scholarly journals Early Adventitial Activation and Proliferation in a Mouse Model of Arteriovenous Stenosis: Opportunities for Intervention

2021 ◽  
Vol 22 (22) ◽  
pp. 12285
Author(s):  
Jenq-Shyong Chan ◽  
Yang Wang ◽  
Virgilius Cornea ◽  
Prabir Roy-Chaudhury ◽  
Begoña Campos
Keyword(s):  
Mouse Model ◽  
Cellular Proliferation ◽  
Neointimal Hyperplasia ◽  
Geographical Location ◽  
Macrophage Infiltration ◽  
Endothelial Cell Proliferation ◽  
Cellular Phenotype ◽  
Infiltrating Cells ◽  
Immunohistochemical Analyses ◽  
Over Time

Background: Arteriovenous fistula (AVF) stenosis remains an important cause of AVF maturation failure, for which there are currently no effective therapies. We examined the pattern and phenotype of cellular proliferation at different timepoints in a mouse model characterized by a peri-anastomotic AVF stenosis. Methods: Standard immunohistochemical analyses for cellular proliferation and macrophage infiltration were performed at 2, 7 and 14 d on our validated mouse model of AVF stenosis to study the temporal profile, geographical location and cellular phenotype of proliferating and infiltrating cells in this model. Results: Adventitial proliferation and macrophage infiltration (into the adventitia) began at 2 d, peaked at 7 d and then declined over time. Surprisingly, there was minimal macrophage infiltration or proliferation in the neointimal region at either 7 or 14 d, although endothelial cell proliferation increased rapidly between 2 d and 7 d, and peaked at 14 d. Conclusions: Early and rapid macrophage infiltration and cellular proliferation within the adventitia could play an important role in the downstream pathways of both neointimal hyperplasia and inward or outward remodelling.

scholarly journals Fibrotic Changes and Endothelial-to-Mesenchymal Transition Promoted by VEGFR2 Antagonism Alter the Therapeutic Effects of VEGFA Pathway Blockage in a Mouse Model of Choroidal Neovascularization

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2057 ◽  
Author(s):  
Franco Aparecido Rossato ◽  
Yu Su ◽  
Ashley Mackey ◽  
Yin Shan Eric Ng
Keyword(s):  
Mouse Model ◽  
Choroidal Neovascularization ◽  
Cellular Proliferation ◽  
Age Related Macular Degeneration ◽  
Individual Treatment ◽  
Therapeutic Effects ◽  
Mesenchymal Transition ◽  
Age Related ◽  
Endothelial To Mesenchymal Transition ◽  
Over Time

Many patients with wet age-related macular degeneration do not respond well to anti- vascular endothelial growth factor A (VEGFA) therapy for choroidal neovascularization (CNV), and the efficacy of anti-VEGFA decreases over time. We investigated the hypothesis that fibrotic changes, in particular via endothelial-to-mesenchymal transition (EndoMT), play a role in CNV and alter the therapeutic effects of VEGFA pathway blockage. Induction of EndoMT of primary human retinal endothelial cells led to a significantly reduced response to VEGFA at the level of gene expression, cellular proliferation, migration, and tube formation. Suppression of EndoMT restored cell responsiveness to VEGFA. In a mouse model of spontaneous CNV, fibrotic changes and EndoMT persisted as the CNV lesions became more established over time. VEGFA receptor-2 (VEGFR2) antagonism further induced fibrosis and EndoMT in the CNV. The combination of VEGFR2 antagonism and fibrosis/EndoMT inhibition was more effective than either individual treatment in reducing CNV. Our data indicate that fibrosis and EndoMT are involved in the progression of CNV, are exacerbated by VEGFR2 inhibition, and could provide an explanation for the reduced efficacy of anti-VEGFA treatment over time.

Sa1108 SERUM AMYLOID A PROMOTES INFLAMMATION-ASSOCIATED DAMAGE, MACROPHAGE INFILTRATION AND TUMORIGENESIS IN A MOUSE MODEL OF COLITIS-ASSOCIATED COLON CANCER

2020 ◽  
Vol 158 (6) ◽  
pp. S-278
Author(s):  
Tanja Davis ◽  
Daleen Conradie ◽  
Preetha Shridas ◽  
Marcielle C. de Beer ◽  
Frederick c. de Beer ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Mouse Model ◽  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Macrophage Infiltration ◽  
Amyloid A

Identity Politics and Refugee Policies in Kupang, Eastern Indonesia: A Politico-Historical Perspective

2021 ◽  
pp. 1-14
Author(s):  
Andrey Damaledo
Keyword(s):  
Identity Politics ◽  
Host Country ◽  
Historical Perspective ◽  
Geographical Location ◽  
Policy Implications ◽  
Refugee Status ◽  
Timor Leste ◽  
Displaced People ◽  
Over Time

