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  • 1
    Online-Ressource
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    Abstract 11: The Role of Human Osteopontin Isoforms in Post-Ischemic Neovascularization
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 36, No. suppl_1 ( 2016-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. suppl_1 ( 2016-05)
    Kurzfassung: Coronary and peripheral artery diseases lead to ischemia, initiating processes that promote neovascularization to restore blood flow and preserve tissue function. We demonstrated previously that osteopontin (OPN), a matricellular cytokine, is critical to ischemia-induced neovascularization. Unlike rodents, humans express 3 OPN isoforms (a, b, and c); however, the roles of these isoforms in neovascularization and cell migration remain undefined. To assess how human OPN isoforms affect neovascularization, OPN -/- mice underwent hind limb ischemia surgery. At the time of surgery, 1.5x10 6 lentivirus particles expressing human OPNa, OPNb or OPNc were delivered by intramuscular injection. While OPNa improved limb perfusion 30.4%±0.8 in OPN -/- mice, OPNc improved perfusion by 70.9%±6.3 (d14; p 〈 0.001 vs. LVGFP), as measured by laser Doppler perfusion imaging. Importantly, both OPNa and OPNc isoforms significantly rescued neovascularization better than OPNb (n=6, p 〈 0.05). Isoform effects on vascular volume, density, connectivity and diameter were further assessed using Micro-CT angiograms. OPNa and OPNc rescued limb function compared to control and OPNb treated animals (61.1%±8.2; 76.2%±9.7; p 〈 0.05), as assessed by voluntary running wheel use. To verify the differences in neovascularization were due to divergent effects on receptor binding and/or signaling and not variations in isoform expression, we confirmed similar OPN isoform expression levels by ELISA (n=6, p=ns) and immunofluorescence. OPN isoforms a and c both increased macrophage infiltration 2.5 fold, as assessed by mRNA (d7; p 〈 0.05) and histology, leading to increases in vascular smooth muscle cell (VSMC) infiltration (d7; p 〈 0.05). Several pro-arteriogenic factors were also significantly increased at the mRNA level. Finally, we confirmed in vitro that OPNa and OPNc significantly increased VSMC migration compared to OPN b and control (49.8%±3.1; 75.2%±6.3; p 〈 0.05). In conclusion, human OPN isoforms may exhert divergent effects on neovascularization through varried effects on macrophage and VSMC recruitment. Human OPN isoforms may represent potential new therapeutic targets to promote neovascularization and preserve function in patients with peripheral artery disease.
    Materialart: Online-Ressource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.36.suppl_1.11
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2016
    ZDB Id: 1494427-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
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    Abstract 317: Satellite Cells Influence Collateral Vessel Formation via Paracrine Effects
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 37, No. suppl_1 ( 2017-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 37, No. suppl_1 ( 2017-05)
    Kurzfassung: Satellite cells are myogenic cells that play a critical role in skeletal muscle repair. They serve as stem cells for muscles, remaining dormant in healthy muscle but activating upon injury resulting in increased proliferation and differentiation into myoblasts. Another key aspect of muscle regeneration is reestablishing vascular supply, but the role of satellite cells in this process is not well established though they are known to produce a number of potential paracrine signals. Thus we hypothesized that satellite cells promote vascular growth through paracrine signaling induced by activation following muscle injury or ischemic damage from diseases such as peripheral artery disease. Using a murine model of hind limb ischemia, we showed that satellite cells increased 3.4 fold (p 〈 0.01) in response to ischemia. To determine if satellite cells produce paracrine factors, we used a co-culture system for migration and proliferation. Satellite cells freshly isolated from the ischemic limb led to a 3.5 fold increase in smooth muscle migration (p 〈 0.0001) and a 1.3 fold increase (p 〈 0.01) in smooth muscle proliferation. Additionally, cultured satellite cells increased endothelial cell migration 2.8 fold. These results demonstrate the satellite cells produce paracrine factors which can drive both smooth muscle and endothelial cell migration and proliferation which are required for the development of collateral vessels. To test the potential therapeutic capability of satellite cells, alginate encapsulated satellite cells were delivered in the hind limb ischemic model. Using a whole animal in vivo imager to track luciferase expression of the cells, we found the encapsulated cells were viable for up to 2 weeks. The mice that received satellite cells also had significantly increased perfusion (28%, p 〈 0.05) at 2 weeks as measured by Laser Doppler imaging. In conclusion our studies have shown that satellite cells increase in response to ischemia, produce paracrine factors that increase vascular cell migration in vitro, and lead to functional increases in perfusion in vivo. We believe these results demonstrate the critical role satellite cells play in collateral vessel formation and may be a potential new therapeutic approach for treating peripheral artery disease.
