Neointimal Layer Research Articles

Planar biaxial characterization of diseased human coronary and carotid arteries for computational modeling

Computational models have the potential to provide precise estimates of stresses and strains associated with sites of coronary plaque rupture. However, lack of adequate mathematical description of diseased human vessel wall mechanical properties is hindering computational accuracy. The goal of this study is to characterize the behavior of diseased human coronary and carotid arteries using planar biaxial testing. Diseased coronary specimens exhibit relatively high stiffness (50–210kPa) and low extensibility (1–10%) at maximum equibiaxial stress (250kPa) compared to human carotid specimens and values commonly reported for porcine coronary arteries. A thick neointimal layer observed histologically appears to be associated with heightened stiffness and the direction of anisotropy of the specimens. Fung, Choi–Vito and modified Mooney–Rivlin constitutive equations fit the multiaxial data from multiple stress protocols well, and parameters from representative coronary specimens were utilized in a finite element model with fluid–solid interactions. Computed locations of maximal stress and strain are substantially altered, and magnitudes of maximum principal stress (48–65kPa) and strain (6.5–8%) in the vessel wall are lower than previously predicted using parameters from uniaxial tests. Taken together, the results demonstrate the importance of utilizing disease-matched multiaxial constitutive relationships within patient-specific computational models to accurately predict stress and strain within diseased coronary arteries.

Optical Coherence Tomography in the Era of Drug-Eluting Stents: An Indispensable Workhorse

Copyright: © 2012 Nammas W, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Undoubtedly, the breakthrough introduction of drug-eluting stents (DES) has nearly abolished the need for reintervention, accounting for nearly 10-15% need for target vessel revascularization (TVR) at longterm follow-up [1,2]. Indeed, the enthusiasm associated with the early results of first-generation DES let us believe that the long-standing concern inherent to percutaneous coronary intervention (PCI) has probably come to a pleasant end. After years ‘in duty’, however, worrisome reports have raised concerns about disturbingly high rates of late and very late (after one year) stent thrombosis associated with DES, that frequently culminates into myocardial infarction or, even more gravely, death [3]. Scaring enough, these reports launched a ‘wake-up call’ to carefully evaluate the likely mechanisms underlying this potentially life-menacing event. Insights from histopathological studies suggested that delayed neointimal coverage of DES struts a built-in problem of these devices was reasonably the first ‘suspect’ to condemn [4]. One more suspect was stent strut malapposition, again a favorable position for struts to remain ‘nude’ [5]. In the quest to ‘see what is going on’ in vivo, invasive imaging techniques were called into action. Intravascular ultrasonography (IVUS), the benchmark of these, did demonstrate a 10-20% incidence of strut malapposition associated with DES; almost double that reported following bare-metal stent implantation [6,7]. Unfortunately, however, the resolution of IVUS (100-200 μm) is clearly less sensitive to visualize slight degrees of strut malapposition, and rationally, far below that needed to reveal the ultrathin early and healthy neointimal layer covering stent struts. In this context, an advanced high-resolution imaging tool perfectly capable of portraying the vessel wall-lumen interface has long been awaited.

Circumferential evaluation of the neointima by optical coherence tomography after ABSORB bioresorbable vascular scaffold implantation: Can the scaffold cap the plaque?

ObjectiveTo quantify the circumferential healing process at 6 and 12 months following scaffold implantation. BackgroundThe healing process following stent implantation consists of tissue growing on the top of and in the space between each strut. With the ABSORB bioresorbable vascular scaffold (BVS), the outer circumference of the scaffold is detectable by optical coherence tomography (OCT), allowing a more accurate and complete evaluation of the intra-scaffold neointima. MethodsA total of 58 patients (59 lesions), who received an ABSORB BVS 1.1 implantation and a subsequent OCT investigation at 6 (n=28 patients/lesions) or 12 (n=30 patients with 31 lesions) months follow-up were included in the analysis. The thickness of the neointima was calculated circumferentially in the area between the abluminal side of the scaffold and the lumen by means of an automated detection algorithm. The symmetry of the neointima thickness in each cross section was evaluated as the ratio between minimum and maximum thickness. ResultsThe neointima area was not different between 6 and 12 months follow-up (1.57±0.42mm2 vs. 1.64±0.77mm2; p=0.691). No difference was also found in the mean thickness of the neointima (median [IQR]) between the two follow-up time points (210μm [180–260]) vs. 220μm [150–260]; p=0.904). However, the symmetry of the neointima thickness was higher at 12 than at 6 months follow-up (0.23 [0.13–0.28] vs. 0.16 [0.08–0.21], p=0.019). ConclusionsA circumferential evaluation of the healing process following ABSORB implantation is feasible, showing the formation of a neointima layer, that resembles a thick fibrous cap, known for its contribution to plaque stability.

