ABSTRACT
Abstract Background: Vein graft restenosis has an adverse impact on bridge vessel circulation and patient prognosis after coronary artery bypass grafting. Objectives: We used the extravascular supporter α-cyanoacrylate (α-CA), the local application rapamycin/sirolimus (RPM), and a combination of the two (α-CA-RPM) in rat models of autogenous vein graft to stimulate vein graft change. The aim of our study was to observe the effect of α-CA, RPM, and α-CA-RPM on vein hyperplasia. Methods: Fifty healthy Sprague Dawley (SD) rats were randomized into the following 5 groups: sham, control, α-CA, RPM, and α-CA-RPM. Operating procedure as subsequently described was used to build models of grafted rat jugular vein on carotid artery on one side. The level of endothelin-1 (ET-1) was determined by enzyme-linked immunosorbent assay (ELISA). Grafted veins were observed via naked eye 4 weeks later; fresh veins were observed via microscope and image-processing software in hematoxylin-eosin (HE) staining and immunohistochemistry after having been fixed and stored" (i.e. First they were fixed and stored, and second they were observed); α-Smooth Muscle Actin (αSMA) and von Willebrand factor (vWF) were measured with reverse transcription-polymerase chain reaction (RT-PCR). Comparisons were made with single-factor analysis of variance and Fisher's least significant difference test, with p < 0.05 considered significant. Results: We found that intimal thickness of the α-CA, RPM, and α-CA-RPM groups was lower than that of the control group (p < 0.01), and the thickness of the α-CA-RPM group was notably lower than that of the α-CA and RPM groups (p < 0.05). Conclusion: RPM combined with α-CA contributes to inhibiting intimal hyperplasia in rat models and is more effective for vascular patency than individual use of either α-CA or RPM.
Resumo Fundamento: Reestenose de enxertos venosos tem um impacto adverso na circulação de pontagens e no prognóstico de pacientes após a cirurgia de revascularização miocárdica. Objetivos: Nós utilizamos α-cianoacrilato (α-CA) como suporte extravascular, rapamicina/sirolimus (RPM) como aplicação local e a combinação dos dois (α-CA-RPM) em modelos de enxerto venoso autógeno em ratos para estimular mudança no enxerto venoso. O objetivo do nosso estudo foi observar o efeito de α-CA, RPM e α-CA-RPM na hiperplasia venosa. Métodos: Cinquenta ratos Sprague Dawley (SD) saudáveis foram randomizados nos 5 grupos seguintes: sham, controle, α-CA, RPM e α-CA-RPM. O procedimento operacional descrito subsequentemente foi utilizado para construir modelos de enxertos da veia jugular na artéria carótida em ratos, em um lado. O nível de endotelina-1 (ET-1) foi determinado por ensaio de imunoabsorção enzimática (ELISA). As veias enxertadas foram observadas a olho nu 4 semanas após; as veias frescas foram observadas via microscópio e software de processamento de imagem com coloração hematoxilina-eosina (HE) e imuno-histoquímica depois de serem fixadas e armazenadas; α-actina do músculo liso (αSMA) e o fator de von Willebrand (vWF) foram medidos com reação em cadeia da polimerase-transcriptase reversa (RT-PCR). Realizaram-se as comparações com análise de variância de fator único (ANOVA) e o teste de diferença mínima significativa (LSD) de Fisher, com p < 0,05 sendo considerado estatisticamente significante. Resultados: Nós achamos que a espessura intimal nos grupos α-CA, RPM e α-CA-RPM era menor que no grupo controle (p < 0,01) e a espessura no grupo α-CA-RPM era notavelmente menor que nos grupos α-CA e RPM (p < 0,05). Conclusão: A combinação de RPM e α-CA contribui à inibição de hiperplasia em modelos em ratos e é mais efetivo para patência vascular que uso individual de α-CA ou RPM.
