Establishment of abdominal aortocaval fistula in adenine-induced renal failure rats / 中华肾脏病杂志

Objective:To explore the construction of abdominal aortocaval fistula (ACF) model in adenine-induced renal failure rats, and to provide a suitable animal model for subsequent mechanism and intervention researches.Methods:Adult female Sprague-Dawley rats (250-300 g) were fed with 0.75% adenine diet (renal failure group, n=60) and the same diet without adenine (control group, n=10) for 4 weeks, and the rats were randomly grouped by block randomization method with a ratio of 6∶1. Thirty rats in the renal failure group were randomly selected by block randomization method at a ratio of 1∶1 to undergo laparotomies to establish ACF models (renal failure+ACF group). The serum creatinine, blood urea nitrogen detection and Masson staining were used to evaluate the establishment of renal failure model. Small animal ultrasound imaging system was applied to verify the successful construction of the ACF model. After 6 weeks of ACF observation, blood samples were collected from the heart of rats, and ACF-vascular tissues were collected for pathological study (HE staining). Results:At 4 weeks of feeding, compared with the control group, serum creatinine [(63.8±23.5) μmol/L vs. (33.0±3.8) μmol/L, Z=3.651, P<0.001] and blood urea nitrogen [(13.1±6.9) mmol/L vs. (5.3±0.6) mmol/L, Z=3.254, P=0.001] in the renal failure group were both higher. Masson staining showed renal tubulointerstitial inflammatory cell infiltration, renal tubular epithelial cell atrophy, interstitial fibrosis and vascular injury. Five rats sacrificed after ACF surgeries, and the survival rate was 83.3%. Doppler ultrasound showed turbulent blood flow of arterial to venous shunt at the anastomosis of open ACF (23/25) in the renal failure+ACF group. HE staining showed typical eccentric neointimal hyperplasia in the outflow tract of ACF vein in the renal failure+ACF group. Conclusions:The adenine-induced ACF rat model is successfully constructed, and ACF shows typical eccentric neointimal hyperplasia. The ACF construction would provide a reliable animal model to study the mechanism and intervention of neointimal hyperplasia for autologous arteriovenous fistula.

Lesões Plexiformes em Modelo Experimental de Hipertensão Arterial Pulmonar Induzida por Monocrotalina / Plexiform Lesions in an Experimental Model of Monocrotalin-Induced Pulmonary Arterial Hypertension

Resumo Fundamento O modelo de hipertensão arterial pulmonar induzida por monocrotalina (MCT) é um dos mais reproduzidos atualmente, apresentando como limitação a ausência de lesões plexiformes, manifestações típicas da doença grave em humanos. Objetivo Avaliar a gravidade da arteriopatia pulmonar induzida por MCT por meio dos achados anatomopatológicos pulmonares e cardíacos, evolução clínica e sobrevida em 37 dias. Métodos Foram utilizados 50 ratos machos Wistar divididos em quatro grupos, sendo um controle (n = 10). Os três grupos restantes foram submetidos à inoculação de MCT (60 mg/kg i.p.) e ficaram sob o seu efeito por 15 (n = 10), 30 (n = 10) e 37 dias (n = 20). Ao final de cada período, os animais foram sacrificados, obtendo-se tecidos pulmonar e cardíaco para análise anatomopatológica e morfométrica. Empregou-se o teste Kruskal-Wallis, considerando nível de significância de 5%. Resultados Nos pulmões dos animais MCT foram constatadas lesões referentes à arteriopatia pulmonar, incluindo muscularização das arteríolas, hipertrofia da camada média e lesões neointimais concêntricas. Lesões complexas foram observadas nos grupos MCT, descritas como plexiforme e do "tipo" plexiforme (plexiform-like). A hipertrofia do ventrículo direito foi constatada pelo aumento da espessura e diâmetro dos cardiomiócitos e pelo aumento significativo da espessura da parede do ventrículo direito (p<0,0000). Conclusão O modelo foi capaz de gerar arteriopatia pulmonar moderada-grave associada à hipertrofia do ventrículo direito secundária, com sobrevida de 50% em 37 dias. De nosso conhecimento, este estudo foi o primeiro a constatar a presença de lesões vasculares complexas, semelhantes às observadas em pacientes com hipertensão arterial pulmonar grave, em modelo isolado de MCT. (Arq Bras Cardiol. 2020; 115(3):480-490)