MORPHOLOGY OF VARIOUS VASCULAR GRAFTS IN ARTERIAL FLOW

Aim of the research: to determine the morphological aspects of the application of deep vein to reconstruct the arterial-iliac segment and its comparison with other known vascular grafts. Material and methods. The objects of the study were 20 pedigreeless dogs at a weight of 15,2 ± 3,1 kg. All the dogs underwent aortobifemoral bypass with a combined graft. The samples were taken for morphological study after 3, 6, 9 and 12 months. The complex of histological studies was performed with Leica DMLS microscope (Germany). Results. The histological study of the connective tissue capsule revealed its decrease by 12 months. There is distinct formation of a neointimal layer on the vein inner surface, particularly on the sites of sutures. Neointima appears by three months in the application of the deep vein and by six months if superficial vein is used. Conclusion. The great saphenas demonstrate better adjustment capabilities for the inclusion to the arterial flow in comparison with the superficial vein and may be comparable with an autoartery.

060 Primary cultures of rat medial smooth muscle cells spontaneously develop invadopodia

060 Primary cultures of rat medial smooth muscle cells spontaneously develop invadopodia

Expression and function of calcium-activated potassium channels following in-stent restenosis in a porcine coronary artery model

In-stent restenosis (ISR) occurs due to proliferation and migration of smooth muscle cells from media to intima resulting in re-narrowing of the vessel lumen. This study aims to investigate changes in the three main KCa channels in response to stent implantation in porcine coronary arteries as their expression and function in ISR is yet to be defined. Twenty-eight days after stent implantation, immunofluorescent labelling with anti-desmin and anti-vWF confirm the presence of both endothelial and smooth muscle cells within the neointimal layer. Using real-time PCR, significant increase in the SK3 and IKCa and BKCa channel mRNA was observed within this layer alone. Western blot analysis confirms the expression of KCa channels in neointima. Although expression of BKCa was increased in the neointima in comparison with medial region of the artery, microelectrode recordings showed that the function of this channel was unchanged. However, the presence of functional BKCa in both medial and intimal cells suggests that smooth muscle cells migration may contribute to neointimal hyperplasia.Functional analysis using 1-EBIO and Bradykinin produced hyperpolarization of neointimal but not medial myocytes, which indicated the expression of functional endothelial SK3 and IKCa in the former and not in the latter. The expression of IKCa and SK3 within the neointimal layer suggested that some degree of recovery of both endothelial as well as smooth muscle regeneration had occurred. Future development of selective modulators of IKCa and SK3 channels may decrease the progression of ISR and improve coronary vascular function after stent placement, and is an area for future investigation.