Subject(s)
Animals , Male , Female , Tunica Intima/drug effects , Tunica Intima/pathology , Sirolimus/pharmacology , Cyanoacrylates/pharmacology , Hyperplasia/prevention & control , Time Factors , Enzyme-Linked Immunosorbent Assay , Carotid Arteries/pathology , Carotid Arteries/transplantation , Random Allocation , Coronary Artery Bypass/adverse effects , Reproducibility of Results , Actins/analysis , Treatment Outcome , Rats, Sprague-Dawley , Endothelin-1/blood , Reverse Transcriptase Polymerase Chain Reaction , Cell Proliferation/drug effects , Disease Models, Animal , Drug Combinations , Graft Occlusion, Vascular/etiology , Graft Occlusion, Vascular/pathology , Graft Occlusion, Vascular/prevention & control , Jugular Veins/pathology , Jugular Veins/transplantationABSTRACT
Abstract Background: Restenosis after percutaneous coronary intervention in coronary heart disease remains an unsolved problem. Clusterin (CLU) (or Apolipoprotein [Apo] J) levels have been reported to be elevated during the progression of postangioplasty restenosis and atherosclerosis. However, its role in neointimal hyperplasia is still controversial. Objective: To elucidate the role Apo J in neointimal hyperplasia in a rat carotid artery model in vivo with or without rosuvastatin administration. Methods: Male Wistar rats were randomly divided into three groups: the control group (n = 20), the model group (n = 20) and the statin intervention group (n = 32). The rats in the intervention group were given 10mg /kg dose of rosuvastatin. A 2F Fogarty catheter was introduced to induce vascular injury. Neointima formation was analyzed 1, 2, 3 and 4 weeks after balloon injury. The level of Apo J was measured by real-time PCR, immunohistochemistry and western blotting. Results: Intimal/medial area ratio (intimal/medial, I/M) was increased after balloon-injury and reached the maximum value at 4weeks in the model group; I/M was slightly increased at 2 weeks and stopped increasing after rosuvastatin administration. The mRNA and protein levels of Apo J in carotid arteries were significantly upregulated after rosuvastatin administration as compared with the model group, and reached maximum values at 2 weeks, which was earlier than in the model group (3 weeks). Conclusion: Apo J served as an acute phase reactant after balloon injury in rat carotid arteries. Rosuvastatin may reduce the neointima formation through up-regulation of Apo J. Our results suggest that Apo J exerts a protective role in the restenosis after balloon-injury in rats.
Resumo Fundamento: A reestenose após intervenção coronária percutânea (ICP) após doença coronariana continua um problema não solucionado. Estudos relataram que os níveis de clusterina (CLU), também chamada de apolipoproteína (Apo) J, encontram-se elevados na progressão da reestenose pós-angioplastia e na aterosclerose. Contudo, seu papel na hihperplasia neointimal ainda é controverso. Objetivo: Elucidar o papel da Apo J na hiperplasia neointimal na artéria carótida utilizando um modelo experimental com ratos in vivo, com e sem intervenção com rosuvastatina. Métodos: ratos Wistar machos foram divididos aleatoriamente em três grupos - grupo controle (n = 20), grupo modelo (n = 20), e grupo intervenção com estatina (n = 32). Os ratos no grupo intervenção receberam 10 mg/kg de rosuvastatina. Um cateter Fogarty 2 F foi introduzido para induzir lesão vascular. A formação de neoíntima foi analisada 1, 2, 3 e 4 semanas após lesão com balão. Concentrações de Apo J foram medidas por PCR em tempo real, imuno-histoquímica e western blotting. Resultados: A razão área íntima/média (I/M) aumentou após a lesão com balão e atingiu o valor máximo 4 semanas pós-lesão no grupo modelo; observou-se um pequeno aumento na I/M na semana 2, que cessou após a administração de rosuvastatina. Os níveis de mRNA e proteína da Apo J nas artérias carótidas aumentaram significativamente após administração de rosuvastatina em comparação ao grupo modelo, atingindo o máximo na semana 2, mais cedo em comparação ao grupo modelo (semana 3). Conclusão: A Apo J atuou como reagente de fase aguda após lesão com balão nas artérias carótidas de ratos. A rosuvastatina pode reduzir a formação de neoíntoma por aumento de Apo J. Nossos resultados sugerem que a Apo J exerce um papel protetor na reestenose após lesão com balão em ratos.
