Central role of endogenous Toll-like receptor-2 activation in regulating inflammation, reactive oxygen species production, and subsequent neointimal formation after vascular injury

Background

It is now evident that inflammation after vascular injury has significant impact on the restenosis after revascularization procedures such as angioplasty, stenting, and bypass grafting. However, the mechanisms that regulate inflammation and repair after vascular injury are incompletely understood. Here, we report that vascular injury-mediated cytokine expression, reactive oxygen species (ROS) production, as well as subsequent neointimal formation requires Toll-like receptor-2 (TLR-2) mediated signaling pathway in vivo.

Methods and results

Vascular injury was induced by cuff-placement around the femoral artery in non-transgenic littermates (NLC) and TLR-2 knockout (TLR-2KO) mice. After cuff-placement in NLC mice, expression of TLR-2 was significantly increased in both smooth muscle medial layer and adventitia. Interestingly, we found that inflammatory genes expression such as tumor necrosis factor-α, interleukin-1β (IL-1β), IL-6, and monocyte chemoattractant protein-1 were markedly decreased in TLR-2KO mice compared with NLC mice. In addition, ROS production after vascular injury was attenuated in TLR-2KO mice compared with NLC mice. Since we observed the significant role of endogenous TLR-2 activation in regulating inflammatory responses and ROS production after vascular injury, we determined whether inhibition of endogenous TLR-2 activation can inhibit neointimal proliferation after vascular injury. Neointimal hyperplasia was markedly suppressed in TLR-2KO mice compared with WT mice at both 2 and 4 weeks after vascular injury.

Conclusions

These findings suggested that endogenous TLR-2 activation might play a central role in the regulation of vascular inflammation as well as subsequent neointimal formation in injured vessels.     

Long period of balloon inflation and the implantation of stents potentiate smooth muscle cell death. Possible role of chronic vascular injury in restenosis

BACKGROUND: It has been suggested that the severity of acute vascular injury immediately after percutaneous transluminal coronary angioplasty (PTCA) or stent implantation correlates with the extent of neointimal hyperplasia and restenosis. However, the influence of prolonged or chronic vessel injury on the pathogenesis of restenosis is unclear. METHODS: Rabbit iliac arteries were balloon dilated for a short (1 min) or prolonged (10 min) period of time, or were chronically dilated and received a Palmaz-Schatz stent (balloon inflation for 1 min). All arteries were overexpanded to a balloon:artery ratio of 1.2:1 as determined by angiography. The arteries were removed 30 min and 4 weeks after the angioplasty procedures. The sites of injury were evaluated by gross histology and transmission electron microscopy (TEM). Cell death of medial smooth muscle cells (SMCs) was specified by TEM images 30 min after the procedures. Computer-assisted quantification of the neointimal cross-sectional areas was performed after 4 weeks using a light microscope connected to a digital image analyser. RESULTS: The results show that prolonged balloon dilatation and stent implantation increased necrotic SMC death compared with balloon dilatation for 1 min. After 30 min, increased staining of SMC nuclei, enlarged intercellular spaces and changes in SMC shape in the media indicated cell death induced by prolonged balloon dilatation or chronic stent injury. Stent implantation markedly augmented vessel damage by persistent compression of the media, compared with a balloon dilatation for 1 or 10 min. Both prolonged balloon dilatation and stent implantation increased neointimal hyperplasia at 4 weeks compared with balloon dilatation for 1 min (0.6 3 0.2 and 1.0 3 0.2 mm(2) versus 0.2 3 0.1 mm(2), P < 0.001 versus dilatation for 1 min). CONCLUSION: Prolonged or chronic vascular expansion due to long balloon-inflation periods or the implantation of stents increases medial SMC death, which subsequently stimulates neointimal growth in this restenosis model. Chronic vascular injury may be an important stimulus for restenosis after angioplasty procedures.     

