scholarly journals PFKFB3 gene deletion in endothelial cells inhibits intraplaque angiogenesis and lesion formation in a murine model of venous bypass grafting

Angiogenesis ◽  
2021 ◽  
Author(s):  
Paola Perrotta ◽  
Margreet R. de Vries ◽  
Bart Peeters ◽  
Pieter-Jan Guns ◽  
Guido R. Y. De Meyer ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vein Graft ◽  
Gene Deletion ◽  
Corn Oil ◽  
Lesion Size ◽  
Glycolytic Flux ◽  
M2 Macrophage ◽  
Vein Grafts ◽  
Unstable Plaques ◽  
Cardiac Revascularization

AbstractVein grafting is a frequently used surgical intervention for cardiac revascularization. However, vein grafts display regions with intraplaque (IP) angiogenesis, which promotes atherogenesis and formation of unstable plaques. Graft neovessels are mainly composed of endothelial cells (ECs) that largely depend on glycolysis for migration and proliferation. In the present study, we aimed to investigate whether loss of the glycolytic flux enzyme phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) in ECs inhibits IP angiogenesis and as such prevents unstable plaque formation. To this end, apolipoprotein E deficient (ApoE−/−) mice were backcrossed to a previously generated PFKFB3fl/fl Cdh5iCre mouse strain. Animals were injected with either corn oil (ApoE−/−PFKFB3fl/fl) or tamoxifen (ApoE−/−PFKFB3ECKO), and were fed a western-type diet for 4 weeks prior to vein grafting. Hereafter, mice received a western diet for an additional 28 days and were then sacrificed for graft assessment. Size and thickness of vein graft lesions decreased by 35 and 32%, respectively, in ApoE−/−PFKFB3ECKO mice compared to controls, while stenosis diminished by 23%. Moreover, vein graft lesions in ApoE−/−PFKFB3ECKO mice showed a significant reduction in macrophage infiltration (29%), number of neovessels (62%), and hemorrhages (86%). EC-specific PFKFB3 deletion did not show obvious adverse effects or changes in general metabolism. Interestingly, RT-PCR showed an increased M2 macrophage signature in vein grafts from ApoE−/−PFKFB3ECKO mice. Altogether, EC-specific PFKFB3 gene deletion leads to a significant reduction in lesion size, IP angiogenesis, and hemorrhagic complications in vein grafts. This study demonstrates that inhibition of endothelial glycolysis is a promising therapeutic strategy to slow down plaque progression.

Early Inhibition of P-Selectin/P-Selectin Glycoprotein Ligand-1 Reduces Intimal Hyperplasia in Murine Vein Grafts through Platelet Adhesion

2019 ◽  
Vol 119 (12) ◽  
pp. 2014-2024
Author(s):  
Chi-Nan Tseng ◽  
Ya-Ting Chang ◽  
Cih-Yi Yen ◽  
Mariette Lengquist ◽  
Malin Kronqvist ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Intimal Hyperplasia ◽  
Vein Graft ◽  
Platelet Adhesion ◽  
Time Window ◽  
Early Time ◽  
Leukocyte Recruitment ◽  
Luminal Surface ◽  
Vein Grafts ◽  
Inflammatory Phase

AbstractInflammatory processes contribute to intimal hyperplasia (IH) and long-term failure of vein grafts used in bypass surgery. Leukocyte recruitment on endothelial cells of vessels during inflammation is regulated by P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1), which also mediates the interaction between platelets and endothelial cells in vein grafts transferred to arteries. However, how this pathway causes IH in vein grafts is unclear. In this study, we used a murine model of vein grafting to investigate P-selectin-mediated platelet adhesion, followed by IH. On the luminal surface of the vein graft, leukocyte recruitment occurred mainly in areas with adhered platelets rather than on endothelial cells without adherent platelets 1 hour after vein grafting. Blockage of either P-selectin or PSGL-1 reduced platelet adhesion and leukocyte recruitment on the luminal surface of vein grafts. Inhibition of the P-selectin pathway in vein grafts significantly reduced platelet-mediated leukocyte recruitment and IH of vein grafts 28 days after surgery. The study demonstrates that functional blockage of the P-selectin/PSGL-1 pathway in the early inflammatory phase after vein grafting reduced leukocyte invasion in the vein graft wall and later IH development. The findings imply an attractive early time window for prevention of vein graft failure by manipulating platelet adhesion.

scholarly journals miRNA-126-3p carried by human umbilical cord mesenchymal stem cell enhances endothelial function through exosome-mediated mechanisms in vitro and attenuates vein graft neointimal formation in vivo

