Arterial pO2 stimulates intimal hyperplasia and serum stimulates inward eutrophic remodeling in porcine saphenous veins cultured ex vivo

Joddar, Binata; Shaffer, Rebecca J. G.; Reen, Rashmeet K.; Gooch, Keith J.

doi:10.1007/s10237-010-0224-8

Cited by 4 publications

(7 citation statements)

References 56 publications

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“…However, a number of factors including species differences, anatomical source of the veins and differences in culture methods could have contributed to the discrepant findings. Our results agree with those reported by Gusic et al and Joddar et al, in which minimal NH development was observed in porcine saphenous veins cultured under static culture conditions, in contrast to perfused veins (27, 28). …”

Section: Discussionsupporting

confidence: 94%

“…An ex vivo perfusion system similar to that described (26-28), with modifications of the vessel chamber and the long-term application of laminar flow with various WSS values, was used. Briefly, explanted IJV segments were suspended at their in vivo length (3 to 5 cm) between two stainless steel connectors using surgical sutures, and bathed in a vessel chamber filled with Dulbecco's Modified Eagle Medium (DMEM) supplemented with 30% FCS and antibiotics but no additional growth factors.…”

Section: Methodsmentioning

confidence: 99%

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Prevention of Venous Neointimal Hyperplasia by a Multitarget Receptor Tyrosine Kinase Inhibitor

Kwon

et al. 2015

J Vasc Res

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Background/Aims: Venous neointimal hyperplasia (NH) is the predominant cause of stenosis in hemodialysis arteriovenous grafts (AVG), but there is currently no clinically used therapy to prevent NH. Methods: A porcine AVG model was used to identify potential pharmacological targets to prevent NH. Sunitinib, a broad-spectrum tyrosine kinase inhibitor, was examined as a potential anti-NH drug utilizing in vitro and ex vivo models. Results: In an in vivo porcine model, PDGF, VEGF and their receptors PDGFR-α and VEGFR-2 were upregulated at the venous anastomosis within 2 weeks after AVG placement, with NH development by 4 weeks. Sunitinib inhibited PDGF-stimulated proliferation, migration, phosphorylation of MAPK and PI3K/Akt proteins and changes in the expression of cell-cycle regulatory proteins in vascular smooth-muscle cells as well as VEGF-stimulated endothelial cell proliferation in vitro. In an ex vivo model, significant NH was observed in porcine vein segments perfused for 12 days under pathological shear stress. Sunitinib (100 nM) inhibited NH formation, with the intima-to-lumen area ratio decreasing from 0.45 ± 0.25 to 0.04 ± 0.02 (p < 0.05) with treatment. Conclusion: These findings demonstrate sunitinib to be a potential NH-preventive drug as well as the utility of an ex vivo model to investigate pharmacotherapies under pathophysiological flow conditions.

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Section: Discussionsupporting

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Prevention of Venous Neointimal Hyperplasia by a Multitarget Receptor Tyrosine Kinase Inhibitor

Kwon

et al. 2015

J Vasc Res

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“…In contrast, culturing a porcine femoral artery at arterial pO 2 for 1 week did not influence intimal area or other aspects of its histological appearance. The ability of elevated levels of pO 2 to induce intimal thickening was a robust observation, which occurred (1) in the presence or absence of serum in the culture medium [161], (2) in SV perfused under conditions to mimic a venous mechanical environment or static conditions [161], or (3) in human and porcine saphenous veins [161,162]. SV cultured at arterial pO 2 have elevated markers of oxidative stress and treating the saphenous veins with the exogenous antioxidant N-acetyl-cysteine or upregulating endogenous antioxidant enzymes blocks intimal hyperplasia in human saphenous veins cultured ex vivo at arterial pO 2 [163].…”

Section: Potential Impacts Of Changes In the Chemical Environment On mentioning

confidence: 96%

“…This yields a pO 2 of 140 mmHg, which is greater than the 95 mmHg typical of the arterial circulation and 40 mmHg of the venous circulation. To explore the effect of pO 2 on intimal hyperplasia, Joddar et al cultured porcine SV at various pO 2 values for 1 week [161]. Veins cultured with venous pO 2 had intimal areas indistinguishable from that of freshly isolated SV, but veins cultured with greater pO 2 showed a dose dependent increase in intimal area and cellular proliferation rate (Fig.…”

