Vein Graft Intimal Hyperplasia Research Articles

Inhibition of Mitogen Activated Protein Kinase Activated Protein Kinase II with MMI-0100 reduces intimal hyperplasia ex vivo and in vivo

Vein graft intimal hyperplasia remains the leading cause of graft failure, despite many pharmacological approaches that have failed to translate to human therapy. We investigated whether local suppression of inflammation and fibrosis with MMI-0100, a novel peptide inhibitor of Mitogen Activated Protein Kinase Activated Protein Kinase II (MK2), would be an alternative strategy to reduce cell proliferation and intimal hyperplasia. The cell permeant peptide MMI-0100 was synthesized using standard Fmoc chemistry. Pharmacological doses of MMI-0100 induced minimal human endothelial and smooth muscle cell proliferation (30% and 12% respectively). MMI-0100 suppressed IL-6 expression to control levels, without effect on IL-8 expression. MMI-0100 caused sodium nitroprusside induced smooth muscle cell relaxation and inhibited intimal thickening in human saphenous vein rings in a dose-dependent fashion. In a murine aortic bypass model, MMI-0100 reduced intimal thickness in vein grafts by 72%, and there were fewer F4/80-reactive cells in vein grafts treated with MMI-0100. MMI-0100 prevents vein graft intimal thickening ex vivo and in vivo. These results suggest that inhibition of MK2 with the cell-permeant peptide MMI-0100 may be a novel strategy to suppress fibrotic processes such as vein graft disease.

Statin Therapy and Saphenous Vein Graft Disease After Coronary Bypass Surgery: Analysis From the CASCADE Randomized Trial

Current guidelines recommend statin therapy after coronary artery bypass grafting (CABG) to attain low-density lipoprotein (LDL) levels less than 100 mg/dL. Whether achieving LDL levels less than 70 mg/dL improves postoperative graft patency remains unknown. The CASCADE (Clopidogrel after Surgery for Coronary Artery Disease) trial was a randomized study that evaluated the addition of clopidogrel to aspirin on the development of saphenous vein graft disease after CABG. Patients received the standard of care regarding postoperative statin therapy with targeted LDL levels less than 100 mg/dL. Twelve months postoperatively, patients returned for a coronary angiogram and saphenous vein graft (SVG) intravascular ultrasonogram. In this post hoc analysis, the impact of statin therapy on graft patency and vein graft intimal hyperplasia was assessed. LDL levels significantly declined over the period of the trial (p = 0.002). Twelve months postoperatively, 58.4% patients achieved LDL levels less than 70 mg/dL. Twelve-month graft patency was higher for patients with LDL levels less than 100 mg/dL (96.5%) compared with patients with LDL levels >100 mg/dL (83.3%, p = 0.03), even after adjustment in multivariate analysis (odds ratio [OR], 5.2; 95% confidence interval [CI], 1.3-21.6; p = 0.02). However, no improvement in graft patency was noted with further LDL reduction to less than 70 mg/dL (p = 1.00). Consistent statin use throughout the trial period was independently associated with less vein graft intimal hyperplasia documented by intravascular ultrasound at 12 months (p = 0.04). Statin therapy to achieve LDL levels less than 100 mg/dL was independently associated with improved graft patency in the CASCADE trial. Randomized clinical trials are warranted to prospectively evaluate postoperative LDL reduction to less than 70 mg/dL and its impact on graft patency after CABG.

