Decellularized porcine aortic intima-media as a potential cardiovascular biomaterial.

OBJECTIVES: The aim of this research is to investigate the histological and mechanical properties of decellularized aortic intima-media, a promising cardiovascular biomaterial. METHODS: Porcine aortic intima-media was decellularized using two methods: high hydrostatic pressurization (HHP) and sodium dodecyl sulphate (SDS). The histological properties were characterized using haematoxylin and eosin staining and Elastica van Gieson staining. The mechanical properties were evaluated using a tensile strength test. RESULTS: The structure of the HHP-treated samples was unchanged histologically, whereas that of the SDS-treated samples appeared structurally loose. Consequently, with regard to the mechanical properties of SDS-decellularized intima-media, elastic modulus and tensile strength were significantly decreased. CONCLUSIONS: The decellularization method affected the structure and the mechanical properties of the biomaterial. The HHP-treated sample was structurally and mechanically similar to the untreated control. Its mechanical properties were similar to those of human heart valves and the iliac artery and vein. Our results imply that porcine aortic intima-media that is decellularized with HHP is a potential cardiovascular biomaterial.

Blood vessel-derived acellular matrix for vascular graft application.

To overcome the issues connected to the use of autologous vascular grafts and artificial materials for reconstruction of small diameter (<6 mm) blood vessels, this study aimed to develop acellular matrix- (AM-) based vascular grafts. Rat iliac arteries were decellularized by a detergent-enzymatic treatment, whereas endothelial cells (ECs) were obtained through enzymatic digestion of rat skin followed by immunomagnetic separation of CD31-positive cells. Sixteen female Lewis rats (8 weeks old) received only AM or previously in vitro reendothelialized AM as abdominal aorta interposition grafts (about 1 cm). The detergent-enzymatic treatment completely removed the cellular part of vessels and both MHC class I and class II antigens. One month after surgery, the luminal surface of implanted AMs was partially covered by ECs and several platelets adhered in the areas lacking cell coverage. Intimal hyperplasia, already detected after 1 month, increased at 3 months. On the contrary, all grafts composed by AM and ECs were completely covered at 1 month and their structure was similar to that of native vessels at 3 months. Taken together, our findings show that prostheses composed of AM preseeded with ECs could be a promising approach for the replacement of blood vessels.

Ezetimibe reduces intimal hyperplasia in rabbit jugular vein graft.

BACKGROUND: The selective cholesterol transport inhibitor ezetimibe is widely used to prevent development of atherosclerosis in patients with hypercholesterolemia. However, whether this agent inhibits intimal hyperplasia in autologous vein grafts is unknown. The present study was undertaken to clarify if ezetimibe reduces cell proliferation and intimal hyperplasia in vein grafts. METHODS: Forty-four rabbits were randomly divided into two groups: one group received ezetimibe (0.6 mg/kg/d), and the control group did not. Ezetimibe administration was started 1 week before rabbits underwent interposition reversed autologous jugular vein grafts. The proliferative cells and apoptotic cells were counted in the vein grafts 14 days after implantation, and changes in acetylcholine-induced relaxation and endothelial intracellular concentration of Ca2+ ([Ca2+]i) were examined at 28 days. RESULTS: Ezetimibe reduced serum cholesterol and triglyceride. There were fewer proliferating cells in the ezetimibe group (5.7%±0.2%, n=7) than in the control group (12.8%±0.5%, n=7; P<.0001) and more apoptotic cells in the ezetimibe group (5.3%±0.2%, n=7) than in the control group (2.3%±0.2%, n=7; P<.0001). Intimal hyperplasia was less in the ezetimibe group (46.1±6.0 µm, n=7) than in the control group (76.0±2.5 µm, n=7; P<.01). Acetylcholine-produced endothelium-dependent relaxation was observed only in the ezetimibe group, which was blocked by the nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine. Acetylcholine increased [Ca2+]i only in the ezetimibe group. CONCLUSIONS: Ezetimibe reduced cell proliferation and enhanced cell apoptosis, thus inhibiting intimal hyperplasia in rabbit autologous vein grafts. Ezetimibe restored the acetylcholine-induced increase in [Ca2+]i in endothelial cells and improved endothelium-dependent NO-mediated relaxation in the vein graft. Our results suggest that ezetimibe enhances the function of endothelial NO through an increase in endothelial [Ca2+]i, thus reducing vein graft intimal hyperplasia.

