scholarly journals Effect of Doxycycline on Survival in Abdominal Aortic Aneurysms in a Mouse Model

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Lisa C. Adams ◽  
Julia Brangsch ◽  
Jan O. Kaufmann ◽  
Dilyana B. Mangarova ◽  
Jana Moeckel ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Ex Vivo ◽  
Endothelial Damage ◽  
Aortic Aneurysms ◽  
Clinical Dose ◽  
Doxycycline Treatment ◽  
Abdominal Aortic ◽  
Significant Difference ◽  
Aneurysm Growth

Background. Currently, there is no reliable nonsurgical treatment for abdominal aortic aneurysm (AAA). This study, therefore, investigates if doxycycline reduces AAA growth and the number of rupture-related deaths in a murine ApoE−/− model of AAA and whether gadofosveset trisodium-based MRI differs between animals with and without doxycycline treatment. Methods. Nine ApoE−/− mice were implanted with osmotic minipumps continuously releasing angiotensin II and treated with doxycycline (30 mg/kg/d) in parallel. After four weeks, MRI was performed at 3T with a clinical dose of the albumin-binding probe gadofosveset (0.03 mmol/kg). Results were compared with previously published wild-type control animals and with previously studied ApoE−/− animals without doxycycline treatment. Differences in mortality were also investigated between these groups. Results. In a previous study, we found that approximately 25% of angiotensin II-infused ApoE−/− mice died, whereas in the present study, only one out of 9 angiotensin II-infused and doxycycline-treated ApoE−/− mice (11.1%) died within 4 weeks. Furthermore, doxycycline-treated ApoE−/− mice showed significantly lower contrast-to-noise (CNR) values ( p = 0.017 ) in MRI compared to ApoE−/− mice without doxycycline treatment. In vivo measurements of relative signal enhancement (CNR) correlated significantly with ex vivo measurements of albumin staining (R2 = 0.58). In addition, a strong visual colocalization of albumin-positive areas in the fluorescence albumin staining with gadolinium distribution in LA-ICP-MS was shown. However, no significant difference in aneurysm size was observed after doxycycline treatment. Conclusion. The present experimental in vivo study suggests that doxycycline treatment may reduce rupture-related deaths in AAA by slowing endothelial damage without reversing aneurysm growth.

Abstract 305: Exogenous Vasohibin-2 Exacerbates Angiotensin II-induced Ascending Aortic Aneurysms

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Michihiro Okuyama ◽  
Haruhito A Uchida ◽  
Ryoko Umebayashi ◽  
Yuki Kakio ◽  
Katsuyuki Tanabe ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Ex Vivo ◽  
Aortic Aneurysms ◽  
Vascular Endothelial ◽  
Abdominal Aortic ◽  
Significant Difference ◽  
Mortality Ratio ◽  
Endothelial Growth Factor ◽  
Lac Z ◽  
Normal Laboratory