Subject(s)
Animals , Male , Angioplasty, Balloon, Coronary/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Carotid Artery Injuries/drug therapy , Coronary Restenosis/drug therapy , Clusterin/drug effects , Anticholesteremic Agents/pharmacology , Time Factors , Enzyme-Linked Immunosorbent Assay , Immunohistochemistry , Carotid Arteries/drug effects , Carotid Arteries/pathology , Random Allocation , Blotting, Western , Reproducibility of Results , Treatment Outcome , Tunica Media/drug effects , Tunica Media/pathology , Tunica Intima/drug effects , Tunica Intima/pathology , Rats, Wistar , Protective Agents/pharmacology , Carotid Artery Injuries/etiology , Carotid Artery Injuries/pathology , Coronary Restenosis/etiology , Coronary Restenosis/pathology , Clusterin/analysis , Real-Time Polymerase Chain Reaction , Rosuvastatin Calcium/pharmacologyABSTRACT
AbstractIntroduction:Cardiac allograft vasculopathy (CAV) is a major limitation for long-term survival of patients undergoing heart transplantation (HT). Some immunosuppressants can reduce the risk of CAV.Objectives:The primary objective was to evaluate the variation in the volumetric growth of the intimal layer measured by intracoronary ultrasound (IVUS) after 1 year in patients who received basiliximab compared with that in a control group.Methods:Thirteen patients treated at a single center between 2007 and 2009 were analyzed retrospectively. Evaluations were performed with IVUS, measuring the volume of a coronary segment within the first 30 days and 1 year after HT. Vasculopathy was characterized by the volume of the intima of the vessel.Results:Thirteen patients included (7 in the basiliximab group and 6 in the control group). On IVUS assessment, the control group was found to have greater vessel volume (120–185.43 mm3 vs. 127.77–131.32 mm3; p = 0.051). Intimal layer growth (i.e., CAV) was also higher in the control group (27.30–49.15 mm3 [∆80%] vs. 20.23–26.69 mm3[∆33%]; p = 0.015). Univariate regression analysis revealed that plaque volume and prior atherosclerosis of the donor were not related to intima growth (r = 0.15, p = 0.96), whereas positive remodeling was directly proportional to the volumetric growth of the intima (r = 0.85, p < 0.001).Conclusion:Routine induction therapy with basiliximab was associated with reduced growth of the intima of the vessel during the first year after HT.
ResumoFundamento:A doença vascular do enxerto (DVE) constitui uma grande limitação de sobrevida a longo prazo de pacientes submetidos a transplante cardíaco (TxC). Alguns imunossupressores diminuem o aparecimento da DVE.Objetivos:O principal objetivo foi avaliar, através de ultrassonografia intracoronária (USIC), a variação do crescimento volumétrico da camada íntima e comparar, após um ano, o grupo que recebeu basiliximab com um grupo de controle.Métodos:Treze pacientes de um único centro foram analisados retrospectivamente de 2007 a 2009. As análises foram feitas através de USIC, medindo-se o volume de um segmento coronariano nos primeiros 30 dias e um ano após o TxC. A vasculopatia foi caracterizada pelo volume da camada íntima do vaso.Resultados:O estudo incluiu 13 pacientes (7 no grupo com o basiliximab e 6 no grupo de controle). A análise por USIC revelou que o grupo de controle apresentou maior crescimento volumétrico do vaso (131,32 a 127,77 mm3 x 120 a 185,43 mm3 p = 0,051). O crescimento da camada íntima (CCI) também foi maior no grupo de controle [Basiliximab: 20,23 a 26,69 mm3 (∆ 33%); Controle: 27,30 a 49,15 mm3(∆ 80% p = 0,015)]. De acordo com a regressão univariada, o volume da placa aterosclerótica prévia do doador não teve relação com o crescimento da íntima (r = 0,15, p = 0,96), enquanto que o remodelamento positivo do vaso foi diretamente proporcional ao crescimento da íntima (r = 0,85, p < 0,001).Conclusão:A terapia de indução de rotina com basiliximab está associada à redução do crescimento da camada íntima do vaso no primeiro ano após o transplante cardíaco.
Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Antibodies, Monoclonal/therapeutic use , Coronary Artery Disease/drug therapy , Graft Rejection/drug therapy , Heart Transplantation/adverse effects , Immunosuppressive Agents/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Allografts/drug effects , Allografts/pathology , Biopsy , Case-Control Studies , Coronary Artery Disease/pathology , Coronary Artery Disease/prevention & control , Coronary Artery Disease , Disease Progression , Graft Rejection/pathology , Graft Rejection/prevention & control , Graft Rejection , /antagonists & inhibitors , Plaque, Atherosclerotic/drug therapy , Plaque, Atherosclerotic/pathology , Retrospective Studies , Risk Factors , Statistics, Nonparametric , Time Factors , Treatment Outcome , Tunica Intima/drug effects , Tunica Intima/pathologyABSTRACT
Neointimal proliferation after vascular injury is a key mechanism of restenosis, a major cause of percutaneous transluminal angioplasty failure and artery bypass occlusion. Emodin, an anthraquinone with multiple physiological activities, has been reported to inhibit proliferation of vascular smooth muscle cells (VSMCs) that might cause intimal arterial thickening. Thus, in this study, we established a rat model of balloon-injured carotid artery and investigated the therapeutic effect of emodin and its underlying mechanism. Intimal thickness was analyzed by hematoxylin and eosin staining. Expression of Wnt4, dvl-1, beta-catenin and collagen was determined by immunohistochemistry and/or western blotting. The proliferation of VSMC was evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and electron microscopy. MicroRNA levels were quantified by real-time quantitative PCR. Emodin relieved injury-induced artery intimal thickness. Results of western blots and immunohistochemistry showed that emodin suppressed expression of signaling molecules Wnt4/Dvl-1/beta-catenin as well as collagen protein in the injured artery. In addition, emodin enhanced expression of an artery injury-related microRNA, miR-126. In vitro, MTT assay showed that emodin suppressed angiotensin II (AngII)-induced proliferation of VSMCs. Emodin reversed AngII-induced activation of Wnt4/Dvl-1/beta-catenin signaling by increasing expression of miR-126 that was strongly supported by transfection of mimic or inhibitor for miR-126. Emodin prevents intimal thickening via Wnt4/Dvl-1/beta-catenin signaling pathway mediated by miR-126 in balloon-injured carotid artery of rats.
Subject(s)
Animals , Male , Rats , Adaptor Proteins, Signal Transducing/metabolism , Carotid Arteries/drug effects , Carotid Artery Injuries/drug therapy , Cell Proliferation/drug effects , Emodin/therapeutic use , MicroRNAs/metabolism , Phosphoproteins/metabolism , Rats, Sprague-Dawley , Signal Transduction/drug effects , Tunica Intima/drug effects , Wnt4 Protein/metabolism , beta Catenin/metabolismABSTRACT
To evaluate the effect of tocotrienols on intimal thickening in ascending aorta of cholesterol-fed rabbits. Randomized control trial. The Anatomy department of Army Medical College, Rawalpindi, from March 2009 to February 2010. Thirty, male, New Zealand white rabbits were randomly divided into three equal groups. Group- I was fed normal lab diet for six weeks. For the similar period, group-II and III were given 2% high cholesterol diet. However, group-III diet was also supplemented with tocotrienols [6 mg/kg body weight/day]. By the end of study, aorta was removed from each animal. Cross sections from ascending aorta were processed and embedded in paraffin. Light microscopic examination was performed in H and E and Verhoeff elastic stained slides. Tunica intima in group-I appeared as single layer of squamous endothelial cells, lying on a thin layer of loose connective tissue. High cholesterol diet in group-II induced marked atherosclerotic changes which were characterized by extensive intimal thickening with raised fatty streaks, pools of extracellular lipids, proliferation of smooth muscles and deposition of connective tissue matrix. Intimal thickening was also observed in group-III, but lesions were of lesser degree than group-II [P<0.05]. Histomorphometric analysis revealed significantly [P<0.001] higher thickness of intima in group-II and in group-III when either was compared with group-I. However, thickness of intima was 35% lesser [P<0.05] in group-III than group-II. Tocotrienols has significant potential in suppressing the intimal thickening of aorta in cholesterol-fed rabbits
