Vein Bypass Grafts Research Articles

Abstract 291: Multiple Mechanisms for the Inhibition of Intimal Hyperplasia by Herpes Simplex Virus Strain R7020

Intimal hyperplasia (IH) is the primary cause of vein bypass graft failure. Smooth muscle cells (SMCs) are a key element of IH as they phenotypically switch from a contractile to a synthetic state which may lead to IH. R7020 is an engineered strain of Herpes Simplex Virus-1 which inhibits IH in animal models. Although it has many characteristics which make it a strong candidate for use as a prophylaxis agent how it inhibits IH is not well understood. IH is multifaceted and R7020 infects a wide range of cell types regulating their cellular functions and pathways. Therefore we hypothesized that R7020 inhibits IH by altering multiple cellular functions and cell types. The objective of this study was to identify mechanisms used by R7020 to function in blood vessels that may contribute to its inhibition of IH. In this study the cytopathic effect of R7020 on SMCs was determined in vitro and in a rabbit IH model. The effects of R7020 on SMC viability and the adhesion of peripheral blood mononuclear cells (PBMCs) to SMCs were quantified in the absence and presence of TNF-α. Microarray analysis was used to identify genes whose expression was altered by R7020 in vivo. The cytopathic effects which include filopodia positive for R7020 tegument proteins extending from cell to cell and the formation of syncytia suggest that R7020 remains cell associated after egress and spreads cell to cell instead of by diffusion through the extracellular fluid. The directionality of the filopodia in vivo suggests that the virus preferentially travels from the media towards the intima targeting the SMCs that would lead to IH. The formation of syncytia would also inhibit SMC proliferation as cells that form syncytia do not proliferate. In addition, R7020 induced the fusion of PBMCs with syncytia which may limit the effect of macrophages on IH. Furthermore, R7020 inhibited the proliferative effect of TNF-α, an inflammatory cytokine associated with increased IH. Microarray analysis detected a significant change in the expression of 58 genes in R7020 infected arteries relative to non-infected at 24 h. The encoded proteins are associated with the immune system, cell death, proliferation/motility and vascular tone. Thus this study identifies multiple mechanisms which R7020 may be using to inhibit IH.

Abstract 296: Turbulence in Saphenous Vein Bypass Grafts by Duplex Ultrasound Imaging

Objectives: Turbulent flow distal to stenoses in saphenous vein bypass grafts (SVBG) may influence vein graft remodeling including intimal hyperplasia. This study aims to develop and validate ultrasound indices for turbulence intensity that may be useful in predicting stenosis, occlusion, and remodeling in SVBG. Methods: 25 patients with leg SVBG’s underwent regularly scheduled duplex ultrasounds and simultaneous measurement of turbulence indices, using a Philips iU22 ultrasound module and 9-3 MHz linear transducer. 14 patients had significant stenosis and downstream turbulence. In each of these 14 patients, color Doppler at maximal stenosis was used to determine the color scale to avoid aliasing. Then color Doppler video loops were recorded downstream of the stenosis. Color Doppler videos were also recorded in a normal region absent of stenosis for comparison. Custom image analysis algorithms were used to determine percent area reverse flow (%ARF), reverse mean velocity (RMV), and turbulent flow volume (TFV = %ARF х RMV) as surrogates for turbulence intensity. Results: Peak %ARF was 20±21 in normal segments and 56±27 in turbulent segments (P=.0002). Peak RMV was 7.7±7.6 cm/s in normal segments and 16.7±7.7 cm/s in turbulent segments (P=.01). Peak TFV was 1.3±1.3 m/s in normal segments and 6.5±3.4 m/s in turbulent segments (P=.0001), and correlated with upstream peak systolic velocity (see figure). Conclusions: Surrogates for SVBG turbulence can be detected and quantified using duplex ultrasound. These measures correlate with percent stenosis, and may predict progressive stenosis and remodeling; turbulence imaging may also be useful in situations where a stenosis is inadequately imaged on ultrasound or its hemodynamic significance is uncertain. A larger study with appropriate follow-up to determine clinical and ultrasound outcomes in these patients’ SVBGs is underway.