Objective: Chronic angiotensin II (AngII) infusion promotes both ascending (TAAs) and abdominal aortic aneurysms (AAAs) in mice. Previous studies demonstrated that vascular endothelial growth factor (VEGF) enhanced AngII-induced AAA formation, and VEGF significantly increased AngII-induced AAA diameter in hypercholesterolemic mice. Vasohibin-1 (VASH-1) is induced by VEGF and inhibits angiogenesis at the termination zone under various pathologic conditions such as those of tumors, arterial intimal thickening and retinal neovasucularization. In contrast, a VASH-1 homolog, Vasohibin-2 (VASH-2), promotes angiogenesis at the sprouting front. Therefore, we hypothesized that exogenous VASH-2 influences AngII-induced TAAs in normocholesterolemic mice. The purpose of this study was to examine whether VASH-2 influenced AngII-induced TAAs. Methods and Results: Male C57BL/6J mice (10 weeks old) were fed a normal laboratory diet. Mice were injected 10^9 plaque-forming unit VASH-2 or Lac Z expressing adenovirus (Ad) via tail vein every other week. They were also infused subcutaneously with either AngII (1,000 ng/kg/min) or saline by osmotic mini-pumps for 3 weeks. The study mice had 4 groups: AngII + Ad VASH-2 (n=23), AngII + Ad Lac Z (n=23), Saline + Ad VASH-2 (n=13), Saline + Ad Lac Z (n=9). There were no significant differences between 4 groups in body weight. Plasma total cholesterol and VEGF concentrations were significantly increased in AngII infused groups (P < 0.05). Mortality ratio was 8.7% in AngII + Ad VASH-2 group and 4.3% in AngII + Ad Lac Z group. Intima area of aortic arch was significantly larger in AngII + Ad VASH-2 group than in AngII + Ad Lac Z group (19.78 ± 0.40 mm^3 vs 17.70 ± 0.41 mm^3, P < 0.01). AngII infusion significantly increased ex vivo maximal diameters of abdominal aorta, but there was no significant difference between VASH-2- and Lac Z-injected mice. Conclusion: Exogenous VASH-2 exacerbated AngII-induced ascending aortic aneurysms in male C57BL/6 mice.

Abstract 598: Deletion of Microsomal PGE Synthase-1 Decreases Oxidative Stress and Protects Against Abdominal Aortic Aneurysm Formation in Angiotensin II-Infused Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Miao Wang ◽  
Jane Stubbe ◽  
Eric Lee ◽  
Wenliang Song ◽  
Emanuela Ricciotti ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
Density Lipoprotein Receptor ◽  
The Impact

Microsomal (m) prostaglandin (PG) E 2 synthase(S)-1, an enzyme that catalyzes the isomerization of the cyclooxygenase (COX) product, PGH 2 , into PGE 2 , is a major source of PGE 2 in vivo . mPGES-1 deletion in mice was found to modulate experimentally evoked pain and inflammation and atherogenesis is retarded in mPGES-1 knockout (KO) mice. The impact of mPGES-1 deletion on formation of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) was studied in mice lacking the low density lipoprotein receptor (LDLR −/− ). AngII infusion increased aortic macrophage recruitment and nitrotyrosine staining while upregulating both mPGES-1 and COX-2 and urinary excretion of the major metabolite of PGE 2 (PGE-M). Deletion of mPGES-1 decreased both the incidence and severity of AAA and depressed excretion of both PGE-M and 8, 12-iso-iPF 2a -VI, which reflects lipid peroxidation in vivo . While Ang II infusion augmented prostaglandin biosynthesis, deletion of mPGES-1 resulted in rediversion to PGD 2 , reflected by its major urinary metabolite. However, deletion of the PGD 2 receptor, DP1, did not affect AAA in Ang II infused LDLR −/− mice. These observations indicate that deletion of mPGES-1 protects against AAA formation by AngII in hyperlipidemic mice, perhaps by decreasing oxidative stress. Inhibition of mPGES-1 may represent an effective treatment to limit aneurysm occurrence and expansion.

scholarly journals Morphological and Biomechanical Differences in the Elastase and AngIIapoE−/−Rodent Models of Abdominal Aortic Aneurysms

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Evan H. Phillips ◽  
Alexa A. Yrineo ◽  
Hilary D. Schroeder ◽  
Katherine E. Wilson ◽  
Ji-Xin Cheng ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Aortic Aneurysms ◽  
Circulating Biomarkers ◽  
Induction Method ◽  
Future Studies ◽  
Disease Characteristics ◽  
Abdominal Aortic ◽  
Extracellular Matrix Molecules ◽  
Biomechanical Parameters

