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  • 1
    Online Resource
    Online Resource
    Abstract 616: MicroRNA miR-29b is a Mediator of Aortic Stiffness and Hypertension in a Murine Model of Type 2 Diabetes Mellitus
    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)
    Abstract: Background: Accelerated arterial stiffening is a complication of diabetes mellitus and associated with the development of hypertension. Arterial stiffening results from extensive extracellular matrix remodeling (elastin breakdown, collagen accumulation). MicroRNA miR-29b directly regulates the expression of genes governing fibrosis (such as COL1A1, COL3A1) and elastin breakdown ( MMP2, MMP9 ). However, its impact on aortic stiffness is unclear. Objective: This study was designed to investigate the role of miR-29b as potential mediator of diabetic aortic stiffening. Methods and Results: Serial ex vivo mechanical testing of the thoracic aorta and volume-pressure recording (VPR) based tail-cuff blood pressure measurements revealed that aortic stiffening precedes blood (pulse) pressure elevations in diabetic db/db mice. Vascular stiffening was accompanied by increased elastin fragmentation and collagen deposition (EvG and Picrosirius Red staining). qRT-PCR, in-situ hybridization and immunohistochemistry revealed decreased expression of miR-29b and de-repression of target genes ( Col1A1, COL3A1, MMP2, MMP9 ) in db/db mice compared to controls. Investigating the mechanistic significance of miR-29b for arterial stiffening, forced downregulation of miR-29b (via systemic LNA-miR-29b inhibitor application) results in enhanced elastin fragmentation, increased medial collagen deposition, aortic stiffness and augmented pulse pressure. Conclusions: In conclusion this study identifies miR-29b as a regulator and potential therapeutic target of diabetic aortic stiffening.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.36.suppl_1.616
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
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  • 2
    Online Resource
    Online Resource
    Abstract 297: Segmental Aortic Stiffening is a Mechanism Driving Early Abdominal Aortic Aneurysm Pathogenesis
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 34, No. suppl_1 ( 2014-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. suppl_1 ( 2014-05)
    Abstract: Stiffening of the aortic wall is a phenomenon consistently observed in abdominal aortic aneurysm (AAA). However, its role in AAA pathophysiology is largely undefined. Using an established murine elastase-induced AAA model, we demonstrate that segmental aortic stiffening (SAS) precedes aneurysm growth. Finite elements analysis (FEA)-based wall stress calculations reveal that early stiffening of the aneurysm-prone aortic segment leads to axial (longitudinal) stress generated by cyclic (systolic) tethering of adjacent, more compliant wall segments. Interventional stiffening of AAA-adjacent segments (via external application of surgical adhesive) significantly reduces aneurysm growth. These changes correlate with reduced segmental stiffness of the AAA-prone aorta (due to equalized stiffness in adjacent aortic segments), reduced axial wall stress, decreased production of reactive oxygen species (ROS), attenuated elastin breakdown, and decreased expression of inflammatory cytokines and macrophage infiltration, as well as attenuated apoptosis within the aortic wall. Cyclic pressurization of stiffened aortic segments ex vivo increases the expression of genes related to inflammation and extracellular matrix (ECM) remodeling. Finally, human ultrasound studies reveal that aging, a significant AAA risk factor, is accompanied by segmental infrarenal aortic stiffening. The present study introduces the novel concept of segmental aortic stiffening (SAS) as an early pathomechanism generating aortic wall stress and thereby triggering AAA growth. Therefore monitoring SAS by ultrasound might help to better identify patients at risk for AAA disease and better predict the susceptibility of small AAA to further growth. Moreover our results suggest that interventional mechanical stiffening of the AAA-adjacent aorta may be further tested as a novel treatment option to limit early AAA growth.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.34.suppl_1.297
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
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  • 3
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    Abstract 529: Cbfa1 (Runx2) is a Mediator of Aortic Stiffness and Hypertension in a Murine Model of Diabetes Mellitus Type 2
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 34, No. suppl_1 ( 2014-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. suppl_1 ( 2014-05)
    Abstract: Accelerated arterial stiffening is a complication of diabetes mellitus and associated with the development of hypertension. Arterial stiffening results from extensive extracellular matrix remodeling (elastin breakdown, collagen accumulation). The osteogenic transcription factor Cbfa1 (Runx2) has been identified as a mediator of aortic calcification and regulator of matrix protein expression. However, its impact on aortic stiffness is unclear. This study was designed to elucidate the temporal relation between aortic stiffening and the development of arterial hypertension in a murine model of diabetes mellitus type 2. Moreover we aimed to investigate the role of Cbfa1 as potential mediator diabetic aortic stiffening. Serial ex vivo mechanical testing of the thoracic aorta and volume-pressure recording (VPR) based tail-cuff blood pressure measurements revealed that aortic stiffening precedes blood (pulse) pressure elevations in diabetic db/db mice. Vascular stiffening was accompanied by increased medial collagen deposition Picrosirius Red staining). qRT-PCR and immunohistochemistry revealed enhanced expression of Cbfa1 and target genes (Col1a1, Col1a2, FN1, Spp1) in db/db mice compared to controls. Moreover, overexpression of Cbfa1 in vascular smooth muscle (Cbfa1-smTg mice) results in increased medial collagen deposition, aortic stiffness and augmented pulse pressure. Interestingly, Cbfa1-smTg mice did not exhibit enhanced vascular calcification (by von Kossa and Alizarin Red staining). In conclusion we demonstrated that aortic stiffening precedes the onset of hypertension in db/db mice and identified Cbfa1 as mediator of aortic stiffening - presumably via pro-fibrotic mechanisms.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.34.suppl_1.529
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
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  • 4
