| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 2997062 | Journal of Vascular Surgery | 2008 | 9 Pages |
ObjectiveThis study examined the effect on neointimal hyperplasia of adenovirus-mediated delivery of cellular repressor of E1A-stimulated genes (CREG) to the artery after balloon injury.MethodsSixty rabbits were randomized into three groups and underwent balloon injury in the left common carotid arteries. The injured arterial segment was isolated by two inflated balloon catheters. Saline or recombinant adenovirus expressing CREG or green fluorescent protein was injected into the lumen of the isolated arterial segments and incubated for 30 minutes. The rabbits were euthanized for immunohistochemistry, Western blotting, and morphometric analysis at 3, 7, 14, and 28 days after balloon injury and in vivo gene transfer (5 rabbits for each time point). Common carotid artery angiography was performed before euthanasia.ResultsImmunohistochemistry and Western blot analysis demonstrated that CREG expression was significantly down-regulated in the acute phase of vascular injury and was gradually restored in the resolution phase. The changes of CREG expression were in parallel with those of the smooth muscle cell (SMC) differentiation markers SM α-actin and SM myosin heavy chain in the injured arteries. Adenovirus-mediated CREG transfer markedly increased CREG expression in the injured artery. Consequently, morphometric analysis revealed an approximate 50% reduction in the neointima and the intima/media ratio in CREG-transferred arteries compared with the saline and green fluorescent protein controls. Assay with 5-bromo-2-deoxyuridine showed that CREG transfer significantly inhibited SMC proliferation. In contrast, endothelialization of the injured artery was not affected by CREG transduction as assessed by CD31 immunostaining.ConclusionThese data suggest that forced expression of CREG in the artery wall after acute vascular injury inhibits SMC proliferation, induces cellular differentiation, and attenuates neointimal hyperplasia. CREG delivery may have therapeutic potential for the prevention of restenosis after vascular angioplasty.
Clinical RelevancePostinjury intimal hyperplasia and vascular restenosis remain unsolved problems in the treatment of occlusive vascular diseases. The dedifferentiation of smooth muscle cells in the arterial media and their subsequent migration to and proliferation in the intima are believed to be the main cause of neointimal hyperplasia. In the present study, we report that cellular repressor of E1A-stimulated genes (CREG), a secreted glycoprotein, is downregulated as smooth muscle cells switch from a quiescent, differentiated phenotype to a proliferative, immature phenotype in balloon-injured carotid artery. Adenovirus-mediated local CREG delivery to the injured artery inhibits smooth muscle cell dedifferentiation and proliferation and thus reduces neointimal formation. These results suggest that CREG is a potential candidate for the prevention of restenosis after vascular angioplasty.