    Materialart: Online-Ressource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.37.suppl_1.317
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2017
    ZDB Id: 1494427-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
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    Abstract MP29: Skeletal Muscle Satellite Cells Enhance Vascular Growth Through Paracrine Signaling
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 41, No. Suppl_1 ( 2021-09)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 41, No. Suppl_1 ( 2021-09)
    Kurzfassung: Peripheral arterial disease (PAD) is a major health problem that affects over 200 million people worldwide. Decreased blood flow to the limb muscles leads to ischemia that results in pain, decreased quality of life, and in severe cases amputation. Despite the prevalence and severity of the disease, effective treatment options are still limited. One factor correlated with improved prognosis is the generation of a more robust collateral vessel network. This study hypothesized that skeletal muscle satellite cells, which play a key role in skeletal muscle regeneration, also contribute to vascular regeneration in the setting of ischemia. Specifically, satellite cells are proposed to generate cytokine and growth factors which modulate vascular growth via paracrine signaling. Satellite cells were isolated and cultured for vasculogenic assays include migration co-cultures. Satellite cells encapsulated in alginate were delivered to a hindlimb ischemia model of vascular growth to assess their therapeutic potential in vivo. Gene expression of satellite cells from ischemic tissue was assessed using a microarray. The migration assays demonstrated that satellite cells produce chemokines which increased smooth muscle migration (3.5 fold) and endothelial cell migration (2.8 fold) over control conditions (n = 4, p 〈 0.05) In the hind limb ischemia model, alginate encapsulated satellite cells increased perfusion 17% closer to baseline (68% vs 51%, n = 11, p 〈 0.05) measured via Laser Doppler imaging. Capillary density as measured by Lectin staining increased 1.6 fold and smooth muscle positive vessels increase more than 2 fold (n=6, p 〈 0.05). Finally, Ingenuity pathway analysis of the gene array day suggested that vasculogenic and cell migration pathways were increased. Taken together, these findings demonstrate that satellite cells produce a number of factors that can serve as chemokines in vitro and increase vascular growth in vivo. Further work will explore the mechanisms by which satellite cells exhibit their effects and develop a therapeutic application of satellite cells as a novel treatment for patients with peripheral artery disease.
    Materialart: Online-Ressource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.41.suppl_1.MP29
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2021
    ZDB Id: 1494427-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
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    Endothelial Poldip2 regulates sepsis-induced lung injury via Rho pathway activation
    Oxford University Press (OUP) ; 2022
    In:  Cardiovascular Research Vol. 118, No. 11 ( 2022-08-24), p. 2506-2518
    Details
    In: Cardiovascular Research, Oxford University Press (OUP), Vol. 118, No. 11 ( 2022-08-24), p. 2506-2518
    Kurzfassung: Sepsis-induced lung injury is associated with significant morbidity and mortality. Previously, we showed that heterozygous deletion of polymerase δ-interacting protein 2 (Poldip2) was protective against sepsis-induced lung injury. Since endothelial barrier disruption is thought to be the main mechanism of sepsis-induced lung injury, we sought to determine if the observed protection was specifically due to the effect of reduced endothelial Poldip2. Methods and results Endothelial-specific Poldip2 knock-out mice (EC−/−) and their wild-type littermates (EC+/+) were injected with saline or lipopolysaccharide (18 mg/kg) to model sepsis-induced lung injury. At 18 h post-injection mice, were euthanized and bronchoalveolar lavage (BAL) fluid and lung tissue were collected to assess leucocyte infiltration. Poldip2 EC−/− mice showed reduced lung leucocyte infiltration in BAL (0.21 ± 0.9×106 vs. 1.29 ± 1.8×106 cells/mL) and lung tissue (12.7 ± 1.8 vs. 23 ± 3.7% neutrophils of total number of cells) compared to Poldip2 EC+/+ mice. qPCR analysis of the lung tissue revealed a significantly dampened induction of inflammatory gene expression (TNFα 2.23 ± 0.39 vs. 4.15 ± 0.5-fold, IκBα 4.32 ± 1.53 vs. 8.97 ± 1.59-fold), neutrophil chemoattractant gene expression (CXCL1 68.8 ± 29.6 vs. 147 ± 25.7-fold, CXCL2 65 ± 25.6 vs. 215 ± 27.3-fold) and a marker of endothelial activation (VCAM1 1.25 ± 0.25 vs. 3.8 ± 0.38-fold) in Poldip2 EC−/− compared to Poldip2 EC+/+ lungs. An in vitro model using human pulmonary microvascular endothelial cells was used to assess the effect of Poldip2 knock-down on endothelial activation and permeability. TNFα-induced endothelial permeability and VE-cadherin disruption were significantly reduced with siRNA-mediated knock-down of Poldip2 (5 ± 0.5 vs. 17.5 ± 3-fold for permeability, 1.5 ± 0.4 vs. 10.9 ± 1.3-fold for proportion of disrupted VE-cadherin). Poldip2 knock-down altered expression of Rho-GTPase-related genes, which correlated with reduced RhoA activation by TNFα (0.94 ± 0.05 vs. 1.29 ± 0.01 of relative RhoA activity) accompanied by redistribution of active-RhoA staining to the centre of the cell. Conclusion Poldip2 is a potent regulator of endothelial dysfunction during sepsis-induced lung injury, and its endothelium-specific inhibition may provide clinical benefit.