Section: Potential Impacts Of Changes In the Chemical Environment On mentioning

confidence: 99%

Biomechanics and Mechanobiology of Saphenous Vein Grafts

Gooch

Firstenberg

Shrefler

et al. 2018

Journal of Biomechanical Engineering

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Within several weeks of use as coronary artery bypass grafts (CABG), saphenous veins (SV) exhibit significant intimal hyperplasia (IH). IH predisposes vessels to thrombosis and atherosclerosis, the two major modes of vein graft failure. The fact that SV do not develop significant IH in their native venous environment coupled with the rapidity with which they develop IH following grafting into the arterial circulation suggests that factors associated with the isolation and preparation of SV and/or differences between the venous and arterial environments contribute to disease progression. There is strong evidence suggesting that mechanical trauma associated with traditional techniques of SV preparation can significantly damage the vessel and might potentially reduce graft patency though modern surgical techniques reduces these injuries. In contrast, it seems possible that modern surgical technique, specifically endoscopic vein harvest, might introduce other mechanical trauma that could subtly injure the vein and perhaps contribute to the reduced patency observed in veins harvested using endoscopic techniques. Aspects of the arterial mechanical environment influence remodeling of SV grafted into the arterial circulation. Increased pressure likely leads to thickening of the medial wall but its role in IH is less clear. Changes in fluid flow, including increased average wall shear stress, may reduce IH while disturbed flow likely increase IH. Nonmechanical stimuli, such as exposure to arterial levels of oxygen, may also have a significant but not widely recognized role in IH. Several potentially promising approaches to alter the mechanical environment to improve graft patency are including extravascular supports or altered graft geometries are covered.

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“…We recently reported that SV excised from young, healthy pigs and perfused ex vivo with arterial pO 2 , but not those perfused with lower pO 2 , developed IH as evidence by increased cellular proliferation and intimal thickness relative to freshly isolated SV [ 10 ]. The pO 2 -induced IH occurred in the absence of exposure to an arterial mechanical environment with IH occurring both in porcine SV cultured under venous and static (no flow) mechanical conditions.…”

Section: Introductionmentioning

confidence: 99%

Arterial Levels of Oxygen Stimulate Intimal Hyperplasia in Human Saphenous Veins via a ROS-Dependent Mechanism

et al. 2015

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Saphenous veins used as arterial grafts are exposed to arterial levels of oxygen partial pressure (pO2), which are much greater than what they experience in their native environment. The object of this study is to determine the impact of exposing human saphenous veins to arterial pO2. Saphenous veins and left internal mammary arteries from consenting patients undergoing coronary artery bypass grafting were cultured ex vivo for 2 weeks in the presence of arterial or venous pO2 using an established organ culture model. Saphenous veins cultured with arterial pO2 developed intimal hyperplasia as evidenced by 2.8-fold greater intimal area and 5.8-fold increase in cell proliferation compared to those freshly isolated. Saphenous veins cultured at venous pO2 or internal mammary arteries cultured at arterial pO2 did not develop intimal hyperplasia. Intimal hyperplasia was accompanied by two markers of elevated reactive oxygen species (ROS): increased dihydroethidium associated fluorescence (4-fold, p<0.05) and increased levels of the lipid peroxidation product, 4-hydroxynonenal (10-fold, p<0.05). A functional role of the increased ROS saphenous veins exposed to arterial pO2 is suggested by the observation that chronic exposure to tiron, a ROS scavenger, during the two-week culture period, blocked intimal hyperplasia. Electron paramagnetic resonance based oximetry revealed that the pO2 in the wall of the vessel tracked that of the atmosphere with a ~30 mmHg offset, thus the cells in the vessel wall were directly exposed to variations in pO2. Monolayer cultures of smooth muscle cells isolated from saphenous veins exhibited increased proliferation when exposed to arterial pO2 relative to those cultured at venous pO2. This increased proliferation was blocked by tiron. Taken together, these data suggest that exposure of human SV to arterial pO2 stimulates IH via a ROS-dependent pathway.

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Arterial pO2 stimulates intimal hyperplasia and serum stimulates inward eutrophic remodeling in porcine saphenous veins cultured ex vivo

Cited by 4 publications

References 56 publications

Prevention of Venous Neointimal Hyperplasia by a Multitarget Receptor Tyrosine Kinase Inhibitor

Prevention of Venous Neointimal Hyperplasia by a Multitarget Receptor Tyrosine Kinase Inhibitor

Biomechanics and Mechanobiology of Saphenous Vein Grafts

Arterial Levels of Oxygen Stimulate Intimal Hyperplasia in Human Saphenous Veins via a ROS-Dependent Mechanism

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