Pioglitazone prevents intimal hyperplasia in experimental rabbit vein grafts

Intimal hyperplasia is a major obstacle to patency after vein grafting. Several clinical trials revealed that pioglitazone, a peroxisome proliferator-activated receptor-γ ligand, exerts beneficial actions on cardiovascular complications. We investigated whether pioglitazone modulates intimal hyperplasia in experimental rabbit autologous vein grafts. Male Japanese White rabbits were randomly divided into two groups: one group received pioglitazone as food admixture at a concentration of 0.01%, and the other did not (control). One week later, each group underwent reversed autologous vein bypass grafting of the right common carotid artery using ipsilateral external jugular vein. Pioglitazone therapy was continued after surgery and until harvest. Intimal hyperplasia of the grafted vein was assessed at 28 days. Two weeks after implantation, proliferative cells in the neointima were identified by immunohistochemical staining with Ki-67 monoclonal antibody. To determine apoptotic cells, we performed terminal deoxynucleotidyl transferase-mediated deoxyuride-5'-triphosphate nick-end labeling (TUNEL) staining. Blood samples were collected at 28 days after implantation for measuring metabolic parameters such as plasma glucose and total cholesterol. Adiponectin levels were determined by Western blot analysis. Finally, we assessed adiponectin-related signaling pathway, 5' adenosine monophosphate-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK) in the grafted vein by Western blot analysis. Treatment with pioglitazone markedly inhibited intimal hyperplasia of carotid interposition-reversed jugular vein grafts in the pioglitazone group (0.54 ± 0.04 mm(2)) vs control (0.93 ± 0.04 mm(2); n = 7; P < .01). Pioglitazone treatment reduced the number of Ki-67-positive proliferating cells in the neointima of the vein grafts at 14 days after implantation in the pioglitazone group (4.1% ± 1.1%) vs the controls (16.8% ± 1.7%; P < .05). The frequency of TUNEL-positive apoptotic cells was enhanced by pioglitazone (3.5% ± 0.5%) vs the controls (1.2% ± 0.1%; P < .05). Pioglitazone treatment also increased plasma levels of adiponectin, a vascular protective hormone, and led to an increase in phosphorylation of AMPK and a decrease in phosphorylation of ERK in the grafted vein. Pioglitazone attenuates intimal hyperplasia of the vein graft after autologous bypass grafting by its ability to suppress cell proliferation and enhance apoptosis. Pioglitazone could represent a therapeutic target for the prevention of graft failure after bypass grafting.

Letter by Gasparovic et al Regarding Article, “Aspirin Plus Clopidogrel Versus Aspirin Alone After Coronary Artery Bypass Grafting: The Clopidogrel After Surgery for Coronary Artery Disease (CASCADE) Trial”

We thank Gasparovic et al and Bisdas et al for their interest and insightful comments regarding our recently published Clopidogrel after Surgery for Coronary Artery Disease (CASCADE) study.1 CASCADE was a randomized, placebo-controlled trial that evaluated the impact of adding clopidogrel to aspirin on the process of saphenous vein graft disease after coronary artery bypass graft surgery (CABG).2 Compared with aspirin alone, the combination of aspirin plus clopidogrel did not significantly reduce vein graft intimal hyperplasia 1 year after CABG, as assessed by intravascular ultrasound. Although CASCADE was not powered for angiographic or clinical outcomes, we also did not see a significant difference in vein graft patency or cardiovascular events between the 2 treatment groups.1 As noted by Bisdas et al, 1-year vein graft patency in CASCADE was >90%, in contrast to other recently published CABG studies.3 We attribute our favorable patency data to the early administration of antiplatelet therapy on the day of surgery,2 the frequent …

Letter by Bisdas et al Regarding Article, “Aspirin Plus Clopidogrel Versus Aspirin Alone After Coronary Artery Bypass Grafting: The Clopidogrel After Surgery for Coronary Artery Disease (CASCADE) Trial”

We thank Gasparovic et al and Bisdas et al for their interest and insightful comments regarding our recently published Clopidogrel after Surgery for Coronary Artery Disease (CASCADE) study.1 CASCADE was a randomized, placebo-controlled trial that evaluated the impact of adding clopidogrel to aspirin on the process of saphenous vein graft disease after coronary artery bypass graft surgery (CABG).2 Compared with aspirin alone, the combination of aspirin plus clopidogrel did not significantly reduce vein graft intimal hyperplasia 1 year after CABG, as assessed by intravascular ultrasound. Although CASCADE was not powered for angiographic or clinical outcomes, we also did not see a significant difference in vein graft patency or cardiovascular events between the 2 treatment groups.1 As noted by Bisdas et al, 1-year vein graft patency in CASCADE was >90%, in contrast to other recently published CABG studies.3 We attribute our favorable patency data to the early administration of antiplatelet therapy on the day of surgery,2 the frequent …

Multifaceted Role of Plasminogen Activator Inhibitor-1 in Regulating Early Remodeling of Vein Bypass Grafts