Abstract Background The monocrotaline (MCT)-induced pulmonary arterial hypertension model is one of the most reproduced today, presenting as a limitation the absence of plexiform lesions, typical manifestations of the severe disease in humans. Objective To evaluate the severity of MCT-induced pulmonary arteriopathy by pathological findings of lung and heart tissue samples, clinical course and 37-day survival. Methods Fifty male Wistar rats were divided into one of the four groups - control (CG) (n = 10) and three intervention (MCT) groups. The MCT groups received intraperitoneal injection (60 mg/kg) of MCT and remained exposed to the substance for 15 days (G15, n = 10), 30 days (G30, n = 10) and 37 days (G37, n = 20). At the end of each period, the animals were sacrificed, and pulmonary and cardiac tissues were collected for anatomopathological and morphometric analysis. The Kruskal-Wallis test was used, considering a level of significance of 5%. Results In the lungs of MCT animals, lesions related to pulmonary arteriopathy were found, including muscularization of the arterioles, hypertrophy of the middle layer and concentric neointimal lesions. Complex lesions were observed in MCT groups, described as plexiform and plexiform-like lesions. Right ventricular hypertrophy was evidenced by increased thickness and diameter of the cardiomyocytes and a significant increase in the right ventricular wall thickness (p <0.0000). Conclusion The MCT model was able to generate moderate-severe pulmonary arteriopathy associated with secondary right ventricular hypertrophy. The 37-day survival rate was 50%. To our knowledge, this study was the first to note the presence of complex vascular lesions, similar to those observed in patients with severe pulmonary arterial hypertension, in an isolated MCT model. (Arq Bras Cardiol. 2020; 115(3):480-490)

Total Panax notoginseng saponin inhibits balloon injury-induced neointimal hyperplasia in rat carotid artery models by suppressing pERK/p38 MAPK pathways

Total Panax notoginseng saponin (TPNS) is the main bioactivity compound derived from the roots and rhizomes of Panax notoginseng (Burk.) F.H. Chen. The aim of this study was to investigate the effectiveness of TPNS in treating vascular neointimal hyperplasia in rats and its mechanisms. Male Sprague-Dawley rats were randomly divided into five groups, sham (control), injury, and low, medium, and high dose TPNS (5, 10, and 20 mg/kg). An in vivo 2F Fogarty balloon-induced carotid artery injury model was established in rats. TPNS significantly and dose-dependently reduced balloon injury-induced neointimal area (NIA) (P<0.001, for all doses) and NIA/media area (MA) (P<0.030, for all doses) in the carotid artery of rats, and PCNA expression (P<0.001, all). The mRNA expression of smooth muscle (SM) α-actin was significantly increased in all TPNS groups (P<0.005, for all doses) and the protein expression was significantly increased in the medium (P=0.006) and high dose TPNS (P=0.002) groups compared to the injury group. All the TPNS doses significantly decreased the mRNA expression of c-fos (P<0.001). The medium and high dose TPNS groups significantly suppressed the upregulation of pERK1/2 protein in the NIA (P<0.025) and MA (P<0.004). TPNS dose-dependently inhibited balloon injury-induced activation of pERK/p38MAPK signaling in the carotid artery. TPNS could be a promising agent in inhibiting cell proliferation following vascular injuries.

Influence of Local Myocardial Infarction on Endothelial Function, Neointimal Progression, and Inflammation in Target and Non-Target Vascular Territories in a Porcine Model of Acute Myocardial Infarction