    Materialart: Online-Ressource
    ISSN: 0008-6363 , 1755-3245
    URL: Article
    DOI: 10.1093/cvr/cvab295
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Oxford University Press (OUP)
    Publikationsdatum: 2022
    ZDB Id: 1499917-1
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
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    Reactive Oxygen Species Regulate Osteopontin Expression in a Murine Model of Postischemic Neovascularization
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 32, No. 6 ( 2012-06), p. 1383-1391
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. 6 ( 2012-06), p. 1383-1391
    Kurzfassung: Supplemental Digital Content is available in the text.
    Materialart: Online-Ressource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.112.248922
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2012
    ZDB Id: 1494427-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
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    mRNA-Binding Protein ZFP36 Is Expressed in Atherosclerotic Lesions and Reduces Inflammation in Aortic Endothelial Cells
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 33, No. 6 ( 2013-06), p. 1212-1220
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 33, No. 6 ( 2013-06), p. 1212-1220
    Kurzfassung: We studied the expression and function of an mRNA-binding protein, zinc finger protein-36 (ZFP36), in vascular endothelial cells in vivo and in vitro. We tested the hypotheses that ZFP36 regulates inflammation in vascular endothelial cells and that it functions through direct binding to target cytokine mRNAs. We also tested whether ZFP36 inhibits nuclear factor-κB–mediated transcriptional responses in vascular endothelial cells. Approach and Results— ZFP36 was minimally expressed in healthy aorta but was expressed in endothelial cells overlying atherosclerotic lesions in mice and humans. The protein was also expressed in macrophage foam cells of atherosclerosis. ZFP36 was expressed in human aortic endothelial cells in response to bacterial lipopolysaccharide, glucocorticoid, and forskolin, but not oxidized low-density lipoproteins or angiotensin II. Functional studies demonstrated that ZFP36 reduces the expression of inflammatory cytokines in target cells by 2 distinct mechanisms: ZFP36 inhibits nuclear factor-κB transcriptional activation and also binds to cytokine mRNAs, leading to reduced transcript stability. Conclusions— ZFP36 is expressed in vascular endothelial cells and macrophage foam cells where it inhibits the expression of proinflammatory mRNA transcripts. The anti-inflammatory effects of ZFP36 in endothelial cells occur via both transcriptional and posttranscriptional mechanisms. Our data suggest that enhancing vascular ZFP36 expression might reduce vascular inflammation.