The role of plasminogen activator inhibitor-1 (PAI-1) in vein graft (VG) remodeling is undefined. We examined the effect of PAI-1 on VG intimal hyperplasia and tested the hypothesis that PAI-1 regulates VG thrombin activity. VGs from wild-type (WT), Pai1(-/-), and PAI-1-transgenic mice were implanted into WT, Pai1(-/-), or PAI-1-transgenic arteries. VG remodeling was assessed 4 weeks later. Intimal hyperplasia was significantly greater in PAI-1-deficient mice than in WT mice. The proliferative effect of PAI-1 deficiency was retained in vitronectin-deficient mice, suggesting that PAI-1's antiproteolytic function plays a key role in regulating intimal hyperplasia. Thrombin-induced proliferation of PAI-1-deficient venous smooth muscle cells (SMC) was significantly greater than that of WT SMC, and thrombin activity was significantly higher in PAI-1-deficient VGs than in WT VGs. Increased PAI-1 expression, which has been associated with obstructive VG disease, did not increase intimal hyperplasia. Decreased PAI-1 expression (1) promotes intimal hyperplasia by pathways that do not require vitronectin and (2) increases thrombin activity in VG. PAI-1 overexpression, although it promotes SMC migration in vitro, did not increase intimal hyperplasia. These results challenge the concept that PAI-1 drives nonthrombotic obstructive disease in VG and suggest that PAI-1's antiproteolytic function, including its antithrombin activity, inhibits intimal hyperplasia.

Suppression of postoperative intimal hyperplasia of vein graft with edaravone in a rat model

Postoperative intimal hyperplasia is still the major cause of vein graft occlusion. No medicine, however, can suppress the development of postoperative intimal hyperplasia. Since June 2001, edaravone has been commercially available as the free radical scavenger for acute cerebral infarction. In addition, it is well known that edaravone in lower dosage also suppresses injury to endothelial cells of vessels in vitro. In this study we evaluated the effect of edaravone on the development of postoperative intimal hyperplasia in a rat model. In ten male rats (498 ± 53 g) we interposed the right epigastric vein graft into the common femoral artery. The ten rats were divided into two groups: edaravone group (n = 5) in which there was the preoperaiive administration of edaravone (3.0 mg/kg) into peritoneal cavity, and the control (n = 5) in which the same dose of saline was used. After 4 weeks three sections were taken from the vein grafts and stained with Verhoeff’s and van Gieson’s stains. The intimal areas of the vein graft were measured using computerized planimetry. The averages of the intimal area and serum monocyte chemoattractant protein 1 (MCP-1) level were compared between the two groups. The mean ischemic time was 68 ± 6 min. The average of the intimal area in the edaravone group was significantly lower than the control group (0.05 ± 0.02 mm2 vs. 0.43 ± 0.05 mm2, p < 0.001). The average of serum MCP-1 in the edaravone group was also significantly lower than that of the control group (116 ± 11 pg/mL. vs. 169 ± 10 pg/mL, p < 0.01). Our results suggested that edaravone could suppress postoperative intimal hyperplasia of the vein graft in a rat model.

The relationship between local renin-angiotensin system and intimal proliferation in an organ culture of human saphenous veins

Local renin-angiotensin system (RAS) is implicated in development of intimal hyperplasia after vein bypass grafting, but little is known about the local angiotensin-converting enzyme (ACE) activity and the local responses of angiotensin II (AngII) in vein graft physiology. An organ culture of human saphenous vein was used as a model of vein graft intimal hyperplasia, and the role of local RAS in the development of neointimal proliferation was studied. Segments of saphenous veins were cultured for 14 days. One group was set as control, another two were cultured in medium with captopril, an ACE inhibitor and losartan, an Ang II receptor antagonist, respectively. All specimens were frozen in liquid nitrogen for ACE activity, histology, and immunohistochemistry studies. The concentration of ACE increased 37% in cultured veins to preculture veins. Immunohistochemical localization identified ACE in the endothelial layer of preculture veins and cultured veins, but at a greater density in the intimal hyperplasia of cultured veins. Captopril and losartan significantly reduced neointimal thickness by 49% and 34%, respectively. These data demonstrate that a positive relationship exist between local RAS and intimal proliferation. The use of ACE inhibitors and Ang II receptor antagonists have clinical significance in the prevention and treatment of vein graft disease.