Carbon Monoxide-Induced Early Thrombolysis Contributes to Heme Oxygenase-1-Mediated Inhibition of Neointimal Growth after Vascular Injury in Hypercholesterolemic Mice

Arterial thrombosis is a critical event in the pathogenesis of lesion development. In this study, we evaluated the effect of heme oxygenase-1 (HO-1), a stress-inducible enzyme with vasoprotective functions, on arterial thrombosis following vascular mechanical injury. The carotid arteries of apoE-deficient mice were subjected to angioplasty with a modified beaded-needle. Arterial thrombosis occurred at 12 h after injury. Treatment of the injured vessels with an adenovirus bearing HO-1 gene (Adv-HO-1) (1× 10⁸ pfu), but not saline or empty adenovirus (Adv), immediately after angioplasty resulted in earlier thrombolysis and restoration of blood flow detected at 24 h. Immunohistochemistry revealed that the arterial plasminogen activator inhibitor-1 (PAI-1) expression was markedly reduced in Adv-HO-1-treated injured arteries as compared to control counterparts. The thrombolytic effect was also observed by exposing animals with existing arterial thrombosis to carbon monoxide (CO) (250 ppm, 2 h), a byproduct derived from heme degradation by HO-1. In parallel with less fibrin(ogen) deposition, the macrophage infiltration, monocyte chemoattractant protein-1 expression and neointimal formation assessed at 2 weeks after angioplasty were substantially reduced in injured arteries treated with Adv-HO-1. These results support a role of early thrombolysis induced by CO in HO-1-mediated protection against intimal hyperplasia after vascular injury.     

Modelling intravascular delivery from drug-eluting stents with biodurable coating: investigation of anisotropic vascular drug diffusivity and arterial drug distribution

In-stent restenosis occurs in coronary arteries after implantation of drug-eluting stents with non-uniform restenosis thickness distribution in the artery cross section. Knowledge of the spatio-temporal drug uptake in the arterial wall is useful for investigating restenosis growth but may often be very expensive/difficult to acquire experimentally. In this study, local delivery of a hydrophobic drug from a drug-eluting stent implanted in a coronary artery is mathematically modelled to investigate the drug release and spatio-temporal drug distribution in the arterial wall. The model integrates drug diffusion in the coating and drug diffusion with reversible binding in the arterial wall. The model is solved by the finite volume method for both high and low drug loadings relative to its solubility in the stent coating with varied isotropic–anisotropic vascular drug diffusivities. Drug release profiles in the coating are observed to depend not only on the coating drug diffusivity but also on the properties of the surrounding arterial wall. Time dependencies of the spatially averaged free- and bound-drug levels in the arterial wall on the coating and vascular drug diffusivities are discussed. Anisotropic vascular drug diffusivities result in slightly different average drug levels in the arterial wall but with very different spatial distributions. Higher circumferential vascular diffusivity results in more uniform drug loading in the upper layers and is potentially beneficial in reducing in-stent restenosis. An analytical expression is derived which can be used to determine regions in the arterial with higher free-drug concentration than bound-drug concentration.     

Essential role of Pin1 via STAT3 signalling and mitochondria‐dependent pathways in restenosis in type 2 diabetes

Type 2 diabetes (T2D) is associated with accelerated restenosis rates after angioplasty. We have previously proved that Pin1 played an important role in vascular smooth muscle cell (VSMC) cycle and apoptosis. But neither the role of Pin1 in restenosis by T2D, nor the molecular mechanism of Pin1 in these processes has been elucidated. A mouse model of T2D was generated by the combination of high‐fat diet (HFD) and streptozotocin (STZ) injections. Both Immunohistochemistry and Western blot revealed that Pin1 expression was up‐regulated in the arterial wall in T2D mice and in VSMCs in culture conditions mimicking T2D. Next, increased activity of Pin1 was observed in neointimal hyperplasia after arterial injury in T2D mice. Further analysis confirmed that 10% serum of T2D mice and Pin1‐forced expression stimulated proliferation, inhibited apoptosis, enhanced cell cycle progression and migration of VSMCs, whereas Pin1 knockdown resulted in the converse effects. We demonstrated that STAT3 signalling and mitochondria‐dependent pathways played critical roles in the involvement of Pin1 in cell cycle regulation and apoptosis of VSMCs in T2D. In addition, VEGF expression was stimulated by Pin1, which unveiled part of the mechanism of Pin1 in regulating VSMC migration in T2D. Finally, the administration of juglone via pluronic gel onto injured common femoral artery resulted in a significant inhibition of the neointima/media ratio. Our findings demonstrated the vital effect of Pin1 on the VSMC proliferation, cell cycle progression, apoptosis and migration that underlie neointima formation in T2D and implicated Pin1 as a potential therapeutic target to prevent restenosis in T2D.     