Targeted Disruption of the Prostaglandin E 2 E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Restenosis after angioplasty remains a major clinical problem. Prostaglandin E(2) (PGE(2)) plays an important role in vascular homeostasis. The PGE(2) receptor E-prostanoid 2 (EP2) is involved in the proliferation and migration of various cell types. We aimed to determine the role of EP2 in the pathogenesis of neointimal formation after vascular injury. Wire-mediated vascular injury was induced in the femoral arteries of male wild-type (EP2+/+) and EP2 gene-deficient (EP2-/-) mice. In EP2+/+ mice, EP2 mRNA expression was increased in injured vessels for at least 4 weeks after vascular injury. Neointimal hyperplasia was markedly accelerated in EP2-/- mice, which was associated with increased proliferation and migration of vascular smooth muscle cells (VSMCs) and increased cyclin D1 expression in the neointima layer. Platelet-derived growth factor-BB (PDGF-BB) treatment resulted in more significant cell proliferation and migration in VSMCs of EP2-/- mice than in those of EP2+/+ mice. Activation and overexpression of EP2 attenuated PDGF-BB-elicited cell proliferation and migration, induced G(1)→S-phase arrest and reduced PDGF-BB-stimulated extracellular signal-regulated kinase phosphorylation in EP2+/+ VSMCs. These findings reveal a novel role of the EP2 receptor in neointimal hyperplasia after arterial injury. The EP2 receptor may represent a potential therapeutic target for restenosis after angioplasty.

Activation of Endothelin-1 Receptor Signaling Pathways Is Associated With Neointima Formation, Neoangiogenesis and Irreversible Pulmonary Artery Hypertension in Patients With Congenital Heart Disease

It is unclear why some patients, who undergo complete repair or palliative surgery for congenital heart disease (CHD), still develop irreversible pulmonary artery hypertension (PAH). There is no consensus to preoperationally assess the reversible and irreversible pulmonary vasculopathy seen in PAH. The peri-operative pulmonary hemodynamic data of 16 CHD patients (reversible PAH, n = 6; irreversible PAH, n = 10) were analyzed. The lung biopsies were also performed during surgery for defining histopathological characteristics as well as immunohistochemical expression of endothelin-1 (ET-1), endothelin-1 receptors (ETR), and its downstream signaling markers in the small pulmonary arteries and arterioles. Neointimal formation and neoangiogenesis was characterized by increased intimal layer immunoreactivity for α-SMA, Factor VIII, CD34, and VEGF. Neointimal formation was found in 90% of patients and neoangiogenesis was found in 80% of patients with irreversible PAH. Neither was present in the reversible PAH group and the control group. Expression of ET-1 and ETR in the neointimal layer of the pulmonary arterioles was upregulated in irreversible PAH, and immunoreactivity of phospho-Akt, phospho-ERK1/2, and phospho-mTOR was also increased in irreversible PAH. Increased expression of ET-1, ETR, and activation of signaling pathways were observed in the pulmonary arteries and arterioles of irreversible PAH patients associated with CHD. Activation of these pathways might in turn lead to neointimal formation and neoangiogenesis and thus might contribute to irreversible pulmonary vascular abnormalities.

S95 Application of proteomics to explore the pathobiology of pulmonary arterial hypertension

Introduction and ObjectivePulmonary arterial hypertension (PAH) is a poorly understood debilitating disorder which is characterised by increased resistance to the pulmonary blood flow caused by the remodelling of the pulmonary...

Role of Lysyl Oxidases in Neointima Development in Vascular Allografts

Background: Extracellular matrix deposition is the main factor inducing stenotic lesions in arterial grafts. Lysyl oxidases (LOX) play a key role in stabilizing collagen and elastin. Objective: To examine the repair response to arterial allografts in terms of LOX expression and collagen/elastin deposition using LOX inhibitors. Methods: Lewis/Fisher-344 rats were used as donors/recipients. Donor segments were grafted to the right iliac artery of recipients and retrieved 14/30 (short-term) or 90/180 days (long-term) after surgery. One group of animals was injected with a potent irreversible LOX inhibitor daily for 30 days. Results: Intimal hyperplasia increased in thickness until 90/180 days postsurgery. Elastin showed great expression in the neointima at 14/30 days and in the media at 90/180 days. LOX/LOXL1 were similarly expressed in the arterial wall during the first month. In the long term, their overexpression was confined to neointimal layers. At 14 days, collagen types I/III were identified in the grafts. The neointima acquired collagen I over time. In the group of animal treated with the LOX inhibitor, intimal hyperplasia was significantly inhibited. Conclusion: LOX were overexpressed in late stages of intimal hyperplasia in the allografts. LOX inhibitors prevented the development of the neointimal layer, such that their modulation could reduce the excessive extracellular matrix deposition that leads to stenosis.

