scholarly journals Adventitial recruitment of Lyve-1- macrophages drives aortic aneurysm in an angiotensin-2-based murine model.

2021 ◽  
Author(s):  
Antigona Ulndreaj ◽  
Angela Li ◽  
Yonghong Chen ◽  
Rickvinder Besla ◽  
Shaun Pacheco ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Neutralizing Antibody ◽  
Aortic Dilatation ◽  
Protective Effects ◽  
Abdominal Aortic ◽  
Suprarenal Aorta ◽  
Selective Targeting ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Macrophage Accumulation

Objective: Aortic macrophage accumulation is characteristic of the pathogenesis of abdominal aortic aneurysm (AAA) but the mechanisms of macrophage accumulation and their phenotype are poorly understood. Lyve-1+ resident aortic macrophages independently self-renew and are functionally distinct from monocyte-derived macrophages recruited during inflammation. We hypothesized that Lyve-1+ and Lyve-1- macrophages differentially contribute to aortic aneurysm. Approach and Results: Angiotensin-2 and beta-aminopropionitrile (AT2/BAPN) were administered to induce AAA in C57BL/6J mice. Using immunohistochemistry, we demonstrated primarily adventitial accumulation of aortic macrophages, and in association with areas of elastin fragmentation and aortic dissection. Compared to controls, AAA was associated with a relative percent depletion of Lyve-1+ resident aortic macrophages and accumulation of Lyve-1- macrophages. Using CD45.1/CD45.2 parabiosis, we demonstrated aortic macrophage recruitment in AAA. Depletion of aortic macrophages in CCR2-/- mice was associated with reduced aortic dilatation indicating the functional role of recruitment from the bone marrow. Depletion of aortic macrophages using anti- Macrophage Colony Stimulating Factor 1 Receptor (MCSF1R)-neutralizing antibody reduced the incidence of AAA. Conditional depletion of Lyve-1+ aortic macrophages was achieved by generating Lyve-1 wt/cre Csf1rfl/fl mice. Selective depletion of Lyve-1+ aortic macrophages had no protective effects following AT2/BAPN administration and resulted in increased aortic dilatation in the suprarenal aorta. Conclusions: Aortic macrophage accumulation in AAA derives from adventitial recruitment of Lyve-1- macrophages, with relative percent depletion of Lyve-1+ macrophages. Selective targeting of macrophage subtypes represents a potential novel therapeutic avenue for the medical treatment of AAA.

Localized Administration of Doxycycline Suppresses Aortic Dilatation in an Experimental Mouse Model of Abdominal Aortic Aneurysm

2006 ◽  
Vol 20 (2) ◽  
pp. 228-236 ◽  
Author(s):  
Michel A. Bartoli ◽  
Federico E. Parodi ◽  
Jack Chu ◽  
Monica B. Pagano ◽  
Dongli Mao ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Mouse Model ◽  
Aortic Dilatation ◽  
Abdominal Aortic ◽  
Experimental Mouse Model ◽  
Experimental Mouse

Lipid Levels In Patients With Abdominal Aortic Dilatation And Abdominal Aortic Aneurysm (Aaa)

2019 ◽  
Vol 287 ◽  
pp. e160-e161
Author(s):  
M. Kabardieva ◽  
A. Komlev ◽  
I. Kuchin ◽  
A. Kolegaev ◽  
P. Lepilin ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Aortic Dilatation ◽  
Lipid Levels ◽  
Abdominal Aortic

scholarly journals Deficiency of peroxiredoxin 2 exacerbates angiotensin II-induced abdominal aortic aneurysm

2020 ◽  
Vol 52 (9) ◽  
pp. 1587-1601
Author(s):  
Se-Jin Jeong ◽  
Min Ji Cho ◽  
Na Young Ko ◽  
Sinai Kim ◽  
In-Hyuk Jung ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Negative Regulator ◽  
Aortic Dilatation ◽  
Ang Ii ◽  
Peroxiredoxin 2 ◽  
Structural Deterioration ◽  
Abdominal Aortic