Noncanonical Matrix Metalloprotease-1-Protease-activated Receptor-1 Signaling Triggers Vascular Smooth Muscle Cell Dedifferentiation and Arterial Stenosis

Vascular injury that results in proliferation and dedifferentiation of vascular smooth muscle cells (SMCs) is an important contributor to restenosis following percutaneous coronary interventions or plaque rupture. Protease-activated receptor-1 (PAR1) has been shown to play a role in vascular repair processes; however, little is known regarding its function or the relative roles of the upstream proteases thrombin and matrix metalloprotease-1 (MMP-1) in triggering PAR1-mediated arterial restenosis. The goal of this study was to determine whether noncanonical MMP-1 signaling through PAR1 would contribute to aberrant vascular repair processes in models of arterial injury. A mouse carotid arterial wire injury model was used for studies of neointima hyperplasia and arterial stenosis. The mice were treated post-injury for 21 days with a small molecule inhibitor of MMP-1 or a direct thrombin inhibitor and compared with vehicle control. Intimal and medial hyperplasia was significantly inhibited by 2.8-fold after daily treatment with the small molecule MMP-1 inhibitor, an effect that was lost in PAR1-deficient mice. Conversely, chronic inhibition of thrombin showed no benefit in suppressing the development of arterial stenosis. Thrombin-PAR1 signaling resulted in a supercontractile, differentiated phenotype in SMCs. Noncanonical MMP-1-PAR1 signaling resulted in the opposite effect and led to a dedifferentiated phenotype via a different G protein pathway. MMP-1-PAR1 significantly stimulated hyperplasia and migration of SMCs, and resulted in down-regulation of SMC contractile genes. These studies provide a new mechanism for the development of vascular intimal hyperplasia and suggest a novel therapeutic strategy to suppress restenosis by targeting noncanonical MMP-1-PAR1 signaling in vascular SMCs.     

Angina pectoris: interventional therapies and treatment of restenosis

Angina pectoris is a clinical syndrome of symptoms caused by myocardial ischaemia due to oxygen demand exceeding supply. The most common cause is coronary artery stenosis due to progressive atherosclerotic disease. Angina has a prevalence of approximately 5% and increases with age. Despite improvements in treatment there remains a yearly mortality of 2-3%. A major advance in the treatment of symptomatic angina was the introduction of percutaneous transluminal coronary angioplasty (PTCA). This initial enthusiasm was dampened by significant numbers developing symptomatic restenosis from vascular elastic recoil and neointimal hyperplasia (NI). The widespread introduction of stent deployment following the initial angioplasty reduced the rates of elastic recoil but failed to prevent NI and may actually stimulate it. Currently, there is much interest in mechanisms that alter cell proliferation thereby decreasing NI. Techniques include brachytherapy, photodynamic therapy and drug-eluting stents. Provisional data for these new stents, which slowly release medication that inhibits cell turnover, are very good with few occurrences of restenosis. Results from larger randomised trials are awaited.     

Cardiovascular stent design and vessel stresses: a finite element analysis

Intravascular stents of various designs are currently in use to restore patency in atherosclerotic coronary arteries and it has been found that different stents have different in-stent restenosis rates. It has been hypothesized that the level of vascular injury caused to a vessel by a stent determines the level of restenosis. Computational studies may be used to investigate the mechanical behaviour of stents and to determine the biomechanical interaction between the stent and the artery in a stenting procedure. In this paper, we test the hypothesis that two different stent designs will provoke different levels of stress within an atherosclerotic artery and hence cause different levels of vascular injury. The stents analysed using the finite-element method were the S7 (Medtronic AVE) and the NIR (Boston Scientific) stent designs. An analysis of the arterial wall stresses in the stented arteries indicates that the modular S7 stent design causes lower stress to an atherosclerotic vessel with a localized stenotic lesion compared to the slotted tube NIR design. These results correlate with observed clinical restenosis rates, which have found higher restenosis rates in the NIR compared with the S7 stent design. Therefore, the testing methodology outlined here is proposed as a pre-clinical testing tool, which could be used to compare and contrast existing stent designs and to develop novel stent designs.     

Fabrication of drug-eluting covered stents with micropores and differential coating of heparin and FK506

To reduce in-stent restenosis rates, we developed a novel drug-eluting covered stent with a microporous elastometric covered film, in which its luminal surface was flat and immobilized with heparin for anticoagulation and its outer surface immobilized with FK506 to prevent neointimal hyperplasia. One month after implantation into the bilateral common carotid arteries, all stented arteries were patent and the luminal surfaces were fully covered with a confluent of endothelial cells irrespective of the drug immobilization. In the control group, which consisted of covered stents without drug immobilization, intensive inflammatory cells adjacent to the stents and neointimal hyperplasia, indicating vascular injury, were observed. In contrast, in the developed drug-eluting stents, only a few inflammatory cells around the stent strut and covered film were observed, and there was no significant neointimal thickening.     