Aspirin Plus Clopidogrel Versus Aspirin Alone After Coronary Artery Bypass Grafting

Background— Clopidogrel inhibits intimal hyperplasia in animal studies and therefore may reduce saphenous vein graft (SVG) intimal hyperplasia after coronary artery bypass grafting. The Clopidogrel After Surgery for Coronary Artery DiseasE (CASCADE) study was undertaken to evaluate whether the addition of clopidogrel to aspirin inhibits SVG disease after coronary artery bypass grafting, as assessed at 1 year by intravascular ultrasound. Methods and Results— In this double-blind phase II trial, 113 patients undergoing coronary artery bypass grafting with SVGs were randomized to receive aspirin 162 mg plus clopidogrel 75 mg daily or aspirin 162 mg plus placebo daily for 1 year. The primary outcome was SVG intimal hyperplasia (mean intimal area) as determined by intravascular ultrasound at 1 year. Secondary outcomes were graft patency, major adverse cardiovascular events, and major bleeding. One-year intravascular ultrasound and coronary angiography were performed in 92 patients (81.4%). At 1 year, SVG intimal area did not differ significantly between the 2 groups (4.1±2.0 versus 4.5±2.1 mm 2 , aspirin-clopidogrel versus aspirin-placebo, P =0.44). Overall 1-year graft patency was 95.2% in the aspirin-clopidogrel group compared with 95.5% in the aspirin-placebo group ( P =0.90), and SVG patency was 94.3% in the aspirin-clopidogrel group versus 93.2% in the aspirin-placebo group ( P =0.69). Freedom from major adverse cardiovascular events at 1 year was 92.9±3.4% in the aspirin-clopidogrel group and 91.1±3.8% in the aspirin-placebo group ( P =0.76). The incidence of major bleeding at 1 year was similar for the 2 groups (1.8% versus 0%, aspirin-clopidogrel versus aspirin-placebo, P =0.50). Conclusions— Compared with aspirin monotherapy, the combination of aspirin plus clopidogrel did not significantly reduce the process of SVG intimal hyperplasia 1 year after coronary artery bypass grafting. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00228423.

E0128 Angiotensin-(1-7) inhibits vascular remodelling in rat jugular vein grafts via reduced ERK1/2 and p38 MAPK activity

ObjectsTo evaluate the effects of Ang-(1-7) on vascular remodelling in vein grafts.Methodsa model of autologous jugular vein grafts in rats was established. With this model system, rats (n=12 per group)...

Characterization of the Inhibition of Vein Graft Intimal Hyperplasia by a Biodegradable Vascular Stent

Characterization of biodegradable stent vein graft thickening. Polydioxanone vascular sutures (PDSs) were used in a biodegradable arteriovenous bypass model. Twenty-four rabbits underwent carotid interposition bypass via ipsilateral jugular vein. One half received the stent (PDS group) and the remaining half a simple vein graft (controls). Group subsets received external stent removal or sham-control exploration at 4 and 12 weeks. At 4 and 12 weeks, the PDS group had significantly less medial and intimal thickening than the control group (P < 0.05), and there were fewer proliferating smooth muscle cells and extra cellular matrix formation than the control group at every interval. At 12 weeks, partial stent degradation occurred without deleterious effects. Furthermore proliferating cell nuclear antigen (PCNA), angiotensin type 1 receptor (AT1R), and transforming growth factor beta 1 (TGF-β1) levels were significantly lower than the control group. The external stent inhibited medial and intimal hyperplasia, an effect that remains after the material has completely degraded. This PDS stent is feasible option for vein grafts.

The Role of ex-vivo Gene Therapy of Vein Grafts with Egr-1 Decoy in the Suppression of Intimal Hyperplasia