Surgical marking pen dye inhibits saphenous vein cell proliferation and migration in saphenous vein graft tissue

Markers containing dyes such as crystal violet (CAS 548-62-9) are routinely used on the adventitia of vein bypass grafts to avoid twisting during placement. Because little is known about how these dyes affect vein graft healing and function, we determined the effect of crystal violet on cell migration and proliferation, which are responses to injury after grafting. Fresh human saphenous veins were obtained as residual specimens from leg bypass surgeries. Portions of the vein that had been surgically marked with crystal violet were analyzed separately from those that had no dye marking. In the laboratory, they were split into easily dissected inner and outer layers after removal of endothelium. This cleavage plane was within the circular muscle layer of the media. Cell migration from explants was measured daily as either (1) percentage of migration-positive explants, which exclusively measures migration, or (2) number of cells on the plastic surrounding each explant, which measures migration plus proliferation. Cell proliferation and apoptosis (Ki67 and TUNEL staining, respectively) were determined in dye-marked and unmarked areas of cultured vein rings. The dose-dependent effects of crystal violet were measured for cell migration from explants as well as for proliferation, migration, and death of cultured outer layer cells. Dye was extracted from explants with ethanol and quantified by spectrophotometry. There was significantly less cell migration from visibly blue compared with unstained outer layer explants by both methods. There was no significant difference in migration from inner layer explants adjacent to blue-stained or unstained sections of vein because dye did not penetrate to the inner layer. Ki67 staining of vein in organ culture, which is a measure of proliferation, progressively increased up to 6days in nonblue outer layer and was abolished in the blue outer layer. Evidence of apoptosis (TUNEL staining) was present throughout the wall and not different in blue-stained and unstained vein wall segments. Blue outer layer explants had 65.9± 8.0ng dye/explant compared with 2.1± 1.3 for nonblue outer layer explants. Dye applied invitro to either outer or inner layer explants dose dependently inhibited migration (IC50∼10ng/explant). The IC50s of crystal violet for outer layer cell proliferation and migration were 0.1 and 1.2μg/mL, whereas the EC50 for death was between 1 and 10μg/mL. Crystal violet inhibits venous cell migration and proliferation, indicating that alternative methods should be considered for marking vein grafts.

Feasibility and safety of transradial coronary interventions using a 6.5-F sheathless guiding catheter in patients with small radial arteries.

This study investigated the feasibility and the safety of using a 6.5-French sheathless guide catheter in patients with small radial arteries. The small size of radial arteries is a limitation of transradial coronary intervention. A new sheathless guiding catheter with a diameter almost 2-Fr smaller than conventional sheaths and a full-length hydrophilic coating has been introduced. A total of 148 patients from three French hospitals were consecutively enrolled from March 2009 to February 2012. They underwent transradial approach (TRA) for percutaneous coronary interventions (PCI) using the 6.5-F ASAHI sheathless Eaucath guiding catheter system. Among the 148 patients enrolled, 95 were females (64%), and 183 lesions were treated. Procedural success rate was 100%. Thirteen patients (9%) underwent same-procedure multivessel interventions for the right and left coronary artery. Among the group of 46 patients undergoing bifurcation PCI, 35 (76%) bifurcated lesions were treated with a kissing balloon technique, one patient had a saphenous vein bypass graft lesion requiring filter wire placement prior to intervention, nine (6.1%) patients required rotational atherectomy, thrombus-aspiration catheters were used in 19 (12.8%) patients, fractional flow reserve (FFR)-guided PCI in 10 (6.7%) patients, alcohol septal ablation in three (2%) patients. Ten (6.7%) cases of chronic total occlusion were successfully treated in nine (6.1%) patients using the hydrophilic catheter. No radial artery site complications was noted. The use of sheathless guiding catheters is a safe, effective method for PCI via TRA in small radial arteries without catheter-related complications.

Implantation of the eSVS Mesh: modification of recommended technique.

