Reduction Of Neointimal Hyperplasia Research Articles

Mast cell activation and degranulation in acute artery injury: A target for post-operative therapy.

The increasing incidence of cardiovascular disease (CVD) has led to a significant ongoing need to address this surgically through coronary artery bypass grafting (CABG) and percutaneous coronary interventions (PCI). From this, there continues to be a substantial burden of mortality and morbidity due to complications arising from endothelial damage, resulting in restenosis. Whilst mast cells (MC) have been shown to have a causative role in atherosclerosis and other vascular diseases, including restenosis due to vein engraftment; here, we demonstrate their rapid response to arterial wire injury, recapitulating the endothelial damage seen in PCI procedures. Using wild-type mice, we demonstrate accumulation of MC in the femoral artery post-acute wire injury, with rapid activation and degranulation, resulting in neointimal hyperplasia, which was not observed in MC-deficient KitW-sh/W-sh mice. Furthermore, neutrophils, macrophages, and T cells were abundant in the wild-type mice area of injury but reduced in the KitW-sh/W-sh mice. Following bone-marrow-derived MC (BMMC) transplantation into KitW-sh/W-sh mice, not only was the neointimal hyperplasia induced, but the neutrophil, macrophage, and T-cell populations were also present in these transplanted mice. To demonstrate the utility of MC as a target for therapy, we administered the MC stabilizing drug, disodium cromoglycate (DSCG) immediately following arterial injury and were able to show a reduction in neointimal hyperplasia in wild-type mice. These studies suggest a critical role for MC in inducing the conditions and coordinating the detrimental inflammatory response seen post-endothelial injury in arteries undergoing revascularization procedures, and by targeting the rapid MC degranulation immediately post-surgery with DSCG, this restenosis may become a preventable clinical complication.

Nanofiber-coated, tacrolimus-eluting sutures inhibit post-operative neointimal hyperplasia in rats.

Post-operative complications of vascular anastomosis procedures remain a significant clinical challenge and health burden globally. Each year, millions of anastomosis procedures connect arteries and/or veins in vascular bypass, vascular access, organ transplant, and reconstructive surgeries, generally via suturing. Dysfunction of these anastomoses, primarily due to neointimal hyperplasia and the resulting narrowing of the vessel lumen, results in failure rates of up to 50% and billions of dollars in costs to the healthcare system. Non-absorbable sutures are the gold standard for vessel anastomosis; however, damage from the surgical procedure and closure itself causes an inflammatory cascade that leads to neointimal hyperplasia at the anastomosis site. Here, we demonstrate the development of a novel, scalable manufacturing system for fabrication of high strength sutures with nanofiber-based coatings composed of generally regarded as safe (GRAS) polymers and either sirolimus, tacrolimus, everolimus, or pimecrolimus. These sutures provided sufficient tensile strength for maintenance of the vascular anastomosis and sustained drug delivery at the site of the anastomosis. Tacrolimus-eluting sutures provided a significant reduction in neointimal hyperplasia in rats over a period of 14days with similar vessel endothelialization in comparison to conventional nylon sutures. In contrast, systemically delivered tacrolimus caused significant weight loss and mortality due to toxicity. Thus, drug-eluting sutures provide a promising platform to improve the outcomes of vascular interventions without modifying the clinical workflow and without the risks associated with systemic drug delivery.

B-MODE ULTRASOUND-GUIDED LOW-LEVEL FOCUSED-ULTRASOUND SONODYNAMIC THERAPY OF NEOINTIMAL HYPERPLASIA USING PHOTOFRIN-LOADED MICROBUBBLES

In vascular surgery, neointimal hyperplasia is a significant clinical phenomenon because it reduces the long-term effectiveness of surgical and endovascular procedures. We devised an experimental sonodynamic therapy protocol and tested its efficacy on neointimal hyperplasia reduction in this study, in which diagnostic B-mode ultrasound is paired with focused-ultrasound with the goal of greater safety.

Ultrasound- guided polyhydroxy fullerene – loaded microbubbles- mediated pulsed low level focused ultrasound sonodynamic therapy of neointimal hyperplasia accompanied by catheter- based radium-226 brachytherapy

Background and Aims : Neointimal hyperplasia is usually defined in an artery as thickening of the intimal layer after an injury such as angioplasty, stenting or surgical repair. In this study, we investigated effect of sonodynamic therapy combined with brachytherapy on neointimal hyperplasia reduction.

