Cell proliferation detected using [18F]FLT PET/CT as an early marker of abdominal aortic aneurysm

Abstract Background Abdominal aortic aneurysm (AAA) is a focal aortic dilatation progressing towards rupture. Non-invasive AAA-associated cell proliferation biomarkers are not yet established. We investigated the feasibility of the cell proliferation radiotracer, fluorine-18-fluorothymidine ([18F]FLT) with positron emission tomography/computed tomography (PET/CT) in a progressive pre-clinical AAA model (angiotensin II, AngII infusion). Methods and Results Fourteen-week-old apolipoprotein E-knockout (ApoE−/−) mice received saline or AngII via osmotic mini-pumps for 14 (n = 7 and 5, respectively) or 28 (n = 3 and 4, respectively) days and underwent 90-minute dynamic [18F]FLT PET/CT. Organs were harvested from independent cohorts for gamma counting, ultrasound scanning, and western blotting. [18F]FLT uptake was significantly greater in 14- (n = 5) and 28-day (n = 3) AAA than in saline control aortae (n = 5) (P < 0.001), which reduced between days 14 and 28. Whole-organ gamma counting confirmed greater [18F]FLT uptake in 14-day AAA (n = 9) compared to saline-infused aortae (n = 4) (P < 0.05), correlating positively with aortic volume (r = 0.71, P < 0.01). Fourteen-day AAA tissue showed increased expression of thymidine kinase-1, equilibrative nucleoside transporter (ENT)-1, ENT-2, concentrative nucleoside transporter (CNT)-1, and CNT-3 than 28-day AAA and saline control tissues (n = 3 each) (all P < 0.001). Conclusions [18F]FLT uptake is increased during the active growth phase of the AAA model compared to saline control mice and late-stage AAA.

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

Annals of Vascular Surgery ◽

10.1007/s10016-006-9017-z ◽

2006 ◽

Vol 20 (2) ◽

pp. 228-236 ◽

Cited By ~ 45

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

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Relationship between inflammation and progression of an abdominal aortic aneurysm in a rabbit model based on 18F-FDG PET/CT imaging

Vascular ◽

10.1177/1708538118768126 ◽

2018 ◽

Vol 26 (6) ◽

pp. 571-580 ◽

Cited By ~ 1

Author(s):