Objectives To test the hypothesis that vein graft intimal hyperplasia can be significantly suppressed by a single intra-operative transfection of the graft with a decoy oligonucleotide (ODN) binding the transcription factor Egr-1. Design Experimental study. Materials and methods Jugular vein to carotid artery interposition grafts in rabbits were treated with Egr-1 decoy, mutant decoy ODN, vehicle alone, using a non-distending pressure of 300 mmHg for 20 min, or were left untreated. All animals were fed a 2% cholesterol diet. The animals were sacrificed after 48 h, 6 weeks and 12 weeks. Paraffin-embedded vein sections were subjected to angiometric analysis. Results Successful delivery of the ODN was confirmed by DAPI staining. Quantitative real-time PCR revealed a 60% decrease of the Egr-1 gene expression in the animals in which the Egr-1 decoy ODN was delivered. Cellular proliferation was also significantly decreased as indicated by the Ki-67 labelling index. An increase in intimal and medial thickness was found in all vein grafts. However, intimal thickness was significantly reduced in the grafts treated with Egr-1 decoy ODN, whereas luminal area was significantly increased. Conclusion A single intra-operative pressure-mediated transfection of vein grafts with Egr-1 decoy ODN significantly suppresses intimal hyperplasia in a rabbit hypercholesterolaemic model.

Smooth muscle cells in porcine vein graft intimal hyperplasia are derived from the local vessel wall.

Accelerated intimal hyperplasia (IH) is an important cause of morbidity and mortality in patients with atherosclerotic vascular disease treated with bypass vein grafts. We used an interposition vein graft model to determine the source of neointimal cells in a clinically relevant large animal model. Jugular vein segments from sex-mismatched, MHC-in-bred pigs were implanted into common carotid arteries bilaterally and harvested up to 8 weeks postsurgery for stereological, histological, and immunofluorescence analyses. Progressive IH lesions contained macrophages and smooth muscle cells (SMC). Fluorescent in situ hybridization following grafting of female veins into male arteries revealed that only ∼10% of the SMC were male, confirming that the majority of intimal SMC derived from the local vessel wall. The majority of neointimal SMC in the IH seen after interposition vein grafting derive from the engrafted local vessel wall. These are the first results from a clinically relevant large animal model that confirm data from rodent models. They have implications for the utility of therapeutic stem cells in this type of intimal hyperplasia.

Abstract 5775: C57BL/6 NK Cell Gene Complex Crucially Involved in General Vascular Remodelling

Background The immune system plays an important role in vascular remodelling. Inflammatory cells as monocytes, CD4+ and CD8+ T cells were already proven to be modulators of vascular remodelling. Recently, NK cells were indicated to contribute to vascular remodelling in processes of revascularisation and atherosclerotic lesion development. Interestingly, C57BL/6 mice display profound induced vascular remodelling, eg in arteriogenesis, restenosis and vein grafting, whereas BALB/c mice display much less remodelling. Moreover, these two mouse strains are different in their NK cell receptor gene complex (NKC), which codes for activating and inhibitory NK cell receptors. Aim To demonstrate that C57BL/6 NKC is crucially involved in modulating vascular remodelling in general. Material &amp; Methods C57BL/6, BALB/c and BALB.B6- CMV1 r (CMV1 r ) mice, of which the latter is congenic for the C57BL/6 NKC, were used in two different models of vascular remodelling, induction of restenosis by femoral artery cuff placement and vein grafting by placement of a venous interposition in the mouse carotid artery. Vascular remodelling was monitored by morphometry and immunohistology. Results After cuff-placement the congenic CMV1r mice showed progressive formation of neointima (4745 um2), comparative to C57BL/6 (4459 um2), and significantly more than BALB/c mice (1247 um2), that displayed very little formation of neointima. Vein graft remodelling in CMV1 r mice showed stronger intimal hyperplasia in vein grafts (0.22mm2) compared to both C57BL/6 mice (0.15mm2) and BALB/c mice (0.11mm2). Importantly, CMV1 r displayed an inflammatory infiltrate similar to that of C57BL/6 mice, whereas BALB/c mice show hardly any inflammatory cell influx into the vessel wall. Conclusion These data demonstrate that the C57BL/6 NK cell gene locus is involved in the induction of profound vascular remodelling in general. Furthermore, the observed differences in inflammatory infiltrate between the three mouse strains strongly suggest that the C57BL/6 NK receptor repertoire might be involved in triggering an immune response that is associated with profound vascular remodelling.

