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  • 11
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    Online Resource
    Unravelling atherosclerotic heterogeneity by single cell RNA sequencing
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Current Opinion in Lipidology Vol. 29, No. 6 ( 2018-12), p. 488-489
    Details
    In: Current Opinion in Lipidology, Ovid Technologies (Wolters Kluwer Health), Vol. 29, No. 6 ( 2018-12), p. 488-489
    Type of Medium: Online Resource
    ISSN: 0957-9672 , 1473-6535
    URL: Article
    DOI: 10.1097/MOL.0000000000000559
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 2026990-0
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  • 12
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    Online Resource
    Human and murine fibroblast single-cell transcriptomics reveals fibroblast clusters are differentially affected by ageing and serum cholesterol
    Oxford University Press (OUP) ; 2023
    In:  Cardiovascular Research Vol. 119, No. 7 ( 2023-07-04), p. 1509-1523
    Details
    In: Cardiovascular Research, Oxford University Press (OUP), Vol. 119, No. 7 ( 2023-07-04), p. 1509-1523
    Abstract: Specific fibroblast markers and in-depth heterogeneity analysis are currently lacking, hindering functional studies in cardiovascular diseases (CVDs). Here, we established cell-type markers and heterogeneity in murine and human arteries and studied the adventitial fibroblast response to CVD and its risk factors hypercholesterolaemia and ageing. Methods and results Murine aorta single-cell RNA-sequencing analysis of adventitial mesenchymal cells identified fibroblast-specific markers. Immunohistochemistry and flow cytometry validated platelet-derived growth factor receptor alpha (PDGFRA) and dipeptidase 1 (DPEP1) across human and murine aorta, carotid, and femoral arteries, whereas traditional markers such as the cluster of differentiation (CD)90 and vimentin also marked transgelin+ vascular smooth muscle cells. Next, pseudotime analysis showed multiple fibroblast clusters differentiating along trajectories. Three trajectories, marked by CD55 (Cd55+), Cxcl chemokine 14 (Cxcl14+), and lysyl oxidase (Lox+), were reproduced in an independent RNA-seq dataset. Gene ontology (GO) analysis showed divergent functional profiles of the three trajectories, related to vascular development, antigen presentation, and/or collagen fibril organization, respectively. Trajectory-specific genes included significantly more genes with known genome-wide associations (GWAS) to CVD than expected by chance, implying a role in CVD. Indeed, differential regulation of fibroblast clusters by CVD risk factors was shown in the adventitia of aged C57BL/6J mice, and mildly hypercholesterolaemic LDLR KO mice on chow by flow cytometry. The expansion of collagen-related CXCL14+ and LOX+ fibroblasts in aged and hypercholesterolaemic aortic adventitia, respectively, coincided with increased adventitial collagen. Immunohistochemistry, bulk, and single-cell transcriptomics of human carotid and aorta specimens emphasized translational value as CD55+, CXCL14+ and LOX+ fibroblasts were observed in healthy and atherosclerotic specimens. Also, trajectory-specific gene sets are differentially correlated with human atherosclerotic plaque traits. Conclusion We provide two adventitial fibroblast-specific markers, PDGFRA and DPEP1, and demonstrate fibroblast heterogeneity in health and CVD in humans and mice. Biological relevance is evident from the regulation of fibroblast clusters by age and hypercholesterolaemia in vivo, associations with human atherosclerotic plaque traits, and enrichment of genes with a GWAS for CVD.