FSP-1 silencing in bone marrow cells suppresses neointima formation in vein graft.

RATIONALE: Fibroblast-specific protein 1 (FSP-1) plays multiple roles in promoting cell proliferation and motility. Increased FSP-1 expression in smooth muscle cells (SMCs) has been associated with their enhanced proliferation. OBJECTIVE: To study how FSP-1 contributes to neointima formation of vein grafts. METHODS: Arteriovenous grafts were created in wild-type or FSP-1-GFP mice (green fluorescent protein expression regulated by FSP-1 promoter). The effects of FSP-1 on bone marrow (BM) cell migration and on SMC proliferation were studied in vivo and in vitro. RESULTS: On creation of a vein graft, there was rapid deposition of platelets on the denuded surface leading to secretion of the chemokine stromal cell-derived factor-1α (SDF-1α). This was followed by recruitment of BM-derived cells expressing the SDF-1α receptor CXCR4; homing of FSP-1-positive cells was found to be dependent on platelet-derived SDF-1α. FSP-1 was expressed in 8% of the BM cells, and 20% of these express CD45; 85% of FSP-1-positive cells express CD11b. We found that the FSP-1-positive cells migrated into the vein graft in a Rac-1-dependent fashion. FSP-1 expression was also found to stimulate proliferation of SMCs through a MEK5-ERK5 signaling pathway that can be suppressed by a dominant-negative Rac1. Consequently, knocking down FSP-1 expression in BM cells prevented neointimal formation. CONCLUSIONS: BM-derived FSP-1(+) cells enhance neointima formation through an increase in transendothelial invasion with stimulation of SMC proliferation. The Rac1 and ERK5 signaling cascade mediate FSP-1-induced responses in SMCs and BM cells. This novel pathophysiology suggests a new therapeutic target, FSP-1, for preventing the development of neointima in vein grafts.

Rapamycin-loaded nanoparticles for inhibition of neointimal hyperplasia in experimental vein grafts.

BACKGROUND: Nanoparticles (NPs) possess several advantages as a carrier system for intracellular delivery of therapeutic agents. Rapamycin is an immunosuppressive agent which also exhibits marked antiproliferative properties. We investigated whether rapamycin-loaded NPs can reduce neointima formation of vein graft disease in a rat model. METHODS: Poly(lactic-co-glycolic acid) (PLGA) NPs-containing rapamycin was prepared using an oil/water solvent evaporation technique. The size and morphology of the NP were determined by dynamic light scattering methodology and electron microscopy. In vitro cytotoxicity of blank, rapamycin-loaded PLGA NPs was studied using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Excised rat jugular vein was treated ex vivo with blank NPs, or rapamycin-loaded NPs, and then interposed back into the carotid artery position using a cuff technique. Grafts were harvested for 21 days and subjected to morphometric analysis as well as immunohistochemical analysis and Western blotting. RESULTS: Rapamycin was efficiently loaded in PLGA NPs with an encapsulation efficiency of 87.6%. The average diameter of NPs was 180.3 nm. The NPs-containing rapamycin at 1 ng/mL significantly inhibited vascular smooth muscular cells proliferation. Measurement of rapamycin levels in vein grafts showed that the concentration of rapamycin in vein grafts at 3 weeks after grafting was 0.9 ± 0.1 µg/g. In grafted veins without treatment, intima-media thickness was 300.4 ± 181.5 µm at 21 days after grafting, whereas veins treated with rapamycin-loaded NPs showed a reduction of intimal-media thickness of 150.2 ± 62.5 µm (p = 0.001). Cell proliferation was measured by proliferating cell nuclear antigen immunohistochemistry staining. As expected, proliferating cell nuclear antigen index declined from 83.4% ± 7.4% to 66.2% ± 4.5% in vein grafts after 3 weeks (p = 0.002). Platelet endothelial cell adhesion molecule (PECAM-1/CD31) staining was used to measure luminal endothelial coverage in grafts and indicated a high level of endothelialization at 21 days after grafting, with no significant effect of blank or rapamycin-loaded NPs group. Western blot analysis showed that treatment with rapamycin-loaded PLGA NPs markedly attenuated phosphorylation and activation of S6 kinase 1 phosphorylation and inactivation of 4E (eIF4E)-binding protein 1, both in vascular smooth muscular cells and vein grafts at 7 and 21 days after grafting. CONCLUSIONS: We conclude that sustained-release rapamycin from rapamycin-loaded NPs inhibits vein graft thickening without affecting the endothelial cells in rat carotid vein-to-artery interposition grafts; thus, this may be a promising therapy for the treatment of vein graft disease.