Therapeutic approach against intimal hyperplasia of vein grafts through endothelial nitric oxide synthase/nitric oxide (eNOS/NO) and the Rho/Rho-kinase pathway

Late graft failure of autologous vein grafts is associated with intimal hyperplasia resulting from the migration and proliferation of vascular smooth muscle cells (VSMCs). Endothelial nitric oxide synthase (eNOS) is an enzyme that synthesizes nitric oxide (NO). An impairment of NO-mediated vasorelaxation and increases in cell proliferation occurs in vein grafts after the surgery and these pathophysiological changes cause intimal thickening. The Rho/Rho-kinase pathway negatively regulates eNOS and is involved in intimal hyperplasia. Several studies have been conducted with the goal of controlling intimal hyperplasia targeting eNOS/NO and the Rho/Rho-kinase pathway. The oral administration of drugs, such as Rho-kinase inhibitor, L: -arginine, beta-blocker and statins, significantly suppressed intimal thickening in animal models. This study revealed that statins upregulate eNOS through Rho-kinase inhibition to suppress intimal hyperplasia. The intraluminal gene transfer of eNOS inhibited intimal hyperplasia, thereby reducing the cell proliferation. These approaches are thus considered to be potentially promising therapeutic modalities for graft failure.

Adventitial delivery of platelet-derived endothelial cell growth factor gene prevented intimal hyperplasia of vein graft

Adventitial delivery of platelet-derived endothelial cell growth factor gene prevented intimal hyperplasia of vein graft

Adventitial delivery of platelet-derived endothelial cell growth factor gene prevented intimal hyperplasia of vein graft

Platelet-derived endothelial cell growth factor (PD-ECGF), also known as thymidine phosphorylase (TP) reportedly inhibits vascular smooth muscle cells (VSMCs) migration and proliferation. We hypothesized that adventitial administration of the PD-ECGF/TP gene will suppress intimal hyperplasia and prevent vein graft failure. The study used 68 female rabbits. Rabbit jugular vein was autogenously transplanted into carotid artery with a cuff anastomotic technique. To define vascular wall gene transfer efficiency, poloxamer hydrogel (20%) containing plasmid vector encoding the LacZ gene and different concentrations of trypsin (0%, 0.1%, 0.25%, and 0.5%, n = 5 for each group) was applied to the adventitia of the vein graft. Gene transfer efficiency was evaluated 7 days later by X-gal staining. An additional 48 rabbits received poloxamer hydrogel (20%) containing 0.25% trypsin and the human PD-ECGF/TP gene, LacZ gene, or saline. Intima thickness was evaluated at 2 and 8 weeks after grafting (n = 8 for each group at each time point). Transgene expression was examined by reverse transcriptase-polymerase chain reaction, immunoblotting assay, and immunohistochemical staining. Immunohistochemical staining was also used to determine VSMC proliferation, heme oxygenase-1 expression, and macrophage infiltration. Incorporation of trypsin into the poloxamer hydrogel significantly increased vessel wall gene transfer. Trypsin at 0.25% and 0.5% resulted in higher gene transfer at the same level without effecting intimal hyperplasia and inflammation; thus, trypsin at 0.25% concentration was used for subsequent experiments. Compared with the LacZ and saline groups, grafts receiving the PD-ECGF/TP gene significantly reduced intimal thickness at 2 and 8 weeks after treatment. The ratio of proliferative VSMC was lower in PD-ECGF/TP treated grafts. Histologic examination of the PD-ECGF/TP transgene grafts demonstrated high expression of heme oxygenase-1, which has been reported to inhibit VSMC proliferation, suggesting that heme oxygenase-1 may be important in the inhibition effect of PD-ECGF/TP on VSMC. No neoplastic or morphologic changes were found in the remote organs. A safe and highly efficient gene transfer method was developed by using poloxamer hydrogel and a low concentration of trypsin. Neointimal hyperplasia was significantly reduced by adventitial application of the PD-ECGF/TP gene to the vein graft. Our data suggest that adventitial delivery of the PD-ECGF/TP gene after grafting may be promising method for preventing vein graft failure.

