In Vivo Blockade of Tumor Necrosis Factor-α Accelerates Functional Endothelial Recovery After Balloon Angioplasty

Krasinski, Kevin; Spyridopoulos, Ioakim; Kearney, Marianne; Losordo, Douglas W.

doi:10.1161/hc4001.098046

Cited by 48 publications

(53 citation statements)

References 22 publications

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“…23 Those findings lend credence to the hypothesis that TNF-␣, expressed by VSMCs and endothelial cells at the injured vascular site, 25 inhibits endothelial regrowth 22 and promotes intimal hyperplasia. 26 Whether E2F-1 restores endothelial regrowth in vivo, mimicking its effects on cultured endothelial cells, is not yet clear.…”

Section: Discussionmentioning

confidence: 72%

“…First, TNF-␣ has been implicated as an important cytokine, triggering endothelial apoptosis in vitro and in vivo. 23 TNF-␣, which originally was reported to induce liver cell apoptosis, 24 was found by Losordo et al 22 to induce apoptosis of HUVECs with the greatest effect on HUVECs in G 1 . Interestingly, TNF-␣ itself promoted G 1 arrest of the endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Other reports found that this transcription factor can prevent TNF-␣-induced endothelial cell apoptosis in vitro, 22 closely mimicking the effects of a soluble TNF-␣ receptor, a specific TNF-␣ antagonist. 23 To additionally study these divergent responses to E2F-1, we investigated the ability of E2F-1 to influence NF-B activity in primary HAECs and found that the tumor suppressor E2F-1 inhibits expression of the cell adhesion molecules VCAM-1, ICAM-1, and E-selectin in the HAECs pretreated with sublethal concentrations of TNF-␣ and that this inhibition correlates with suppression of NF-B activity and hypophosphorylation of IB-␣, the levels of which are stabilized in TNF-␣-exposed endothelial cells overexpressing E2F-1. In addition, we demonstrated that diminished expression of the adhesion molecules in the E2F-1-transduced endothelial cells markedly reduces adhesion of a monocytic cell line (U937) to the transduced endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

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E2F-1 Regulates Nuclear Factor-κB Activity and Cell Adhesion

Chen¹,

Capps²,

Willerson³

et al. 2002

Circulation

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Background-The transcription factor E2F-1 promotes vascular smooth muscle cell apoptosis and is reported to inhibit apoptosis induced by tumor necrosis factor (TNF)-␣ in endothelial cells. Whether E2F-1 overexpression exerts potentially antiinflammatory effects in endothelial cells is not known. Methods and Results-By immunoblotting and immunofluorescence, TNF-␣ treatment of human aortic endothelial cells (HAECs) with the control vector Ad.null was followed by rapid nuclear translocation of nuclear factor (NF)-B p65, whereas nuclear translocation of p65 was markedly reduced in HAECs overexpressing E2F-1. Electrophoretic mobility shift assay and gel shift analysis of nuclear cell extracts confirmed that HAECs treated with a recombinant adenovirus encoding E2F-1 failed to associate with the binding domain of p65. Stimulation of the Ad.null-infected endothelial cells with TNF-␣ resulted in enhanced expression of endothelial intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, and E-selectin and enhanced adhesion of monocytic U937 cells to the HAECs. Adhesion molecule expression and cell adhesion were reduced in E2F-1-transduced HAECs, associated with a marked decrease in phosphorylated IB-␣, required for nuclear translocation of NF-B p65. Conclusions-These

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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E2F-1 Regulates Nuclear Factor-κB Activity and Cell Adhesion

Chen¹,

Capps²,

Willerson³

et al. 2002

Circulation

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“…Gene expression is also absent in control-stented arteries from the iliac artery proximal to VEGF stent site and from native rabbit SMCs. mal proliferation have also been demonstrated for estradiol, 15 tumor necrosis factor-soluble receptor, 23 and HMG CoA reductase inhibitors, 24,25 emphasizing the concept that acceleration of endothelial recovery may be an alternative strategy for the prevention of neointimal proliferation.…”

Section: Discussionmentioning

confidence: 94%

Local Gene Transfer of phVEGF-2 Plasmid by Gene-Eluting Stents

et al. 2004

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Background— Drug-eluting stents represent a useful strategy for the prevention of restenosis using various antiproliferative drugs. These strategies share the liability of impairing endothelial recovery, thereby altering the natural biology of the vessel wall and increasing the associated risk of stent thrombosis. Accordingly, we tested the hypothesis that local delivery via gene-eluting stent of naked plasmid DNA encoding for human vascular endothelial growth factor (VEGF)-2 could achieve similar reductions in neointima formation while accelerating, rather than inhibiting, reendothelialization. Methods and Results— phVEGF 2-plasmid (100 or 200 μg per stent)–coated BiodivYsio phosphorylcholine polymer stents versus uncoated stents were deployed in a randomized, blinded fashion in iliac arteries of 40 normocholesterolemic and 16 hypercholesterolemic rabbits. Reendothelialization was nearly complete in the VEGF stent group after 10 days and was significantly greater than in control stents (98.7±1% versus 79.0±6%, P <0.01). At 3 months, intravascular ultrasound analysis revealed that lumen cross-sectional area (4.2±0.4 versus 2.27±0.3 mm 2 , P <0.001) was significantly greater and percent cross-sectional narrowing was significantly lower (23.4±6 versus 51.2±10, P <0.001) in VEGF stents compared with control stents implanted in hypercholesterolemic rabbits. Transgene expression was detectable in the vessel wall along with improved functional recovery of stented segments, resulting in a 2.4-fold increase in NO production. Conclusions— Acceleration of reendothelialization via VEGF-2 gene–eluting stents provides an alternative treatment strategy for the prevention of restenosis. VEGF-2 gene–eluting stents may be considered as a stand-alone or combination therapy.