The eSVS Mesh is a knitted wire lattice manufactured in cylindrical sheaths of various diameters, designed to be placed around the outer surface of a saphenous vein graft before use in coronary surgery. The goal is to improve long-term vein graft patency by preventing expansive endothelial injury obviating neointimal hyperplasia and subsequent graft atherosclerosis. Since the First-In-Man feasibility trial of the eSVS Mesh, postmarket studies in Europe and a feasibility trial in the United States are ongoing. Consensus from the principal investigators indicated the trials had confounding variables that may impact results other than evaluation of the eSVS Mesh alone. With input from these investigators, the recommended operative technique has been modified for future trials by removing the mesh from proximal and distal anastomoses and eliminating the use of fibrin sealant. These changes allow for use of an implant technique closer to standard vein bypass grafting and a more focused evaluation of the eSVS Mesh.

A multiscale computational framework to understand vascular adaptation

The failure rate for vascular interventions (vein bypass grafting, arterial angioplasty/stenting) remains unacceptably high. Over the past two decades, researchers have applied a wide variety of approaches to investigate the primary failure mechanisms, neointimal hyperplasia and aberrant remodeling of the wall, in an effort to identify novel therapeutic strategies. Despite incremental progress, specific cause/effect linkages among the primary drivers of the pathology, (hemodynamic factors, inflammatory biochemical mediators, cellular effectors) and vascular occlusive phenotype remain lacking. We propose a multiscale computational framework of vascular adaptation to develop a bridge between theory and experimental observation and to provide a method for the systematic testing of relevant clinical hypotheses. Cornerstone to our model is a feedback mechanism between environmental conditions and dynamic tissue plasticity described at the cellular level with an agent based model. Our implementation (i) is modular, (ii) starts from basic mechano-biology principle at the cell level and (iii) facilitates the agile development of the model.

Outcome and graft patency in coronary artery bypass grafting with coronary endarterectomy.

BackgroundControversy persists regarding the use of coronary endarterectomy (CE) in patients with severe coronary artery disease. We compared the comorbidities and perioperative characteristics of patients undergoing coronary artery bypass grafting (CABG) with and without CE.MethodsThis study was performed in two private hospitals in Shiraz, Iran from May 2010 to December 2011 on 967 patients who underwent CABG without CE and 84 patients who underwent CABG with CE (the CE+ group). After follow-up at 9.66±3.65 months post-surgery, 28 patients from the CE+ group underwent angiography to evaluate the patency of grafts and native coronary vessels.ResultsPatients in the CE+ group had a more prevalent history of diabetes (48% vs. 36%) and number of diseased vessels (2.88±0.39 vs. 2.70±0.85). The overall hospital mortality was 1.8%, and no significant difference was observed between the two groups. In the 28 patients who underwent reangiography, 113 vessels were bypassed and 29 endarterectomies were performed, mostly on the left anterior descending artery (12 endarterectomies) and the right coronary artery (8 endarterectomies). In the endarterectomized vessels, a 66% patency rate was found in both the grafts and the native vessels. The native coronary vessels were more likely to be patent when the left internal mammary artery was used as a conduit than when a saphenous vein bypass graft was used.ConclusionThe lack of a significant difference in postoperative complications in patients who underwent CABG with or without CE may indicate that CE does not expose patients to a higher risk of complications. Since most of the endarterectomized vessels were shown to be patent during the follow-up period, we propose that endarterectomy is a viable option for patients with severely diseased vessels.

Arm Veins versus Contralateral Greater Saphenous Veins for Lower Extremity Bypass Reconstruction: Preliminary Data of a Randomized Study