Ex vivo carbon monoxide delivery inhibits intimal hyperplasia in arterialized vein grafts.

AIMS: Veins are still the best conduits available for arterial bypass surgery. When these arterialized vein grafts fail, it is often due to the development of intimal hyperplasia (IH). We investigated the feasibility and efficacy of the ex vivo pre-treatment of vein grafts with soluble carbon monoxide (CO) in the inhibition of IH. METHODS AND RESULTS: The inferior vena cava was excised from donor rats and placed as an interposition graft into the abdominal aorta of syngeneic rats. Prior to implantation, vein grafts were stored in cold Lactated Ringer (LR) solution with or without CO saturation (bubbling of 100% CO) for 2 h. Three and 6 weeks following grafting, vein grafts treated with cold LR for 2 h developed IH, whereas grafts implanted immediately after harvest demonstrated significantly less IH. Treatment in CO-saturated LR significantly inhibited IH and reduced vascular endothelial cell (VEC) apoptosis. Electron microscopy revealed improved VEC integrity with less platelet/white blood cell aggregation in CO-treated grafts. The effects of CO in preventing IH were associated with activation of hypoxia inducible factor-1α (HIF-1α) and an increase in vascular endothelial growth factor (VEGF) expression at 3-6 h after grafting. Treatment with a HIF-1α inhibitor completely abrogated the induction of VEGF by CO and reversed the protective effects of CO on prevention of IH. CONCLUSION: Ex vivo treatment of vein grafts in CO-saturated LR preserved VEC integrity perioperatively and significantly reduced neointima formation. These effects appear to be mediated through the activation of the HIF1α/VEGF pathway.

Short-term effects of double-layer autologous vein graft on restraint of excessive distension and alleviation of neointimal hyperplasia in a porcine saphenous vein graft model.

Although the use of external vein graft support seems a promising approach to prevent neointimal hyperplasia and wall thickening in vein grafts, its extensive clinical application still has a long way to go. The aim of this study was to evaluate short-term effects of self-designed double-layer autologous saphenous vein graft on restraining excessive distension of vein graft and alleviating neointimal hyperplasia in a porcine model. Left and right hind femoral arteries of 24 white pigs were randomly divided into an experimental group (double-layer vein graft) and a control group (single-layer vein graft). After 1 h of implantation, then 1, 2, and 4 weeks later, the mean inner diameter of the vein grafts in the experimental group measured by Doppler-ultrasound was 2.7 ± 0.1, 2.8 ± 0.1, 2.9 ± 0.1, and 3.1 ± 0.1 mm, respectively; mean peak blood flow velocity measured by Doppler-ultrasound was 96.7 ± 12.8, 93.7 ± 11.5, 89.4 ± 9.6 and 84.6 ± 10.1 cm/s, respectively, while the mean neointimal thicknesses were 47.1 ± 7.7, 93.7 ± 15.1, and 177.4 ± 25.5 µm at 1, 2 and 4 weeks, respectively. As compared to the control group, inner diameter and neointimal thickness of vein grafts in the experimental group were significantly lower, while mean peak blood flow velocity was significantly higher at 1, 2, and 4 weeks after implantation. The proliferation index in the experimental group was also significantly lower within 4 weeks after implantation. The self-designed double-layer autologous saphenous vein graft restrains early excessive distension of vein graft and alleviates early neointimal hyperplasia.

Periadventitial rapamycin-eluting microbeads promote vein graft disease in long-term pig vein-into-artery interposition grafts.

