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  • Ovid Technologies (Wolters Kluwer Health)  (40)
  • 1
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    Abstract 073: Expression of Axl in Innate Immune Cells Contributes to Kidney Dysfunction and Onset of Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Hypertension Vol. 66, No. suppl_1 ( 2015-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 66, No. suppl_1 ( 2015-09)
    Abstract: Introduction: We previously reported that expression of the receptor tyrosine kinase Axl in hematopoietic cells is critical for kidney dysfunction in early hypertension. Here we investigated the role of Axl expression in innate immune cells in deoxycorticosterone acetate (DOCA)-salt induced hypertension. Methods and Results: RAG1-/- mice lack adaptive immune cells and displayed the same (~25 mmHg) increase in systolic blood pressure (BP) as C57BL/6J mice after 1 week of DOCA-salt. While in metabolic cages RAG1-/- drank more (14.3±0.9 mL) than C57BL/6J mice (10.6±2.5 mL) per day after 1 week of DOCA-salt. Ultrasound imaging confirmed that RAG1-/- had ~20 % larger kidneys vs. C57BL/6J mice after DOCA-salt. RAG1-/- kidneys accumulated 2 times more fluid (2.8±0.1 %) compared to C57BL/6J mice (1.4±0.5 %) after DOCA-salt. Flow cytometry on kidneys from RAG1-/- confirmed absence of T and B lymphocytes, while DOCA-salt increased presence of macrophages (1.1±0.3 x10 9 ) compared to C57BL/6J mice (0.6±0.1 x10 9 ). We successfully generated Axl/RAG1 double knockout mice and subjected the littermates to 1 week of DOCA-salt. Increases in systolic BP were the same in Axl/RAG1+/+ and Axl/RAG1-/- littermate mice. No differences were found in kidney volumes between the Axl/RAG1 genotypes as well. However, 24 hrs excretion volumes increased in Axl/RAG1-/- (50±6 %) compared to Axl/RAG1+/+ (31±6 %) littermates. Finally, renal artery blood flow velocity (611±52 mm/s) and resistive index (0.62±0.03) were reduced in Axl/RAG1+/+ but not in Axl/RAG1-/- mice (665±45 mm/s and 0.68±0.01, respectively) when compared to their controls. Conclusions: Our findings suggest that mice lacking lymphocytes compensate by increasing kidney macrophages that contribute to initial increase in BP. Depletion of Axl in innate immune cells partially reverses kidney dysfunction by improving renal artery function in early hypertension.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.66.suppl_1.073
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 2094210-2
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  • 2
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    Abstract 001: Axl Expression by CD4+ T Lymphocytes Promotes Salt-Dependent Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Hypertension Vol. 64, No. suppl_1 ( 2014-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 64, No. suppl_1 ( 2014-09)
    Abstract: Introduction: Our laboratory has shown that Axl, a receptor tyrosine kinase, is important in both vascular and immune functions during deoxycorticosterone acetate (DOCA)-salt hypertension. We hypothesized that Axl activity specifically in T lymphocytes could explain the dependence of hypertension on Axl. Methods and Results: We did adoptive transfers of either Axl+/+ or Axl-/- CD4+ T cells to RAG1-/- mice that lack mature T cells. Once CD4+ T cell repopulations were confirmed, we induced DOCA-salt hypertension for 6 weeks. Systolic blood pressure (BP, mmHg) increased by 20±5 in Axl+/+RAG-/- mice after DOCA-salt, but Axl-/- RAG-/- mice had increases in BP by only 6+3 after 6 weeks of DOCA-salt. We isolated naïve CD4+ T cells from both Axl+/+ and Axl-/- littermates and primed them under either Th1 or Th2 polarizing conditions in culture. Production of interferon gamma (IFN-γ ng/mL) was significantly decreased (-23%, p 〈 0.05) in Axl-/- (396±23) compared to Axl+/+ (512±42) under Th1-priming. However, Axl had no effect on interleukin 4 (IL-4, ng/mL) production under Th2 polarizing conditions. Intracellular staining of the Th1/Th2 cells with IFN-γ and IL-4 antibodies by flow cytometry confirmed expression of cytokines in culture media. Complete blood counts showed that Axl-/- mice had significantly lower white blood cells due to decreased numbers of lymphocytes (4.5±0.7x10 9 ) compared to Axl+/+ mice (7.8±0.7x10 9 ). We found a higher population of AnnexinV (marker of early apoptosis)-positive peripheral leukocytes in Axl-/- mice (10±1%) compared to Axl+/+ (4±1%) by flow cytometry; while the percentages of dead cells (~10%) were similar between Axl+/+ and Axl-/- mice. Conclusions: Altogether we show that expression of Axl by T cells drives salt-induced hypertension. The mechanism of Axl-dependent effects on T cells occurs via T-cell-dependent expression of the pro-inflammatory cytokine IFN-γ. In addition, Axl plays a role in inhibiting lymphocyte apoptosis in the circulation. Future work will focus on how Axl expression in T cells affects T cell-dependent vascular remodeling during hypertension.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.64.suppl_1.001
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 2094210-2