Bare, Bio-Active and Hydrogel-Coated Coils for Endovascular Treatment of Experimentally Induced Aneurysms

Endovascular treatments of cerebral aneurysms with bare platinum coils have a higher rate of recurrence compared to surgical clipping. This may be related to failed vessel wall reconstruction since histological and scanning electron microscopy results following embolization failed to demonstrate neoendothelialization over the aneurysm neck. The present study tried to elucidate whether the use of modified coils resulted in a better rate of reconstructing the vessel wall over the aneurysm neck in experimental aneurysms. Aneurysms were created in 20 rabbits by intraluminal elastase incubation of the common carotid artery. Five animals each were assigned to the following groups: untreated, bare platinum coils, bioactive coils with polyglycolic/polylactic acid coating, and hydrogel-coated platinum coils. After 12 months, angiography, histology and scanning electron microscopy was performed. No neoendothelial layer was visualized in the bioactive and bare coil groups with a tendency to an increased layering of fibroblasts along the bioactive coils at the aneurysm fundus. However, at the aneurysm neck perfused clefts were present and although a thin fibrinous layer was present over some coils, no bridging neointimal or neoendothial layer was noted over different coils. Following loose Hydrogel coiling, a complete obliteration of the aneurysm was present with neoendothelialization present over different coil loops. The study demonstrates that with surface coil modifications complete and stable aneurysm obliteration may become possible. A smooth and dense surface over the aneurysm neck may be necessary for endothelial cells to bridge the aneurysm neck and to lead to vessel wall reconstruction.

Use of an Expanded Polytetrafluoroethylene Patch as an Artificial Leaflet in Mitral Valve Plasty: An Early Experience

The purpose of this study was to examine the usefulness of polytetrafluoroethylene (PTFE) patches as artificial mitral leaflets in complex mitral valve plasty. Nineteen patients (mean age, 66 +/- 9 years) who were in need of mitral valve replacement successfully underwent mitral valve plasty with enlargement of the basal anterior leaflet using a PTFE patch. Operative and in-hospital mortality was 0%. Patients were followed-up by maintaining their history, physical examinations, and echocardiography. The mean follow-up period was 30 +/- 15 months (2 to 52 months) with one late mortality and one reoperation. A thin neointimal layer was observed on the explanted PTFE patch. The PTFE patch maintained its pliability with no signs of calcification, excessive thickening, or perforation for 4 years. Mean motion angle of the patch on echocardiography decreased from 41.1 +/- 10.6 to 35.2 +/- 12.5 degrees (p < 0.05) during 26.7 +/- 15.5 months of study (range, 6-46 months). The mean mitral valve area was 2.9 +/- 0.7 cm(2) at last follow-up. The PTFE patches may be a promising material for artificial mitral leaflets.

Analysis of the long-term effects of drug-eluting stents on coronary arterial wall morphology as assessed by virtual histology intravascular ultrasound

Animal models show impairment of arterial healing after drug-eluting stents (DES) compared with bare-metal stents (BMS). Virtual histology intravascular ultrasound (VH-IVUS) offers an opportunity to assess lesion morphology in vivo. We used VH-IVUS in 80 patients to assess long-term (median = 10 months) native artery vascular responses after 76 implantations of DES compared with 32 BMS. The presence of "necrotic core abutting the lumen" was evaluated at baseline and follow-up. At baseline, necrotic core abutting the lumen through the stent struts was observed in 76% of DES and 75% of BMS. Although the percentage of necrotic core within the plaque behind the stents did not change during follow-up in DES (23% [18%, 28%] to 22% [17%, 27%], P = .57) or BMS (22% [19%, 27%] to 20% [12%, 26%], P = .29), necrotic core abutting the lumen through the stent struts decreased more in BMS (75% to 19%, P < .001) than DES (76% to 61%, P = .036) because of the lack of an overlying, protective neointima in DES-treated lesions. Furthermore, within the adjacent reference segments, the incidence of necrotic core abutting the lumen decreased in BMS-treated lesions (proximal 23% to 0%, P = .023; distal 21% to 0%, P = .023), but not in DES (proximal 22% to 17%, P = .48; distal 23% to 21%, P = .82). Serial VH-IVUS analysis of DES-treated lesions showed a greater frequency of unstable lesion morphometry at follow-up compared with BMS. The apparent mechanism was a suppression of the protective neointimal hyperplasia layer coupled with a lack of vulnerable plaque resolution at reference segments in DES compared with BMS.