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Qingxi Qu ◽  
Limei Wang ◽  
Weidong Bing ◽  
Yanwen Bi ◽  
Chunmei Zhang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Umbilical Cord ◽  
Vein Graft ◽  
Fluorescent Microscopy ◽  
Tube Formation ◽  
Human Umbilical Cord ◽  
Neointimal Formation ◽  
Vein Grafts

Abstract Background The aim of this study was to determine whether the combination of MSC implantation with miRNA-126-3p overexpression would further improve the surgical results after vein grafting. Methods human umbilical cord MSCs (hucMSCs) and human umbilical vein endothelial cells (HUVECs) were isolated from human umbilical cords and characterized by a series of experiments. Lentivirus vector encoding miRNA-126-3p was transfected into hucMSCs and verified by PCR. We analyzed the miRNA-126-3p-hucMSC function in vascular endothelial cells by using a series of co-culture experiments. miRNA-126-3p-hucMSCs-exosomes were separated from cell culture supernatants and identified by WB and TEM. We validated the role of miRNA-126-3p-hucMSCs-exosomes on HUVECs proliferative and migratory and angiogenic activities by using a series of function experiments. We further performed co-culture experiments to detect downstream target genes and signaling pathways of miRNA-126-3p-hucMSCs in HUVECs. We established a rat vein grafting model, CM-Dil-labeled hucMSCs were injected intravenously into rats, and the transplanted cells homing to the vein grafts were detected by fluorescent microscopy. We performed historical and immunohistochemical experiments to exam miRNA-126-3p-hucMSC transplantation on vein graft neointimal formation and reendothelialization in vitro. Results We successfully isolated and identified primary hucMSCs and HUVECs. Primary hucMSCs were transfected with lentiviral vectors carrying miRNA-126-3p at a MOI 75. Co-culture studies indicated that overexpression of miRNA-126-3p in hucMSCs enhanced HUVECs proliferation, migration, and tube formation in vivo. We successfully separated hucMSCs-exosomes and found that miRNA-126-3p-hucMSCs-exosomes can strengthen the proliferative, migratory, and tube formation capacities of HUVECs. Further PCR and WB analysis indicated that, SPRED-1/PIK3R2/AKT/ERK1/2 pathways are involved in this process. In the rat vein arterialization model, reendothelialization analysis showed that transplantation with hucMSCs modified with miRNA-126-3p had a higher reendothelialization of the vein grafts. The subsequent historical and immunohistochemical examination revealed that delivery with miRNA-126-3p overexpressed hucMSCs significantly reduced vein graft intimal hyperplasia in rats. Conclusion These results suggest hucMSC-based miRNA-126-3p gene therapy may be a novel option for the treatment of vein graft disease after CABG.

Extracellular signal-regulated kinase inhibition prevents venous adaptive remodeling via regulation of Eph-B4

Vascular ◽  
2021 ◽  
pp. 170853812199985
Author(s):  
Yuanyuan Guo ◽  
Fan Zhu ◽  
Xiong Zhang ◽  
Guangmin Wu ◽  
Pinting Fu ◽  
...  
Keyword(s):  
Western Blotting ◽  
Vein Graft ◽  
Artery Bypass ◽  
Bypass Graft ◽  
Graft Loss ◽  
Elastic Fibers ◽  
Sprague Dawley ◽  
Vein Grafts ◽  
Graft Stenosis

Objectives Vein graft adaptation (VGA) is a process that vein as a vascular graft conduits in arterial reconstructive surgery; VGA can lead to postoperative vein graft stenosis (VGS) and complications after coronary artery bypass graft and other peripheral artery bypass surgeries. VGA is characterized by vein graft loss the venous features without exhibiting arterial features; furthermore, the activation of ERK inhibited the maintenance of venous properties of the vein graft. We hypothesized that ERK inhibition can affect vein VGS through regulating the expression of EphB4. Methods Rat vein transplantation model was established using wild-type and EphB4+/− Sprague-Dawley rats. Hematoxylin-eosin, Masson, Verhoeff, actin staining, and immunohistochemistry were applied to observe the structure of the vein grafts. Vascular smooth muscle cells (VSMCs) were isolated from the vein and vein grafts. Western blotting was used to determine the expression of p-ERK1/2 and EphB4, and immunofluorescence was applied to detect the expression and location of EphB4. Cell wound scratch assay and CCK8 assay were used to determine the migration and proliferation of VSMCs. Real-time polymerase chain reaction was used to determine the mRNA expression of EphB4. Results Western blotting in vein sample and vein graft sample detected p-ERK1/2 and ERK1/2 expression in both EphB4+/+ and EphB4+/− rats. The expression of p-ERK was increased in vein graft compared to vein. Immunofluorescence in VSMCs form EphB4+/+ and EphB4+/− rats detected EphB4 expression in both cells, and the expression of EphB4 was increased in VSMCs form EphB4+/+ rats. SCH772984 reduces the proliferation and migration of VSMCs. Inhibition of ERK suppressed the increase of vein graft wall thickness, and the expression of collagen fibers, elastic fibers, and α-actin was decreased. Vein graft from EphB4+/− rats reduces the expression of EphB4, and SCH772984 suppressed the decrease of EphB4 in vivo. Vein graft from EphB4+/− rats increased the expression of EphB4, and SCH772984 suppressed the increase of EphB4 in vivo. Conclusions The inhibition of ERK1/2 suppressed the process of VGS by decreasing the proliferation of VSMCs. The ERK-inhibitor SCH772984 suppressed the level of VGS by extending the time of EphB4 expression during the process of VGA, thus maintaining the venousization of vein graft. The mechanism may be that the inhibitor SCH772984 suppresses the level of VGS by extending the time of EphB4 expression during the process of VGA. Therefore, our research provides a new target of VGS treatment by inhibiting the expression of ERK1/2 through the process of VGA.