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  • 3
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    Axl Mediates Vascular Remodeling Induced by Deoxycorticosterone Acetate–Salt Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2007
    In:  Hypertension Vol. 50, No. 6 ( 2007-12), p. 1057-1062
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 50, No. 6 ( 2007-12), p. 1057-1062
    Abstract: Axl, a receptor tyrosine kinase, was recently identified as a novel candidate gene in a genetic model of salt-sensitive hypertension (Sabra rat). Our group first reported that Axl plays a significant role in vascular remodeling in response to injury. Here we investigated the role of Axl in the pathogenesis of hypertension in a deoxycorticosterone acetate (DOCA)–salt model. Hypertension was induced in Axl wild-type (Axl +/+ ) mice and Axl-deficient (Axl −/− ) mice by uninephrectomy and DOCA-salt for 6 weeks. Controls were uninephrectomized and received tap water and regular chow ad libitum. DOCA-salt treatment increased systolic blood pressure by 25 mm Hg in both genotypes after 1 week. Systolic blood pressure remained significantly elevated in Axl +/+ DOCA, whereas systolic blood pressure levels in Axl −/− DOCA mice were the same as controls at 6 weeks. DOCA-salt increased relative kidney weight and glomerular hypertrophy by 40% compared with controls in both genotypes. Consistent with levels of systolic blood pressure, endothelium-dependent vasorelaxation was impaired in Axl +/+ DOCA mice compared with Axl +/+ controls, whereas in Axl −/− DOCA mice relaxation responses were similar to Axl −/− controls. In addition, endothelium-independent vasorelaxation was improved in Axl −/− DOCA mice compared with Axl +/+ DOCA mice. Nitrotyrosine and phospho-Akt immunoreactivity was significantly reduced in arteries from Axl −/− DOCA mice compared with Axl +/+ DOCA mice. The remodeling index of the mesenteric artery (media:lumen ratio) was significantly increased in Axl +/+ DOCA mice compared with Axl −/− DOCA mice. Finally, increased vascular apoptosis in the Axl −/− DOCA mice suggests a likely mechanism for Axl-dependent effects on hypertension. These data strengthen the pathogenic role for Axl in salt-sensitive hypertension.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.107.096289
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2007
    detail.hit.zdb_id: 2094210-2
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  • 4
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    Abstract 359: Hemodynamic Differences in Normal and Stress Conditions between SJL/J and C3HeB/FeJ Inbred Mouse Strains
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Hypertension Vol. 60, No. suppl_1 ( 2012-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 60, No. suppl_1 ( 2012-09)
    Abstract: Introduction: SJL/J (SJL) mice have elevated (80beats/min) heart rate (HR) compared to C3HeB/FeJ (C3HeB) mouse strain then measured by tail-cuff plethysmography. SJL and C3HeB are differed in behavioral phenotypes. The goal of this study was to investigate hemodynamic responses to normal and stress conditions between SJL and C3HeB inbred mouse strains. Methods and Results: Radio telemetry was used for continuous recordings of HR and systolic blood pressure (SBP) in C3HeB (n=5-10) and SJL (n=4-10) mice. We found that both strains showed normal circadian rhythms with little differences in HR and SBP. However, a locomotor activity (LA) of SJL was lower compared to C3HeB (7.8±0.4 vs. 10.0±0.1counts) during the lights off period. A correlation between LA and HR was reduced in SJL (R 2 =0.27) compared to C3HeB (R 2 =0.67) during the lights off period. After a mild stress (transfer to a cage) SJL had a slight HR elevation (70 beats/min) compared to C3HeB in first 5min. LA and SBP were similar between inbred strains after a novel cage test. The HR changes were significantly higher (2.5-fold, p 〈 0.05) in SJL vs. C3HeB during first 5min (30min of restraining period) on the first day of tail-cuff training. Five days of tail-cuff procedures resulted in 2-fold elevation of HR in SJL compared to C3HeB for 30min restraining period. Interestingly, changes in SBP were similar between mouse strains on first day, while SBP showed a trend to be 2-fold higher in SJL vs. C3HeB for 30min on day five. Autonomic control of HR was determined by pharmacological blockages in mice. Atropine (1mg/kg, i.p.) caused significantly greater increases in HR in SJL (160+8beats/min, p 〈 0.05) compared to C3HeB (62+11beats/min). Administration of propranolol (4mg/kg, i.p.) resulted in similar HR reductions between these strains. Conclusions: We found that SJL mice are susceptible to elevation of hemodynamic parameters after chronic stress. An increase in sympathetic nervous system activity may explain HR differences between SJL and C3HeB inbred strains. This study was supported in part by funds from Russian Program "Scientific and scientific-pedagogical personnel of innovative Russia" for 2009-2013 GK№14.740.11.0923 and HL105623 (VAK)
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.60.suppl_1.A359