The aim of this randomized study was to determine whether arm vein (AV) or contralateral greater saphenous vein (CGSV) is the better alternative vein source for lower extremity bypass reconstruction. Consecutive patients with absent ipsilateral greater saphenous vein undergoing lower extremity revascularization were allocated to group A (AV bypass) or B (CGSV bypass). From 6, 2010, to 11, 2013, 64 patients (32 each group) were randomized. In all, 29 of 93 patients had to be excluded for various reasons. Median age was 76 years vs. 71 years (P = 0.01) for group A and B patients. There were no statistically significant differences regarding gender, cardiovascular risk factors, redo bypass procedures (P = 0.77), below-knee bypass procedures (P = 0.61), median bypass length (P = 0.6), and median length of incision on ipsilateral leg to perform anastomoses (P = 0.2) between group A and B patients, respectively. Incisions for vein harvest were longer in group A (P = 0.003). Overall surgical site infections (SSIs, P = 1.0) and SSI from vein harvest (P = 1.0) were equally distributed. No patient was lost to follow-up (17 vs. 18 months, P = 0.74). There was no statistically significant difference regarding primary (P = 0.77) and secondary (P = 0.25) patency rates at 1 year (group A: 52% vs. group B: 54% and group A: 72% vs. group B: 61%) and at 2 years (52% vs. 48% and 64% vs. 61%), respectively. There were 4 vs. 6 major amputations (P = 0.23) and 5 vs. 2 deaths (P = 0.1) in groups A and B during follow-up. Preliminary results suggest that both AV and CGSV may serve as a secondary vein bypass graft equally well.

Sequential vein bypass grafting is not associated with an increase of either in-hospital or mid-term adverse events in off-pump coronary artery bypass grafting.

Background:The impact of sequential vein bypass grafting on clinical outcomes is less known in off-pump coronary artery bypass grafting (CABG). We aimed to evaluate the effects of sequential vein bypass grafting on clinical outcomes in off-pump CABG.Methods:From October 2009 to September 2013 at the Fuwai Hospital, 127 patients with at least one sequential venous graft were matched with 127 patients of individual venous grafts only, using propensity score matching method to obtain risk-adjusted outcome comparison. In-hospital measurement was composite outcome of in-hospital death, myocardial infarction (MI), stroke, requirement for intra-aortic ballon pump (IABP) assistance and prolonged ventilation. Major adverse cardiac events (MACEs: Death, MI or repeat revascularization) and angina recurrence were considered as mid-term endpoints.Results:No significant difference was observed among the groups in baseline characteristics. Intraoperative mean blood flow per vein graft was 40.4 ml in individual venous grafts groups versus 59.5 ml in sequential venous grafts groups (P < 0.001). There were no differences between individual and sequential venous grafts groups with regard to composite outcome of in-hospital mortality, MI, stroke, IABP assistance and prolonged ventilation (11.0% vs. 14.2%, P = 0.45). Individual in-hospital measurement also did not differ significantly between the two groups. At about four years follow-up, the survival estimates free from MACEs (92.5% vs. 97.3%, P = 0.36) and survival rates free of angina recurrence (80.9% vs. 85.5%, P = 0.48) were similar among individual and sequential venous grafts groups with a mean follow-up of 22.5 months. In the Cox regression analysis, sequential vein bypass grafting was not identified as an independent predictor of both MACEs and angina recurrence.Conclusions:Compared to individual vein bypass grafting, sequential vein bypass grafting was not associated with an increase of either in-hospital or mid-term adverse events in patients undergoing off-pump CABG.

左側開胸アプローチにて旧大伏在静脈バイパスグラフトに中枢側吻合をおいた再OPCABG の1 例

左側開胸アプローチにて旧大伏在静脈バイパスグラフトに中枢側吻合をおいた再OPCABG の1 例

TRANSFORMING GROWTH FACTOR BETA DRIVES A DISTINCT DIABETES PHENOTYPE IN HUMAN SAPHENOUS VEIN SMOOTH MUSCLE CELLS VIA UPREGULATION OF MICRORNA-143/145

IntroductionPatients with Type 2 diabetes mellitus (T2DM) suffer premature cardiovascular disease and poor prognosis after revascularisation procedures. Following saphenous vein bypass grafting, smooth muscle cell (SMC) plasticity is vital to...