An abdominal aortic aneurysm (AAA) is a potentially fatal cardiovascular disease with multifactorial development and progression. Two preclinical models of the disease (elastase perfusion and angiotensin II infusion in apolipoprotein-E-deficient animals) have been developed to study the disease during its initiation and progression. To date, most studies have usedex vivomethods to examine disease characteristics such as expanded aortic diameter or analytic methods to look at circulating biomarkers. Herein, we provide evidence fromin vivoultrasound studies of the temporal changes occurring in biomechanical parameters and macromolecules of the aortic wall in each model. We present findings from 28-day studies in elastase-perfused rats and AngIIapoE−/−mice. While each model develops AAAs specific to their induction method, they both share characteristics with human aneurysms, such as marked changes in vessel strain and blood flow velocity. Histology and nonlinear microscopy confirmed that both elastin and collagen, both important extracellular matrix molecules, are similarly affected in their levels and spatial distribution. Future studies could make use of the differences between these models in order to investigate mechanisms of disease progression or evaluate potential AAA treatments.

Abstract 461: Cilnidipine Attenuated Angiotensin II-induced Abdominal Aortic Aneurysms in Apolipoprotein E-deficient Mice

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Yuki Kakio ◽  
Haruhito A Uchida ◽  
Ryoko Umebayashi ◽  
Jun Wada
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Angiotensin Ii ◽  
Apolipoprotein E ◽  
Ex Vivo ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Osmotic Minipumps ◽  
Abdominal Aortic ◽  
Deficient Mice

Objective: Chronic infusion of angiotensin II (AngII) promotes development of abdominal aortic aneurysms (AAAs) in hypercholesterolemic mice. Previous studies have shown that local inflammation and increased oxidative stress plays an important role on formation of AAAs. In addition, it is reported that voltage-dependent N-type Ca2+ channels in endothelial cells contribute to oxidative stress-related endothelial dysfunction induced by AngII in mice. Therefore, we hypothesized that cilnidipine, an N/L-type calcium channel blocker, exerts vasoprotective effect by inhibiting inflammation and superoxide generation in mice. The purpose of this study was to evaluate whether cilnidipine influenced AngII-induced AAAs. Methods and Results: Male apolipoprotein E deficient mice (8-12 weeks old) were fed a normal laboratory diet. Mice were infused subcutaneously with either cilnidipine or vehicle by osmotic minipumps. Three days later, mice were also infused subcutaneously with either AngII (1,000 ng/kg/min, n = 14-16) or saline (n = 4) each by osmotic minipumps for 4 weeks. AngII increased systolic blood pressure. Cilnidipine decreased blood pressure in AngII-infused mice, but had not effect during saline infusion. AngII infusion did not alter serum cholesterol concentrations. However, cilnidipine slightly decreased serumcholesterol concentrations in AngII-infused mice. Cilnidipine had no effect on body weights, heart rates, and urine total protein, but mildly restored plasma renin activity that were suppressed by AngII infusion. Cilnidipine did not affect ex vivo measurement of maximal diameter of abdominal aorta (1.04 ± 0.09 mm vs 1.11 ± 0.06 mm, n.s.) in saline infused mice. AngII infusion significantly increased ex vivo maximal diameters of abdominal aortas, but was attenuated by cilnidipine (1.79 ± 0.59 mm vs 1.26 ± 0.38 mm, P < 0.05). In addition, cilnidipine significantly reduced the incidence of AngII-induced AAAs (Cilnidipine: 38 %, Vehicle: 88 %; P < 0.05). Furthermore, gelatin zymography demonstrated that cilnidipine diminished AngII-induced increase in aortic MMP-9 protein abundance. Conclusion: Cilnidipine attenuated AngII-induced AAAs in male apolipoprotein E deficient mice.

scholarly journals [18F]Fluorothymidine Uptake in the Porcine Pancreatic Elastase-Induced Model of Abdominal Aortic Aneurysm

2021 ◽  
Vol 7 (8) ◽  
pp. 130
Author(s):  
Richa Gandhi ◽  
Joanna Koch-Paszkowski ◽  
Charalampos Tsoumpas ◽  
Marc A. Bailey
Keyword(s):  
Murine Model ◽  
Ex Vivo ◽  
Aortic Rupture ◽  
Aortic Aneurysms ◽  
Preclinical Model ◽  
Pancreatic Elastase ◽  
Abdominal Aortic ◽  
Pet Ct ◽  
Porcine Pancreatic Elastase