BACKGROUND: Patients with acute myocardial infarction (AMI) have worse clinical outcomes than those with stable coronary artery disease despite revascularization. Non-culprit lesions of AMI also involve more adverse cardiovascular events. This study aimed to investigate the influence of AMI on endothelial function, neointimal progression, and inflammation in target and non-target vessels. METHODS: In castrated male pigs, AMI was induced by balloon occlusion and reperfusion into the left anterior descending artery (LAD). Everolimus-eluting stents (EES) were implanted in the LAD and left circumflex (LCX) artery 2 days after AMI induction. In the control group, EES were implanted in the LAD and LCX in a similar fashion without AMI induction. Endothelial function was assessed using acetylcholine infusion before enrollment, after the AMI or sham operation, and at 1 month follow-up. A histological examination was conducted 1 month after stenting. RESULTS: A total of 10 pigs implanted with 20 EES in the LAD and LCX were included. Significant paradoxical vasoconstriction was assessed after acetylcholine challenge in the AMI group compared with the control group. In the histologic analysis, the AMI group showed a larger neointimal area and larger area of stenosis than the control group after EES implantation. Peri-strut inflammation and fibrin formation were significant in the AMI group without differences in injury score. The non-target vessel of the AMI also showed similar findings to the target vessel compared with the control group. CONCLUSION: In the pig model, AMI events induced endothelial dysfunction, inflammation, and neointimal progression in the target and non-target vessels.

Resultado clínico del tratamiento endovascular con balón liberador de fármaco en el paciente claudicante con enfermedad femoropoplítea / Clinical Outcome of Drug-Eluting Balloon Endovascular Treatment for Femoropopliteal Lesions in Patients with Intermittent Claudication

RESUMEN Introducción: La restenosis continúa siendo el gran desafío de la terapia endovascular, por esa razón, se han desarrollado balones liberadores de fármaco (BLF) con la finalidad de reducir la restenosis. El objetivo de este trabajo es analizar los resultados de esta terapia. Material y métodos: Se realizó un análisis retrospectivo de 40 extremidades de pacientes claudicantes con lesiones femoro-poplíteas tratados con BLF. Resultados: Se obtuvo el éxito técnico en las 40 (100%) extremidades tratadas con una media de seguimiento de 11,1 mes sin evidencia de complicaciones graves relacionadas con el tratamiento con un 92,5% de las extremidades asintomáticas durante el seguimiento. En tres extremidades se realizó una nueva angioplastia por recidiva sintomática. Conclusiones: El BLF ha probado ser una herramienta útil, segura y eficaz para el tratamiento de lesiones de novo y restenosis intrastent; no obstante, en las lesiones TASC C-D se requiere la utilización de un mayor número de stents.

ABSTRACT Background: Restenosis continues to be the great challenge of endovascular therapy, and drug-eluting balloons (DEB) have been developed to reduce it. The aim of this study was to analyze the results of this therapy. Methods: A retrospective analysis of 40 limbs with femoropopliteal lesions treated with DEB was conducted in patients with intermittent claudication. Results: Technical success was obtained in the 40 (100%) limbs treated, without evidence of serious complications related with treatment, and with 92.5% of asymptomatic limbs during the follow-up period of 11.1 months. In three limbs, a new angioplasty was performed due to symptomatic recurrence. Conclusions: The drug-eluting balloon has proven to be a useful, safe and effective tool for the treatment of de novo and in-stent restenosis lesions; however, TASC C-D lesions require the use of greater number of stents.

Effect of ginsenoside Rg3 on intimal proliferation and apoptosis of vascular smooth muscle cells after vascular injury in rats / 中草药

Objective: To investigate the effects of ginsenoside Rg3 on intimal proliferation and apoptosis of vascular smooth muscle cells after vascular injury in rats. Methods: Forty Sprague Dawley rats were divided into four groups randomly including Sham operation group, model group, ginsenoside Rg3 low-dose group (5 mg/kg), and ginsenoside Rg3 high-dose group (10 mg/kg). The carotid artery intima injury model was established by inflation balloons. From the next day after modeling, the rats were treated with ginsenoside Rg3 by ig administation in ginsenoside Rg3 groups, and rats in Sham operation group and model group were administered with same amount of normal saline. The injured common carotid arteries were harvested after 14 d and morphological changes of injured arteries were observed by HE staining. Terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) was used to detect the apoptosis of smooth muscle cells; Western blotting and qRT-PCR were used to detect the expression of Fas and anti-apoptotic gene Bcl-2. Results: Compared with the Sham operation group, the vascular neointima of rats in model group was significantly thicker, and the ratio of intima/media area and the apoptosis rate of neointimal hyperplasia were significantly increased. The expression of apoptosis-related gene Fas and anti-apoptotic gene Bcl-2 was significantly increased. Compared with model group, ginsenoside Rg3 (5 and 10 mg/kg) significantly alleviated vascular intimal hyperplasia, the intima/media area ratio and the expression of Bcl-2 was significantly decreased, and the apoptosis rate of smooth muscle cells in the neointimal area and the expression of Fas in injured vessels were significantly increased. Conclusion: Ginsenoside Rg3 can reduce the vascular neointimal hyperplasia induced by balloon injury with the possible underlying mechanism to promote the apoptosis of smooth muscle cells.

