title: Efficacy of fragmin/protamine microparticles containing fibroblast growth factor-2 (F/P MPs/FGF-2) to induce collateral vessels in a rabbit model of hindlimb ischemia.
abstract: OBJECTIVE
  The localized delivery of exogenous, angiogenic growth factors such as fibroblast growth factor (FGF)-2 has become a promising alternative treatment of peripheral artery disease (PAD) and critical limb ischemia (CLI). The present study describes the efficacy of fragmin/protamine microparticles containing FGF-2 (F/P-MPs/FGF-2) to promote vessel growth in a rabbit model of hindlimb ischemia.
  
  
  METHODS
  A total of 24 rabbits were used to construct a model of hindlimb ischemia by resection of the left femoral artery. The rabbits were randomly divided into four groups 10 days after surgery (day 0); group A: control (non-treated; 1 mL of phosphate-buffered saline [PBS]); group B: FGF-2 (100 μg FGF-2 in 1 mL PBS)-treated; group C: F/P-MPs (12 mg dried F/P MPs in 1 mL PBS)-treated; and group D; F/P MPs/FGF-2 (100 μg FGF-2 and 12 mg dried F/P MPs in 1 mL PBS)-treated (n = 6 each). The drugs were administered intramuscularly to each group. Blood flow and blood pressure were measured in each group on days 0, 14, and 28. Angiography was performed to assess arteriogenesis on day 28. The number of capillaries on day 28 was determined by direct counting CD31(-) and α-smooth muscle antibody (α-SMA)-positive vessels.
  
  
  RESULTS
  Neither death nor wound infection was observed throughout the experiment. The F/P MPs/FGF-2-treated group showed marked improvement in the blood flow ratio, blood pressure ratio, and capillary number in comparison to the control group, FGF-2-treated group, and F/P MPs-treated group. The F/P MPs-treated group showed intermediate improvement in blood flow ratio and capillary number in comparison to the control group and FGF-2-treated group.
  
  
  CONCLUSIONS
  The F/P MPs/FGF-2-treated group strongly induced functional collateral vessels in the rabbit model of hindlimb ischemia, indicating a possible therapy for PAD.
authors.affiliation: Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Horio
authors.forename: Masanori
authors.initials: M
authors.lastname: Fujita
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ishihara
authors.forename: Satoko
authors.initials: S
authors.lastname: Kishimoto
authors.forename: Shingo
authors.initials: S
authors.lastname: Nakamura
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hase
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Maehara
mesh_terms: D000199:Actins / Q000378:metabolism; D000704:Analysis of Variance; D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry*; D001794:Blood Pressure / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002626:Chemistry, Pharmaceutical; D003097:Collateral Circulation / Q000187:drug effects*; D017985:Dalteparin / Q000737:chemistry*; D004195:Disease Models, Animal; D004337:Drug Carriers; D004339:Drug Compounding; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage* / Q000737:chemistry; D006494:Heparin Antagonists / Q000737:chemistry*; D006614:Hindlimb; D007150:Immunohistochemistry; D007273:Injections, Intramuscular; D007511:Ischemia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010316:Particle Size; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011479:Protamines / Q000737:chemistry*; D011817:Rabbits; D011859:Radiography; D012039:Regional Blood Flow / Q000187:drug effects; D013997:Time Factors
chemical_list: D000199:Actins; D043925:Angiogenesis Inducing Agents; D000925:Anticoagulants; D004337:Drug Carriers; D006494:Heparin Antagonists; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011479:Protamines; D016222:Fibroblast Growth Factor 2; D017985:Dalteparin