    Type of Medium: Online Resource
    ISSN: 0008-6363 , 1755-3245
    URL: Article
    DOI: 10.1093/cvr/cvad016
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1499917-1
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  • 13
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    Protective role of chaperone-mediated autophagy against atherosclerosis
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 14 ( 2022-04-05)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 14 ( 2022-04-05)
    Abstract: Chaperone-mediated autophagy (CMA) contributes to regulation of energy homeostasis by timely degradation of enzymes involved in glucose and lipid metabolism. Here, we report reduced CMA activity in vascular smooth muscle cells and macrophages in murine and human arteries in response to atherosclerotic challenges. We show that in vivo genetic blockage of CMA worsens atherosclerotic pathology through both systemic and cell-autonomous changes in vascular smooth muscle cells and macrophages, the two main cell types involved in atherogenesis. CMA deficiency promotes dedifferentiation of vascular smooth muscle cells and a proinflammatory state in macrophages. Conversely, a genetic mouse model with up-regulated CMA shows lower vulnerability to proatherosclerotic challenges. We propose that CMA could be an attractive therapeutic target against cardiovascular diseases.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2121133119
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 14
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    Online Resource
    The Human-Specific and Smooth Muscle Cell-Enriched LncRNA SMILR Promotes Proliferation by Regulating Mitotic CENPF mRNA and Drives Cell-Cycle Progression Which Can Be Targeted to Limit Vascular Remodeling
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Circulation Research Vol. 125, No. 5 ( 2019-08-16), p. 535-551
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 125, No. 5 ( 2019-08-16), p. 535-551
    Abstract: In response to blood vessel wall injury, aberrant proliferation of vascular smooth muscle cells (SMCs) causes pathological remodeling. However, the controlling mechanisms are not completely understood. Objective: We recently showed that the human long noncoding RNA, SMILR , promotes vascular SMCs proliferation by a hitherto unknown mechanism. Here, we assess the therapeutic potential of SMILR inhibition and detail the molecular mechanism of action. Methods and Results: We used deep RNA-sequencing of human saphenous vein SMCs stimulated with IL (interleukin)-1α and PDGF (platelet-derived growth factor)-BB with SMILR knockdown (siRNA) or overexpression (lentivirus), to identify SMILR -regulated genes. This revealed a SMILR-dependent network essential for cell cycle progression. In particular, we found using the fluorescent ubiquitination-based cell cycle indicator viral system that SMILR regulates the late mitotic phase of the cell cycle and cytokinesis with SMILR knockdown resulting in ≈10% increase in binucleated cells. SMILR pulldowns further revealed its potential molecular mechanism, which involves an interaction with the mRNA of the late mitotic protein CENPF (centromere protein F) and the regulatory Staufen1 RNA-binding protein. SMILR and this downstream axis were also found to be activated in the human ex vivo vein graft pathological model and in primary human coronary artery SMCs and atherosclerotic plaques obtained at carotid endarterectomy. Finally, to assess the therapeutic potential of SMILR , we used a novel siRNA approach in the ex vivo vein graft model (within the 30 minutes clinical time frame that would occur between harvest and implant) to assess the reduction of proliferation by EdU incorporation. SMILR knockdown led to a marked decrease in proliferation from ≈29% in controls to ≈5% with SMILR depletion. Conclusions: Collectively, we demonstrate that SMILR is a critical mediator of vascular SMC proliferation via direct regulation of mitotic progression. Our data further reveal a potential SMILR-targeting intervention to limit atherogenesis and adverse vascular remodeling.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.119.314876
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1467838-X
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  • 15