BACKGROUND: Neointima formation and atherosclerosis compromise long-term graft patency in aortocoronary and peripheral vein bypass grafts. We investigated the short- and long-term effects of periadventitial application of a sustained-release formulation of rapamycin on experimental pig vein grafts with similar dimensions and kinetics to human saphenous vein bypass grafts. METHODS AND RESULTS: Periadventitial application of rapamycin-eluting polyvinyl alcohol microspheres (60 microg . cm(-2)) to porcine saphenous vein-to-carotid artery interposition grafts inhibited vein graft positive and vascular smooth muscle cell proliferation in 1-week grafts. It also decreased neointima formation and wall thickening in 4-week vein grafts compared with controls. The inhibition of vein graft thickening was not sustained; however, a catch-up phenomenon was observed, and there was no therapeutic benefit evident in 12-week grafts. Increasing the dose of rapamycin to 120 microg . cm(-2) was associated with significant local toxicity manifest by high rates of graft rupture (25%), inhibition of adventitial neoangiogenesis, and a paradoxical acceleration of vein graft disease as evidenced by increased vascular smooth muscle cell proliferation. CONCLUSIONS: Local toxicity and poor long-term efficacy limits the clinical applicability of locally applied, sustained rapamycin release in vein graft disease.

Effect of matrix metalloproteinase-9 knockout on vein graft remodelling in mice.

Long-term success in vein grafting for bypassing arteries blocked by atherosclerosis is limited by migration and proliferation of smooth muscle cells to form a neointima. Matrix metalloproteinases (MMPs), in particular MMP-2 and MMP-9, are implicated in neointimal formation by freeing smooth muscle cells from the cell-matrix contacts that normally restrict migration. We investigated the role of MMP-9 in vein grafts directly, using knockout mice. Vein grafts in MMP-9(-/-) and wild-type mice had similar luminal and graft areas at 1, 4 and 8 weeks after engraftment, increasing with time. There was a relationship between the perimeter of the external elastic lamina and graft thickness (indicating graft remodelling) in MMP-9(-/-) mice at 1 week after surgery not apparent in control mice until later (r(2) = 0.933 for MMP-9(-/-) mice, r(2) = 0.040 for wild-type mice). Grafts in MMP-9(-/-) mice had 6-fold more pro- and active MMP-2 (p = 0.013, p = 0.026) than grafts in wild-type mice. Grafts from MMP-9(-/-) mice also had more collagen (p = 0.046 at 8 weeks), without any difference in cell number. Thus, while a lack of MMP-9 did not alter vein graft wall area or cellularity, grafts from MMP-9(-/-)mice accumulated more collagen and had earlier linear expansive remodelling, possibly due to an early compensatory increase in MMP-2.

[Application of endovascular covered stent for treating vertebral dissecting aneurysm and carotid-cavernous fistula].

OBJECTIVE: To investigate the therapeutic effects of endovascular covered stent on vertebral dissecting aneurysm and carotid-cavernous fistula (CCF). METHODS: From March 2006 to May 2007, Jostent coronary stent grafts were used to treat 4 patients with vertebral dissecting aneurysm and 3 patients with CCF. The patients of vertebral dissecting aneurysm were male and 37- 57-years-old, the lesion was located on the left vertebral artery in 3 patients and on the right vertebral artery in 1 patient, with the primary symptoms of sudden headache and vomiting; CT scan demonstrated subarachnoid hemorrhage; and the medical history varied from 2 days to 10 years. The patients of CCF were male and 35- 51-years-old, the lesion was located on the left carotid artery in 2 patients and on the right carotid artery in 1 patient, with the primary symptoms of headache, lateral exophthalmos, eyeball distending pain, conjunctive hyperemia and impaired eyesight; all 3 patients got head injury 2 days to 1 month before the appearance of symptoms and 1 of them had a history of severe nosebleed; and the medical history ranged from 1 week to 2 months. RESULTS: For the patients with vertebral dissecting aneurysm, complete obliteration of aneurysms was achieved, the circulations of the vertebral artery, the adjacent posterior inferior cerebellar artery and the adjacent anterior inferior cerebellar artery were smooth, no complications relative to operation occurred, and no recurrence of symptoms and intracranial rehaemorrhagia were observed during the follow-up period of 8 months-2 years. For the patients with CCF, the fistula were completely obliterated, the circulation of carotid artery was smooth, the exophthalmus and conjunctiva hyperemia were improved obviously 3 days after operation, the eyesight of patient was improved at different levels over the follow-up period of 1-3 months. CONCLUSION: Endovascular covered stent is a new and useful tool for the treatment of vertebral dissecting aneurysm and CCF.

Adenoviral activin A expression prevents vein graft intimal hyperplasia in a rat model.

