Using this study, we showed that the combination of hypertension and degeneration of elastic lamina by lysyl oxidase inhibition in mice resulted in formation of aortic aneurysms that recapitulate key features of human aortic aneurysms with site-specific phenotypes. In addition, we showed critical roles of high blood pressure in the formation of aortic aneurysms, establishing a causal link between hemodynamic conditions and aortic aneurysm formation in animals.

Daugherty et al. developed an abdominal aortic aneurysm model in genetically atherosclerosis-prone mice by continuously infusing angiotensin-II [20, 21]. In their angiotensin-II-induced aortic aneurysm model, apolipoprotein E (ApoE)-knockout mice or fat-fed low-density lipoprotein (LDL) receptor knockout mice was used [20, 21]. Morphological and histological characteristics of angiotensin-II-induced abdominal aortic aneurysms in these knockout mice were similar to the abdominal aortic aneurysms in our model, indicating that common molecular mechanisms potentially exist between these two models in respect to abdominal aortic aneurysms. Interestingly, angiotensin-II infusion in ApoE-knockout or LDL receptor knockout mice did not cause thoracic aortic aneurysm [20, 21]. In contrast, aneurysm formation in our model occurred not only in the abdominal aorta but also in the thoracic aorta involving the ascending aorta.

Direct application of calcium chloride to the descending thoracic aorta through thoracotomy can cause aneurysmal formation in the aortic segment that was exposed to calcium chloride [22]. The advantage of the calcium application model is that aneurysmal dilatation occurred in almost all animals [22]. However, the aneurysmal dilatation in their model was mild, i.e., 25 % dilatation comparing to 50 % in our model. More importantly, in our model, both abdominal and thoracic aneurysms were induced by the same pharmacological treatments. Our model may be more suitable for studying differential underlying mechanisms and treatment strategies between thoracic and abdominal aortic aneurysms.

In our model, the aneurysms at the two aneurysm-prone regions were induced by the same systemic pharmacological treatment. However, they exhibited different morphological and histological features that closely resembled human aortic aneurysms at the respective locations. Morphological and histological differences observed between thoracic and abdominal aortic aneurysms in this model may suggest that differential responses to the combination of hypertension and lysyl oxidase inhibition at these two regions of the aorta lead to different phenotypes of aneurysms.

Morphological and histological differences between thoracic and abdominal aortas in this model and in humans may be due to the differences in developmental origins of smooth muscle cells [23, 24]. Embryologically programmed differences of vascular smooth muscle cells may determine the site-specific phenotypes of aneurysms at the two regions [23–25]. More importantly, different pharmacological strategies may be needed to prevent growth and rupture of aneurysms at these two different locations.

Interestingly, normalization of blood pressure by an antihypertensive agent dramatically reduced the incidence of aneurysms and almost completely abolished histological changes associated with angiotensin-II and BAPN treatment in this model. We were able to reproduce thoracic and abdominal aortic aneurysms when DOCA-salt hypertension was used. Captopril did not reduce the incidence of aortic aneurysm in DOCA-salt-hypertensive mice, further suggesting critical roles of hypertension in this model.

It should be noted that although our mouse model replicated key features of thoracic and abdominal aortic aneurysms in humans, aneurysms in this model did not form spontaneously but were induced by two pharmacological interventions, which potentially bypassed some of the early critical events that lead to aortic aneurysm in humans.