VascularDifferential gender- and species-specific formation of aneurysms using a novel method of inducing abdominal aortic aneurysms
Introduction
Several experimental methods have been used to induce experimental abdominal aortic aneurysms (AAAs) in animal models. While there is no perfect model for murine development of AAAs that has universal applicability, we developed a model of topical elastase application to produce aneurysms in the infrarenal aorta that is reproducible and easy to perform. To date, the external elastase model has not been tested in mice.
Various experimental AAA models have had varying incidences of AAA development among different murine strains. For example, Thompson et al. showed AAA resistance in wild-type B6129/SvEv, SvJ, and CBA mice using the elastase perfusion model. Intermediate susceptibility to AAAs was found in Balb/c mice, among others, while C57BL/6 was highly susceptible to AAA formation [1]. Also, as many knockout strains are on different genetic backgrounds, it must be known if the control animals of the same background develop AAAs for comparisons and conclusions to be valid. Therefore, models should be tested on more than one strain of mouse.
In addition, confirmation that the female resistance to AAA formation is maintained with external elastase application is necessary for utilization of this model in further studies of gender differences. There have been several studies from our lab, utilizing the elastase perfusion model, demonstrating that females are protected from AAA formation [2], [3], [4], [5]. The mechanisms underlying this gender difference are not completely clear. Some evidence exists that macrophage infiltration is inhibited, thus decreasing the inflammatory reaction in females as compared with males. Matrix metalloproteinase 9 (MMP9), a crucial proteinase in AAA development released by macrophages, is decreased in females [3]. Cho et al. [4] and Sinha et al. [5] have demonstrated that neutrophils and certain proinflammatory mediators, such as chemokines and cytokines, are decreased in females compared with males during AAA formation. Thus, both direct and indirect mechanisms have been documented showing that estradiol exerts protection from AAA formation females.
The objective of this study was to test this novel model of AAA formation in different murine strains, in both male and female mice.
Section snippets
Animal surgery
After induction of general anesthesia with isoflurane, male and female mice, both C57BL/6 and B6129 strains, obtained from Jackson Laboratories (Bar Harbor, ME) (8 wk, 20–30 g) (n = 5 for each of eight groups) had their abdominal aorta exposed via midline laparotomy. Aortic diameter was measured using a video micrometer (Nikon Elements software; Nikon, Melville, NY) in three locations: just below the renal arteries, mid–abdominal aorta, and at the iliac bifurcation. The infrarenal aorta was
AAA phenotype is confirmed in males and females in C57BL/6 and B6129 strains
AAA phenotype, as defined by a 50% increase in aortic diameter at harvest compared to baseline, occurred in 100% of males (5 of 5 for both strains) treated with external elastase (Fig. 1). In addition, 90% of female mice (4 of 5 of the C57BL/6 and 5 of 5 of the B6129) also formed AAAs. Visually at harvest, treated animals had thin-walled, fusiform AAAs, similar to those seen in humans. None of the control animals in any group (male and female, both strains) developed AAAs (0 of 20). The aortic
Discussion
In the present study, we have documented that external elastase application to the infrarenal aorta results in the ability to generate AAAs in two strains of mice, and equally in male and female mice. As opposed to previous work, the ME B6129 mice formed larger aneurysms than their C57BL/6 counterparts. In this model the AAA phenotype (as determined by aortic diameter and disrupted elastic laminae by van Gieson stain) occurs in association with an increase in Mac-2-stained cells in both the
Conclusions
In contrast to previous studies, which have documented vast variability in AAA formation between mouse strains and genders, the external elastase model of AAA formation produced significant aortic dilatation in males and females of two strains of mice despite differences in inflammatory cells. This study further serves to highlight the variability in rodent AAA models and substantiates the external elastase model for studying AAAs in future, as it can be easily duplicated in both genders and in
Acknowledgment
This work was supported by NIH R01 HL081629-01, NIH R01 supplemental HL081629-03S1, and the University of Michigan Cardiovascular Center Aortic Program Research Fellowship 2009–2010.
References (9)
- et al.
Decreased collagen and increased matrix metalloproteinase-13 in experimental abdominal aortic aneurysms in males compared with females
Surgery
(2010) - et al.
Differential regulation of aortic growth in male and female rodents is associated with AAA development
J Surg Res
(2009) - et al.
The role of adenosine A2A receptor signaling in bronchiolitis obliterans
Ann Thorac Surg
(2009) - et al.
Adenosine signaling via the adenosine 2B receptor is involved in bronchiolitis obliterans development
J Heart Lung Transplant
(2010)
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