Improvement of neointimal hyperplasia using protoporphyrin- IX- loaded pesda microbubbles- mediated B-mode ultrasound- guided extracorporeal pulsed low- level focused confocal dual frequency ultrasound sonodynamic therapy

Background and Aims: In this study, we developed an experimental ultrasound- based sonodynamic therapy protocol, and investigated its effectiveness on neointimal hyperplasia reduction, wherein diagnostic B- mode ultrasound is combined with focused- ultrasound, with a goal of increased safety.

Neointimal hyperplasia reduction, using synthetic antisense oligodeoxynucleotides - loaded pesda microbubbles- mediated B-mode ultrasound- guided extracorporeal pulsed low- level focused confocal dual frequency ultrasound transfection therapy

Background and Aims: In this study, we developed an experimental ultrasound- mediated transfection therapy system and investigated its effectiveness on intimal hyperplasia reduction, wherein diagnostic ultrasound is combined with ultrasound system, with a goal of increased safety.

Abstract 238: Distinct Vascular Effects of Celecoxib and Rofecoxib in vivo

Randomized controlled trials of cyclooxygenase (COX)-2 selective NSAIDs revealed that these drugs confer a cardiovascular hazard, resulting mainly from suppression of COX-2 derived prostacyclin (PGI2). Disruption of rodent COX-2-derived PGI2 in vascular cells and cardiomyocytes has recapitulated all elements of the cardiovascular hazard attributable to NSAIDs in humans. To investigate further the impact of COX-2 inhibition in the vasculature, we examined the effects of therapeutic concentrations of two selective COX-2 inhibitors, celecoxib and rofecoxib, on thrombosis and vascular injury. Furthermore, we used RNA sequencing (RNA-Seq) to assess whether celecoxib and rofecoxib might elicit distinct genomic effects in mouse aorta. Celecoxib (100 mg/Kg) and rofecoxib (50 mg/Kg) caused a selective and equipotent COX-2 inhibition as indicated by measuring thromboxane (TXB-M, an in vivo index of COX-1 activity) and prostacyclin (PGI-M, an in vivo index of COX-2 activity) urinary metabolites by mass spectrometry. Both celecoxib and rofecoxib augmented platelet deposition and prolonged platelet disaggregation after laser-induced injury in the cremaster arterioles. A similar effect was observed in mice lacking PGI2 receptor IP. There was no additional pro-thrombotic effect of the drugs on an IPKO background, consistent with suppression of COX-2 dependent PGI2 mediating the predisposition to thrombosis induced by celecoxib and rofecoxib. Celecoxib, but not rofecoxib, caused a reduction of neointimal hyperplasia and the intima/media ratio of injured femoral artery at 3 weeks after wire injury. RNA-seq analysis revealed 903 transcripts differentially expressed between celecoxib and control group and 3,127 transcripts between rofecoxib and control group (at a false discovery rate of 10%) in mouse aorta. Thus, both celecoxib and rofecoxib cause a similar predisposition to thrombosis in mice. Celecoxib, but not rofecoxib, reduces neointimal hyperplasia after vascular injury and COX-2 independent genetic actions might modulate this effect. The predisposition to thrombosis and attenuation of the response to vascular injury by celecoxib recapitulates what has been found in humans.

Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo

Atherosclerosis, the build-up of occlusive, lipid-rich plaques in arterial walls, is a focal trigger of chronic coronary, intracranial, and peripheral arterial diseases, which together account for the leading causes of death worldwide. Although the directed treatment of atherosclerotic plaques remains elusive, macrophages are a natural target for new interventions because they are recruited to lipid-rich lesions, actively internalize modified lipids, and convert to foam cells with diseased phenotypes. In this work, we present a nanomedicine platform to counteract plaque development based on two building blocks: first, at the single macrophage level, sugar-based amphiphilic macromolecules (AMs) were designed to competitively block oxidized lipid uptake via scavenger receptors on macrophages; second, for sustained lesion-level intervention, AMs were fabricated into serum-stable core/shell nanoparticles (NPs) to rapidly associate with plaques and inhibit disease progression in vivo. An AM library was designed and fabricated into NP compositions that showed high binding and down-regulation of both MSR1 and CD36 scavenger receptors, yielding minimal accumulation of oxidized lipids. When intravenously administered to a mouse model of cardiovascular disease, these AM NPs showed a pronounced increase in lesion association compared with the control nanoparticles, causing a significant reduction in neointimal hyperplasia, lipid burden, cholesterol clefts, and overall plaque occlusion. Thus, synthetic macromolecules configured as NPs are not only effectively mobilized to lipid-rich lesions but can also be deployed to counteract atheroinflammatory vascular diseases, highlighting the promise of nanomedicines for hyperlipidemic and metabolic syndromes.

Elsibucol inhibits atherosclerosis following arterial injury: Multifunctional effects on cholesterol levels, oxidative stress and inflammation

Background: Elsibucol is a metabolically stable derivative of probucol with antioxidant, anti-inflammatory and antiproliferative properties. Here we investigated the effect of elsibucol on the development of atherosclerosis following arterial injury in hypercholesterolemic rabbits. Methods and results: New Zealand White rabbits were fed a high cholesterol diet that was supplemented or not with 0.5% elsibucol, 1% elsibucol or 1% probucol. An angioplasty of the iliac artery was performed after 3 weeks of diet. We found that treatment with elsibucol significantly decreases blood total cholesterol, LDLc and triglyceride levels. This is associated with a significant 46% reduction of neointimal hyperplasia following arterial injury. Interestingly, the effect of elsibucol on cholesterol levels and neointimal formation appears to be more pronounced than that of probucol. In vitro, elsibucol reduces vascular smooth muscle cell proliferation without affecting cell viability. In vivo, treatment with elsibucol is associated with a significant reduction of cellular proliferation (PCNA immunostaining), oxidative stress (nitrotyrosine immunostaining), VCAM-1 expression and macrophage infiltration in injured arteries. Despite its potent effect on neointimal hyperplasia, elsibucol does not prevent endothelial healing (Evans blue staining) following arterial injury. Conclusions: In hypercholesterolemic animals, elsibucol inhibits atherosclerosis and preserves endothelial healing following arterial injury. The mechanisms involved include lowering of blood cholesterol levels together with a reduction of oxidative stress and inflammation in injured arteries.

Increasing our IQ of vascular smooth muscle cell migration with IQGAP1. Focus on “IQGAP1 links PDGF receptor-β signal to focal adhesions involved in vascular smooth muscle cell migration: role in neointimal formation after vascular injury”

<i>Increasing our IQ of vascular smooth muscle cell migration with IQGAP1</i>. Focus on “IQGAP1 links PDGF receptor-β signal to focal adhesions involved in vascular smooth muscle cell migration: role in neointimal formation after vascular injury”

TCT-637 A Novel Bioactive and Coating-Free Stent Surface Exhibits a Reduction in Neointimal Hyperplasia by Decreasing Platelet Aggregation and Promoting Endothelialization

TCT-637 A Novel Bioactive and Coating-Free Stent Surface Exhibits a Reduction in Neointimal Hyperplasia by Decreasing Platelet Aggregation and Promoting Endothelialization

A novel polymer‐free paclitaxel‐eluting stent with a nanoporous surface for rapid endothelialization and inhibition of intimal hyperplasia: Comparison with a polymer‐based sirolimus‐eluting stent and bare metal stent in a porcine model