Lysophosphatidic acid-induced arterial wall remodeling: Requirement of PPARγ but not LPA1 or LPA2 GPCR

Lysophosphatidic acid (LPA) and its ether analog alkyl-glycerophosphate (AGP) elicit arterial wall remodeling when applied intralumenally into the uninjured carotid artery. LPA is the ligand of eight GPCRs and the peroxisome proliferator-activated receptor γ (PPARγ). We pursued a gene knockout strategy to identify the LPA receptor subtypes necessary for the neointimal response in a non-injury model of carotid remodeling and also compared the effects of AGP and the PPARγ agonist rosiglitazone (ROSI) on balloon injury-elicited neointima development. In the balloon injury model AGP significantly increased neointima; however, rosiglitazone application attenuated it. AGP and ROSI were also applied intralumenally for 1h without injury into the carotid arteries of LPA1, LPA2, LPA1&2 double knockout, and Mx1Cre-inducible conditional PPARγ knockout mice targeted to vascular smooth muscle cells, macrophages, and endothelial cells. The neointima was quantified and also stained for CD31, CD68, CD11b, and α-smooth muscle actin markers. In LPA1, LPA2, LPA1&2 GPCR knockout, Mx1Cre transgenic, PPARγfl/−, and uninduced Mx1Cre×PPARγfl/− mice AGP- and ROSI-elicited neointima was indistinguishable in its progression and cytological features from that of WT C57BL/6 mice. In PPARγ−/− knockout mice, generated by activation of Mx1Cre-mediated recombination, AGP and ROSI failed to elicit neointima and vascular wall remodeling. Our findings point to a difference in the effects of AGP and ROSI between the balloon injury- and the non-injury chemically-induced neointima. The present data provide genetic evidence for the requirement of PPARγ in AGP- and ROSI-elicited neointimal thickening in the non-injury model and reveal that the overwhelming majority of the cells in the neointimal layer express α-smooth muscle actin.

Histological Demonstration of Healing in Experimental Aneurysms

Recanalisation of aneurysms after interventional therapy is still an unsolved problem. The aim of this study is to demonstrate the angiographic and histological evidence of healing after endovascular embolisation of experimental aneurysms. We evaluated the healing reaction in experimental aneurysms treated with HydroCoils and platinum coils. After microsurgical construction of aneurysms in 24 rabbits, embolisation was performed. Four animals were sacrificed immediately after embolisation and 5 after 1 month, 3 months and 6 months, respectively, the remaining served as control group. Serial plastic-embedded ground sections of the parent arteries-aneurysm complexes were evaluated by light microscopy. Thrombus organisation in the aneurysms resulted in fibrovascular tissue formation between bare platinum and HydroCoils from the walls of the aneurysms towards the centre of the sac over time. In the clefts between HydroCoils only thin strands of granulation tissue were observed. From one month on, there was a neointimal layer covering the coil mass at the aneurysm orifice. Progressive occlusion by the expanding hydrogel polymers on the coils seemed to result in a durable healing reaction in the aneurismal sac in a short-term follow-up period.

GLUT1-induced cFLIP expression promotes proliferation and prevents apoptosis in vascular smooth muscle cells.