Subject(s)
Male , Animals, Laboratory , Tunica Intima/drug effects , Aorta/drug effects , Rabbits , Cholesterol , Random Allocation , Microscopy, Polarization , AtherosclerosisABSTRACT
La disfunción endotelial (DE) se presenta en pacientes con hipercolesterolemia, hipertensión arterial, obesidad y diabetes mellitus. Evidencias sugieren un papel de los glicosaminoglicanos en la DE. Evaluamos el efecto del sulodexide (SLD), un glicosaminoglicano utilizado en el tratamiento de la albuminuria y la enfermedad isquémica en pacientes diabéticos, sobre la relajación arterial y los cambios morfológicos en un modelo experimental de diabetes tipo 1. La diabetes se indujo a ratas Sprague Dawley administrando estreptozotocina (STZ), 60 mg/kg, i.v. Los animales fueron distribuidos en los siguientes grupos: I= control, II= diabéticas, III: control + sulodexide, IV= diabéticas + sulodexide (15 mg/kg/día s.c). A los 3 meses fueron sacrificados, las aortas extraídas para evaluar la relajación vascular inducida por acetilcolina (Ach) y nitroprusiato de sodio en anillos precontraídos con fenilefrina. Fueron evaluadas histológicamente mediante microscopía de luz y coloraciones diversas. El SLD in vitro no modificó la tensión basal de los anillos arteriales en reposo o precontraídos con fenilefrina. La diabetes disminuyó la capacidad de relajación arterial en respuesta a la Ach en un 28,8-35,1% vs control, efecto que fue prevenido por SLD. No se observó diferencia significativa en la relajación inducida por nitroprusiato sódico entre los grupos. El estudio histológico en los animales diabéticos mostró alteraciones estructurales, particularmente en la íntima y la adventicia, cambios que fueron prevenidos por el tratamiento con SLD. Nuestros resultados apoyan la potencial utilidad terapéutica del SLD en el tratamiento de la disfunción endotelial.
Endothelial dysfunction (ED) is observed in patients with hypercholesterolemia, arterial hypertension, obesity and diabetes mellitus. Recent evidences suggest the involvement of glycosaminoglycans(GSG) in ED. We evaluated the effect of sulodexide (SLD), a natural GSG used in albuminuria and ischemic diabetes treatment, on arterial relaxation and vascular morphological changes in a diabetic type I model. Diabetes was induced, in Sprague-Dawley rats by streptozotocine (STZ) administration, 60 mg, iv. Rats were divided into four groups; I: control, II: diabetics, III: control + SLD, IV: diabetics treated with SLD (15 mg/day). After three months, phenylephrine precontracted aortic rings were used to evaluate acetylcholine (ACh) and sodium nitroprusside (NPS) relaxation capacities. Light microscopy of aorta was done with several staining procedures. In vitro, SLD did not change smooth muscle tone in resting or phenylephrine precontracted aortic rings. In diabetic rats, ACh relaxation was 28.8-35.1% lower than in control rats. Diabetic rats treated with SLD showed aortic ACh relaxation similar to control rats. No significative statistical difference was found in endothelium-independent NPS relaxation, between the different groups. Light microscopy histological studies revealed important morphological alterations, particularly in intima and adventitia layers of aortic artery; those changes were dramatically reversed in SLD treated rats. Our experiments support the conclusion that SLD is a potential drug for improving endothelial dysfunction in diabetes.