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    Online Resource
    Abstract 314: A Stent to Prevent: A Translational Approach Towards Small Abdominal Aortic Aneurysm (AAA) Therapy
    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)
    Abstract: Background: Abdominal aortic aneurysm (AAA) is defined as a permanent dilation of the abdominal aorta that is highly lethal in case of rupture. Current therapeutic approaches are limited to open surgery or stent-based endovascular aortic repair (EVAR) to exclude large sized AAA ( 〉 5.5 cm) from the circulation. However, to date there is no effective therapy to prevent small AAA formation and progression. Nonetheless, options for small AAA disease are highly desirable as even small AAA may rupture and app. 70% of all small AAA will grow and eventually require surgical repair. Objective: Building on our previous experimental research findings we present a novel therapeutic approach for early AAA intervention. Methods and Results: Our recent biomechanical studies in a murine model of AAA development (elastase model) as well as in human aortae indicate that early AAA growth is critically driven by a stiffness gradient between a stiff AAA segment and the adjacent more compliant aorta. As a promising therapeutic intervention, we found that stiffening of the AAA-adjacent aorta (by external glue application) was sufficient to stop murine AAA formation. In a translational approach we now aim to develop an intravascular stent prototype that is deployed in the neck region of a developing AAA to increase the mechanical stiffness of the AAA-adjacent aorta. We hypothesize that this intervention will decrease the aortic stiffness gradient towards the AAA segment – thereby preventing further AAA growth. Stent prototypes with varying designs will be tested in a pig model of AAA disease that closely resembles the human anatomic situation. Conclusion: This project demonstrates a highly promising opportunity to directly translate novel pathomechanistic insights into AAA pathobiology from bench to bedside application and stop early AAA progression in humans.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.37.suppl_1.314
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
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  • 5
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    Online Resource
    Abstract 465: Nicotine Differentially Influences Segmental Aortic Stiffening
    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)
    Abstract: Background: Arterial stiffness is a major risk factor for various cardiovascular diseases and contributes to the development of abdominal aortic aneurysms (AAA). In this context, differential aortic stiffening of adjacent aortic segments increases aortic wall stress and accelerates the disease. Smoking is a major risk factor for AAA, in part due to nicotine. In this study, we investigated aortic stiffening of the thoracic and abdominal aorta and analyzed stiffness-related gene expression. Methods: 36 WT mice (C57BL/6) mice were infused with nicotine or PBS using osmotic mini pumps for 42 days. Thoracic segment (TS) and abdominal segment (AS) aortic stiffness were analyzed using ultrasound (M-Mode and PW). TS and AS were further investigated by ex vivo myograph measurements. Gene expression for TMIP2, MT1-MMP, MMP2, collagen type I and type III was performed for both segments separately. Results: Myograph measurements revealed increased strain within the AS after 2 weeks (p 〈 .05) in response to nicotine (vs. PBS), but no stiffening of the TS. After 6 weeks, the AS showed additional increases in strain with nicotine (p 〈 .05); however, only minor increases in stiffness could be observed for the TS. Ultrasound M-Mode results confirmed the myograph results. Nicotine treatment also led to increased aortic pulse wave velocity (PWV) after 2 weeks (p 〈 .05) and 6 weeks (p 〈 .05). Gene expression analysis revealed up-regulation in the TS and AS of MT1-MMP and MMP2 after 2 weeks of nicotine, while TIMP2 was downregulated, and collagen type I and type III were up-regulated in both TS and AS (p 〈 .05). After 6 weeks, there were no longer significant differences in either segment for any of these genes. Discussion: Aortic stiffening in response to nicotine varies between the TS and AS segment over a time course of 6 weeks. This leads to an increased stiffness gradient between the TS and AS. Gene expression changes in stiffness-related genes occurred in response to nicotine, although no difference appeared between the segments. We conclude that the difference in stiffness development for TS and AS could be based on a different basic morphological structure involving elastin and collagen load, and that these responses may in part explain nicotine’s role in promoting AAA.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.37.suppl_1.465
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
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  • 6
    Online Resource
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    Abstract 567: Transcription Factor Runx2 is Induced in Vascular Aging and May Promote Age-related Arterial Stiffness
    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)
    Abstract: Background: Arterial stiffening is a hallmark of vascular aging and may constitute a critical mechanism linking age to increased cardiovascular risk. However, up to now there is no therapy available to efficiently and specifically target age-related arterial stiffening. We recently identified the osteogenic transcription factor Runx2 as an inducer of diabetic arterial stiffness. Objective: The present study investigated the role of Runx2 in the setting of age-related arterial stiffness. Methods and Results: Aortic stiffness – quantified by ex vivo mechanical testing (pressure myography) – was markedly increased in 1-year old male C57Bl/6 mice compared to young (10 week-old) controls. At the same time, Runx2 was aberrantly upregulated in the medial layer of aged aortae, coming along with significant medial fibrosis. Additionally, we detected increased aortic expression of interleukin 6 ( Il6 ) – a key cytokine involved in vascular “inflammaging”. Mechanistically, we found IL-6-induced RUNX2 expression in aortic smooth muscle cells (SMCs) via a NFkB-dependent pathway. Conclusion: In conclusion this study suggests Runx2 as a potential mediator of age-related arterial fibrosis and stiffness warranting further interventional/therapeutic studies.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.36.suppl_1.567
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1494427-3
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