scholarly journals Torsion Does Not Affect Early Vein Graft Patency in the Rat Femoral Artery Model

2018 ◽  
Vol 35 (04) ◽  
pp. 299-305
Author(s):  
Amro Harb ◽  
Maxwell Levi ◽  
Akio Kozato ◽  
Yelena Akelina ◽  
Robert Strauch
Keyword(s):  
Vein Graft ◽  
Graft Failure ◽  
Blood Flow Rate ◽  
Graft Patency ◽  
Sprague Dawley ◽  
Rat Models ◽  
Vein Grafts ◽  
Sprague Dawley Rats ◽  
Training Courses ◽  
Vein Graft Failure

Background Torsion of vein grafts is a commonly cited reason for graft failure in clinical setting. Many microsurgery training courses have incorporated vein graft procedures in their curricula, and vein graft torsion is a common technical error made by the surgeons in these courses. To improve our understanding of the clinical reproducibility of practicing vein graft procedures in microsurgery training courses, this study aims to determine if torsion can lead to early vein graft failure in nonsurvival surgery rat models. Methods Sprague-Dawley rats were divided into five cohorts with five rats per cohort for a total of 25 rats. Cohorts were labeled based on degree of vein graft torsion (0, 45, 90, 135, and 180 degrees). Torsion was created in the vein grafts at the distal arterial end by mismatching sutures placed between the proximal end of the vein graft and the distal arterial end. Vein graft patency was then verified 2 and 24 hours postoperation. Results All vein grafts were patent 2 and 24 hours postoperation. At 2 hours, the average blood flow rate measurements for 0, 45, 90, 135, and 180 degrees of torsion were 0.37 ± 0.02, 0.38 ± 0.04, 0.34 ± 0.01, 0.33 ± 0.01, and 0.29 ± 0.02 mL/min, respectively. At 24 hours, they were 0.94 ± 0.07, 1.03 ± 0.15, 1.26 ± 0.22, 1.41 ± 0.11, and 0.89 ± 0.15 mL/min, respectively. Conclusion Torsion of up to 180 degrees does not affect early vein graft patency in rat models. To improve the clinical reproducibility of practicing vein graft procedures in rat models, we suggest that microsurgery instructors assess vein graft torsion prior to clamp release, as vessel torsion does not seem to affect graft patency once the clamps are removed.

Tubular Nitinol Knit Meshes for External Reinforcement of Saphenous Vein Grafts: A Numerical Design Study

2008 ◽  
Author(s):  
Thomas Franz ◽  
Helena van der Merwe ◽  
Peter Zilla ◽  
Deon Bezuidenhout ◽  
B. Daya Reddy
Keyword(s):  
Mechanical Properties ◽  
Saphenous Vein ◽  
Vein Graft ◽  
Fe Method ◽  
Luminal Diameter ◽  
Vein Grafts ◽  
Saphenous Vein Grafts ◽  
Vascular Bypass ◽  
External Reinforcement ◽  
The Difference

The difference in mechanical properties between grafts and host arteries is a complicating factor for vascular bypass surgery and can cause patho-physiological problems after implantation [1–7]. Diffuse and focal intimal hyperplasia, one of the key factors of vein graft failure, has been attributed to over-distension and diametric irregularities of the veins when exposed to the arterial circulation [8]. The external reinforcement of saphenous vein grafts with open-mesh knitted Nitinol structures is suggested to prevent over-distension, smooth the luminal diameter, and address the mismatch in mechanical properties of vein graft and host vessel. The objectives of this work were: 1) development of Finite Element (FE) models of knitted Nitinol structures to assess mechanical behaviour and structural properties, e.g. vascular compliance, and 2) proof of feasibility of the FE method developed for structural design optimisation of the Nitinol mesh.