Antisense oligodeoxyribonucleotide as to the growth factor midkine suppresses neointima formation induced by balloon injury

Restenosis is the major clinical problem of angioplasty. We have previously shown that neointima formation is strikingly suppressed in midkine (MK)-deficient mice. Neointima formation is restored if MK protein is administrated to the deficient mice. MK is a heparin-binding growth factor and implicated in the migration of inflammatory cells and vascular smooth muscle cells. Consistently, the suppression of neointima formation in the deficient mice is accompanied by suppression of recruitment of inflammatory cells into the vascular wall. Here, we evaluated the potential of MK antisense oligodeoxyribonucleotide (ODN) for the prevention of restenosis. We cloned the cDNA of rabbit MK, which showed a strongly conserved sequence in mammals. The balloon injury induced MK expression, with the maximum level occurring 7-14 days after angioplasty, in the rabbit carotid artery. Two antisense ODNs suppressed the production of MK in a rabbit kidney cell line, RK13 cells, one of which was then transfected into the arterial wall by means of lipofection immediately after balloon treatment. The antisense ODN suppressed MK induction in vivo and consequently suppressed neointima formation to 60% of the control level. These results suggest that MK is a candidate molecular target for the therapy for vascular restenosis.     

Interference of IP-10 Expression Inhibits Vascular Smooth Muscle Cell Proliferation and Intimal Hyperplasia in Carotid Artery: A New Insight in the Prevention of Restenosis

After vascular angioplasty, vascular smooth muscle cell (VSMC) proliferation causes atherosclerosis and intimal hyperplasia leading to restenosis. Interferon-γ-inducible protein (IP)-10 plays a role in atherogenesis, but the mechanism remains unclear. We evaluated the role of IP-10 in intimal hyperplasia and restenosis. IP-10 expression was determined in arterial specimens from 20 arteriosclerotic obliteration patients and 6 healthy individuals. VSMCs were stimulated in vitro with IFN-γ and transfected with IP-10 siRNA. Silencing was verified with RT-PCR/Western blot; cell proliferation rate was detected by methyl-thiazol-tetrazolium. The carotid artery model of atherosclerosis injury was established with IP-10 siRNA. IP-10 expression was detected at 1 and 4 weeks using RT-PCR and immunohistochemistry. Artery morphology was assessed with hematoxylin-and-eosin staining, and intimal hyperplasia was evaluated by electron microscopy. IP-10 was overexpressed in arteriosclerotic obliteration group compared with control group (P < 0.05). IP-10 expression in transfected group was significantly lower than in untransfected group. The intima-to-media ratio of transfected group at 4 weeks was lower than that of untransfected group (P < 0.01). The transfected group exhibited more regular intimal structure and less hyperplasia under electron microscopy. We, therefore, concluded that IP-10 played an important role in intimal hyperplasia as siRNA-mediated IP-10 silencing inhibited aberrant VSMCs hyperplasia and reduced restenosis.     

Biodegradable stents as a platform to drug loading

Despite technical and mechanical improvement in coronary stents the incidence of restenosis caused by in-stent neointimal hyperplasia remains high. Oral administration of numerous pharmacological agents has failed to reduce restenosis after coronary stenting in humans, possibly owing to insufficient local drug concentration. Therefore, drug-eluting stents were developed as a vehicle for local drug administration. The authors developed a new drug-eluting polymer stent that is made of poly-l-lactic acid polymer mixed with tranilast, an anti-allergic drug that inhibits the migration and proliferation of vascular smooth muscle cells induced by platelet-derived growth factor and transforming growth factor->1. Polymer stents might be superior to polymer-coated metallic stents as local drug delivery stents in terms of biodegradation and the amount of loaded drug. Drug-mixed polymer stents can be loaded with a larger amount of drug than can drug-coated metallic stents because the polymer stent struts can contain the drug. Clinical application is required to assess the safety and efficacy of drug-eluting polymer stents against stent restenosis.     

