Study Of Pathological Morphology Comparison In Different Rodent Models And The Therapeutic Effect Of Anti-angiotension In The Development Of AAAs

Chapter1. The establishment and comparative study of three types of rodent abdominal aortic aneurysms modelsObjective:To investigate the feasibility of the animal research application by establishment and comparison of three different types of models.Method:C57BL/6(20) and ApoE-/-(10) mice were used to eastablish three different abdominal aortic aneurysm (AAA) models by PPE intraluminal infusion for about5min, CaC12solution gauze adventitial infusion for15min and Ang Ⅱ minipump continuous subcutaneous infusion for28days. PBS infusion was accordingly applied for the control groups. Doppler ultrasound was applied to detect the diameter of the abdominal aortic and the location of the aneurysm. The time of operaion and aneurysm formation was recorded; the percentage of the aneurysm formation and mortality of animal models were also calculated.Result:Three types of AAA models were successfully established. The process of PPE model establishment was more challenged, consequently the operation time was longer (52.6±5.1min), compared to40.7±4.3min in CaC12model and7.8±3.6min in Ang Ⅱ model, but the percentage of the aneurysm formation of PPE model was100%and the survival time of PPE and CaCl2model are longer than Ang Ⅱ model, almost all alive in4weeks follow-up compared to60%alive in Ang Ⅱ model. The process of CaCl2and Ang Ⅱ model establishment was relatively easy, however, the mortality of Ang Ⅱ model was much higher than PPE and CaCl2model.Conclusion:PPE, CaCl2and Ang Ⅱ AAA models are stable models for further animal research. Moreover, the findings of our study support that the three types of animal models of AAAs may provide intriguing mechanistic insights into the human disease and are suitable for evaluation of medicine therapy in AAA. Chapter2. The comparison study of morphology and pathogenesis in three different types of abdominal aortic aneurysm modelsObjective:To observe the pathomorphological characteristics of three different models of abdominal aortic aneurysm (AAA) and investigate the common pathogenesis in the three different models of AAA.Methods:As compared to the aortae of normal mice, HE, EVG, Immunohistochemistry staining technique were applied to detect the Morphological and phathological changes in the tissue specimens, such as the pattern of elastin degeneration was recorded, the quantity of different inflammatory cells infiltration, angiogenesis and lymphangiogenesis were counted.Results:In PPE model, there was extensive destruction of the elastic lamellae and the adventitial region was occupied by a pronounced inflammatory infiltrate, predominantly containing macrophages. Neutrophils were present on the peripheral aspects of the adventitia surrounding the aorta; One fascinating aspect of angiotensin Ⅱ model is the aneurysm localization to the suprarenal segment of the aorta. The precipitating event that occurs within days of AngⅡ infusion appears to be medial macrophage accumulation in the region that is prone to AAA formation, associated with elastin degradation. Subsequently there were gross dissections of the aortas leading to prominent vascular hematomas and enhanced extracellular matrix deposition and infiltration of other leukocyte populations, primarily macrophages. The dilated region of the aorta gradually regained circumferential elastin fibers and completely re-endothelialized. Prominent neovascularization was present throughout the lumen of the remodeled tissue; In CaC12models, the abluminal incubation of calcium chloride also led to structural disruption of the medial layer and inflammatory responses. This inflammation occurred on the luminal and medial aspect of the artery. But, there is no obvious angiogenesis and lymphangiogenesis in this model.Conclusion:Although there were different pathomorphological changes in the three types of AAA models, the common pathological charateristics were still existed, such as transmural inflammatory cells infiltration, adventitial angiogenesis and lymphangiogenesis and so on. Since the similar pathogenesis as human, PPE and Ang Ⅱ model were considered to be kind of ideal models for animal research. Chapter3. The application of anti-angiotension in the development of abdominal aortic aneurysmObject:To elucidate the effect of angiotension on the progression of AAA and validate the therapeutic effect of anti-angiotension based treatment on AAAMethod:The C57BL/6(15) and ApoE-/-male mice were devided into two groups:treated group and control. AAA was induced either in male ApoE-/-mice by subcutaneous infusion of1OOOng/kg/min Ang Ⅱ for28days or in mail C57BL/6mice by transient intra-aortic infusion of PPE. In the treated group, all the mice were daily treated with10mg/kg telmisartan7days before aneurym establishment; Doppler ultrasound was applied to detect the diameter of the abdominal aortic and the location of the aneurysm. The percentage of the aneurysm formation and mortality of animal models were also calculated. Morover, histopathology and gene profiling were used to evaluate therapeutic efficacy.Results:The telmisartan almost completely prevented PPE-induced AAA formation in C57BL/6mice and suppressed Ang Ⅱ-induced increase in systolic blood pressure, preserved medial elastin and smooth musclesm and attenuated macrophage infiltration and angiogenesis within aortic adventitia. Moreover, ARB therapy dramatically downregulated the gene expression levels of certain proteinases, chemokines and their receptors, Cytokines, and adhesion molecules at the aneurismal lesions. There was no obvious side effect in the dose of1Omg/kg.Conclusion:The application of telmisartan can play a significant anti-angiotension effect, which can successfully prevent the progression and formation of AAA; and the anti-angiotension therapy is highly efficacious and safe in suppressing experimental AAA.