Mao-Xiao Nie ◽

Xue-Hui Zhang ◽

Yun-Feng Yan ◽

Quan-Ming Zhao

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Fdg Pet ◽

Blood Collection ◽

Abdominal Aortic ◽

Pet Ct ◽

Aneurysm Development ◽

18F Fdg ◽

Fdg Pet Ct ◽

Aneurysm Diameter

Objective To explore the relationship between abdominal aortic aneurysm development and inflammation in the rabbit through the establishment of a rabbit infrarenal abdominal aortic aneurysm model and the use of 18F-FDG PET/CT imaging. Methods Twenty male New Zealand rabbits were administered an elastase intracavity perfusion to induce an infrarenal abdominal aortic aneurysm model. Prior to surgery, the rabbits underwent abdominal aorta ultrasonic testing and blood collection from the ear veins. Of the original 20 rabbits, 10 rabbits were euthanized two weeks after the operation following ultrasonic testing, PET/CT scanning and blood collection, and their arterial tissue samples were prepared for pathological and immunohistochemical staining. The remaining 10 rabbits were euthanized four weeks after the operation following ultrasonic testing, PET/CT scanning and blood collection, and the arterial tissue samples were prepared for pathological and immunohistochemical staining. Results Compared with the preoperative measurement, the maximum growth rate of the aneurysm diameter is 89.21 ± 0.02% (the absolute increase in diameter is 2.040 ± 0.376 mm) two weeks after the operation. Compared with the two-week postoperative value, the maximum growth rate of the aneurysm diameter is 15.8 ± 0.01% (the absolute increase in diameter is 0.684 ± 0.115 mm) four weeks after the operation. Compared with the preoperative values, the blood MMP-2 and MMP-9 levels significantly increase two weeks after surgery, P < 0.05. Compared with the two-week postoperative values, the blood MMP-2 and MMP-9 levels significantly decrease after four weeks post-surgery, P < 0.05. At two weeks after the operation, the SUVmax and the TBR of the 18F-FDG PET/CT of the AAA wall are 0.90 ± 0.03 and 1.19 ± 0.09, respectively. At four weeks after the operation, the SUVmax and the TBR of the 18F-FDG PET/CT of the AAA wall are 0.35 ± 0.05 and 1.15 ± 0.12, respectively. Compared with two weeks after the operation, the SUVmax significantly decreases at four weeks after the operation, P < 0.05. Compared with two weeks after the operation, there is no significant difference in the TBR at four weeks after the operation, P > 0.05. Immunohistochemical staining shows that the CD68-positive cell rate at four weeks after the operation significantly decreases ( P < 0.05) compared with the CD68-positive cell rate at two weeks after the operation. Conclusion In the early stages of abdominal aortic aneurysm development, the inflammatory response of the arterial wall is significant, the local metabolic activity is strengthened, the SUVmax value of 18F-FDG is high, and the abdominal aortic aneurysm diameter experiences rapid growth. In the later stages of abdominal aortic aneurysm development, the diameter continues to increase; however, there are decreases in the wall inflammatory response, the local metabolic activity, and the SUVmax value of 18F-FDG. Thus, inflammation plays an important role in the early development of abdominal aortic aneurysm.

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

Atherosclerosis ◽

10.1016/j.atherosclerosis.2019.06.483 ◽

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

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

Experimental & Molecular Medicine ◽

10.1038/s12276-020-00498-3 ◽

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.

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Assessment of different quantification metrics of [18F]-NaF PET/CT images of patients with abdominal aortic aneurysm

Journal of Nuclear Cardiology ◽

10.1007/s12350-020-02220-2 ◽

2020 ◽

Author(s):

Mercy I. Akerele ◽

Nouf A. Mushari ◽

Rachael O. Forsythe ◽

Maaz Syed ◽

Nicolas A. Karakatsanis ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Ct Images ◽

Abdominal Aortic ◽

Pet Ct

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

Physiological Genomics ◽

10.1152/physiolgenomics.00044.2011 ◽

2011 ◽

Vol 43 (17) ◽

pp. 993-1003 ◽

Cited By ~ 42

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.

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Aortic wall cell proliferation via basic fibroblast growth factor gene transfer limits progression of experimental abdominal aortic aneurysm

Journal of Vascular Surgery ◽

10.1016/j.jvs.2004.06.018 ◽

2004 ◽

Vol 40 (3) ◽

pp. 512-518 ◽

Cited By ~ 19

Author(s):

Katsuyuki Hoshina ◽

Hiroyuki Koyama ◽

Tetsuro Miyata ◽

Hiroshi Shigematsu ◽

Tsuyoshi Takato ◽

...

Keyword(s):

Cell Proliferation ◽

Abdominal Aortic Aneurysm ◽

Growth Factor ◽

Aortic Aneurysm ◽

Aortic Wall ◽

Fibroblast Growth ◽

Factor Gene ◽

Wall Cell ◽

Abdominal Aortic ◽

Growth Factor Gene

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Abdominal Aortic Aneurysm With Bony Erosion Mimicking Recurrent Non–Hodgkin Lymphoma on FDG PET/CT

Clinical Nuclear Medicine ◽

10.1097/rlu.0b013e3182638301 ◽

2013 ◽

Vol 38 (5) ◽

pp. e233-e235

Author(s):

Dae-Weung Kim ◽

Woo Hyoung Kim ◽

Chang Guhn Kim

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Hodgkin Lymphoma ◽

Fdg Pet ◽

Non Hodgkin Lymphoma ◽

Abdominal Aortic ◽

Pet Ct ◽

Fdg Pet Ct ◽

Bony Erosion

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.117.309999 ◽

2017 ◽

Vol 37 (11) ◽

pp. 2171-2181 ◽

Cited By ~ 27

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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