Administration of a High-Dose Erythropoietin-Stimulating Agent in Hemodialysis Patients is Associated with Late Arteriovenous Fistula Failure

PURPOSE: Investigating the risk of vascular access failure is critical for maintenance hemodialysis (MHD) patients. Erythropoietin stimulating agents (ESA) typically used for anemia of chronic kidney disease (CKD) may also stimulate neointimal hyperplasia, which is the most important factor in late arteriovenous fistula (AVF) failure. The aim of this study was to investigate whether ESA treatment is associated with late AVF failure. MATERIALS AND METHODS: The late AVF failure group comprised 51 patients who underwent percutaneous intervention or surgery for fistula revision after successful use for at least three months. There were 51 controls whose AVF had been patent for at least 24 months. RESULTS: The mean time from the first cannulation to late loss of AVF patency was 8.4±4.2 months. The average weekly dose of ESA was significantly higher in patients with AVF failure (4782.2±2360.5 IU/mL/wk vs. 7161.8±2775.2 IU/mL/wk, p<0.001). The only independent predictor of late AVF failure in multivariate analysis was high average ESA dose (odds ratio=1.015, 95% confidence interval=1.002–1.028, p=0.022). CONCLUSION: Patients with late AVF patency loss exhibit an association with a higher dose of ESA, although causality is unproven. Further study to elucidate potential mechanisms is warranted.

Chronic renal failure promotes intimal hyperplasia of arteriovenous fistula in mice / 基础医学与临床

Objective To find the effect of chronic renal failure on the development of neointimal hyperplasia and the role of monocyte chemokine-1 (MCP-1) after arteriovenous fistula in mice.Methods We created AVF (common carotid artery to jugular vein in an end-to-end anastomosis) in mice with or without chronic renal failure (renal ablation or sham operation).The outflow of AVF was harvested at 3 weeks postoperative the vascular tissue.The pathological changes were examined.The level of blood urea nitrogen (BUN) and the degree of intimal hyperplasia were analysed.The protein and mRNA expression of alpha smooth muscle actin (SMA), Ki-67,NF-κB and MCP-1 were detected by immunohistochemistry, RT-PCR and Western blot.Results 1)Compared with the control group, the blood BUN level of the experimental group was significantly higher and the intimal hyperplasia was more serious, meanwhile, the lumen was more narrow (P<0.05).2)In the experimental group, the expression of α-SMA, Ki-67, NF-κB and MCP-1 was significantly increased (P<0.05).3)MCP-1 promoted the proliferation of vascular smooth muscle cells.Conclusions Chronic renal failure promote the development of neointimal hyperplasia, which may be related to the increase of MCP-1 expression.

Inhibitory effect of evodiamine on neointima hyperplasia of rat carotid arteries with balloon injury / 中国药学杂志