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    The function of miR-143, miR-145 and the MiR-143 host gene in cardiovascular development and disease
    Elsevier BV ; 2019
    In:  Vascular Pharmacology Vol. 112 ( 2019-01), p. 24-30
    Details
    In: Vascular Pharmacology, Elsevier BV, Vol. 112 ( 2019-01), p. 24-30
    Type of Medium: Online Resource
    ISSN: 1537-1891
    URL: Article
    DOI: 10.1016/j.vph.2018.11.006
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 2089264-0
    SSG: 15,3
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  • 16
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    Online Resource
    Reversal of Hypoxia in Murine Atherosclerosis Prevents Necrotic Core Expansion by Enhancing Efferocytosis
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 34, No. 12 ( 2014-12), p. 2545-2553
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. 12 ( 2014-12), p. 2545-2553
    Abstract: Advanced murine and human plaques are hypoxic, but it remains unclear whether plaque hypoxia is causally related to atherogenesis. Here, we test the hypothesis that reversal of hypoxia in atherosclerotic plaques by breathing hyperoxic carbogen gas will prevent atherosclerosis. Approach and Results— Low-density lipoprotein receptor–deficient mice (LDLR -/- ) were fed a Western-type diet, exposed to carbogen (95% O 2 , 5% CO 2 ) or air, and the effect on plaque hypoxia, size, and phenotype was studied. First, the hypoxic marker pimonidazole was detected in murine LDLR -/- plaque macrophages from plaque initiation onwards. Second, the efficacy of breathing carbogen (90 minutes, single exposure) was studied. Compared with air, carbogen increased arterial blood pO 2 5-fold in LDLR -/- mice and reduced plaque hypoxia in advanced plaques of the aortic root (−32%) and arch (−84%). Finally, the effect of repeated carbogen exposure on progression of atherosclerosis was studied in LDLR -/- mice fed a Western-type diet for an initial 4 weeks, followed by 4 weeks of diet and carbogen or air (both 90 min/d). Carbogen reduced plaque hypoxia (−40%), necrotic core size (−37%), and TUNEL + (terminal uridine nick-end labeling positive) apoptotic cell content (−50%) and increased efferocytosis of apoptotic cells by cluster of differentiation 107b + (CD107b, MAC3) macrophages (+36%) in advanced plaques of the aortic root. Plaque size, plasma cholesterol, hematopoiesis, and systemic inflammation were unchanged. In vitro, hypoxia hampered efferocytosis by bone marrow–derived macrophages, which was dependent on the receptor Mer tyrosine kinase. Conclusions— Carbogen restored murine plaque oxygenation and prevented necrotic core expansion by enhancing efferocytosis, likely via Mer tyrosine kinase. Thus, plaque hypoxia is causally related to necrotic core expansion.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.114.304023
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 1494427-3
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  • 17
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    Abstract 532: Periadventitial Adenoviral Ang-1/2 Gene Transfer Interferes with Atherosclerotic Plaque Progression and Angiogenesis in the Carotid Artery of LDLr -/- ApoB100/100 Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 32, No. suppl_1 ( 2012-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. suppl_1 ( 2012-05)
    Abstract: Accumulation of macrophages, red blood cells and lipids in atherosclerotic plaques is associated with plaque rupture. It has been shown that macrophages and erythrocytes can enter the plaque also via plaque microvasculature originating from the adventitia. Furthermore, it has been reported that in advanced or ruptured human coronary lesions the microvessel density is increased and these microvessels are leaky. The leaky phenotype is characterized by poor pericyte coverage and dysfunctional inter-endothelial junctions. As angiopoietins are involved in angiogenic growth and maturation, we hypothesized that periadventitial Ang-1 or Ang-2 gene transfer would reduce atherogenesis and affect microvasculature in mouse carotid artery. To study this, atherosclerosis was induced by placing a perivascular silastic collar around the carotid artery of LDLr -/- ApoB100/100 mice fed a high cholesterol (0,15 %) diet for 3 weeks. Simultaneous to surgery adenoviral gene transfer (5μl, 5 