Hypersensitivity and inflammatory responses to polymers may be responsible for late stent thrombosis after implantation of a drug-eluting stent (DES). Polymer-free DES may reduce the prevalence of these adverse reactions in vessels. We evaluated a polymer-free paclitaxel-eluting-stent with a nanoporous surface (nano-PES) for endothelialization and inhibition of neointimal hyperplasia by optical coherence tomography (OCT) and pathology in a porcine model. Nano-PES with high-dose (HD) and low-dose (LD) paclitaxel (1.0 μg/mm(2) and 0.4 μg/mm(2), respectively) was compared with a sirolimus-eluting stent (SES) and bare-metal stent (BMS) in a porcine model. Fifty-three stents (14 HD, 14 LD, 14 SES, 11 BMS) were implanted in 18 minipigs. At 14 days, nano-PES with HD and LD showed more complete endothelialization compared with SES. BMS had 100% endothelial coverage. At 28 days, a significant reduction in neointimal hyperplasia was detected by OCT in the nano-PES HD group compared with BMS. No benefit in prevention of the neointimal hyperplasia was observed in the nano-PES LD group. Nano-PES stents showed decreased deposition of fibrin and inflammation compared with SES. Pharmacokinetic studies revealed that nano-PES could effectively deliver the drug to the local coronary artery and it released the drug more rapidly than SES. Such a release profile was favorable for rapid endothelialization of nano-PES. The present study showed the nano-PES to be a new drug-delivery technology; that it used a nanoporous stent surface; that it offered desirable drug-elution properties without the use of polymers; that it may translate into an improved safety profile for next-generation DES.

Human Mesenchymal Stromal Cells (MSCs) Reduce Neointimal Hyperplasia in a Mouse Model of Flow-Restriction by Transient Suppression of Anti-Inflammatory Cytokines

Mesenchymal stromal cells from human bone marrow (hMSCs) were observed to produce therapeutic benefits in some models for cardiac and vascular injuries but their mode of action was not defined. We tested the effects of hMSCs in models for restricted vascular flow. We made model for restricted vascular flow produced by permanent ligation of a carotid artery and injected hMSCs to clarify the effects of hMSCs to vascular lesions. Seven, 14, and 28 days after infusion of hMSCs into the cardiac left ventricle of the mice, there was a significant reduction in neointimal hyperplasia (p<0.05). Seven days after administration of the hMSCs, macrophages infiltration into the ligated artery and serum levels of monocyte chemoattractive protein-1 (MCP-1/CCL-2) (p<0.05) were reduced. However, no hMSCs were detected in the lesions by sensitive PCR assays. We then observed that the serum level of MCP-1 was a potential biomarker for the therapeutic effects of hMSCs in a mouse model for high-fat-diet. These results indicated the administration of hMSCs decreased the initial and excess inflammatory responses to carotid artery ligation. The decrease in inflammatory response apparently decreased the subsequent neointimal hyperplasia.

Insulin enhances the effect of nitric oxide at inhibiting neointimal hyperplasia in a rat model of type 1 diabetes.

Diabetes confers greater restenosis from neointimal hyperplasia following vascular interventions. While localized administration of nitric oxide (NO) is known to inhibit neointimal hyperplasia, the effect of NO in type 1 diabetes is unknown. Thus the aim of this study was to determine the efficacy of NO following arterial injury, with and without exogenous insulin administration. Vascular smooth muscle cells (VSMC) from lean Zucker (LZ) rats were exposed to the NO donor, DETA/NO, following treatment with different glucose and/or insulin concentrations. DETA/NO inhibited VSMC proliferation in a concentration-dependent manner to a greater extent in VSMC exposed to normal-glucose vs. high-glucose environments, and even more effectively in normal-glucose/high-insulin and high-glucose/high-insulin environments. G(0)/G(1) cell cycle arrest and cell death were not responsible for the enhanced efficacy of NO in these environments. Next, type 1 diabetes was induced in LZ rats with streptozotocin. The rat carotid artery injury model was performed. Type 1 diabetic rats experienced no significant reduction in neointimal hyperplasia following arterial injury and treatment with the NO donor PROLI/NO. However, daily administration of insulin to type 1 diabetic rats restored the efficacy of NO at inhibiting neointimal hyperplasia (60% reduction, P < 0.05). In conclusion, these data demonstrate that NO is ineffective at inhibiting neointimal hyperplasia in an uncontrolled rat model of type 1 diabetes; however, insulin administration restores the efficacy of NO at inhibiting neointimal hyperplasia. Thus insulin may play a role in regulating the downstream beneficial effects of NO in the vasculature.

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.