OBJECTIVE: To examine the inhibitory effects of evodiamine on vascular neointimal hyperplasia in balloon-injured carotid artery of rats and explore the possible mechanisms. METHODS: Healthy male Sprague Dawley rat vascular neointimal hyperplasia model was made by rubbing the endothelia of common carotid artery with a balloon, and then the rats were randomly divided into sham operation control group, model control group, evodiamine low(40 mg · kg-1) and high(80 mg· kg-1) dose groups. Evodiamine was intragastric administration for 14 consecutive days, and the sham operation or control rats were given with distilled water. After consecutive 14 d, the neointimal hyperplasia degree was observed by histopathological alterations and by calculating the proliferating cell nuclear antigen(PCNA) positive cells expression percentage in the common carotid arter-y. The levels of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) in plasma of rats were measured respectively. The mRNA expressions of PCNA, endothelial nitric oxide synthase(eNOS) and SM α-actin in carotid artery wall were analyzed separately by real time RT-PCR. RESULTS: The neointimal hyperplasia was very serious, as evidenced by thickened neointima and narrowed lumen in carotid artery balloon-injured rats (model control group). Compared with the model control group, evodiamine 40 and 80 mg · kg-1 administration could significantly ameliorate the histopathology of common carotid artery, decrease the positive expression rate of PCNA, but increase the levels of NO, cGMP in plasma of rats, downregulate the PCNA mRNA expression and upregulate mRNA expressions of eNOS and SM α-actin, respectively. CONCLUSION: Evodiamine can depress the vascular neointimal hyperplasia induced by artery endothelia rubbing in rats, the mechanism may be related, at least partly, to the promotion of NO production.

Inhibitory effects of ginsenoside Re on vascular neointimal hyperplasia induced by balloon-injury and ERK signaling in rats / 中国药学杂志

OBJECTIVE: To investigate the inhibitory effect of ginsenoside Re on vascular neointimal hyperplasia induced by balloon-injury and probe its molecular mechanism in rats. METHODS: The rat carotid artery neointimal hyperplasia model was established by rubbing the endothelia with a balloon in male Sprague-Dawley rats, then animals were intrapritoneally injected with distilled water in model group and sham operation group or with ginsenoside Re 6, 12 and 24 mg·kg-1·d-1 in other endothelia rubbed groups. After 14 consecutive days, the injuried artery was taken for H&E staining, the histopathological observation and detecting the neointimal area as well as the ratio of neointimal area/media area were taken to evaluate the vescular intimal hyperplasia level. For probing the molecular mechanism, the expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) was detected at the transcript levels by real time RT-PCR, and the protein expressions of MKP-1 and phosphorylation extracellular signal-regulated kinase 1/2 (pERK12) were examined by immunohistochemistry and analyzed with Image-Pro Plus. RESULTS: Compared with the endothelia rubbing model group, ginsenoside Re 6, 12, 24 mg·kg-1·d-1 medications significantly improved the histopathological changes induced by baloon-injury, decreased the elevated neointimal area and the ratio of neointimal area/media area induced by baloon-injury; ginsenoside Re administration could also down-regulate the elevated pERK1/2 protein expression, and significantly up-regulated the decreased MPK-1 mRNA and protein expressions induced by baloon-injury. CONCLUSION: Ginsenoside Re inhibits the vascular neointimal hyperplasia induced by baloon-injury in rats, the molecular mechanism is related to its inhibition effect on ERK signaling.

Different Responses of Neointimal Cells to Imatinib Mesylate and Rapamycin Compared with Normal Vascular Smooth Muscle Cells

PURPOSE: This study was designed to investigate whether vascular smooth muscle cells (VSMC) from the neointima showed any different response to antiproliferative agents, such as rapamycin or imatinib mesylate, compared to VSMCs from normal artery. MATERIALS AND METHODS: Intimal hyperplasia was made by carotid balloon in jury in male rats. Neointimal cells at 4 weeks after injury and normal VSMCs were extracted by enzymatic isolation method and cultured. Cell viability and proliferation were tested in VSMCs from injured left carotid artery and uninjured right carotid artery. Tests were repeated with rapamycin, imatinib mesylate or both in various concentrations. RESULTS: Rapamycin decreased cell viability only at a high concentration of 10(-5) M in uninjured VSMCs. Combined drugs decreased cell viability at a lower concentration of 10(-7) M in uninjured VSMCs, and at a higher concentration of 10(-5) M in neointimal cells. Overall, rapamycin showed cytocidal effects at a high concentration of 10(-5) M, whereas imatinib did not. Cell proliferation of neointima was significantly decreased along with the drug concentration. Cell proliferation of uninjured VSMCs was significantly decreased at higher drug concentrations. Combined drug therapy showed synergistic effects. Overall, neointimal cells are more susceptible to the antiproliferative effects of the drugs. CONCLUSION: Neointimal cells from the injured carotid artery are more susceptible to the antiproliferative effect of imatinib and rapamycin. Both drugs can be a used for the prevention of intimal hyperplasia, which could be investigated through further in vivo studies.