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“…A recent in vivo study demonstrated that TNF-␣ positively modulates occlusive arterial lesions that form in response to low shear stress. 9 Anti-TNF-␣ approaches attenuate intimal thickening after balloon angioplasty, 10 but unfortunately such approaches may also abrogate host arteriogenic responses. As it becomes apparent that multiple vascular processes proceed by way of inflammatory mediators, 11 additional research must explore the mechanisms for specificity (occlusive versus enlargement) in these pathways.…”

Section: Discussionmentioning

confidence: 99%

Direct Evidence for Tumor Necrosis Factor-α Signaling in Arteriogenesis

et al. 2002

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Background-Arteriogenesis serves as an efficient mechanism for flow restoration after arterial occlusion. This process is associated with inflammatory mediators such as tumor necrosis factor-␣ (TNF-␣), although their role in arteriogenesis remains unclear. We hypothesized that arteriogenesis is reduced in mice lacking functional TNF-␣ or p55 receptor. To test this hypothesis, we developed a novel microsphere-based murine model of hindlimb perfusion measurement. Methods and Results-Unilateral femoral arteries of nude (nϭ9), TNF-␣ Ϫ/Ϫ (nϭ9), TNF-␣ receptor p55 Ϫ/Ϫ (nϭ8), and p75 Ϫ/Ϫ (nϭ8) mice as well as their appropriate genetic background controls were occluded. The nude mice underwent laser Doppler hindlimb flux measurements preoperatively, postoperatively, and after 7 days. Seven days after ligation, all animals underwent tissue perfusion determinations using fluorescent microspheres. Laser Doppler findings confirmed acute decrease in flux with falsely normal values after 1 week. Microsphere results from control mice showed perfusion restoration to values Ϸ50% of normal within 7 days. Key Words: collateral circulation Ⅲ inflammation Ⅲ microspheres Ⅲ blood flow Ⅲ remodeling A rteriogenesis (remodeling of preexistent arteriolar collateral networks into large collateral conductance arteries) serves as the most efficient mechanism to restore flow after arterial occlusion. 1 Perivascular inflammation and monocyte/macrophage accumulation accompany this process. 2 Tumor necrosis factor-␣ (TNF-␣) is an important proximal mediator of inflammation. Most prototypical inflammatory TNF-␣ signaling occurs by TNF-␣ binding to its p55 receptor. 3 Previous studies have associated TNF-␣ with arteriogenesis. 2 We hypothesized that arteriogenesis proceeds by way of TNF-␣ signaling via the p55 receptor. Specifically, we hypothesized that arteriogenesis is reduced in mice lacking functional TNF-␣ or p55 receptor. We developed and validated a novel model of perfusion measurement in the mouse hindlimb to test this hypothesis. Methods Animal ModelThis study conforms to the Guide for the Care and Use of Laboratory Animals (NIH publication No. 85-23, revised 1996). Nine athymic nude, 8 TNF-␣ receptor p55Ϫ/Ϫ3,4 (N5 backcross onto C57BL/6J, maintained by brother/sister matings) and 9 TNF-␣ Ϫ/Ϫ5(on B6x129 F1 background, maintained by sister/brother matings) (both provided by Dr Carl K. Edwards III, Amgen, Inc, Thousand Oaks, Calif), 8 TNF-␣ receptor p75 Ϫ/Ϫ , 7 B6x129, and 9 C57BL/6J (Jackson Laboratory, Bar Harbor, Maine) mice underwent unilateral femoral artery ligation. The right femoral artery was ligated immediately distal to the inguinal ligament. Because collateral arteries develop from preexisting arteriolar connections spanning from the profunda femoris and circumflexa femoris to the genualis and saphena parva arteries, 4 the femoral artery was not excised to leave these vessels intact. In rabbits, this technique does not lead to ischemia in the region of collateral artery growth or distal to the site of ligation. 5 Wounds were cl...

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In Vivo Blockade of Tumor Necrosis Factor-α Accelerates Functional Endothelial Recovery After Balloon Angioplasty

Cited by 48 publications

References 22 publications

E2F-1 Regulates Nuclear Factor-κB Activity and Cell Adhesion

E2F-1 Regulates Nuclear Factor-κB Activity and Cell Adhesion

Local Gene Transfer of phVEGF-2 Plasmid by Gene-Eluting Stents

Direct Evidence for Tumor Necrosis Factor-α Signaling in Arteriogenesis

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