Abstract Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease characterized by structural deterioration of the aorta caused by inflammation and oxidative stress, leading to aortic dilatation and rupture. Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, has been reported as a potential negative regulator of inflammatory vascular diseases, and it has been identified as a protein that is increased in patients with ruptured AAA compared to patients with nonruptured AAA. In this study, we demonstrated that PRDX2 was a pivotal factor involved in the inhibition of AAA progression. PRDX2 levels were increased in AAA compared with those in normal aortas in both humans and mice. Ultrasound imaging revealed that the loss of PRDX2 accelerated the development of AAA in the early stages and increased AAA incidence in mice infused with angiotensin II (Ang II). Prdx2−/− mice infused with Ang II exhibited increased aortic dilatation and maximal aortic diameter without a change in blood pressure. Structural deterioration of the aortas from Prdx2−/− mice infused with Ang II was associated with increases in the degradation of elastin, oxidative stress, and intramural thrombi caused by microhemorrhages, immature neovessels, and the activation of matrix metalloproteinases compared to that observed in controls. Moreover, an increase in inflammatory responses, including the production of cell adhesion molecules and the accumulation of inflammatory cells and proinflammatory cytokines due to PRDX2 deficiency, accelerated Ang II-induced AAA progression. Our data confirm that PRDX2 plays a role as a negative regulator of the pathological process of AAA and suggest that increasing PRDX2 activity may be a novel strategy for the prevention and treatment of AAA.

scholarly journals Transcriptional profiling and network analysis of the murine angiotensin II-induced abdominal aortic aneurysm

2011 ◽  
Vol 43 (17) ◽  
pp. 993-1003 ◽  
Author(s):  
Joshua M. Spin ◽  
Mark Hsu ◽  
Junya Azuma ◽  
Maureen M. Tedesco ◽  
Alicia Deng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Network Analysis ◽  
Aortic Aneurysm ◽  
Mapk Signaling ◽  
Aortic Dilatation ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
Aneurysm Development

We sought to characterize temporal gene expression changes in the murine angiotensin II (ANG II)-ApoE−/− model of abdominal aortic aneurysm (AAA). Aortic ultrasound measurements were obtained over the 28-day time-course. Harvested suprarenal aortic segments were evaluated with whole genome expression profiling at 7, 14, and 28 days using the Agilent Whole Mouse Genome microarray platform and Statistical Analysis of Microarrays at a false discovery rate of <1%. A group of angiotensin-treated mice experienced contained rupture (CR) within 7 days and were analyzed separately. Progressive aortic dilatation occurred throughout the treatment period. However, the numerous early expression differences between ANG II-treated and control were not sustained over time. Ontologic analysis revealed widespread upregulation of inflammatory, immune, and matrix remodeling genes with ANG II treatment, among other pathways such as apoptosis, cell cycling, angiogenesis, and p53 signaling. CR aneurysms displayed significant decreases in TGF-β/BMP-pathway signaling, MAPK signaling, and ErbB signaling genes vs. non-CR/ANG II-treated samples. We also performed literature-based network analysis, extracting numerous highly interconnected genes associated with aneurysm development such as Spp1, Myd88, Adam17 and Lox. 1) ANG II treatment induces extensive early differential expression changes involving abundant signaling pathways in the suprarenal abdominal aorta, particularly wide-ranging increases in inflammatory genes with aneurysm development. 2) These gene expression changes appear to dissipate with time despite continued growth, suggesting that early changes in gene expression influence disease progression in this AAA model, and that the aortic tissue adapts to prolonged ANG II infusion. 3) Network analysis identified nexus genes that may constitute aneurysm biomarkers or therapeutic targets.

scholarly journals Induction of Heme Oxygenase‐1 Is Linked to the Severity of Disease in Human Abdominal Aortic Aneurysm