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 2094210-2
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  • 5
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    Vascular Remodeling : Hemodynamic and Biochemical Mechanisms Underlying Glagov’s Phenomenon
    Ovid Technologies (Wolters Kluwer Health) ; 2007
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 27, No. 8 ( 2007-08), p. 1722-1728
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 27, No. 8 ( 2007-08), p. 1722-1728
    Abstract: This review focuses attention on the need to identify specific molecular pathways that explain the relationship of physical parameters and arterial remodeling. Recent studies have begun to define the transduction pathways in the artery wall that determine their ability to respond to the physical forces exerted by blood flow.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.106.129254
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2007
    detail.hit.zdb_id: 1494427-3
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  • 6
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    Abstract 317: A Congenic Mouse Model for Carotid Intima-Media Thickening Demonstrates that Leukocyte Infiltration is a Genetically Regulated Trait
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 33, No. suppl_1 ( 2013-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 33, No. suppl_1 ( 2013-05)
    Abstract: We demonstrated that inflammation and intima-media thickening (IMT) are increased in carotids exposed to low blood flow in the SJL/J (SJL) mouse strain compared to other strains. We identified three novel quantitative trait loci (QTLs) on chromosomes (chr) 2, 11, and 18 that control IMT in a genetic cross between C3HeB/FeJ (C3H/F) and SJL mice. Using a genetic backcross of C3H/FxSJL we measured inflammation in carotid IMT as a quantitative trait. Immunostaining for CD45+ (a pan-specific leukocyte marker) was performed on carotids from C3H/F, SJL, F1 and N2 progeny to measure leukocyte infiltration. A QTL for CD45+ cell infiltration was identified on chr11 (17cM, LOD=2.3). Interval mapping showed that the CD45+ locus accounted for 8% of the variation in the C3H/FxSJL backcross. Importantly, the CD45+ locus co-localized with our previously reported intima modifier 2 (Im2) locus. We created two Im2 congenic mice (C3H/F.SJL.11.1 and C3H/F.SJL.11.2) to define the contribution of chr11 to IMT. The C3H/F.SJL.11.1 congenic mouse showed elevated CD45+ staining in the vascular wall in response to low flow. Thus, the CD45+ trait partially explains the intima trait. This reveals a potential mechanistic relationship between leukocyte infiltration and IMT in response to decreased blood flow.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.33.suppl_1.A317
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1494427-3
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  • 7
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    Axl, A Receptor Tyrosine Kinase, Mediates Flow-Induced Vascular Remodeling
    Ovid Technologies (Wolters Kluwer Health) ; 2006
    In:  Circulation Research Vol. 98, No. 11 ( 2006-06-09), p. 1446-1452
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 98, No. 11 ( 2006-06-09), p. 1446-1452
    Abstract: Intima-media thickening (IMT) in response to hemodynamic stress is a physiological process that requires coordinated signaling among endothelial, inflammatory, and vascular smooth muscle cells (VSMC). Axl, a receptor tyrosine kinase, whose ligand is Gas6, is highly induced in VSMC after carotid injury. Because Axl regulates cell migration, phagocytosis and apoptosis, we hypothesized that Axl would play a role in IMT. Vascular remodeling in mice deficient in Axl (Axl −/− ) and wild-type littermates (Axl +/+ ) was induced by ligation of the left carotid artery (LCA) branches maintaining flow via the left occipital artery. Both genotypes had similar baseline hemodynamic parameters and carotid artery structure. Partial ligation altered blood flow equally in both genotypes: increased by 60% in the right carotid artery (RCA) and decreased by 80% in the LCA. There were no significant differences in RCA remodeling between genotypes. However, in the LCA Axl −/− developed significantly smaller intima+media compared with Axl +/+ (31±4 versus 42±6×10 −6 μm 3 , respectively). Quantitative immunohistochemistry of Axl −/− LCA showed increased apoptosis compared with Axl +/+ (5-fold). As expected, p-Akt was decreased in Axl −/− , whereas there was no difference in Gas6 expression. Cell composition also changed significantly, with increases in CD45 + cells and decreases in VSMC, macrophages, and neutrophils in Axl −/− compared with Axl +/+ . These data demonstrate an important role for Axl in flow-dependent remodeling by regulating vascular apoptosis and vascular inflammation.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/01.RES.0000223322.16149.9a
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2006
    detail.hit.zdb_id: 1467838-X
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  • 8