Subject(s)
Animals , Male , Rats , Aorta/drug effects , Aortic Diseases/prevention & control , Diabetes Mellitus, Experimental/drug therapy , Diabetic Angiopathies/prevention & control , Endothelium, Vascular/drug effects , Glycosaminoglycans/therapeutic use , Hypoglycemic Agents/therapeutic use , Vasodilation/drug effects , Acetylcholine/pharmacology , Aorta/pathology , Aorta/physiopathology , Aortic Diseases/etiology , Aortic Diseases/pathology , Aortic Diseases/physiopathology , Drug Evaluation, Preclinical , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/physiopathology , Diabetic Angiopathies/etiology , Diabetic Angiopathies/pathology , Diabetic Angiopathies/physiopathology , Endothelium, Vascular/ultrastructure , Glycosaminoglycans/metabolism , Glycosaminoglycans/pharmacology , Hypoglycemic Agents/pharmacology , Nitroprusside/pharmacology , Rats, Sprague-Dawley , Tunica Intima/drug effects , Tunica Intima/ultrastructureABSTRACT
OBJETIVO: A neoproliferação intimal e o remodelamento têm sido implicados como os maiores fatores causadores de reestenose. O objetivo deste trabalho é estudar a ação da L-arginina por via oral, nesses dois fatores, após lesão por balão, em artérias ilíacas de coelhos hipercolesterolêmicos. MÉTODOS: Foram utilizados dezenove coelhos, que foram divididos em dois grupos: controle (GC) e arginina (GA), respectivamente com dezenove e dezessete artérias estudadas. Os animais foram submetidos a lesão por balão de angioplastia, em suas artérias ilíacas, quinze dias após início de dieta hipercolesterolêmica a 2 por cento. A seguir, os animais do GA passaram a receber uma solução de L-arginina, por via oral, na dose de 1 g/kg/dia. Após o sacrifício, no 15° dia após a lesão por balão, procedeu-se a cortes histológicos das artérias, as quais foram coradas e fixadas. Utilizou-se como representativa do desenvolvimento da lesão a razão da área da neoíntima (em mm²) pela camada média (em mm²). Por sua vez, a razão da área total do vaso em sua porção medial (de maior contato com o balão) pela área total do vaso no segmento referencial (de menor contato com o balão) foi a definidora do remodelamento. RESULTADOS: A média do espessamento neointimal (NI/M) foi de 0,8151±0,2201 no GC e de 0,3296±0,1133 no GA. Não houve diferença entre os tipos de remodelamento entre os dois grupos estudados. CONCLUSÃO: No modelo experimental utilizado, a L-arginina foi capaz de reduzir o espessamento intimal em coelhos hipercolesterolêmicos e não teve ação sobre o remodelamento arterial.
OBJECTIVE: It has been implied that neointimal proliferation and remodeling are the major causes of restenosis. The objective of this study is to assess the effect of orally administered L-arginine on these two factors in hypercholesterolemic rabbits that had suffered an injury to their iliac arteries caused by a catheter balloon. METHODS: The study included nineteen rabbits that were divided in two groups: control (CG) and arginine (AG). There were 19 arteries studied from the control group and 17 in the arginine group. The animals were placed on a 2 percent hypercholesterolemic diet for 15 days and then submitted to a balloon angioplasty in order to produce a lesion in their iliac arteries. Next, the AG animals were given a 1g/kg/day oral dose of a L-arginine solution. The animals were sacrificed 15 days after the angioplasty procedure and histological artery sections were prepared, stained and fixed. The ratio between the neointimal area (in mm²) and the media layer (in mm²) was used to represent lesion development. In order to determine remodeling, the ratio between the total area of the medial portion of the vessel (greater balloon contact) and the total area of the reference segment of the vessel (less balloon contact) was used. RESULTS: Mean neointimal thickness (NI/M) was 0.8151±0.2201 in CG and 0.3296±0.1133 in AG. Remodeling patterns for the two groups studied were similar. CONCLUSION: In the experimental model used, L-arginine was able to reduce intimal tissue thickness in hypercholesterolemic rabbits but did not act on artery remodeling.
Subject(s)
Animals , Male , Rabbits , Angioplasty, Balloon/adverse effects , Arginine/pharmacology , Hypercholesterolemia , Iliac Artery/injuries , Tunica Intima/drug effects , Disease Models, Animal , Endothelium, Vascular/drug effects , Iliac Artery/drug effects , Iliac Artery/pathology , Tunica Intima/pathologyABSTRACT
The complete spectrum of estrogen vascular effects remains unclear. In particular, estrogen effects in the vascular response to profound injury in males have not been explored in detail. Therefore, we submitted 44 male New Zealand rabbits weighing 3.4 ± 0.6 kg to overdistention balloon injury of the right iliac artery. Rabbits were given 17ß-estradiol (5.45 æmol/day, sc) or vehicle for 7 days before and 14 days after injury, when the arteries were examined by post-mortem histomorphometry. Arteriographic caliber was assessed in vivo at baseline and before sacrifice. On day 14 after injury, in vivo arteriographic caliber (baseline = 2.44 ± 0.43 mm) was decreased by 23.1 ± 0.1 percent in controls and by 44.5 ± 0.1 percent in estrogen-treated rabbits (P < 0.001). Neither the neointimal area nor the neointima/media area ratio changed after estrogen treatment. Collagen fraction was increased in the media and neointima of estrogen-treated rabbits vs control (1.38 ± 1.30 vs 0.35 ± 0.67, respectively, P = 0.01). Taken together, these findings suggest that estrogen increased negative vascular remodeling. Transcription of endothelial and inducible nitric oxide synthases (eNOS and iNOS) was analyzed by RT-PCR. eNOS mRNA expression was marginally increased after estrogen (P = 0.07) and injury. iNOS mRNA was increased 2- to 3-fold on day 14 after injury. With estrogen treatment, iNOS mRNA increased in uninjured arteries and exhibited a further 5.5-fold increase after injury. We concluded that estrogen increased lumen loss after balloon injury in male rabbits, likely by increased negative remodeling, which may be related to increased iNOS transcriptional rates.