Enhanced expression of the facilitative glucose transporter, GLUT1, has been shown to inhibit apoptosis in several cell systems including vascular smooth muscle cells (VSMCs). A decrease in apoptosis could lead to increased VSMC numbers in neointimal and medial arterial layers under several pathologic conditions. The hypothesis underlying these studies is that GLUT1 induces expression of antiapoptotic and prosurvival genes that increase VSMC survival. Transcriptomic analysis of A7r5 VSMCs, in which GLUT1 was acutely overexpressed, showed a 2.14-fold increase in c-FLICE inhibitory protein (cFLIP), which promotes cellular growth and prevents apoptosis through caspase 8 binding. We confirmed that overexpression of GLUT1 induced mRNA and protein expression of both the long and short isoforms of cFLIP (cFLIP(L) and cFLIP(S)) in primary and stable immortalized VSMC lines as well as in aortas from GLUT1 transgenic mice. Increased GLUT1 reduced VSMC death by more than twofold after serum withdrawal, as evidenced by decreased caspase 3 activity and Trypan blue exclusion studies. GLUT1 overexpression resulted in a greater than twofold increase in proliferating cell nuclear antigen expression and live cell numbers, consistent with augmented VSMC proliferation. Lentiviral knockdown of cFLIP(L) showed that cFLIP(L) was necessary for the proproliferative and antiapoptotic effects of GLUT1 overexpression. Taken together, these data suggest that GLUT1 induction of cFLIP(L) expression augments proliferation and prevents apoptosis in VSMCs.

Flavonoids from Inula britannica L. inhibit injury-induced neointimal formation by suppressing oxidative-stress generation

Aim of the study We aimed to investigate whether and how the total flavonoid extracts (TFE) from Inula britannica L. block neointimal hyperplasia induced by balloon injury in rats. Materials and methods Rats were administered orally TFE doses of 12.5, 25 and 50 mg/kg/d by gastric gavage from 3 days before balloon injury to 14 days after the injury. The ratio of intima (I) to media (M) thickness (I/M) in carotid arteries was examined by morphological analyses. The MDA content and SOD activity in plasma were measured. The O 2 − production in vascular tissues was detected in situ. The expression of p47 phox in carotid arteries was analyzed by Western blot analysis and immunohistochemistry. Results The rats treated with TFE 50 mg/kg/d showed a reduction in neointimal hyperplasia, and the ratio of I/M of balloon injured-carotid arteries was significantly reduced by over 70% after TFE treatment, compared with the injured group. The inhibitory effect of TFE on neointimal hyperplasia was almost consistent with that of atorvastatin, a positive control. The plasma SOD activity was obviously increased by TFE treatment ( P < 0.01), while plasma MDA production was markedly decreased by TFE treatment ( P < 0.05). On day 14 after balloon injury, the carotid arteries showed an increase in O 2 − production that was most evident in the neointimal and medial layer of the vessel. Thus, TFE significantly inhibited injury-induced O 2 − production and p47 phox expression in carotid arteries. Conclusion Our results suggest that TFE inhibit the neointimal hyperplasia after balloon injury, at least partly, by suppressing oxidative-stress generation.

A Randomized Optical Coherence Tomography Study of Coronary Stent Strut Coverage and Luminal Protrusion With Rapamycin-Eluting Stents

We used optical coherence tomography, which has a resolution of <20 microm, to analyze thin layers of neointima in rapamycin-eluting coronary stents. Lack of neointimal coverage has been implicated in the pathogenesis of drug-eluting coronary stent thrombosis. Angiography and intracoronary ultrasound lack the resolution to examine this. We conducted a randomized trial in patients receiving polymer-coated rapamycin-eluting stents (Cypher, Cordis, Johnson & Johnson, Miami, Florida) and nonpolymer rapamycin-eluting stents (Yukon, Translumina, Hechingen, Germany) to examine neointimal thickness, stent strut coverage, and protrusion at 90 days. Twenty-four patients (n = 12 for each group) underwent stent deployment and invasive follow-up at 90 days with optical coherence tomography. The primary end point was binary stent strut coverage. Coprimary end points were neointimal thickness and stent strut luminal protrusion. No patient had angiographic restenosis. For polymer-coated and nonpolymer rapamycin-eluting stents, respectively, mean (SD), neointimal thickness was 77.2 (25.6) microm versus 191.2 (86.7) mum (p < 0.001). Binary stent strut coverage was 88.3% (11.8) versus 97.2% (6.1) (p = 0.030). Binary stent strut protrusion was 26.5% (17.5) versus 4.8% (8.6) (p = 0.001). Mean neointimal thickness for the polymer-coated rapamycin-eluting stent was significantly less than the nonpolymer rapamycin-eluting stent but as a result coverage was not homogenous, with >10% of struts being uncovered. High-resolution imaging allowed development of the concept of the protrusion index, and >25% of struts protruded into the vessel lumen with the polymer-coated rapamycin-eluting stent compared with <5% with the nonpolymer rapamycin-eluting stent. These findings may have important implications for the risk of stent thrombosis and, therefore, future stent design. (An optical coherence tomography study to determine stent coverage in polymer coated versus bare metal rapamycin eluting stents. ORCA 1, from the Optimal Revascularization of the Coronary Arteries group; ISRCTN42475919).