Effects of Combination Therapy with Celecoxib and Doxycycline on Neointimal Hyperplasia and Inflammatory Biomarkers in Coronary Artery Disease Patients Treated with Bare Metal Stents

PURPOSE: Cyclooxygenase (COX)-2 and matrix metalloproteinase (MMP)-9 play a key role in the pathogenesis of in-stent restenosis. We investigated the effect of a short-term therapy of celecoxib, a COX-2 inhibitor, with or without doxycycline, an MMP inhibitor, after coronary stenting on inflammatory biomarkers and neointimal hyperplasia. MATERIALS AND METHODS: A total of 75 patients (86 lesions) treated with bare metal stents were randomized into three groups: 1) combination therapy (200 mg celecoxib and 20 mg doxycycline, both twice daily), 2) celecoxib (200 mg twice daily) only, and 3) non-therapy control. Celecoxib and doxycycline were administered for 3 weeks after coronary stenting. The primary endpoint was neointimal volume obstruction by intravascular ultrasound (IVUS) at 6 months. The secondary endpoints included clinical outcomes, angiographic data, and changes in blood levels of inflammatory biomarkers. RESULTS: Follow-up IVUS revealed no significant difference in the neointimal volume obstruction among the three treatment groups. There was no difference in cardiac deaths, myocardial infarctions, target lesion revascularization or stent thrombosis among the groups. Blood levels of high-sensitivity C-reactive protein, soluble CD40 ligand, and MMP-9 varied widely 48 hours and 3 weeks after coronary stenting, however, they did not show any significant difference among the groups. CONCLUSION: Our study failed to demonstrate any beneficial effects of the short-term therapy with celecoxib and doxycycline or with celecoxib alone in the suppression of inflammatory biomarkers or in the inhibition of neointimal hyperplasia. Large scale randomized trials are necessary to define the role of anti-inflammatory therapy in the inhibition of neointimal hyperplasia.

Comparison of bare metal stent and paclitaxel-eluting stent using a novel rat aorta stent model

The purpose of our study was to create a novel rat aorta stent implantation model. Stainless steel bare metal stents (BMS) or paclitaxel-eluting stents (PES) were implanted in male Sprague-Dawley rats (BW 400 +/- 20 g). Two and four weeks after stent implantation, the aorta were collected, fixed with 2% glutaraldehyde, and cut into two segments. One segment was used for scanning electron microscopy analysis to evaluate re-endothelialization, and the other segment was used to calculate the neointimal area. At 2 weeks after stenting, the appearance of neointimal hyperplasia was less in the PES group than in the BMS group. At 4 weeks after stenting, no significant difference in neointimal hyperplasia was observed between two groups. On the other hand, the PES group showed more thrombus formation and less re-endothelialization compared to the BMS group. This study demonstrated the ability of a novel rat model of aorta stenting via a common carotid artery to measure the efficacy and safety of commercially available drug-eluting stents.

Progress on microRNAs and their roles in vascular diseases / 国际外科学杂志

MicroRNAs as a novel class of endogenous gene regulators at post-transcription level have been found to play important roles in many biological processes including cellular differentiation, proliferation, apoptosis and regulation of development. The biological mechanisms of microRNAs involved in the pathogenesis of various diseases have been revealed gradually. This paper reviews the Current situation and progress on the microRNAs and their roles in vascular diseases.