Autologus vein grafts are used for coronary artery and infra-inguinal bypass procedures. Although initially successful, long-term patency rates are limited by lumen occlusion due to neointima formation by smooth muscle cell hyperplasia. Gene therapy to prevent this smooth muscle cell proliferation has been studied extensively with limited success. Activin A, a member of the transforming growth factor-beta super family, promotes the contractile phenotype of smooth muscle cells. Maintaining the contractile phenotype could be a novel strategy to prevent intimal hyperplasia. In an epigastric vein-to-common femoral artery interposition grafts rat model, activin A over-expression resulted in a significant decrease in intimal cross-sectional area and percentage stenosis as compared to the control group. BrdU staining identified lower proliferation rates of the smooth muscle cells in the group treated with activin A. We report for the first time evidence that activin A can diminish vein graft failure in a rat model supporting a novel strategy to prevent intimal hyperplasia.

The myofibrosis mechanism of differentiation growth factor-8 on rat abdominal aorta grafts.

OBJECTIVE: The objective of this study was to investigate the role of differentiation growth factor-8 (GDF-8) in inhibiting myofibrosis of abdominal aorta grafts. METHODS: Male Spague-Dawley (SD) rats that received abdominal aorta grafts from male Wistar rats were randomly divided into 2 groups: prolonged cold ischemia (PCI) and control groups. Hematoxylin-eosin (HE) staining was performed to examine aortic graft morphology and to measure neointimal thickness. RT-PCR demonstrated the expression of GDF-8. Immunohistochemical staining (IHC) was performed to detect the expression of Smad4, a pivotal molecule of the transforming, growth factor-beta (TGF-beta)/Smad signal pathway. RESULTS: The intimal thickness increased by 14 days following transplantation in the PCI group (P<.05), reaching 381.952+/-44.334 microm at 28 days, which was higher than that of the control group (56.898+/-17.543 microm; P<.05). The GDF-8 expression in the PCI group was only 3.6%-33.8% of that among the control group. There was a much higher expression of Smad4 on the endothelium of the PCI than the control group at the same time. CONCLUSIONS: Prolonged cold ischemia accelerated grafts myofibrosis by down-regulating the expression of GDF-8, which plays a key role in the myofibrosis process of rat abdominal aortic grafts.

Interferon-gamma induces human vascular smooth muscle cell proliferation and intimal expansion by phosphatidylinositol 3-kinase dependent mammalian target of rapamycin raptor complex 1 activation.

Interferon (IFN)-gamma, a cytokine characteristically expressed in arteriosclerotic diseases, acts directly on vascular smooth muscle cells to induce cellular proliferation and intimal expansion. Signaling by the mammalian target of rapamycin raptor complex, known as mTORC1, is associated with cell growth and is active within arteriosclerotic lesions but is not known to be triggered by proinflammatory factors in vascular smooth muscle cells. We investigated the mechanisms for the proarteriosclerotic effects of IFN-gamma in the absence of leukocytes by exploiting the species specificity of this cytokine in a chimeric model of immunodeficient mouse recipients bearing human coronary artery grafts and intravenously inoculated with adenovirus encoding a human IFN-gamma transgene. We found that IFN-gamma-mediated vascular smooth muscle cell proliferation and intimal expansion were associated with phosphorylation of the mTORC1 effector ribosomal protein S6 kinase 1, that the graft morphological changes and S6 kinase 1 activation were inhibited by the mTORC1 inhibitor rapamycin in vivo, and that IFN-gamma-induced mTORC1 signaling was dependent on phosphatidylinositol 3-kinase activity under serum-free conditions in vitro. Our work establishes an immunologic stimulus for mTORC1 signaling in vascular smooth muscle cells, emphasizes that mTORC1 activation is critical in immune-mediated vascular remodeling, and provides further mechanistic insight into the successful clinical application of rapamycin therapy for atherosclerosis and graft arteriosclerosis.

Differential effects of everolimus and cyclosporine A on intimal alpha-actin-positive cell dynamics of carotid allografts in mice.