A Novel Mechanism of Vascular Smooth Muscle Cell Regulation by Notch

See related article, pages 1483–1491 The Notch family of receptors, Notch1 to -4, are heterodimer transmembrane proteins, consisting of an extracellular domain and a noncovalently linked intracellular domain (ICD). Upon interaction with the DSL family of proteins (Jagged, Delta-like) on neighboring cells, Notch undergoes proteolytic cleavage, which frees the ICD from the plasma membrane. This results in translocation of the ICD into the nucleus, where it forms a complex with the CSL family of transcriptional repressors (CBF1/RBP-Jk), removing the repression and allowing for target gene (Hes, Hey) transcription.1,2 Tissue distribution of the Notch proteins varies widely. Notch1 and -4 are predominantly endothelial, prominent in both arteries and veins, and present in all stages of development (embryonic to adult); the expression of Notch2 is typically confined to pulmonary endothelium, but Notch3 is primarily expressed in adult arterial vascular smooth muscle cells (VSMCs) in large conduit, pulmonary, and systemic resistance arteries.3 This specific pattern of temporal and spatial distribution correlate to diverse functions of the Notch family in vascular development and physiology in vertebrates reported to date.4 In the cardiovascular system, Notch signaling plays a role in several aspects of vascular development, including vasculogenesis, angiogenesis, differentiation, vascular remodeling, and VSMC maturation. Notch1 and -4 signaling appears critical in vasculogenesis and angiogenesis during early development, when it interacts with vascular endothelial growth factor signaling to specify artery–vein differentiation of endothelial cells (ECs). Transgenic mice deficient for Notch1 fail to undergo embryonic angiogenic remodeling, and vascular development is arrested at the primitive undifferentiated plexus, resulting in an embryonic lethal phenotype. Notch2-null mutations likewise result in embryonic lethality characterized by multiple large and small vessel aneurysms. Notch4 deletion results in no obvious phenotypic alteration. Notch3−/− mice are viable; however, they fail to develop proper arterial VSMC phenotype, resulting in vein-like …

Accelerated intimal hyperplasia in aortocoronary internal mammary vein grafts in minipigs

BackgroundMore than 50% of aortocoronary saphenous vein grafts are occluded 10 years after surgery. Intimal hyperplasia is the initial critical step in the progression toward occlusion. Internal mammary veins, which are physiologically prone to less hydrostatic pressure, may undergo an accelerated progression to intimal hyperplasia and thus be suitable for investigation of the mechanisms of aortocoronary vein graft disease.MethodsSix minipigs underwent aortocoronary bypass grafting using standard cardiopulmonary bypass and cardioplegic arrest. Mammary vein were grafted in a reversed manner from ascending aorta to left anterior descending coronary artery (LAD). The proximal LAD was ligated, rendering the anterior left ventricle vein graft-dependent. Minipigs were killed after 4 weeks, and vein grafts were harvested. Histological and immunohistological investigation were performed with respect to morphometric analysis, endothelial damage/dysfunction (v-Willebrand-factor (vWF)), smooth muscle cells (α-smooth actin) and proliferation rate (proliferation marker Ki 67).ResultsMean intimal area of vein grafts was increased compared to ungrafted mammary veins. Intimal hyperplasia in vein grafts was characterized by massive accumulation of smooth muscle cells with a high proliferation rate and endothelial perturbation. Significant (p = 0.001) intimal hyperplasia of the grafted mammary vein compared to the ungrafted mammary vein was found. These changes were absent in ungrafted mammary veins.ConclusionThe present study demonstrates a pig model of aortocoronary vein graft intimal hyperplasia which is characterized by an accelerated progression within internal mammary veins. The model is suitable to investigate the pathophysiology of aortocoronary vein graft intimal hyperplasia as well as therapeutic approaches.

An Experiment-Based Model of Vein Graft Remodeling Induced by Shear Stress

Vein graft intimal hyperplasia induced by shear stress is considered to be one of the major causes of vein graft failure. We have developed a mathematical model of vein graft intimal hyperplasia induced by shear stress based on experimental data. Intimal thickness and the rate of intimal thickness change are expressed as functions of shear stress and time. The model coefficients are derived from animal experiments where bilateral rabbit carotid vein grafts are exposed to different shear stress levels. Morphology data of the vein grafts are obtained over multiple time points. The model describes the well-known behavior of intimal thickening, which is inversely related to shear stress. It also depicts the time-dependent behavior of vein graft intimal hyperplasia. Finally, the model is used to simulate the intimal growth around a focal stenosis, which was created by ligating the middle of a vein graft using a suture. Simulation results and experimental data agree qualitatively, and demonstrate that the intima thickens more distal to the stenosed area. These experiments establish the potential of the general experiment-based approach for predicting human vein graft remodeling. Other mechanical and biological factors can be included following a similar approach in order to obtain a more accurate vein graft remodeling model.