The Correlation Between Computed Tomography (CT) and Duplex Evaluation of Vein Bypass Grafts and Their Relationship to Graft Failure

The Correlation Between Computed Tomography (CT) and Duplex Evaluation of Vein Bypass Grafts and Their Relationship to Graft Failure

Safety and Effectiveness of Drug-Eluting Versus Bare-Metal Stents in Saphenous Vein Bypass Graft Percutaneous Coronary Interventions: Insights From the Veterans Affairs CART Program

BackgroundStenosis of saphenous vein grafts (SVGs) after coronary artery bypass grafting (CABG) is common and often requires percutaneous coronary interventions (PCI) for treatment. However, data for the effectiveness of drug-eluting stents (DES) versus bare-metal stents (BMS) in SVG-PCI are unclear. ObjectivesThis study sought to examine the association between DES versus BMS used during SVG PCI and clinical outcomes in the national Veterans Affairs integrated healthcare system. MethodsWe studied a national cohort of 2,471 post-CABG veterans undergoing SVG-PCI between 2008 and 2011 at all Veterans Affairs hospitals and compared clinical outcomes of between those receiving DES and BMS. Clinical outcomes included procedural complications, myocardial infarction (MI), and all-cause mortality. Comparisons were made in a propensity-matched cohort using Cox proportional hazards regression models. ResultsDES were used in 1,549 SVG-PCI patients (63%) and the use of DES increased progressively with each calendar year (50% in 2008 to 69% in 2011). Incidence of procedural complications was low and comparable in both groups (2.8% among BMS vs. 2.3% among DES patients; p = 0.54). During long-term (>2 years) follow-up, use of DES was associated with lower mortality than BMS (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.57 to 0.89) and similar rates of MI (HR: 0.94; 95% CI: 0.71 to 1.24) in the propensity-matched cohort. ConclusionsIn a national cohort of veterans, we observed widespread and increasing use of DES during SVG-PCI. In long-term follow-up, compared with BMS, DES use was safe and effective in SVG-PCI patients.

Outcomes of complex femorodistal sequential autologous vein and biologic prosthesis composite bypass grafts

Femorodistal autologous vein bypass proves to be the preferred surgical therapy for long arterial occlusions and provides excellent early and long-term results in critical lower limb ischemia. Whenever vein length was insufficient and two distal outflow arteries were present, a sequential composite bypass configuration was chosen with human umbilical vein (HUV) or ovine collagen prosthesis (Omniflow II; Bio Nova International Pty Ltd, North Melbourne, Australia) as the proximal prosthetic part of the bypass. Single-center experience with this technique regarding limb salvage, graft function, secondary reinterventions, and biodegeneration is presented. Between January 1998 and January 2009, 122 consecutive sequential composite bypass operations were performed on 116 patients for short-distance claudication (2), chronic critical ischemia (117), or acute ischemia (3) in the absence of sufficient autologous vein length. HUV was used in 90 cases and Omniflow II in 32 cases. Grafts were followed by duplex scan supplemented by angiography in case of recurrent ischemia with prospective documentation of follow-up data in a computerized vascular database. Retrospective analysis of graft patency, limb salvage, and aneurysmal degeneration of the biologic prosthesis was performed. Mean follow-up was 59 ± 45.5 months (range, 1-161 months). The 30-day mortality was 4.1%. Early postoperative complete or partial bypass thrombosis developed in 16% (20 cases) and required successful revision in 16 cases. During follow-up, 30 complete and 12 partial bypass occlusions occurred, necessitating selective surgical or interventional revision. Primary, primary assisted, and secondary patency rates and the limb salvage rate were 48%, 62%, 71%, and 87%, respectively, after 5 years and 26%, 46%, 54%, and 77%, respectively, after 10 years for all bypasses. Late biodegeneration of HUV prostheses was detected in four instances. Late graft patency and limb salvage were good. These factors, combined with a tolerable rate of late aneurysmal degeneration, justify the use of biologic vascular conduits and autologous vein for complex femorodistal reconstructions.