The porcine pancreatic elastase (PPE) model is a common preclinical model of abdominal aortic aneurysms (AAA). Some notable characteristics of this model include the low aortic rupture rate, non-progressive disease course, and infra-renal AAA formation. Enhanced [18F]fluorothymidine ([18F]FLT) uptake on positron emission tomography/computed tomography (PET/CT) has previously been reported in the angiotensin II-induced murine model of AAA. Here, we report our preliminary findings of investigating [18F]FLT uptake in the PPE murine model of AAA. [18F]FLT uptake was found to be substantially increased in the abdominal areas recovering from the surgery, whilst it was not found to be significantly increased within the PPE-induced AAA, as confirmed using in vivo PET/CT and ex vivo whole-organ gamma counting (PPE, n = 7; controls, n = 3). This finding suggests that the [18F]FLT may not be an appropriate radiotracer for this specific AAA model, and further studies with larger sample sizes are warranted to elucidate the pathobiology contributing to the reduced uptake of [18F]FLT in this model.

scholarly journals Animal Model Dependent Response to Pentagalloyl Glucose in Murine Abdominal Aortic Injury

2021 ◽  
Vol 10 (2) ◽  
pp. 219
Author(s):  
Jennifer L. Anderson ◽  
Elizabeth E. Niedert ◽  
Sourav S. Patnaik ◽  
Renxiang Tang ◽  
Riley L. Holloway ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Aortic Injury ◽  
Aortic Aneurysms ◽  
Maximum Diameter ◽  
Ultrasound Images ◽  
Infrarenal Aorta ◽  
High Frequency Ultrasound ◽  
Abdominal Aortic ◽  
Pentagalloyl Glucose

Abdominal aortic aneurysms (AAAs) are a local dilation of the aorta and are associated with significant mortality due to rupture and treatment complications. There is a need for less invasive treatments to prevent aneurysm growth and rupture. In this study, we used two experimental murine models to evaluate the potential of pentagalloyl glucose (PGG), which is a polyphenolic tannin that binds to and crosslinks elastin and collagen, to preserve aortic compliance. Animals underwent surgical aortic injury and received 0.3% PGG or saline treatment on the adventitial surface of the infrarenal aorta. Seventeen mice underwent topical elastase injury, and 14 mice underwent topical calcium chloride injury. We collected high-frequency ultrasound images before surgery and at 3–4 timepoints after. There was no difference in the in vivo effective maximum diameter due to PGG treatment for either model. However, the CaCl2 model had significantly higher Green–Lagrange circumferential cyclic strain in PGG-treated animals (p < 0.05). While ex vivo pressure-inflation testing showed no difference between groups in either model, histology revealed reduced calcium deposits in the PGG treatment group with the CaCl2 model. These findings highlight the continued need for improved understanding of PGG’s effects on the extracellular matrix and suggest that PGG may reduce arterial calcium accumulation.

Abstract 404: Cilostazol Attenuated Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E--Deficient Mice

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Ryoko Umebayashi ◽  
Haruhito A Uchida ◽  
Hirofumi Makino
Keyword(s):  
Angiotensin Ii ◽  
Apolipoprotein E ◽  
Ex Vivo ◽  
Experimental Studies ◽  
Gelatin Zymography ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Maximal Diameter ◽  
Abdominal Aortic ◽  
Deficient Mice

