Polymeric-based perivascular delivery of a nitric oxide donor inhibits intimal thickening after balloon denudation arterial injury: role of nuclear factor-kappaB.
OBJECTIVE
To examine the effect of a polymeric-based periadventitial delivery of a nitric oxide (NO)-releasing diazeniumdiolate, spermine/NO (SPER/NO), on balloon injury-induced neointimal hyperplasia in rat ileofemoral arteries.


BACKGROUND
Reduced local bioavailability and adverse side effects limit systemic administration of NO to modulate vascular response to injury.


METHODS
A polylactic-polyglycolic acid polymeric matrix containing 2.5% SPER/NO (w/w) was applied around the injured arteries. Quantitative histomorphometry was performed at day 14, proliferating cell nuclear antigen (PCNA) immunohistochemistry at day 3 to assess effects on smooth muscle proliferation and electrophoretic mobility shift assay to evaluate effects on transcription factor, nuclear factor-kappaB (NF-kappaB).


RESULTS
Treatment with SPER/NO reduced the intimal area (0.011 +/- 0.009 vs. 0.035 +/- 0.006 mm2 control, p < 0.01) and the intima to media ratio (0.089 +/- 0.062 vs. 0.330 +/- 0.057 control, p < 0.005). Spermine/nitric oxide produced a profound inhibition of PCNA-positive cells (>75%, p < 0.005) and significantly suppressed the injury-induced activation of NF-kappaB. Vascular cyclic guanosine monophosphate (cGMP) levels were elevated after treatment with the SPER/NO (0.28 +/- 0.03 vs. 0.17 +/- 0.02 pmol/mg tissue control, p < 0.01). The inhibitory effects on neointimal proliferation were localized to the site of application of SPER/NO and were not associated with any changes in platelet aggregation or bleeding time. Neither SPER nor polymer alone had any significant effects on any of the variables examined.


CONCLUSIONS
Polymeric-based perivascular delivery of a NO donor produces a marked localized inhibition of neointimal proliferation in balloon-injured arteries. This phenomenon is associated with suppression of NF-kappaB activation and elevation of the vascular cGMP at the site of injury.
Kaul
S
S
Burns and Allen Research Institute and the Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. Kaul@cshs.org
Cercek
B
B
Rengstrom
J
J
Xu
X P
XP
Molloy
M D
MD
Dimayuga
P
P
Parikh
A K
AK
Fishbein
M C
MC
Nilsson
J
J
Rajavashisth
T B
TB
Shah
P K
PK
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D001760:Bleeding Time; D002455:Cell Division / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D016503:Drug Delivery Systems; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D019344:Lactic Acid; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D010974:Platelet Aggregation; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013096:Spermine / Q000008:administration & dosage*; D017539:Tunica Intima / Q000187:drug effects* / Q000293:injuries / Q000473:pathology
D016328:NF-kappa B; D011108:Polymers; D018809:Proliferating Cell Nuclear Antigen; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D013096:Spermine; D009569:Nitric Oxide; D019344:Lactic Acid; D006152:Cyclic GMP