8 The resulting high-conductance vessels rapidly increase blood flow, unlike capillaries formed via angiogenesis or vasculogenesis. This process represents structural

remodeling of existing vessels, driven in part by changes in vessel shear stress, and is not simply a result of permanent vasodilation.9 The increase in shear stress activates endothelial cells to release factors Inhibitors,research,lifescience,medical that recruit monocytes to the collaterals. These monocytes produce the multiple mediators of arteriogenesis and induce inflammation.9 The local inflammatory environment plays an important role in providing signals vital to the enlargement of the collaterals. Similarly, inflammatory foci in tissues have been characterized by uncontrolled angiogenesis, and angiogenesis is important in the

spread of malignancy.10 Therapeutic angiogenesis for critical limb ischemia is delivered via gene vectors or Inhibitors,research,lifescience,medical cell implantation. Gene Therapy In vivo gene transfer techniques for vascular applications include 1) viral gene transfer: retrovirus, adenovirus, adeno-associated virus, or hemagglutinating virus of Japan (Sendai virus); 2) liposomal gene transfer using Inhibitors,research,lifescience,medical cationic liposomes; and 3) naked plasmid DNA transfer. Initially, single applications of therapy were the norm, but this has now changed to multiple applications over a 4- to 8-week interval to allow for continued priming of the area targeted for angiogenesis. Jeffrey Isner is credited with popularizing therapeutic angiogenesis with his group’s first trials using an isoform Inhibitors,research,lifescience,medical of vascular endothelial cell growth factor (VEGF165) on a plasmid. Table 1 shows the numerous patient series and controlled studies that have been performed in this area and the reported clinical outcomes demonstrating clinical efficacy for the treatment.11, 12 Since then, numerous angiogenic growth factors, such as VEGF121, VEGF-2, basic fibroblast growth factor (FGF), and hepatocyte growth factor Inhibitors,research,lifescience,medical (HGF) have been and continue to be tested

in clinical trials (Table 1). In addition to intramuscular injection of naked plasmid DNA, adenoviral delivery of angiogenic growth factors has also been used in these trials. Table 1 Results of gene therapy for critical limb ischemia. TRAFFIC: In the Therapeutic Angiogenesis Dacomitinib with Recombinant Fibroblast Growth Factor-2 (rFGR-2) for Intermittent Claudication (TRAFFIC) study,13 one or two doses of intra-arterial rFGF-2 were infused in 190 patients with intermittent claudication. Of those 190 patients, 174 reached the 90-day outcome mark, and they demonstrated an increase in walking time of 0.60 minutes with placebo, 1.77 minutes with a single dose, and 1.54 minutes with a double dose (P = 0.075). Intra-arterial rFGF-2 resulted in a significant increase in peak walking time at 90 days.