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    Bcr Kinase Activation by Angiotensin II Inhibits Peroxisome Proliferator-Activated Receptor γ Transcriptional Activity in Vascular Smooth Muscle Cells
    Ovid Technologies (Wolters Kluwer Health) ; 2009
    In:  Circulation Research Vol. 104, No. 1 ( 2009-01-02), p. 69-78
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 104, No. 1 ( 2009-01-02), p. 69-78
    Abstract: Bcr is a serine/threonine kinase activated by platelet-derived growth factor that is highly expressed in the neointima after vascular injury. Here, we demonstrate that Bcr is an important mediator of angiotensin (Ang) II and platelet-derived growth factor–mediated inflammatory responses in vascular smooth muscle cells (VSMCs). Among transcription factors that might regulate Ang II–mediated inflammatory responses we found that ligand-mediated peroxisome proliferator-activated receptor (PPAR)γ transcriptional activity was significantly decreased by Ang II. Ang II increased Bcr expression and kinase activity. Overexpression of Bcr significantly inhibited PPARγ activity. In contrast, knockdown of Bcr using Bcr small interfering RNA and a dominant-negative form of Bcr (DN-Bcr) reversed Ang II–mediated inhibition of PPARγ activity significantly, suggesting the critical role of Bcr in Ang II–mediated inhibition of PPARγ activity. Point-mutation and in vitro kinase analyses showed that PPARγ was phosphorylated by Bcr at serine 82. Overexpression of wild-type Bcr kinase did not inhibit ligand-mediated PPARγ1 S82A mutant transcriptional activity, indicating that Bcr regulates PPARγ activity via S82 phosphorylation. DN-Bcr and Bcr small interfering RNA inhibited Ang II–mediated nuclear factor κB activation in VSMCs. DN-PPARγ reversed DN-Bcr–mediated inhibition of nuclear factor κB activation, suggesting that PPARγ is downstream from Bcr. Intimal proliferation in low-flow carotid arteries was decreased in Bcr knockout mice compared with wild-type mice, suggesting the critical role of Bcr kinase in VSMC proliferation in vivo, at least in part, via regulating PPARγ/nuclear factor κB transcriptional activity.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.108.188409
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2009
    detail.hit.zdb_id: 1467838-X
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  • 9
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    Molecular approaches to ependymoma : the next step(s)
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Current Opinion in Neurology Vol. 25, No. 6 ( 2012-12), p. 745-750
    Details
    In: Current Opinion in Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 25, No. 6 ( 2012-12), p. 745-750
    Type of Medium: Online Resource
    ISSN: 1350-7540
    URL: Article
    DOI: 10.1097/WCO.0b013e328359cdf5
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 2026967-5
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  • 10
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    HGNET-BCOR Tumors of the Cerebellum : Clinicopathologic and Molecular Characterization of 3 Cases
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  American Journal of Surgical Pathology Vol. 41, No. 9 ( 2017-09), p. 1254-1260
    Details
    In: American Journal of Surgical Pathology, Ovid Technologies (Wolters Kluwer Health), Vol. 41, No. 9 ( 2017-09), p. 1254-1260
    Abstract: The central nervous system (CNS) high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR) is a recently described molecular entity. We report 3 new CNS HGNET-BCOR cases sharing common clinical presentation and pathologic features. The 3 cases concerned children aged 3 to 7 years who presented with a voluminous mass of the cerebellum. Pathologic features included proliferation of uniform spindle to ovoid cells with fine chromatin associated with a rich arborizing capillary network. Methylation profiling classified these cases as CNS HGNET-BCOR tumors. Polymerase chain reaction analysis confirmed the presence of internal tandem duplications in the C-terminus of BCOR (BCOR-ITD), a characteristic of these tumors, in all 3 cases. Immunohistochemistry showed a strong nuclear BCOR expression. In 2 cases, local recurrence occurred within 6 months. The third case, a patient who received a craniospinal irradiation after total surgical removal followed by a metronomics maintenance with irinotecan, temozolomide, and itraconazole, is still free of disease 14 months after diagnosis. In summary, CNS HGNET-BCOR represents a rare tumor occurring in young patients with dismal prognosis. BCOR nuclear immunoreactivity is highly suggestive of a BCOR-ITD. Whether CNS HGNET-BCOR should be classified among the category of “embryonal tumors” or within the category of “mesenchymal, nonmeningothelial tumors” remains to be clarified. Because CNS HGNET-BCOR share pathologic features and characteristic BCOR-ITD with clear cell sarcoma of the kidney, these tumors may represent local variants of the same entity.
    Type of Medium: Online Resource
    ISSN: 0147-5185
    URL: Article
    DOI: 10.1097/PAS.0000000000000866
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 2029143-7
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