Subject(s)
Animals , Male , Rabbits , Estradiol/pharmacology , Iliac Artery/injuries , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type III/metabolism , Tunica Intima/drug effects , Angiography , Angioplasty, Balloon , Collagen/drug effects , Iliac Artery/drug effects , Iliac Artery/enzymology , Reverse Transcriptase Polymerase Chain Reaction , RNA, Messenger/analysis , Tunica Intima/enzymologyABSTRACT
To assess the effect of a NO-eluting stent on reducing neointimal thickening in a porcine coronary artery stent injury model, sodium nitroprusside (SNP), a NO donor, was incorporated into polyurethane (PU) polymer and coated onto metallic coil stents, and two types of stents with thin and thick barrier coatings were characterized. In vivo biological activity of the NO-eluting stents was assessed by measurement of coronary arterial cGMP levels in 32 pigs/64 arteries at days 1, 2, 7 and 14. Morphometric analyses were performed in 16 pigs to determine the effect of NO-eluting stents on neointimal hyperplasia 28 days following arterial injury. The SNP-coated stents released NO in a controlled manner for up to 4 weeks in the in vitro experiments and an increase in local tissue cGMP levels was demonstrated for up to 14 days. The neointimal area at 28 days was not diminished, however, by NO eluded from either stents of thin or thick barriers (control bare stent - 0.66 mm2, control PU stent - 0.68 mm2, SNP-PU thin coating stent - 0.78 mm2, SNP-PU thick coating stent - 0.85 mm2; all p=NS). In conclusion, the SNP-coated polymer stent exerted a local biological effect on the arterial wall, with sustained elevation of cGMP level. Although local delivery of NO from this device did not reduce neointimal hyperplasia in this porcine model, this polymer-coated stent might be a promising tool for administration of other agents that may modify the reparative tissue responses leading to restenosis.
Subject(s)
Animals , Coated Materials, Biocompatible , Coronary Vessels/injuries , Nitric Oxide/administration & dosage , Stents , Swine , Tunica Intima/drug effects , Wounds and Injuries/pathologyABSTRACT
Retinoic acids may inhibit vascular smooth muscle cell proliferation, but may promote endothelial cell proliferation in cell culture. However, little data are available about the effects of all-trans-retinoic acid (ATRA) on endothelial regeneration and functional recovery in an experimental model of vascular injury. Accordingly, we investigated whether ATRA may attenuate neointima formation and accelerate endothelial regeneration with functional recovery in balloon-injured rat aorta. Twelve-week-old male Sprague-Dawley rats underwent endothelial denudation of the thoracic aorta by balloon injury. Fourteen rats were fed a standard rat pellet diet. Another 14 rats were fed ATRA (1.5 mg/day) for 2 weeks. The animals were killed on day 14 for organ chamber study and morphometric analysis. Rats in the ATRA group had a significantly improved acetylcholine-induced relaxation response than those in control group. However, endothelial independent response was not significantly different between the two groups. The extent of reendothelialization was markedly superior in the ATRA group compared with control group (p>0.05). Furthermore, neointima area and the ratio of neointima to medial area were significantly less in ATRA group than in control group (p>0.05). In conclusion, ATRA may accelerate endothelial regeneration with functional recovery, and attenuate neointima formation in balloon-injured rat aorta.