Endovascular Therapy is Effective Treatment for Focal Stenoses in Failing Infrapopliteal Vein Grafts

To evaluate the efficacy of endovascular therapy for maintaining patency and preserving limbs among patients with failing infrapopliteal bypass grafts. We gathered data from a registry of catheter-based procedures for peripheral artery disease. Of 1554 arteriograms performed from 2006 to 2012, 30 patients had interventions for failing bypass vein grafts to infrapopliteal target vessels. The first intervention for each patient was used in this analysis. Duplex ultrasonography was used within 30 days after intervention and subsequently at 3- to 6-month intervals for graft surveillance. Interventions were performed for duplex ultrasonography surveillance findings in 21 patients and for symptoms of persistent or recurrent critical limb ischemia in 9 patients. Procedural techniques included cutting balloon angioplasty (83%), conventional balloon angioplasty (7%), and stent placement (10%). Procedural success was achieved in all cases. There were no procedure-related complications, amputations, or deaths within 30 days. By Kaplan-Meier analysis, 37% of the patients were free from graft restenosis at 12 months and 31% were at 24 months. Receiver-operating characteristic analysis indicated that a lesion length of 1.75 cm best predicted freedom from restenosis (C statistic: 0.74). Residual stenosis (P = 0.03), patency without reintervention (P = 0.01), and assisted patency with secondary intervention (P = 0.02) rates were superior for short lesions compared with long lesions. The cohort had acceptable rates of adverse clinical outcomes, with 96% of patients free from amputation at both 12 and 24 months; clinical outcomes were also better in patients with short lesions. In this single-center experience with endovascular therapies to treat failing infrapopliteal bypass grafts, rates of limb preservation were high, but the majority of patients developed graft restenosis within 12 months. Grafts with longer stenoses fared poorly by comparison. These data suggest that endovascular interventions to restore or prolong graft patency may be associated with maintained graft patency and that close follow-up with vascular laboratory surveillance is essential.

Surgical management of Syria's war casualties: experience from a French surgical team deployed in the Zaatari refugee camp (Jordan).

In August 2012, the Zaatari refugee camp was opened in Jordan under the auspices of the United Nations High Commissioner for Refugees. France deployed there a surgical facility to treat victims of war trauma. After a phase of intensive care and resuscitation, surgical management meeting the current standards of war surgery was conducted. Then, patients were transferred to a Jordanian civilian hospital or stayed in the Zaatari camp. A retrospective analysis of patient data was performed. From January to March 2013, 95 patients were managed: 85% of patients were male with a median age of 27 years (4-65); 5% of patients were <18 years of age. All patients were Syrian, civilian or members of the "Free Syrian Army." Penetrating trauma accounted for 95% of lesions. A total of 105 surgeries were performed, including: 33 external fixators, 8 laparotomies, 8 nerve repairs, 6 cover flaps, 4 direct arterial repairs, 2 reversed saphenous vein bypass grafts, and 1 amputation. The median length of stay on the wards was 3.71 days; 43% of patients were transferred to Jordanian civilian hospitals. The presence at the Zaatari camp of a surgical facility, which is experienced and specialized in war surgery, is essential, as long as battles are ongoing. Many victims will later require long-term surgical care for the management of the sequelae associated with these traumas.

Time and flow-dependent changes in the p27kip1 gene network drive maladaptive vascular remodeling

Although clinical studies have identified that a single nucleotide polymorphism in the p27(kip1) gene is associated with success or failure after vein bypass grafting, the underlying mechanisms for this difference are not well defined. Using a high-throughput approach in a flow-dependent vein graft model, we explored the differences in p27(kip1)-related genes that drive the enhanced hyperplastic response under low-flow conditions. Bilateral rabbit carotid artery interposition grafts with jugular vein were placed with a unilateral distal outflow branch ligation to create differential flow states. Grafts were harvested at 2 hours and at 1, 3, 7, 14, and 28 days after implantation, measured for neointimal area, and assayed for cell proliferation. Whole-vessel messenger RNA was isolated and analyzed using an Affymetrix (Santa Clara, Calif) gene array platform. Ingenuity Pathway Analysis (Ingenuity, Redwood City, Calif) was used to identify the gene networks surrounding p27(kip1). This gene set was then analyzed for temporal expression changes after graft placement and for differential expression in the alternate flow conditions. Outflow branch ligation resulted in an eightfold difference in mean flow rates throughout the 28-day perfusion period (P < .001). Flow reduction led to a robust hyperplastic response, resulting in a significant increase in intimal area by 7 days (0.13 ± 0.04 mm(2) vs 0.014 ± 0.006 mm(2); P < .005) and progressive growth to 28 days (1.37 ± 0.05 mm(2) vs 0.39 ± 0.06 mm(2); P < .001). At 7 days, low-flow grafts demonstrated a burst of actively dividing intimal cells (36.4 ± 9.4 cells/mm(2) vs 11.5 ± 1.9 cells/mm(2); P = .04). Sixty-five unique genes within the microarray were identified as components of the p27(kip1) network. At a false discovery rate of 0.05, 26 genes demonstrated significant temporal changes, and two dominant patterns of expression were identified. Class comparison analysis identified differential expression of 11 genes at 2 hours and seven genes and 14 days between the high-flow and low-flow grafts (P < .05). At 2 hours, oncostatin M and cadherin 1 were the most differentially expressed. Cadherin 1 and protein kinase B exhibited the greatest differential expression at 14 days. Alterations in flow and shear stress result in divergent patterns of vein graft remodeling. Associated with the dramatic increase in neointimal expansion observed in low-flow vs high-flow grafts is a subset of differentially expressed p27(kip1)-associated genes that correlate with critical stages in the adaptive response. These represent potential biologic targets whose activity may be altered to augment maladaptive vascular remodeling.