Stresses in peripheral arteries following stent placement: a finite element analysis

The success of stents to restore blood flow in atherosclerotic peripheral arteries is low relative to coronary arteries. It has been shown that joint flexion induces a mechanical environment that makes stent placement in these arteries highly incompatible, and damage and destruction of stents has been recorded. However, the effect of this environment on the stresses in the arteries is unknown. It is hypothesised that the stresses induced in arteries as a result of this mechanical environment could be sufficient to explain the relatively low success rates. To investigate this hypothesis, a finite element model of the stent-artery interaction was developed. Following stent expansion, bending was simulated by applying a displacement boundary condition to the artery. It is found that high stresses occur at the proximal/distal ends of the stent. As high stress and vascular injury are hypothesised to cause restenosis, the results presented here suggest that the mechanical environment of peripheral arteries could be the predominant cause of high restenosis rates.     

MCP-1 deficiency is associated with reduced intimal hyperplasia after arterial injury

Monocyte chemoattractant protein (MCP)-1 is abundant in smooth muscle cells (SMC) and macrophages of atherosclerotic plaques and in the injured arterial wall. MCP-1 and its receptor, CCR2, are important mediators of macrophage accumulation and atherosclerotic plaque progression. We have recently reported that CCR2(-/-) mice have a approximately 60% decrease in intimal hyperplasia and medial DNA synthesis in response to femoral arterial injury. We have now examined the response to femoral arterial injury in MCP-1(-/-) mice. MCP-1 deficiency was associated with a approximately 30% reduction in intimal hyperplasia at 4 weeks and was not associated with diminished medial DNA synthesis. Despite inducing tissue factor in SMC culture, MCP-1 deficiency was not associated with a decrease in neointimal tissue factor after injury. These data suggest that MCP-1 and CCR2 deficiencies have distinct effects on arterial injury. The effects of MCP-1 on intimal hyperplasia may be mediated largely through SMC migration.     

Local methylprednisolone delivery using a BiodivYsio phosphorylcholine-coated drug-delivery stent reduces inflammation and neointimal hyperplasia in a porcine coronary stent model

Phosphorylcholine (PC)-coated stents have shown excellent blood and tissue biocompatibility in porcine coronary arteries. The purpose of this study was to determine the efficacy of local methylprednisolone (MP) delivery using PC-coated stents to inhibit inflammatory response and in-stent neointimal hyperplasia in an overstretched porcine coronary model. BiodivYsio (Biocompatibles, Farnham, Surrey, UK) PC-coated drug delivery (DD) stents and DD stents loaded with a high dose of MP (269 microg) were implanted in the coronary arteries of 20 pigs with a balloon/artery ratio of 1.2 : 1. At five days the peri-strut inflammatory response score and thrombus score of the MP-loaded DD stents were lower than in the control stents. The neointimal hyperplasia of MP-loaded DD stents was significantly reduced (0.80 +/- 0.10 versus 0.48 +/- 0.10 mm(2), p < 0.01). At four-week follow-up, the inflammatory response of MP-loaded stents was lower than the control stents, but without significant difference. The MP-loaded stents showed decreased peri-strut arterial injury and in-stent neointimal hyperplasia (2.42 +/- 0.87 versus 1.62 +/- 0.71 mm(2), p < 0.05). It is concluded that local vascular delivery of a high dose of MP from PC-coated DD stents could effectively decrease inflammatory response and thrombus formation after oversized stent deployment and result in a significant reduction of neointimal hyperplasia.     

Intramural delivery of Sirolimus prevents vascular remodeling following balloon injury

OBJECTIVE: Several studies have demonstrated that Sirolimus-eluting stents reduce restenosis in patients with coronary artery disease. Here, we tested whether direct delivery of Sirolimus into the vessel wall during balloon angioplasty can modify vascular remodeling over several weeks. METHODS AND RESULTS: During angioplasty of the rabbit iliac artery we administered an intramural infusion of Sirolimus or its vehicle directly through a balloon catheter into the vessel wall. After 3 weeks neointimal formation was decreased (0.71+/-0.1 vs. 1.4+/-0.12 intima/media ratio), and this process was attributed to the inhibitory properties of Sirolimus on ECM deposition and smooth muscle cell proliferation. Sirolimus also significantly reduced the deposition of elastin, collagen III and fibronectin within the vascular wall. In parallel, proteomic profiles of arterial wall segments were obtained and 485 protein spots were consistently matched between non-dilated and dilated vessels. Differential expression of 12 proteins were observed between the groups and direct sequencing of digested peptides was performed. Local delivery of sirolimus during angioplasty attenuated the expression of structural proteins that included lamin A, vimentin, alpha-1-antitrypsin, and alpha-actin. CONCLUSIONS: Local administration of Sirolimus during angioplasty prevents smooth muscle cell proliferation associated with vascular remodeling as well as the expression of extracellular matrix and structural proteins. Therefore, local injection of Sirolimus during balloon inflation may be an alternative therapeutic approach for preventing restenosis in small stenotic vessels (i.e., <2.5 mm).     