Abstract This article assesses the implementation of Presidential Regulation No. 125 of 2016 concerning the Treatment of Refugees and how it relates to different kinds of bureaucratic labelling of refugees as it unfolds in Indonesia’s region of Kupang. From a politico-historical perspective, Kupang is a useful case-study for elucidating the policy implications of the labelling of refugees, as the region has been hosting different kinds of refugees due to its strategic geographical location that borders Australia and Timor-Leste. Drawing on my fieldwork in Kupang between October 2012 and October 2013, and my intermittent return to the region between January 2017 and February 2019, this article argues that labels for refugees evolve over time in response to the larger sociopolitical situation, but they are formed mostly to serve the interest of the host country rather than those of displaced people. Furthermore, while labelling displaced people as “refugees” has been effective in justifying funding and support, it can also lead to a manipulation of refugee status, and the marginalization and exclusion of refugees.

Macrophage Infiltration and Cellular Proliferation in the Non-Ischemic Kidney and Heart following Prolonged Unilateral Renal Ischemia

2007 ◽  
Vol 106 (3) ◽  
pp. p54-p62 ◽  
Author(s):  
Hirobumi Tokuyama ◽  
Darren J. Kelly ◽  
Yuan Zhang ◽  
Renae M. Gow ◽  
Richard E. Gilbert
Keyword(s):  
Cellular Proliferation ◽  
Renal Ischemia ◽  
Macrophage Infiltration

scholarly journals An acute bleomycin inflammatory and fibrotic mouse model of morphea is dependent upon CXCL9 and CXCR3

2019 ◽  
Author(s):  
Jillian M. Richmond ◽  
Dhrumil Patel ◽  
Tomoya Watanabe ◽  
Colton J. Garelli ◽  
Madhuri Garg ◽  
...  
Keyword(s):  
Mouse Model ◽  
Localized Scleroderma ◽  
Lesional Skin ◽  
Chemokine Expression ◽  
Inflammatory Phase ◽  
Deficient Mice ◽  
Over Time ◽  
Cutaneous Fibrosis

AbstractMorphea, or localized scleroderma, is characterized by an inflammatory phase followed by cutaneous fibrosis, which may lead to disfigurement and/or disability. Previous work from our group showed that the CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in lesional skin of morphea patients. Here, we used an acute inflammatory and fibrotic bleomycin mouse model of morphea to examine the role of the CXCR3 chemokine axis in pathogenesis. We first characterized which cells produce the CXCR3 ligands in the skin using the Reporter of Expression of CXCR3 ligands mouse (REX3). We found that fibroblasts contribute the bulk of CXCL9 and CXCL10, whereas endothelial cells are key dual chemokine producers. Macrophages, which have high MFI of chemokine expression, upregulated CXCL9 production over time, fibroblasts CXCL10 production, and T cells dual chemokine expression. To determine whether bleomycin treatment could directly induce expression of these chemokines, we treated cultured REX3 mouse dermis monolayers in vitro with bleomycin or IFNγ with TNF and found that bleomycin could induce low amounts of CXCL9 directly in fibroblasts, whereas the cytokines were required for optimal CXCL9 and CXCL10 production. To determine whether these chemokines are mechanistically involved in pathogenesis, we induced fibrosis in CXCL9, CXCL10, or CXCR3 deficient mice and found that fibrosis is dependent on CXCL9 and CXCR3. Addition of recombinant CXCL9, but not CXCL10, to cultured mouse fibroblasts induces collagen 1a1 mRNA expression, indicating the chemokine itself can contribute to fibrosis. Taken together, our studies provide evidence that acute intradermal bleomycin administration in mice can model inflammatory morphea, and that CXCL9 and its receptor CXCR3 are mechanistically involved in pathogenesis.One Sentence SummaryCXCL9 drives acute morphea pathogenesis in mice.

scholarly journals Imbalance in the response of pre- and post-synaptic components to amyloidopathy

2019 ◽  
Author(s):  
Terri-Leigh Stephen ◽  
Francesco Tamagnini ◽  
Judith Piegsa ◽  
Katherine Sung ◽  
Joshua Harvey ◽  
...  
Keyword(s):  
Mouse Model ◽  
Synaptic Dysfunction ◽  
Functional Impairments ◽  
Synaptic Terminals ◽  
Diffuse Part ◽  
Initial Area ◽  
Synapse Density ◽  
Synaptic Dynamics ◽  
Underlying Pathology ◽  
Over Time