x 107 pfu/ml) of either Ang-1, Ang-2 or LacZ as a control was applied to the carotid artery (20 mice per group). After 1 or 5 weeks follow-up on high cholesterol diet mice were sacrificed. Plaque size and microvessel density were analyzed with morphometry software (Leica Qwin) using cross-sections stained with hematoxylin and eosin or CD31 respectively. Microvessel ultrastructure was studied using electron microscopy. Ang-2 gene transfer led to significantly smaller plaque area and plaque volume 5 weeks after collar placement compared to LacZ group (2,7 fold, p 〈 0,001 and 3,9 fold, p 〈 0,01 respectively). Also the microvessel density in intima, media and adventitia was lower in the Ang-2 group compared to LacZ (4,5 fold, p 〈 0,05; 7,5 fold p 〈 0,05 and 11,8 fold p 〈 0,05 respectively). Ang-1 gene transfer led to a non-significant trend towards smaller lesions and lower microvessel density compared to LacZ gene transfer. Plaque phenotype was quite fibrous in all groups at 5 weeks, although lesions in Ang-2 group were most human atheroma-like. Electron microscopy showed intact pericyte coverage and endothelial junctions of microvessels in all groups. Endothelial cell morphology after Ang-1 gene transfer showed less filopodia and cytoplasmic vacuoles compared to Ang-2 and LacZ, suggestive of a quiescent phenotype. In conclusion: Ang-2 over expression in mouse carotid arteries led to smaller plaque size and lower microvessel density, suggesting the involvement of angiopoietin signaling in angiogenesis of the atherosclerotic vessel wall.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.32.suppl_1.A532
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 1494427-3
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  • 18
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    Online Resource
    Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signalling
    Oxford University Press (OUP) ; 2022
    In:  Cardiovascular Research Vol. 118, No. 5 ( 2022-03-25), p. 1232-1246
    Details
    In: Cardiovascular Research, Oxford University Press (OUP), Vol. 118, No. 5 ( 2022-03-25), p. 1232-1246
    Abstract: Atherosclerotic plaque hypoxia is detrimental for macrophage function. Prolyl hydroxylases (PHDs) initiate cellular hypoxic responses, possibly influencing macrophage function in plaque hypoxia. Thus, we aimed to elucidate the role of myeloid PHDs in atherosclerosis. Methods and results Myeloid-specific PHD knockout (PHDko) mice were obtained via bone marrow transplantation (PHD1ko, PHD3ko) or conditional knockdown through lysozyme M-driven Cre recombinase (PHD2cko). Mice were fed high cholesterol diet for 6–12 weeks to induce atherosclerosis. Aortic root plaque size was significantly augmented 2.6-fold in PHD2cko, and 1.4-fold in PHD3ko compared to controls but was unchanged in PHD1ko mice. Macrophage apoptosis was promoted in PHD2cko and PHD3ko mice in vitro and in vivo, via the hypoxia-inducible factor (HIF) 1α/BNIP3 axis. Bulk and single-cell RNA data of PHD2cko bone marrow-derived macrophages (BMDMs) and plaque macrophages, respectively, showed enhanced HIF1α/BNIP3 signalling, which was validated in vitro by siRNA silencing. Human plaque BNIP3 mRNA was positively associated with plaque necrotic core size, suggesting similar pro-apoptotic effects in human. Furthermore, PHD2cko plaques displayed enhanced fibrosis, while macrophage collagen breakdown by matrix metalloproteinases, collagen production, and proliferation were unaltered. Instead, PHD2cko BMDMs enhanced fibroblast collagen secretion in a paracrine manner. In silico analysis of macrophage-fibroblast communication predicted SPP1 (osteopontin) signalling as regulator, which was corroborated by enhanced plaque SPP1 protein in vivo. Increased SPP1 mRNA expression upon PHD2cko was preferentially observed in foamy plaque macrophages expressing ‘triggering receptor expressed on myeloid cells-2’ (TREM2hi) evidenced by single-cell RNA, but not in neutrophils. This confirmed enhanced fibrotic signalling by PHD2cko macrophages to fibroblasts, in vitro as well as in vivo. Conclusion Myeloid PHD2cko and PHD3ko enhanced atherosclerotic plaque growth and macrophage apoptosis, while PHD2cko macrophages further activated collagen secretion by fibroblasts in vitro, likely via paracrine SPP1 signalling through TREM2hi macrophages.
