. [4][5][6][7] Direct administration of growth factor protein was initially investigated in animal models of ischemia, which showed significant development of collateral vessels and improvement of the ischemic state. 4,5,8 However, high-dose bolus delivery has a high potential risk of systemic toxicity through cytokine diffusion into the systemic circulation.…”

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

“…This is supported by numerous studies employing VEGF administered either as a recombinant protein or as plasmid DNA, in which a significant induction of angiogenesis is observed only 20 to 30 days following treatment. 20,[49][50][51] There is also the possibility that the doses of VEGF administered were too low. Appropriate therapeutic dosing of VEGF has become an issue of some concern.…”