Blockade of both alpha1A- and alpha1B-adrenergic receptor subtype signaling is required to inhibit neointimal formation in the mouse femoral artery

Attenuation of early restenosis after percutaneous coronary intervention (PCI) is important for the successful treatment of coronary artery disease. Some clinical studies have shown that hypertension is a risk factor for early restenosis after PCI. These findings suggest that alpha(1)-adrenergic receptors (alpha(1)-ARs) may facilitate restenosis after PCI because of alpha(1)-AR's remarkable contribution to the onset of hypertension. In this study, we examined the neointimal formation after vascular injury in the femoral artery of alpha(1A)-knockout (alpha(1A)-KO), alpha(1B)-KO, alpha(1D)-KO, alpha(1A)-/alpha(1B)-AR double-KO (alpha(1AB)-KO), and wild-type mice to investigate the functional role of each alpha(1)-AR subtype in neointimal formation, which is known to promote restenosis. Neointimal formation 4 wk after wire injury was significantly (P < 0.05) smaller in alpha(1AB)-KO mice than in any other group of mice, while blood pressures were not altered in any of the groups of mice after wire injury compared with those before it. These results suggest that lack of both alpha(1A)- and alpha(1B)-ARs could be necessary to inhibit neointimal formation in the mouse femoral artery.     

Late color duplex scanning diagnosis of the areas of endovascular intervention into arteries and lower extremity shunts

The purpose of the study was to assess the areas of balloon angioplasty (BAP) and stenting of lower extremity arteries and femoral, popliteal, mainly, in situ autovenous shunts, by using color duplex scanning (CDS) in the late period of a follow-up. Materials and methods. The CDS technique could diagnose 344 (64%) areas of BAP and stenting of lower extremity arteries and shunts. The echosemiotics of complications typical of a late period was determined. Based on the specified echosemiotics of late complications, the author detected 99 (28.8%) cases of hemodynamically significant complications: BAP and stenting area stenosis (n=25 (7.3%)); BAP area restenosis (reocciusion) (n=33 (9.6%)); stent restenosis (n=19 (5.5%), arterial stenosis proximal and distal to a stent (n=17 4.9%)), and stent breakage (n=5 (1.5%)). Hemodynamically insignificant complications were revealed in 90 (26.2%) cases: intimal dissection in 16 (4.7%) cases, BAP area restenosis in 35 (10%), stent restenosis in 15 (4.4%), and arterial stenosis proximal or distal to the stent and between the stents. In the late period following BAP and stenting aortoiliac patency was 87.50 + 3.18% during a mean follow-up o 27.58 + 1.50 months. In the late period, the patency of the superficial femoral artery (SFR) was 55.41 + 14.43% during a mean follow-up of 22.60 + 2.73 months, that of the popliteal artery (PA) was 67.34 + 15.98% during a mean follow-up of 43.08 + 5.81 months, that of shin arteries was 44.96 + 19.77% during a mean follow-up of 18.76 + 2.58 months, and that of shunts, was 40.89 + 18.47% during a mean follow-up of 23.32 + 2.29 months. Thus, changes caused by the progression of the underlying disease--atherosclerosis were found in the areas of BAP and stenting of lower extremity arteries and shunts. Stent breakage may be due to "metal deterioration" and the presence of a stent in the superficial femoral artery with greatest functional load on extremity movement and flexion. The blood flow spectrum mode recording a local hemodynamic shift with > 2.0-2.5-fold linear blood flow velocity increase in the complication area was leading in the operation of an ultrasound apparatuses in the differential diagnosis of hemodynamically significant and insignificant complications. The results of good late patency of the areas of BAP and stentming of SFR and PA may be accounted for by strict criteria for selecting patients for endovascular surgery, by taking into account the indications for and contraindications to TASC (2001). In our study, 20 endovascular reinterventions (repeated balloon angioplasty, additional stenting stent balloon angioplasty) in complicated areas were performed, which maintained and prolonged the function of segments. The detection of hemodynamically insignificant complications revealed patients who need further meticulous follow-up ultrasound studies.