    Type of Medium: Online Resource
    ISSN: 0008-6363 , 1755-3245
    URL: Article
    DOI: 10.1093/cvr/cvab152
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 1499917-1
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  • 19
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    Online Resource
    Heterogeneity and plasticity in healthy and atherosclerotic vasculature explored by single-cell sequencing
    Oxford University Press (OUP) ; 2019
    In:  Cardiovascular Research Vol. 115, No. 12 ( 2019-10-01), p. 1705-1715
    Details
    In: Cardiovascular Research, Oxford University Press (OUP), Vol. 115, No. 12 ( 2019-10-01), p. 1705-1715
    Abstract: Cellular characteristics and their adjustment to a state of disease have become more evident due to recent advances in imaging, fluorescent reporter mice, and whole genome RNA sequencing. The uncovered cellular heterogeneity and/or plasticity potentially complicates experimental studies and clinical applications, as markers derived from whole tissue ‘bulk’ sequencing is unable to yield a subtype transcriptome and specific markers. Here, we propose definitions on heterogeneity and plasticity, discuss current knowledge thereof in the vasculature and how this may be improved by single-cell sequencing (SCS). SCS is emerging as an emerging technique, enabling researchers to investigate different cell populations in more depth than ever before. Cell selection methods, e.g. flow assisted cell sorting, and the quantity of cells can influence the choice of SCS method. Smart-Seq2 offers sequencing of the complete mRNA molecule on a low quantity of cells, while Drop-seq is possible on large numbers of cells on a more superficial level. SCS has given more insight in heterogeneity in healthy vasculature, where it revealed that zonation is crucial in gene expression profiles among the anatomical axis. In diseased vasculature, this heterogeneity seems even more prominent with discovery of new immune subsets in atherosclerosis as proof. Vascular smooth muscle cells and mesenchymal cells also share these plastic characteristics with the ability to up-regulate markers linked to stem cells, such as Sca-1 or CD34. Current SCS studies show some limitations to the number of replicates, quantity of cells used, or the loss of spatial information. Bioinformatical tools could give some more insight in current datasets, making use of pseudo-time analysis or RNA velocity to investigate cell differentiation or polarization. In this review, we discuss the use of SCS in unravelling heterogeneity in the vasculature, its current limitations and promising future applications.
    Type of Medium: Online Resource
    ISSN: 0008-6363 , 1755-3245
    URL: Article
    DOI: 10.1093/cvr/cvz185
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 1499917-1
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  • 20
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    Online Resource
    Prolonged Hyperoxygenation Treatment Improves Vein Graft Patency and Decreases Macrophage Content in Atherosclerotic Lesions in ApoE3*Leiden Mice
    MDPI AG ; 2020
    In:  Cells Vol. 9, No. 2 ( 2020-02-01), p. 336-
    Details
    In: Cells, MDPI AG, Vol. 9, No. 2 ( 2020-02-01), p. 336-
    Abstract: Unstable atherosclerotic plaques frequently show plaque angiogenesis which increases the chance of rupture and thrombus formation leading to infarctions. Hypoxia plays a role in angiogenesis and inflammation, two processes involved in the pathogenesis of atherosclerosis. We aim to study the effect of resolution of hypoxia using carbogen gas (95% O2, 5% CO2) on the remodeling of vein graft accelerated atherosclerotic lesions in ApoE3*Leiden mice which harbor plaque angiogenesis. Single treatment resulted in a drastic decrease of intraplaque hypoxia, without affecting plaque composition. Daily treatment for three weeks resulted in 34.5% increase in vein graft patency and increased lumen size. However, after three weeks intraplaque hypoxia was comparable to the controls, as were the number of neovessels and the degree of intraplaque hemorrhage. To our surprise we found that three weeks of treatment triggered ROS accumulation and subsequent Hif1a induction, paralleled with a reduction in the macrophage content, pointing to an increase in lesion stability. Similar to what we observed in vivo, in vitro induction of ROS in bone marrow derived macrophages lead to increased Hif1a expression and extensive DNA damage and apoptosis. Our study demonstrates that carbogen treatment did improve vein graft patency and plaque stability and reduced intraplaque macrophage accumulation via ROS mediated DNA damage and apoptosis but failed to have long term effects on hypoxia and intraplaque angiogenesis.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells9020336
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2661518-6
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