Reduction of neointimal hyperplasia in porcine coronary arteries by 2-deoxy-d-glucose

The drug eluting stents have been shown to play a substantial role in preventing in-stent restenosis. This study was initiated to determine the efficacy of 2-deoxy-D-glucose (2-DG) in an in-stent restenosis model for reducing neointimal hyperplasia after coronary stent placement. In a porcine overstretch model, three kinds of stents were investigated (n = 12 per group): bare metal stents (BMS), rapamycin-eluted stents (RES), and BMS after intracoronary short-term application of 2-DG (DGS). After 42 days histomorphometric and histopathological analyses were performed. Neointimal thickness (BMS: 0.38 +/- 0.08, RES: 0.24 +/- 0.11, DGS: 0.15 +/- 0.01), area stenosis (BMS: 47.39 +/- 2.76, RES: 32.2 +/- 2.08, DGS: 29.30 +/- 2.98) did not differ after 42 days between the RES and DGS but were significantly lower as compared to BMS only. Lumen area (BMS: 3.15 +/- 1.53, RES: 4.37 +/- 1.72, DGS: 4.77 +/- 2.14) was significantly higher in the DGS group in comparison to the BMS group. The calculated injury and inflammation scores were similar and re-endothelialization was confirmed in all groups. This study could demonstrate that in porcine stent model neointimal hyperplasia and re-endothelialization after application of 2-DG are comparable to those seen in RES. Thus, 2-DG might be a promising clinical application for coronary stent coating.

Comparison of Sirolimus and Paclitaxel-Eluting Stents for Complex Coronary Lesions: An Intravascular Ultrasound Study

Background/AimsRecent intravascular ultrasound (IVUS) studies of sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) have demonstrated a significant reduction in neointimal hyperplasia (NIH) based on simple coronary lesions. In this study, we evaluated the efficacy of SES and PES using IVUS in complex coronary lesions.MethodsEighty-seven patients in whom 95 drug-eluting stents (66 SES and 29 PES) were implanted in complex coronary lesions were enrolled in this study. Case selection was based on the availability of IVUS and quantitative coronary angiographic (QCA) examinations at the index procedure and at follow-up. The neointimal volume index (volume/length: NIVI) and percent neointimal volume (% NIV) were calculated. The longitudinal length of stented segments without IVUS-detectable NIH was also evaluated.ResultsThe baseline patient demographics were similar between the SES and PES groups. At follow-up, no significant differences were observed in the vessel, plaque, or stent volume indices between the two groups. However, the NIVI and % NIV were significantly lower in the SES group (p<0.01). The longitudinal length of stented segments without IVUS-detectable NIH was significantly higher in the SES group (p<0.01). The net gain was significantly larger in the SES group (2.3±0.7 vs. 2.0×0.6 mm, p=0.025), while the rate of major adverse cardiac events was similar between the two groups.ConclusionsAlthough SES showed significantly greater suppression of NIH at follow-up, both stents were highly effective at inhibiting NIH in complex coronary lesions.

Systemic Immunosuppressive Therapy with Oral Sirolimus after Bare Metal Stent Implantation: The Missing Alternative in the Prevention of Coronary Restenosis after Percutaneous Coronary Interventions

In recent years, percutaneous coronary intervention (PCI) with drug eluting stents (DES) to treat de novo coronary lesions has been associated with a significant reduction of neointimal hyperplasia and in-stent restenosis. However, several publications raise concerns about long-term safety of DES, especially with the emerging anxiety with the problem of late stent thrombosis. Different registries with DES reported a growing incidence of stent thrombosis up to three years after stent implantation. In parallel with DES introduction in clinical practice in the last seven years, we identified six reported observational and randomized clinical experiences assessing the potential role of oral Sirolimus therapy in the prevention of coronary restenosis after bare metal stent implantation. Three observational and three randomized studies were performed during these years. Several implications were drawn: First, systemic therapy was given for only 14 days after PCI; minor transient side effects were observed in 25% of patients and were completely relieved after discontinuation of the drug. Secondly, angiographic restenosis and late loss are strongly related with Sirolimus blood concentration during the first week of treatment and were significantly reduced compared to non therapy. Finally, in the last randomized study, oral Sirolimus plus bare metal stent were cost saving compared to drug eluting stents with a trend to better clinical late outcome with the oral immunosuppressive therapy. The manuscript also reviews recent patents with new drugs, combination of drugs and DES designs which would improve safety and efficacy in the restenosis prevention after angioplasty.