    Materialart: Online-Ressource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.113.301496
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2013
    ZDB Id: 1494427-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
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    Polymerase Delta Interacting Protein 2 Sustains Vascular Structure and Function
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 33, No. 9 ( 2013-09), p. 2154-2161
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 33, No. 9 ( 2013-09), p. 2154-2161
    Kurzfassung: On the basis of previous evidence that polymerase delta interacting protein 2 (Poldip2) increases reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox4) activity in vascular smooth muscle cells, we hypothesized that in vivo knockdown of Poldip2 would inhibit reactive oxygen species production and alter vascular function. Approach and Results— Because homozygous Poldip2 deletion is lethal, Poldip2 +/− mice were used. Poldip2 mRNA and protein levels were reduced by ≈50% in Poldip2 +/− aorta, with no change in p22phox, Nox1, Nox2, and Nox4 mRNAs. NADPH oxidase activity was also inhibited in Poldip2 +/− tissue. Isolated aortas from Poldip2 +/− mice demonstrated impaired phenylephrine and potassium chloride–induced contractions, increased stiffness, and reduced compliance associated with disruption of elastic lamellae and excessive extracellular matrix deposition. Collagen I secretion was elevated in cultured vascular smooth muscle cells from Poldip2 +/− mice and restored by H 2 O 2 supplementation, suggesting that this novel function of Poldip2 is mediated by reactive oxygen species. Furthermore, Poldip2 +/− mice were protected against aortic dilatation in a model of experimental aneurysm, an effect consistent with increased collagen secretion. Conclusions— Poldip2 knockdown reduces H 2 O 2 production in vivo, leading to increases in extracellular matrix, greater vascular stiffness, and impaired agonist-mediated contraction. Thus, unaltered expression of Poldip2 is necessary for vascular integrity and function.
    Materialart: Online-Ressource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.113.301913
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2013
    ZDB Id: 1494427-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
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    Online-Ressource
    Folate Receptor–Targeted Antioxidant Therapy Ameliorates Renal Ischemia–Reperfusion Injury
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Journal of the American Society of Nephrology Vol. 23, No. 5 ( 2012-05), p. 793-800
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 23, No. 5 ( 2012-05), p. 793-800
    Materialart: Online-Ressource
    ISSN: 1046-6673
    URL: Article
    DOI: 10.1681/ASN.2011070711
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2012
    ZDB Id: 2029124-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
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    Increasing nitric oxide bioavailability fails to improve collateral vessel formation in humanized sickle cell mice
    Elsevier BV ; 2022
    In:  Laboratory Investigation Vol. 102, No. 8 ( 2022-08), p. 805-813
    Details
    In: Laboratory Investigation, Elsevier BV, Vol. 102, No. 8 ( 2022-08), p. 805-813
    Materialart: Online-Ressource
    ISSN: 0023-6837
    URL: Article
    DOI: 10.1038/s41374-022-00780-0
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2022
    ZDB Id: 2041329-4
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
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    Online-Ressource
    Abstract 317: Paracrine Effects of Satellite Cells on Collateral Vessel Formation
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 36, No. suppl_1 ( 2016-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. suppl_1 ( 2016-05)
    Kurzfassung: Peripheral artery disease is a major health problem in the United States that effects 8.5 million people and can lead to limb pain, decreased mobility, and in severe cases amputation. The ability to form a robust collateral network to restore blood flow and prevent ischemia leads to a better prognosis and restoration of function. The growth of collaterals is a complex process that involves recruitment of various cell types including smooth muscle cells, endothelial cells, and macrophages. Migration and proliferation of these cells are processes regulated by numerous cytokine and paracrine signals. We hypothesize that an important and novel source of these signals is satellite cells. Satellite cells are myogenic progenitor cells that lie below the basal lamina of muscle fibers. In healthy muscle, the cells are quiescent but in response to injury, such as ischemia, they become activated and proliferate. We hypothesized that activated satellite cells produce factors that will influence critical cells for vessel formation in addition to differentiating to repair muscle. To study the paracrine effects of satellite cells on vascular smooth muscle cells, we used a co-culture system with freshly isolated satellite cells from the ischemic leg as the stimulus. We found that satellite cells significantly increased smooth muscle migration 2.5 fold compared to media alone using a modified Boyden chamber assay. BrdU staining to assess proliferation showed modest increases in smooth muscle proliferation (1.3 fold change, p 〈 0.01). Finally, to investigate these paracrine effects in vivo, we delivered alginate encapsulated satellite cells to mice following the hind limb ischemia procedure, which is a model of collateral growth. We found that mice that received the encapsulated satellite cells had significantly improved perfusion as measured by Laser Doppler imaging at day 14 post surgery when compared to empty capsules (perfusion ratio of 0.87 ± 0.04 (cells) vs 0.68 ± 0.07 (empty capsules), p 〈 0.05). This result demonstrates that satellite cells can positively influence collateral growth in vivo. We believe that satellite cells play a critical role in collateral vessel formation and may potentially be a therapeutic strategy for the treatment of peripheral artery disease.
    Materialart: Online-Ressource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.36.suppl_1.317
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2016
    ZDB Id: 1494427-3
    Standort Signatur Einschränkungen Verfügbarkeit
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