scholarly journals Saphenous Vein Graft Disease Interventions

2021 ◽  
Vol 06 (03) ◽  
pp. 199-208
Author(s):  
Sarita Rao ◽  
K. Roshan Rao ◽  
Achukatla Kumar
Keyword(s):  
Saphenous Vein ◽  
Vein Graft ◽  
Left Internal Mammary Artery ◽  
Saphenous Vein Graft ◽  
Artery Bypass ◽  
Standard Of Care ◽  
Coronary Intervention ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Vein Grafts

AbstractIn the current era, coronary artery bypass grafting (CABG) is being increasingly performed using total arterial revascularization or a hybrid procedure of stenting of non-LAD disease and minimal access left internal mammary artery (LIMA) to LAD grafts, in order to minimize the need for vein grafts. Still, we encounter saphenous vein graft (SVG) disease, and it might require PCI, which often presents with unique challenges. The current favored strategy is to attempt PCI of the native coronary, if feasible, especially in long degenerated SVG disease, as it has shown better short- and long-term outcome. PCI is preferred over repeat CABG for early recurrent symptoms after CABG in patent LIMA graft and amenable anatomy patients. Balloon predilatation is not recommended unless delivery of an EPD or stent is not possible. Distal protection should be considered the standard of care for percutaneous coronary intervention (PCI) in most patients with older vein grafts, as periprocedural myocardial infarction and no reflow are the Achilles heel of SVG PCI. Intragraft vasodilators should be used liberally, even before balloon angioplasty/stenting. Avoid postdilatation, and usage of undersized but a longer stent length to reduce plaque extrusion through stent struts is preferred. Consider thrombectomy in lesions with a heavy thrombus burden. Keep activated clotting time on the higher side than in conventional PCI. Prolonged dual antiplatelet therapy (DAPT) based on the DAPT score is recommended. With all the precautions and care, we still need a fair wind in our favor to sail through the vein grafts disease.

Forearm Cephalic Vein Graft for Short, “Middle”-Flow, Internal Maxillary Artery to Middle Cerebral Artery Bypass

2015 ◽  
Vol 12 (2) ◽  
pp. 99-105 ◽  
Author(s):  
Erez Nossek ◽  
Peter D Costantino ◽  
David J Chalif ◽  
Rafael A Ortiz ◽  
Amir R Dehdashti ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Saphenous Vein ◽  
Vein Graft ◽  
Artery Bypass ◽  
Cephalic Vein ◽  
Maxillary Artery ◽  
Internal Maxillary Artery ◽  
Vein Grafts ◽  
Graft Length

Abstract BACKGROUND The cervical carotid system has been used as a source of donor vessels for radial artery or saphenous vein grafts in cerebral bypass. Recently, internal maxillary artery to middle cerebral artery bypass has been described as an alternative, with reduction of graft length potentially correlating with improved patency. OBJECTIVE To describe our experience using the forearm cephalic vein grafts for short segment internal maxillary artery to middle cerebral artery bypasses. METHODS All vein grafts were harvested from the volar forearm between the proximal cubital fossa where the median cubital vein is confluent with the cephalic vein and the distal wrist. RESULTS Six patients were treated with internal maxillary artery to middle cerebral artery bypass. In 4, the cephalic vein was used. Postoperative angiography demonstrated good filling of the grafts with robust distal flow. There were no upper extremity vascular complications. All but 1 patient (mortality) tolerated the procedure well. The other 3 patients returned to their neurological baseline with no new neurological deficit during follow-up. CONCLUSION The internal maxillary artery to middle cerebral artery “middle” flow bypass allows for shorter graft length with both the proximal and distal anastomoses within the same microsurgical field. These unique variable flow grafts represent an ideal opportunity for use of the cephalic vein of the forearm, which is more easily harvested than the wider saphenous vein graft and which has good match size to the M1/M2 segments of the middle cerebral artery. The vessel wall is supple, which facilitates handling during anastomosis. There is lower morbidity potential than utilization of the radial artery. Going forward, the cephalic vein will be our preferred choice for external carotid-internal carotid transplanted conduit bypass.