Objective: Chronic infusion of angiotensin II (AngII) promotes development of abdominal aortic aneurysms (AAAs) in hypercholesterolemic mice. Previous studies have shown that local inflammation and increased oxidative stress plays an important role on formation of AAAs. Cilostazol, a phosphodiesterase-3 inhibitor with antiplatelet aggregation and vasodilatory effects, exerts vasoprotective effect by inhibiting inflammation and superoxide generation in several experimental studies. The purpose of this study was to evaluate whether cilostazol influenced AngII-induced AAAs. Methods and Results: Male apolipoprotein E deficient mice (8-12 weeks old) were fed with either normal diet or cilostazol-containing (0.1% wt/v) diet. After 1 week of cilostazol administration, mice were infused subcutaneously with either AngII (1,000 ng/kg/min, n = 16 -18) or saline (n = 5 - 6) by osmotic minipumps for 4 weeks. AngII equivalently increased systolic blood pressure, irrespective of cilostazol adminstration. Cilostazol had no effect on serum cholesterol concentrations, triglycerides, high-density lipoprotein-cholesterol, body weights, heart rates, and systolic blood pressures. Cilostazol did not affect ex vivo measurement of maximal diameter of abdominal aorta (0.88 ± 0.04 mm vs 0.88 ± 0.03 mm, n.s.) in saline infused-mice. AngII infusion significantly increased ex vivo maximal diameters of abdominal aortas but cilostazol administration attenuated (1.94 ± 0.16 mm vs 1.53 ± 0.17 mm, P < 0.05). In addition, gelatin zymography demonstrated that cilostazol diminished AngII-induced increase in aortic MMP-2 activity (P < 0.05). Conclusion: Cilostazol attenuated AngII-induced AAAs in male apolipoprotein E deficient mice.

Abstract 473: Dissecting Aortic Aneurym in Angiotensin II - Infused Mice: The Mechanisms Behind Lesion Variability

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Bram Trachet ◽  
Alessandra Piersigilli ◽  
Lydia Aslanidou ◽  
Rodrigo A Fraga-Silva ◽  
Jessica Sordet-Dessimoz ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Ex Vivo ◽  
Intramural Hematoma ◽  
Celiac Artery ◽  
Elastin Degradation ◽  
Abdominal Aortic ◽  
Thoracic And Abdominal ◽  
Aortic Dissections ◽  
Dissecting Aneurysms

Angiotensin II-infused mice develop dissecting aneurysms, characterized by intramural rather than intraluminal thrombus, suprarenal rather than infrarenal lesions, medial dissections rather than circumferential elastin degradation and a variability in lesion shape that remained as yet unexplained. In order to provide insight into these intriguing lesions we scanned murine aortas at baseline and after 10, 18 and 29 days of Angiotensin II infusion, both in vivo (ultrasound, micro-CT) and ex vivo (phase-contrast X-ray tomographic microscopy). Dissecting aneurysms of varying severity occurred in 31/34 mice. All of these were characterized by a medial tear near the ostium of thoracic and abdominal aortic side branches, with a predilection for the left and ventral aspects of the ostium of the celiac artery. In 25/31 animals an intramural hematoma was formed. Fully ruptured branch ostia occurred significantly more often in the supraceliac aorta, affecting in particular the left suprarenal artery (the first branch cranial to the celiac artery, 23/25). Animals with a thoracic tear (6/31) had significantly larger intramural hematoma than animals with an abdominal tear (p<0.05), and the length of the hematoma correlated to the number of ruptured side branches (r 2 =0.78). In 11 mice a parallel false channel was formed. The volume of free-flowing intramural blood in the false channel was significantly larger for left than for ventral tears, but was not related to the length of the tear. Our data suggest that (i) medial tears are the primary event in dissecting AAA formation, (ii) an intramural hematoma is formed if the adventitia covering the medial tear dissects and leads to the accumulation of intramural blood from ruptured side branches, (iii) adventitial dissection and hematoma formation progress in the direction of least resistance/smallest side branches (i.e. cranial of the celiac artery) and (iv) a false channel is formed if the radial expansion of the adventitia due to blood flowing out of the medial tear acts in the same (leftward) direction as the expansion due to a ruptured left suprarenal artery. We conclude that Ang II-infused mice can be a valuable model to study the under-researched role of side branches in the formation and progression of aortic dissections.

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