2021 ◽  
Author(s):  
Anja Hofmann ◽  
Margarete Müglich ◽  
Steffen Wolk ◽  
Yazan Khorzom ◽  
Pamela Sabarstinski ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Heme Oxygenase ◽  
Case Fatality ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Severity Of Disease ◽  
Abdominal Aortic ◽  
Risk Of Rupture

Background Rupture of abdominal aortic aneurysm (rAAA) is associated with high case fatality rates, and risk of rupture increases with the AAA diameter. Heme oxygenase‐1 (gene HMOX1 , protein HO‐1) is a stress‐induced protein and induction has protective effects in the vessel wall. HMOX1 −/− mice are more susceptible to angiotensin II‐induced AAA formation, but the regulation in human nonruptured and ruptured AAA is only poorly understood. Our hypothesis proposed that HO‐1 is reduced in AAA and lowering is inversely associated with the AAA diameter. Methods and Results AAA walls from patients undergoing elective open repair (eAAA) or surgery because of rupture (rAAA) were analyzed for aortic HMOX1 /HO‐1 expression by quantitative real‐time polymerase chain reaction and Western blot. Aortas from patients with aortic occlusive disease served as controls. HMOX1 /HO‐1 expression was 1.1‐ to 7.6‐fold upregulated in eAAA and rAAA. HO‐1 expression was 3‐fold higher in eAAA specimen with a diameter >84.4 mm, whereas HO‐1 was not different in rAAA. Other variables that are known for associations with AAA and HO‐1 induction were tested. In eAAA, HO‐1 expression was negatively correlated with aortic collagen content and oxidative stress parameters H 2 O 2 release, oxidized proteins, and thiobarbituric acid reactive substances. Serum HO‐1 concentrations were analyzed in patients with eAAA, and maximum values were found in an aortic diameter of 55 to 70 mm with no further increase >70 mm, compared with <55 mm. Conclusions Aortic HO‐1 expression was increased in eAAA and rAAA. HO‐1 increased with the severity of disease but was additionally connected to less oxidative stress and vasoprotective mechanisms.

scholarly journals Granulocyte-Macrophage Colony-Stimulating Factor inStaphylococcus aureus-Induced Arthritis

1998 ◽  
Vol 66 (2) ◽  
pp. 853-855 ◽  
Author(s):  
Margareta Verdrengh ◽  
Andrej Tarkowski
Keyword(s):  
Tissue Injury ◽  
Favorable Effect ◽  
Protective Effects ◽  
Colony Stimulating Factor ◽  
Bacterial Inoculation ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
The Impact ◽  
Stimulating Factor

ABSTRACT Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that is able to increase not only the production of phagocytic cells but also their efficacy with respect to, e.g., bactericidal properties. In this study, we wanted to analyze the impact of GM-CSF on experimental Staphylococcus aureus-induced arthritis. For that purpose, mice were administered GM-CSF before and after bacterial inoculation. Although there was an increase in the total number of leukocytes as well as in the granulocyte fraction, there was no favorable effect on the severity of arthritis or on survival rates. There were no obvious differences between the GM-CSF-pretreated animals and controls with regard to growth of staphylococci in joints and kidneys 4 days after the bacterial inoculation. In contrast, mice that had been pretreated with GM-CSF prior to bacterial inoculation showed approximately four times lower numbers of bacteria in their blood 24 h later. These results, along with those of our previous studies, suggest that on the one hand the granulocyte is the main protective cell during the course of S. aureus infection but that on the other hand, upregulation of granulocyte-macrophage production will not exert any additional protective effects with respect to tissue injury.

scholarly journals Granulocyte-macrophage colony-stimulating factor (GM-CSF) in human long- term bone marrow cultures: endogenous production in the adherent layer and effect of exogenous GM-CSF on granulomonopoiesis