BACKGROUND: We recently demonstrated that donor medial cells are replaced by smooth muscle alpha-actin (SMA)-expressing host cells in murine carotid allografts. In this study, we investigated neointimal cell dynamics including effects of cyclosporine A (CsA) and everolimus (SDZ RAD, Certican). To obtain a functional readout, we measured the effects of these treatments on cardiac allografts. METHODS: Heterotopic heart allotransplantation was performed between C57BL/6 (B6) and BALB/c (B/c) mice. Orthotopic carotid artery allotransplantation was performed between B6 and B/c mice expressing green fluorescent protein (GFP). Both strains served as donors and recipients. Groups of mice were treated for 4 and 8 weeks (heart and carotid recipients, respectively) with placebo, CsA 20 mg/kg per day, or everolimus 1.0 mg/kg per day using Alzet minipumps. At 2, 4, and 8 weeks, carotid grafts were harvested for histology. RESULTS: In the GFP-B/c to B6 strain combination, everolimus but not CsA significantly reduced neointima formation and accumulation of SMA-positive host (non-GFP) cells at doses that did not fully suppress heart rejection. In the B6 to GFP-B/c strain combination, everolimus and CsA strongly prevented heart rejection under treatment, partly suppressed neointima formation, and completely prevented SMA-positive host (GFP) cell accumulation. CONCLUSIONS: Donor-derived cells expressing SMA never appear in the neointima, and such cells are completely recipient derived. Adequate immunosuppression delays or prevents the disappearance of donor cells and the appearance of host cells in the graft, a phenomenon apparently associated with the neointima formation. Even immunosuppression sufficient to prevent heart allograft rejection under treatment completely, diminishes neointima formation only by approximately 50%.

Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice.

Recent evidence indicates that vascular progenitor cells may be the source of smooth muscle cells (SMCs) that accumulate in atherosclerotic lesions, but the origin of these progenitor cells is unknown. To explore the possibility of vascular progenitor cells existing in adults, a variety of tissues from ApoE-deficient mice were extensively examined. Immunohistochemical staining revealed that the adventitia in aortic roots harbored large numbers of cells having stem cell markers, e.g., Sca-1(+) (21%), c-kit(+) (9%), CD34(+) (15%), and Flk1(+) cells (4%), but not SSEA-1(+) embryonic stem cells. Explanted cultures of adventitial tissues using stem cell medium displayed a heterogeneous outgrowth, for example, islands of round-shaped cells surrounded by fibroblast-like cell monolayers. Isolated Sca-1(+) cells were able to differentiate into SMCs in response to PDGF-BB stimulation in vitro. When Sca-1(+) cells carrying the LacZ gene were transferred to the adventitial side of vein grafts in ApoE-deficient mice, beta-gal(+) cells were found in atherosclerotic lesions of the intima, and these cells enhanced the development of the lesions. Thus, a large population of vascular progenitor cells existing in the adventitia can differentiate into SMCs that contribute to atherosclerosis. Our findings indicate that ex vivo expansion of these progenitor cells may have implications for cellular, genetic, and tissue engineering approaches to vascular disease.

Inhibition of accelerated atherosclerosis in vein grafts by placement of external stent in apoE*3-Leiden transgenic mice.

OBJECTIVE: Vein grafts fail because of the development of intimal hyperplasia and accelerated atherosclerosis. Placement of an external stent around vein grafts resulted in an inhibition of intimal hyperplasia in several animal studies. Here, we assess the effects of external stenting on accelerated atherosclerosis in early vein grafts in carotid arteries in hypercholesterolemic apolipoprotein E*3-Leiden transgenic mice. METHODS AND RESULTS: Venous interposition grafting was performed in apolipoprotein E*3-Leiden mice fed standard chow or a highly cholesterol-rich diet for 4 weeks. After engraftment, external stents with different inner diameters (0.4 or 0.8 mm) were placed. In unstented vein grafts in hypercholesterolemic mice, thickening up to 50 times the original thickness, with foam cell-rich lesions, calcification, and necrosis, was observed within 28 days. The atherosclerotic lesions observed show high morphological resemblance to atherosclerotic lesions observed in human vein grafts. In stented vein grafts in hypercholesterolemic mice, no foam cell accumulation or accelerated atherosclerosis was observed. Compared with unstented vein grafts, stenting of vein grafts in a hypercholesterolemic environment resulted in a 94% reduction of vessel wall thickening. These effects were independent of stent size. CONCLUSIONS: Extravascular stent placement results in strong inhibition of accelerated vein graft atherosclerosis in hypercholesterolemic transgenic mice and thereby provides a perspective for therapeutic intervention in vein graft diseases.