Suppression of Neointimal Hyperplasia by External Application of Cilostazol-Eluting Film at Anastomotic Sites in a Canine Model / 日本心臓血管外科学会雑誌

Neointimal hyperplasia is the principal mechanism of graft failure in coronary artery bypass surgery. Systemic administration of cilostazol has been reported to suppress neointimal hyperplasia in some vascular injury models. We sought to deliver cilostazol locally in an attempt to augment its beneficial effect to inhibit neointimal hyperplasia at an anastomotic site. We examined whether the external application of a novel cilostazol-eluting film can inhibit neointimal hyperplasia in a vascular anastomosis model. Canine femoral artery graft interposition was performed in 20 beagle dogs, assigned to 4 groups of 5 dogs each : a graft interposition without copolymer of L-lactide and ε-caprolactone (P (LA/CL) ) film (control group) and groups with P (LA/CL) film containing cilostazol of either 10 mg, 40 mg, or 80 mg doses. All the cilostazol-eluting film with 10 mg, 40 mg, and 80 mg dose groups had a reduced intima/media ratio compared to the control group (0.15±0.03, 0.11±0.03, and 0.12±0.03, vs. 0.31±0.03, <i>p</i><0.05). Immunohistochemical analyses for proliferating cell nuclear antigens revealed reduced cellular proliferating activity associated with decreased α-actin positive cells in the cilostazol-eluting film groups compared to the control group. External application of cilostazol-eluting film can inhibit neointimal hyperplasia, at least in part, by inhibiting smooth muscle cell proliferation in the intima.

Alagebrium Chloride, a Novel Advanced Glycation End-Product Cross Linkage Breaker, Inhibits Neointimal Proliferation in a Diabetic Rat Carotid Balloon Injury Model

BACKGROUND AND OBJECTIVES: Vascular perturbation induced by advanced glycation end-products (AGEs) leads to progression of atherosclerosis, plaque instability, and vascular inflammation, which results in a higher risk of neointimal proliferation. Here we investigated the inhibitory effect of alagebrium chloride (ALT-711), a breaker of AGE-based cross links, on neointimal proliferation in a carotid artery balloon injury model in diabetic rats induced by streptozotocin (STZ). MATERIALS AND METHODS: Rat aortic vascular smooth muscle cells (RASMCs) were treated with 1-100 microM of alagebrium added 24 hours before the addition of AGEs. This in vivo study was done using 8-week-old male rats that were injected intraperitoneally with 80 mg/kg STZ. Sixteen weeks later, the diabetic rats were treated with 10 mg/kg alagebrium for 4 weeks, after which carotid artery balloon injury was induced. After 4 weeks, the animals were sacrificed for histological analysis. RESULTS: Proliferation of RASMCs was significantly inhibited in alagebrium-treated cells. Alagebrium dose-dependently inhibited AGE-mediated formation of reactive oxygen species (ROS), extracellular signal-regulated kinase phosphorylation, and cyclooxygenase-2 expression. The cellular mechanisms of AGE-induced connective tissue and extracellular matrix expression were decreased in the alagebrium-treated group. This in vivo study shows that expression of AGE receptors and neointima hyperplasia are significantly suppressed in balloon-injured rats treated with alagebrium. CONCLUSION: Alagebrium treatment in diabetic rats significantly inhibits neointimal hyperplasia after carotid balloon injury due to its inhibition of intracellular ROS synthesis, which results in inhibition of RASMCs proliferation.

Effect of Udenafil on Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia in Rat Carotid Artery Injury Model

BACKGROUND AND OBJECTIVES: Neointimal hyperplasia, which was caused by smooth muscle cell proliferation, was noted to occur after performing percutaneous coronary intervention. Phosphodiesterase type 5 (PDE5) inhibitor has been shown to inhibit smooth muscle cell proliferation. Udenafil is one of the PDE5 inhibitors, and it is also expected to inhibit smooth muscle cell proliferation and reduce neointimal hyperplasia. We investigated the effect of udenafil on the smooth muscle cell proliferation and neointimal hyperplasia that occurs after balloon injury in the carotid arteries of rats. MATERIALS AND METHODS: Smooth muscle cells were treated with 1 mM, 100 micrometer, 10 micrometer, 1 micrometer and 100 nM concentrations of udenafil. The viability of the smooth muscle cells was evaluated by MTT assay. The carotid arteries of rats were injured with a balloon catheter. Udenafil (100 micrometer, 10 micrometer and 1 micrometer) was applied on the carotid artery adventitia after balloon injury. At 21 days after treatment, the carotid arteries were harvested and stained with H & E. The neointima and media area were measured with a computerized image analysis program. RESULTS: In the in vitro experiment, treatment with 1 mM udenafil reduced smooth muscle cell viability by 68.8+/-4.42% compared to the control group. In the balloon injured rat carotid artery, treatment with 100 micrometer udenafil reduced the neointima area by 71.8% compared to the control group. CONCLUSION: Udenafil administration effectively inhibited smooth muscle cell proliferation and it reduced neointimal hyperplasia in the balloon-injured rat carotid artery.

