Intimal hyperplasia is a normal adaptive response
of arteries against hemodynamic stress and also is
an exaggerated healing process after arterial injuries
such as bypass grafting, endarterectomy, and balloon
angioplasty with or without stenting. Neointimal
hyperplasia develops through a complex process
including platelet aggregation, leukocyte chemotaxis,
VSMC proliferation and migration, ECM alterations,
and endothelial cell proliferation.[
10]
The intimal response that develops after arterial
damage is observed in three stages. Smooth muscle
cell proliferation begins in the first 24 hours.
After endothelium damage develops, the damaged
area is coated with platelets. Following adhesion,
platelets release vasoactive and thrombotic factors
in their granules (serotonin, adenosine diphosphate,
fibrinogen, and Von Willebrand factor) and release
growth factors (PDGF, transforming growth factor,
and epidermal growth factor). Mitogenic growth
factors initiate the proliferation of smooth muscle
cells. Proliferated smooth muscle cells in the media
layer migrate to the intima and lead to intimal
hyperplasia. On Days 3 and 14, these smooth muscle
cells migrate to the intima, and neointima and
neointimal hyperplasia develop. In the third stage,
smooth muscle cells create a layer that results in the
narrowing of the vessel lumen rapidly.[11,12]
Cilostazol has many pharmacological effects
including vasodilation, inhibition of platelet activation
and aggregation, thrombosis inhibition, increased
blood flow to the limbs, improvement in serum lipids
with the reduction of triglycerides and elevation
of high-density lipoprotein cholesterol, and VSMC
growth inhibition.[13] Owing to these effects,
cilostazol is used to reduce the risk of restenosis and
repeat revascularization after percutaneous coronary
interventions.[14]
Cilostazol is used for the treatment of peripheral
arterial occlusive disease by oral delivery.[15] Systemic
administration of cilostazol at 30 mg/kg per oral
twice per day was reported to inhibit neointimal
formation in balloon-injured rat carotid arteries by
32%.[16]
In a study, Yamamoto et al.[17] showed that locally
applied cilostazol inhibited neointimal hyperplasia
and medial thickening in a vein graft model. A 1-cm
segment of the right femoral vein was harvested
and transplanted into the abdominal aorta in an
end-to-end fashion. In the cilostazol-treated group,
rats with the anastomotic stricture received a topical
application of 20 mg of cilostazol dissolved in 200 µL
of dimethyl sulfoxide containing 25% Pluronic® gel
(Letco Medical, Decatur, AL, USA) around the
interposed graft. The rats in the control group
received the dimethyl sulfoxide Pluronic® gel without
cilostazol. The effectiveness of cilostazol applied
locally to implanted vein grafts was demonstrated in
suppressing neointimal hyperplasia in this rat model.
Bilateral reversed jugular vein interposition grafts
of the common carotid artery were performed in
12 Beagle dogs. Starting from seven days before
surgery, either cilostazol (30 mg/day; n=6) or a placebo
(n=6) was given orally twice daily. Vein grafts were
harvested at Week 1 or Week 4. At Week 1 after
implantation, the cilostazol group showed significantly
less cell proliferation than the placebo group. At Week
4 after implantation, the intimal and medial thickness
was significantly thinner in the cilostazol group than
in the placebo group.[18]
Cilostazol is an agent with a pleiotropic mechanism
of action and multiple beneficial effects through
a combination of vasodilation, platelet inhibition,
antiproliferative effect, and lipid-lowering properties.
Based on these properties, cilostazol has shown
promising effects in the management of atherosclerotic
vascular disease in coronary, cerebrovascular, and
peripheral arteries.[19]
The primary limitation of our study was the lack of
molecular data. In the future, we plan to perform a study
on a higher budget and include immunohistochemistry
data and oxidative stress parameters.
In conclusion, our study results showed that
reduction in the lumen area and diameter after
anastomosis were significantly improved in the
cilostazol group compared to the control group. The
area of intima and intima/media ratio was smaller
in the cilostazol group compared to those in the
control group, and the difference was statically
significant. The medial area of the cilostazol group
was significantly higher than the control group.
Based on these findings, cilostazol may be useful for preventing intimal hyperplasia and smooth muscle
cell proliferation after vascular surgery.
Ethics Committee Approval: The study protocol was
approved by the Dokuz Eylül University Faculty of Medicine
Ethics Committee (date: 16.12.2011, no: 69/2011). The
study was conducted in accordance with the principles of the
Declaration of Helsinki.
Data Sharing Statement: The data that support the
findings of this study are available from the corresponding
author upon reasonable request.
Author Contributions: Idea/concept, design, critical
review: A.C.E.; Data collection and/or processing, writing
the article, control/supervision: Ç.B.; Literature review,
analysis and/or interpretation, writing the article: U.K.
Conflict of Interest: The authors declared no conflicts
of interest with respect to the authorship and/or publication
of this article.
Funding: The authors received no financial support for
the research and/or authorship of this article.
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