Flavonoids from Inula Britannica L. inhibits injury‐induced neointimal hyperplasia through suppressing oxidative stress generation

The total flavonoid extracts (TFE) were prepared from Inula Britannica L., containing 45.5% quercetin, 25.85% luteolin, 12.96% 6‐methoxyluteolin, 4.33% spinacetin and 1.85% isorhamnetin. To explore the effect of TFE on neoinimal hyperplasia induced by balloon injury, the rats administered orally TFE at doses of 12.5, 25, and 50mg/kg/d by gastric gavage from 3 days before balloon injury to 14 days after the injury, respectively. We found that the rats treated with high dose of TFE (50 mg) showed a reduced neointimal hyperplasia, and the ratio of intima (I) to media (M) area (I/M) of balloon injured‐carotid arteries was significantly reduced by over 70% after TFE treatment, compared with model group. The inhibitory effect of TFE (50 mg) on neointimal hyperplasia was almost consistent with Atorvastatin, as a positive control. The plasma SOD activity was obviously increased in TFE (50 mg)‐treated group (P &lt; 0.01), meanwhile, plasma MDA production was markedly decreased (P &lt; 0.05). At 14 days after balloon injury, the neointimal and medial layer of the carotid arteries showed an increase in O2? production. TFE (50 mg) significantly prevented the injury‐induced O2? production, and inhibited the injury‐induced p47phox expression in carotid arteries. These results suggest that the TFE inhibits the neointimal hyperplasia induced by balloon injury through suppressing oxidative stress generation.

Formulation of Nanoparticle-Eluting Stents by a Cationic Electrodeposition Coating Technology: Efficient Nano-Drug Delivery via Bioabsorbable Polymeric Nanoparticle-Eluting Stents in Porcine Coronary Arteries

The objective of this study was to formulate a nanoparticle (NP)-eluting drug delivery stent system by a cationic electrodeposition coating technology.Nanoparticle-mediated drug delivery systems (DDS) are poised to transform the development of innovative therapeutic devices. Therefore, we hypothesized that a bioabsorbable polymeric NP-eluting stent provides an efficient DDS that shows better and more prolonged delivery compared with dip-coating stent.We prepared cationic NP encapsulated with a fluorescence marker (FITC) by emulsion solvent diffusion method, succeeded to formulate an NP-eluting stent with a novel cation electrodeposition coating technology, and compared the in vitro and in vivo characteristics of the FITC-loaded NP-eluting stent with dip-coated FITC-eluting stent and bare metal stent.The NP was taken up stably and efficiently by cultured vascular smooth muscle cells in vitro. In a porcine coronary artery model in vivo, substantial FITC fluorescence was observed in neointimal and medial layers of the stented segments that had received the FITC-NP-eluting stent until 4 weeks. In contrast, no substantial FITC fluorescence was observed in the segments from the polymer-based FITC-eluting stent or from bare metal stent. The magnitudes of stent-induced injury, inflammation, endothelial recovery, and neointima formation were comparable between bare metal stent and NP-eluting stent groups.Therefore, this NP-eluting stent is an efficient NP-mediated DDS that holds as an innovative platform for the delivery of less invasive nano-devices targeting cardiovascular disease.