Mechanisms of restenosis after vascular reconstruction / 国际外科学杂志

Restenosis is the major causee which leads to arterial occlusion and graft failure after vascular reconstruction.Thus to clarif the mechanism of restenosis is of great importance to prevent and treat postprocedural restenosis and improve long-term graft patency.Current studies on restenosis focus on elastic recoil,thrombosis,inflammatory reaction,neointimal hyperplasia and vascular remodeling,herein,we reviewed literatures.

The Origin of Neointimal Smooth Muscle Cells in Transplant Arteriosclerosis from Recipient Bone-marrow Cells in Rat Aortic Allograft / 华中科技大学学报（医学）（英德文版）

In order to investigate the origin of neointimal smooth muscle cells in transplant arteriosclerosis in rat aortic allograft, sex-mismatched bone marrow transplantation was performed from male Wistar rats to female Wistar rats. Four weeks after transplantation, the aortic transplant model was established by means of micro-surgery in rats. The recipients were divided into 4 groups: female Wistar-female Wistar aortic isografts, female SD-female Wistar aortic allografts, male SD-male Wistar aortic allografts, female SD-chimera Wistar aortic allografts. Eight weeks after transplantation, aortic grafts were removed at autopsy and processed for histological evaluation and immunohistochemistry. The results indicated that excessive accumulation of α-SMA-positive smooth muscle cells resulted in significant neointima formation and vascular lumen stricture in rat aortic allografts.Neointima assay revealed that the neointimal area and NIA/MA ratio of transplanted artery were significantly increased in all of aortic allograft groups as compared with those in aortic isograft group (P＜0.01). Neointimal smooth muscle cells were harvested from cryostat sections of aortic allograft by microdissection method. The Sry gene-specific PCR was performed, and the result showed that a distinct DNA band of 225 bp emerged in the male-male aortic allograft group and chimera aortic allograft group respectively, but not in the female-female aortic allograft group. It was suggested that recipient bone-marrow cells, as the origin of neointimal smooth muscle cells, contributed to the pathological neointimal hyperplasia of aortic allograft and transplant arteriosclerosis.

A Slight Variation in the Age of Rats Commonly used as a Carotid Artery Injury Model Results in a Large Difference in Neointima Formation

BACKGROUND AND OBJECTIVES: The degree of neointima formation after infliction of a carotid artery balloon injury in rats varies greatly depending on the sex, age, species and operational method. Strong variation is common, even within only a single control. This study attempted to find if there was any significant difference in neointima formation following a carotid artery balloon injury in 6 to 12 week old rats; the age commonly used in these types of experiments. MATERIALS AND METHODS: A balloon injury was inflicted on the carotid arteries of male SpragueDawley rats at 6 (n=9, 250-270 g), 8 (n=8, 280-300 g) and 11 weeks (n=10, 320-340 g) of age. Two weeks postoperation, a histomorphometric analysis was carried out. The vascular smooth muscle cell proliferation was measured in situ via BrdU incorporation 2 days after injury infliction. RESULTS: The neointima areas of the 6 week (0.22+/-0.04 mm2) and 8 week old groups (0.17+/-0.08 mm2) were 3.1 and 2.4 times larger than that of the 11 week old group (0.07+/-0.03 mm2). The mitotic index was significantly reduced in 11 week old group (n=4, 9.22+/-1.51%) compared to those of the 6 (n=4, 25.03+/-3.92%) and 8 week old (n=4, 21.66+/-3.66%) groups. CONCLUSION: Special care should be taken when interpreting neointima formation, as even a slight variation in the age and weight in 6 to 12 week old (250-340 g) rats; the age commonly used in these types of experiments, results in an unexpectedly large difference.