title: Stent-based controlled release of intravascular angiostatin to limit plaque progression and in-stent restenosis.
abstract: OBJECTIVE
  To evaluate the importance of angiogenesis in plaque progression after stent placement, this study examines stent-based controlled delivery of the antiangiogenic agent, angiostatin, in a rabbit model.
  
  
  METHODS
  Controlled release biodegradable microspheres delivering angiostatin or polymer-only microspheres (polylactic-co-glycolic-acid-polyethylene glycol; PLGA/PEG) were loaded in channeled stents, anchored, and deployed in the aorta of adult New Zealand white rabbits (n = 6 animals per group, three each per time point). The stented aortas were harvested at 7 days and 28 days and evaluated for neovascularization, local inflammation, vascular smooth muscle cell proliferation, and in-stent plaque progression.
  
  
  RESULTS
  At 7 days, neovascularization was significantly decreased in the angiostatin groups (1.6 +/- 1.6 neovessels per mm(2) plaque) versus the control group (15.4 +/- 2.6 neovessels per mm(2) plaque; P =.00081), as were local inflammation where angiostatin-treated groups demonstrated significantly lower macrophage recruitment per cross section (34.9 +/- 4.9 cells per cross section) relative to the control group (55.2 +/- 3.84 cells per cross section; P =.0037). And a significant decrease in the overall vascular smooth muscle cell proliferation (143.8 +/- 26.3 Ki-67 positive cells per mm(2)) relative to the control group (263.2 +/- 16.6 Ki-67 positive cells per mm(2); P =.00074). At both 7 and 28 days, in-stent plaque progression in the angiostatin groups was successfully limited relative to the control group by 54% (0.255 +/- 0.019% of cross section; P =.00016) and 19% (1.981 +/- 0.080; P =.0033) respectively and resulted in reduction of in-stent restenosis relative to the control group.
  
  
  CONCLUSIONS
  Angiostatin-eluting stents may limit neovascularity after arterial implantation, offer insight into in-stent restenosis, and allow future refinement of bioactive stent designs and clinical strategies, particularly in light of evidence that intimal smooth muscle cells may in part be marrow-derived.
authors.affiliation: Department of Cardiovascular and Interventional Radiology, Stanford University School of Medicine, 300 Pasteur Dr. H3648, Stanford, California, 94305, USA.
authors.forename: Fumikiyo
authors.initials: F
authors.lastname: Ganaha
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Kao
authors.forename: Humberto
authors.initials: H
authors.lastname: Wong
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Elkins
authors.forename: Jane
authors.initials: J
authors.lastname: Lee
authors.forename: Shoreh
authors.initials: S
authors.lastname: Modanlou
authors.forename: Ceron
authors.initials: C
authors.lastname: Rhee
authors.forename: Michael D
authors.initials: MD
authors.lastname: Kuo
authors.forename: Eser
authors.initials: E
authors.lastname: Yuksel
authors.forename: Pamela N
authors.initials: PN
authors.lastname: Cifra
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Waugh
authors.forename: Michael D
authors.initials: MD
authors.lastname: Dake
mesh_terms: D000704:Analysis of Variance; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D043168:Angiostatins / Q000008:administration & dosage*; D000818:Animals; D001012:Aorta, Abdominal / Q000473:pathology; D001157:Arterial Occlusive Diseases / Q000473:pathology*; D020099:Coated Materials, Biocompatible; D005782:Gels; D006083:Graft Occlusion, Vascular / Q000517:prevention & control*; D008297:Male; D008863:Microspheres; D011817:Rabbits; D015607:Stents
chemical_list: D020533:Angiogenesis Inhibitors; D020099:Coated Materials, Biocompatible; D005782:Gels; D043168:Angiostatins