AbstractAlzheimer’s disease (AD)-associated synaptic dysfunction drives the progression of pathology from its earliest stages. Aβ species, both soluble and in plaque deposits, have been causally related to the progressive, structural and functional impairments observed in AD. It is, however, still unclear how Aβ plaques develop over time and how they progressively affect local synapse density and turnover. Here we observed, in a mouse model of AD, that Aβ plaques grow faster in the earlier stages of the disease and if their initial area is > 500 µm2; this may be due to deposition occurring in the diffuse part of the plaque. In addition, synaptic turnover is higher in the presence of amyloid pathology and this is paralleled by a reduction in pre-but not post-synaptic densities. Plaque proximity does not appear to have an impact on synaptic dynamics. These observations indicate an imbalance in the response of the pre- and post-synaptic terminals and that therapeutics, alongside targeting the underlying pathology, need to address changes in synapse dynamics.

scholarly journals Isoform-Specific Roles of ERK1 and ERK2 in Arteriogenesis

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 38 ◽  
Author(s):  
Nicolas Ricard ◽  
Jiasheng Zhang ◽  
Zhen W. Zhuang ◽  
Michael Simons
Keyword(s):  
Endothelial Cells ◽  
Intracellular Signaling ◽  
Clinical Importance ◽  
Macrophage Infiltration ◽  
Endothelial Cell Proliferation ◽  
Vascular Endothelial ◽  
Ischemic Event ◽  
Intracellular Signaling Pathway ◽  
First Time

Despite the clinical importance of arteriogenesis, this biological process is poorly understood. ERK1 and ERK2 are key components of a major intracellular signaling pathway activated by vascular endothelial growth (VEGF) and FGF2, growth factors critical to arteriogenesis. To investigate the specific role of each ERK isoform in arteriogenesis, we used mice with a global Erk1 knockout as well as Erk1 and Erk2 floxed mice to delete Erk1 or Erk2 in endothelial cells, macrophages, and smooth muscle cells. We found that ERK1 controls macrophage infiltration following an ischemic event. Loss of ERK1 in endothelial cells and macrophages induced an excessive macrophage infiltration leading to an increased but poorly functional arteriogenesis. Loss of ERK2 in endothelial cells leads to a decreased arteriogenesis due to decreased endothelial cell proliferation and a reduced eNOS expression. These findings show for the first time that isoform-specific roles of ERK1 and ERK2 in the control of arteriogenesis.

scholarly journals Pirfenidone inhibits cryoablation induced local macrophage infiltration along with its associated TGFb1 expression and serum cytokine level in a mouse model

Cryobiology ◽  
2018 ◽  
Vol 82 ◽  
pp. 106-111 ◽  
Author(s):  
Yangkui Gu ◽  
Govindarajan Srimathveeravalli ◽  
Liqun Cai ◽  
Eisuke Ueshima ◽  
Majid Maybody ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cytokine Level ◽  
Macrophage Infiltration ◽  
Serum Cytokine Level ◽  
Serum Cytokine

scholarly journals Role of CX3CR1 signaling in malignant transformation of gliomas

2020 ◽  
Vol 22 (10) ◽  
pp. 1463-1473 ◽  
Author(s):  
Sungho Lee ◽  
Khatri Latha ◽  
Ganiraju Manyam ◽  
Yuhui Yang ◽  
Arvind Rao ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Mouse Model ◽  
Malignant Transformation ◽  
Microvessel Density ◽  
Progression Free Survival ◽  
Macrophage Infiltration ◽  
M2 Macrophage ◽  
Low Grade ◽  
Free Survival

Abstract Background Chemokine signaling may contribute to progression of low-grade gliomas (LGGs) by altering tumor behavior or impacting the tumor microenvironment. In this study, we investigated the role of CX3C chemokine receptor 1 (CX3CR1) signaling in malignant transformation of LGGs. Methods Ninety patients with LGGs were genotyped for the presence of common CX3CR1 V249I polymorphism and examined for genotype-dependent alterations in survival, gene expression, and tumor microenvironment. A genetically engineered mouse model was leveraged to model endogenous intracranial gliomas with targeted expression of CX3C ligand 1 (CX3CL1) and CX3CR1, individually or in combination. Results LGG patients who were heterozygous (V/I; n = 43) or homozygous (I/I; n = 2) for the CX3CR1 V249I polymorphism had significantly improved median overall (14.8 vs 9.8 y, P < 0.05) and progression-free survival (8.6 vs 6.5 y, P < 0.05) compared with those with the wild type genotype (V/V; n = 45). Tumors from the V/I + I/I group exhibited significantly decreased levels of CCL2 and MMP9 transcripts, correlating with reduced intratumoral M2 macrophage infiltration and microvessel density. In an immunocompetent mouse model of LGGs, coexpression of CX3CL1 and CX3CR1 promoted a more malignant tumor phenotype characterized by increased microglia/macrophage infiltration and microvessel density, resulting in shorter survival. Conclusions CX3CR1 V249I polymorphism is associated with improved overall and progression-free survival in LGGs. CX3CR1 signaling enhances accumulation of tumor associated microglia/macrophages and angiogenesis during malignant transformation.

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