Meta-Iodobenzylguanidine, an Inhibitor of Arginine-Dependent Mono(ADP-ribosyl)ation, Prevents Neointimal Hyperplasia

The association of ADP-ribosylation with cell proliferation and ischemia-reperfusion injury suggests that it may be a suitable target for therapeutic control of revascularization-induced injury. The purpose of this study was to investigate the inhibitory actions of ADP-ribosylation inhibitors on restenosis. In organ culture, the poly(ADP-ribose) polymerase (PARP) inhibitor 3,4-dihydro-5-methylisoquinolinone (PD128763) was unable to prevent neointimal hyperplasia, whereas the arginine-dependent mono(ADP-ribosyl)transferase (ART) inhibitor meta-iodobenzylguanidine (MIBG) was highly effective (EC(50) 21 microM). Treatment with 3-aminobenzamide (3AB), a less potent ART inhibitor, also produced a significant reduction in neointimal hyperplasia. Single doses (25 mM) of MIBG and 3AB were also applied within a fibrin coagulum directly to the adventitial surface of the porcine femoral artery after balloon catheter injury in vivo. MIBG reduced the neointimal index, measured 14 days after angioplasty, by 82%, whereas 3AB was ineffective. However, when extended to 45 days, the neointimal index was not significantly decreased by MIBG treatment relative to control. Assessment of MIBG release from the fibrin glue showed that the bulk of the compound was eluted within 3 days, suggesting that the vehicle was not suitable for long-term delivery. On the other hand, direct infusion of MIBG into vessels was able to reduce neointimal hyperplasia over 14 days in organ culture. These data support the conclusion that the cellular retention characteristics of MIBG contribute significantly to the efficacy of this compound. Based on these results, ART, but not PARP, may be a credible target for therapeutic treatment of restenosis.

β-Arrestins Regulate Atherosclerosis and Neointimal Hyperplasia by Controlling Smooth Muscle Cell Proliferation and Migration

Atherosclerosis and arterial injury-induced neointimal hyperplasia involve medial smooth muscle cell (SMC) proliferation and migration into the arterial intima. Because many 7-transmembrane and growth factor receptors promote atherosclerosis, we hypothesized that the multifunctional adaptor proteins beta-arrestin1 and -2 might regulate this pathological process. Deficiency of beta-arrestin2 in ldlr(-/-) mice reduced aortic atherosclerosis by 40% and decreased the prevalence of atheroma SMCs by 35%, suggesting that beta-arrestin2 promotes atherosclerosis through effects on SMCs. To test this potential atherogenic mechanism more specifically, we performed carotid endothelial denudation in congenic wild-type, beta-arrestin1(-/-), and beta-arrestin2(-/-) mice. Neointimal hyperplasia was enhanced in beta-arrestin1(-/-) mice, and diminished in beta-arrestin2(-/-) mice. Neointimal cells expressed SMC markers and did not derive from bone marrow progenitors, as demonstrated by bone marrow transplantation with green fluorescent protein-transgenic cells. Moreover, the reduction in neointimal hyperplasia seen in beta-arrestin2(-/-) mice was not altered by transplantation with either wild-type or beta-arrestin2(-/-) bone marrow cells. After carotid injury, medial SMC extracellular signal-regulated kinase activation and proliferation were increased in beta-arrestin1(-/-) and decreased in beta-arrestin2(-/-) mice. Concordantly, thymidine incorporation and extracellular signal-regulated kinase activation and migration evoked by 7-transmembrane receptors were greater than wild type in beta-arrestin1(-/-) SMCs and less in beta-arrestin2(-/-) SMCs. Proliferation was less than wild type in beta-arrestin2(-/-) SMCs but not in beta-arrestin2(-/-) endothelial cells. We conclude that beta-arrestin2 aggravates atherosclerosis through mechanisms involving SMC proliferation and migration and that these SMC activities are regulated reciprocally by beta-arrestin2 and beta-arrestin1. These findings identify inhibition of beta-arrestin2 as a novel therapeutic strategy for combating atherosclerosis and arterial restenosis after angioplasty.