SS11 Geometric Remodeling of Vein Bypass Grafts and the Impact on Graft Failure

SS11 Geometric Remodeling of Vein Bypass Grafts and the Impact on Graft Failure

168 Exploring the Role of Microrna-21 On Human Saphenous Vein Smooth Muscle Cell Function

IntroductionMicroRNAs (miRs) are short, non-coding RNAs that negatively regulate gene expression and are reportedly dysregulated in pathological conditions. MiR-21 is expressed throughout the cardiovascular (CV) system and particularly in vascular...

Abstract 165: cAMP-Phosphodiesterase 1C Regulates Neointimal Hyperplasia by Controlling Platelet-Derived Growth Factor Receptor ß Degradation via the Endosome-Lysosome Pathway

Neointimal hyperplasia is associated with the development of diverse vascular diseases such as atherosclerosis, vein bypass graft disease and restenosis after percutaneous coronary interventions. Vascular injury-mediated neointimal hyperplasia involves the phenotypic modulation, migration and proliferation of vascular smooth muscle cells (VSMCs). Cyclic nucleotide is vital in regulating VSMC migration and proliferation, which are controlled by cyclic nucleotide phosphodiesterase (PDE) isozymes. To identify the regulation and function of PDEs in VSMC pathogenesis of vascular diseases, we performed systematic screening for all 22 known PDE genes in normal contractile VSMCs and proliferating synthetic VSMCs. Interestingly, we observed that expression of PDE1C was very low in normal contractile VSMCs but drastically elevated in synthetic VSMCs in vitro as well as in vivo in various mouse models of vascular injuries, including carotid artery ligation, femoral artery wire injury and vein bypass graft. Consistently, PDE1C is also highly induced in VSMCs in neointimal lesion of human coronary artery. More importantly, injury-induced neointimal formation was significantly attenuated in pde1c-deficient mice or by perivascular administration of PDE1 inhibitor. Furthermore, PDE1 inhibition also reduced the spontaneous vascular remodeling of human saphenous vein explant in an ex vivo culture model. Mechanistic studies revealed that PDE1C plays a critical role in regulating the stability of PDGF receptor beta (PDGFR-β). We found that PDE1C knockdown or inhibition markedly decreased the levels of PDGFR-β protein but not mRNA, which was blocked by endosome and lysosome inhibitors. Furthermore, PDE1C inhibition is capable of promoting PDGFR-β internalization and attenuating PDGFR-β membrane accumulation. Finally, we found that PDE1C co-localized with PDGFR-β on cell membrane, which was able to regulate PDGFR-β protein degradation through modulating a transmembrane adenylyl cyclase-cAMP-PKA signaling. Taken together, our present data demonstrated that PDE1C plays a critical role in regulating VSMC proliferation and neointimal hyperplasia, in part, through promoting endosome/lysosome dependent PDGFR-β protein degradation.