Stent-based controlled release of intravascular angiostatin to limit plaque progression and in-stent restenosis.
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.
Ganaha
Fumikiyo
F
Department of Cardiovascular and Interventional Radiology, Stanford University School of Medicine, 300 Pasteur Dr. H3648, Stanford, California, 94305, USA.
Kao
Edward Y
EY
Wong
Humberto
H
Elkins
Christopher J
CJ
Lee
Jane
J
Modanlou
Shoreh
S
Rhee
Ceron
C
Kuo
Michael D
MD
Yuksel
Eser
E
Cifra
Pamela N
PN
Waugh
Jacob M
JM
Dake
Michael D
MD
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
D020533:Angiogenesis Inhibitors; D020099:Coated Materials, Biocompatible; D005782:Gels; D043168:Angiostatins