Blood ◽  
1991 ◽  
Vol 78 (5) ◽  
pp. 1230-1236 ◽  
Author(s):  
P Charbord ◽  
E Tamayo ◽  
S Saeland ◽  
V Duvert ◽  
J Poulet ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Culture Medium ◽  
Neutralizing Antibody ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Bone Marrow Cultures ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract This study was designed to assess the presence of endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF) within adherent layers of human Dexter-type cultures and to investigate the effect on granulomonopoiesis of adding exogenous GM-CSF to the culture medium. The presence of GM-CSF was demonstrated using a bioassay, in which adherent layers from normal bone marrows gave rise to endogenous granulocyte-macrophage colony-forming units (CFU-GM) that were specifically inhibited by increasing amounts of an anti-GM-CSF neutralizing antibody. Using an immunoassay, the estimated amounts of GM-CSF were less than or equal to 40 pg per flask in adherent layers, while remaining undetectable in supernatants. The addition of 10 ng or purified recombinant GM-CSF per milliliter of culture medium increased slightly the CFU-GM output over a 5-week culture period. The addition of 50 ng/mL decreased significantly the CFU-GM output after 5 weeks of culture. This decrease was associated with major modifications of the adherent layer cell composition. Large round or ovoid macrophages were generated at the expense of the interdigitated and elongated stromal cells and the extracellular fibronectin network was no longer observed. These studies suggest that GM-CSF production by accessory cells (stromal cells and/or monocytes) is almost equal to its consumption by hematopoietic cells, a situation similar to that found in long-term cultures of murine marrows. They also show that the maintenance of granulomonopoiesis is decreased by adding more than 10 ng/mL of exogenous GM-CSF to the culture medium, which is related to the induction of adherent macrophages, the disappearance of the major smooth-muscle-like stromal cell component of the adherent layer, and that of the fibronectin extracellular matrix.

scholarly journals TGFβ (Transforming Growth Factor-β) Blockade Induces a Human-Like Disease in a Nondissecting Mouse Model of Abdominal Aortic Aneurysm

2017 ◽  
Vol 37 (11) ◽  
pp. 2171-2181 ◽  
Author(s):  
Fabien Lareyre ◽  
Marc Clément ◽  
Juliette Raffort ◽  
Stefanie Pohlod ◽  
Meghana Patel ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Growth Factor ◽  
Aortic Aneurysm ◽  
Aortic Wall ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Aortic Dilatation ◽  
Intraluminal Thrombus ◽  
Abdominal Aortic ◽  
New Models

Objective— Current experimental models of abdominal aortic aneurysm (AAA) do not accurately reproduce the major features of human AAA. We hypothesized that blockade of TGFβ (transforming growth factor-β) activity—a guardian of vascular integrity and immune homeostasis—would impair vascular healing in models of nondissecting AAA and would lead to sustained aneurysmal growth until rupture. Approach and Results— Here, we test this hypothesis in the elastase-induced AAA model in mice. We analyze AAA development and progression using ultrasound in vivo, synchrotron-based ultrahigh resolution imaging ex vivo, and a combination of biological, histological, and flow cytometry-based cellular and molecular approaches in vitro. Systemic blockade of TGFβ using a monoclonal antibody induces a transition from a self-contained aortic dilatation to a model of sustained aneurysmal growth, associated with the formation of an intraluminal thrombus. AAA growth is associated with wall disruption but no medial dissection and culminates in fatal transmural aortic wall rupture. TGFβ blockade enhances leukocyte infiltration both in the aortic wall and the intraluminal thrombus and aggravates extracellular matrix degradation. Early blockade of IL-1β or monocyte-dependent responses substantially limits AAA severity. However, blockade of IL-1β after disease initiation has no effect on AAA progression to rupture. Conclusions— Endogenous TGFβ activity is required for the healing of AAA. TGFβ blockade may be harnessed to generate new models of AAA with better relevance to the human disease. We expect that the new models will improve our understanding of the pathophysiology of AAA and will be useful in the identification of new therapeutic targets.

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