Storage solutions for vein grafts

2021 ◽  
pp. 237-242
Author(s):  
Minh Quan Vu ◽  
Pierre-Emmanuel Noly ◽  
Walid Ben Ali ◽  
Louis P. Perrault
Keyword(s):  
Vein Graft ◽  
Graft Patency ◽  
Storage Conditions ◽  
Solid Organ ◽  
Bypass Grafting ◽  
Arterial Bypass ◽  
Vein Grafts ◽  
Storage Solutions ◽  
Graft Storage ◽  
Storage Solution

Even though total arterial revascularization is increasingly used, saphenous vein grafts are still the most commonly used conduits for coronary arterial bypass grafting worldwide. Every surgeon should keep in mind that a vascular graft is living tissue with active metabolism, analogous to a solid organ for transplant, and should understand the impact of the choice of the storage solution. Unfortunately, the choice of the storage solution is usually not the result of a thoughtful review of alternatives and evidence but is a function of habit, convenience, and availability. The ideal storage solution should preserve and restore endothelial functional after harvesting. Much effort has been invested in finding ways to avoid or prevent endothelial lesions during harvesting and storage, as well as delaying vein graft dilatation after coronary arterial bypass grafting. After a brief reminder of the vein graft failure pathophysiology, this chapter discusses storage conditions using the existing graft storage solutions and their influence on endothelial function and graft patency. The use of external stenting for vein grafts is addressed elsewhere.

scholarly journals Partial Inhibition of Glycolysis Reduces Atherogenesis Independent of Intraplaque Neovascularization in Mice

2020 ◽  
Vol 40 (5) ◽  
pp. 1168-1181 ◽  
Author(s):  
Paola Perrotta ◽  
Bieke Van der Veken ◽  
Pieter Van Der Veken ◽  
Isabel Pintelon ◽  
Laurence Roosens ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Adhesion Molecule ◽  
Plaque Formation ◽  
Intercellular Adhesion Molecule ◽  
Glycolytic Flux ◽  
M2 Macrophage ◽  
Metabolic Switch ◽  
Necrosis Factor Alpha ◽  
Partial Inhibition ◽  
Inhibition Of Glycolysis

Objective: Intraplaque neovascularization is an important feature of unstable human atherosclerotic plaques. However, its impact on plaque formation and stability is poorly studied. Because proliferating endothelial cells generate up to 85% of their ATP from glycolysis, we investigated whether pharmacological inhibition of glycolytic flux by the small-molecule 3PO (3-[3-pyridinyl]-1-[4-pyridinyl]-2-propen-1-one) could have beneficial effects on plaque formation and composition. Approach and Results: ApoE −/ − (apolipoprotein E deficient) mice treated with 3PO (50 µg/g, ip; 4×/wk, 4 weeks) showed a metabolic switch toward ketone body formation. Treatment of ApoE −/− Fbn1 C1039G+/− mice with 3PO (50 µg/g, ip) either after 4 (preventive, twice/wk, 10 weeks) or 16 weeks of Western diet (curative, 4×/wk, 4 weeks) inhibited intraplaque neovascularization by 50% and 38%, respectively. Plaque formation was significantly reduced in all 3PO-treated animals. This effect was independent of intraplaque neovascularization. In vitro experiments showed that 3PO favors an anti-inflammatory M2 macrophage subtype and suppresses an M1 proinflammatory phenotype. Moreover, 3PO induced autophagy, which in turn impaired NF-κB (nuclear factor-kappa B) signaling and inhibited TNF-α (tumor necrosis factor-alpha)–mediated VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) upregulation. Consistently, a preventive 3PO regimen reduced endothelial VCAM-1 expression in vivo. Furthermore, 3PO improved cardiac function in ApoE −/− Fbn1 C1039G+/− mice after 10 weeks of treatment. Conclusions: Partial inhibition of glycolysis restrained intraplaque angiogenesis without affecting plaque composition. However, less plaques were formed, which was accompanied by downregulation of endothelial adhesion molecules—an event that depends on autophagy induction. Inhibition of coronary plaque formation by 3PO resulted in an overall improved cardiac function.

Prevalence and outcomes of intermediate saphenous vein graft lesions: Findings from the stenting of saphenous vein grafts randomized-controlled trial

2013 ◽  
Vol 168 (3) ◽  
pp. 2468-2473 ◽  
Author(s):  
Abdul-rahman R. Abdel-karim ◽  
Monica Da Silva ◽  
Christopher Lichtenwalter ◽  
James A. de Lemos ◽  
Owen Obel ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Saphenous Vein ◽  
Vein Graft ◽  
Saphenous Vein Graft ◽  
Controlled Trial ◽  
Vein Grafts ◽  
Randomized Controlled ◽  
Saphenous Vein Grafts
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