**1. Introduction**

An aortic aneurysm is defined as a permanent localized dilation of the aorta with at least a 50% increase in diameter compared with a normal aortic diameter [1]. Aortic aneurysms can be classified according to location as thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA). TAA occurs in all-age people without sexual dimorphism and is highly associated with hereditary conditions [2]. By contrast, AAA is typically associated with aging, male sex, smoking, atherosclerosis, and hypertension [3–5]. AAA is the most common form of aortic aneurysm [6], affecting 4–8% of men and 0.5–1.5% of women over the age of 60 and currently accounting for nearly 2% of all deaths in Western countries [2, 3, 7]. Aortic aneurysm is an asymptomatic condition that tends to progress over time with a high mortality rate (65–85%) if rupture occurs [8]. Unfortunately, repair through open or endovascular surgery is currently the only therapeutic option for aortic aneurysm; no drug has been approved for treatment of this devastating disease [3, 5]. One of the major barriers in the field is a lack of an animal model that fully resembles human aortic aneurysm.

Over the last few decades, a number of rodent models of AAA and TAA have been developed and have been increasingly utilized to be used in understanding the etiology of human AAA and TAA [2, 9–11]. Aortic aneurysm animal models can be classified into three groups [2, 9–11]: (1) genetically predisposed animal models (i.e., fibrillin-1 (FBN1) mutation (Marfan syndrome) mouse model [2, 12]), (2) chemical-induced animal models (i.e., Ang II infusion hyperlipidemia mouse model [9, 13]), and (3) physical or surgical animal models (i.e., decellularized aortic xenograft rat model [10, 14]). Among them, calcium chloride adventitial application model [15, 16], porcine pancreatic elastase (PPE) model [17, 18], and Ang II infusion hyperlipidemia mouse model [13, 19–23] are the commonest animal models currently studied in the world.

One of the fundamental pathological characteristics in human TAA and AAA is thoracic aortic dissection (TAD) and abdominal aortic dissection (AAD), both of which can lead to aneurysmal rupture with high mortality [1–7]. Many genetically predisposed animal models have TAD and AAD (i.e., fibrillin-1 mutation mouse model [2, 12]). Some of the chemical-induced animal models also have TAD and AAD (i.e., fibrillin-1 mutation and Ang II infusion hyperlipidemia mouse models [13, 19–23]). Recently, a new chemical-induced mouse model for more potently induction of TAD and AAD was developed by administration of β-aminopropionitrile monofumarate (BAPN) to mice to inhibit lysyl oxidase (LOX) and/or Ang II infusion [24, 25]. Kurihara et al. demonstrated that BAPN/Ang II induced TAD in 100% of FVB mice [24]. Ren et al. confirmed this finding and further demonstrated that BAPN/Ang II induced TAD and AAD in 75% of C57BL/6J mice, whereas BAPN alone induced TAD in 87% of C57BL/6J [25].

Although no single animal model fully reproduces the histological characteristics and natural history of the human aortic aneurysm, each of these animal models more or less recapitulate human aortic aneurysm and have significantly contributed to the current understanding of clinical management and treatment of patients with AAA and TAA [2, 9–11]. Several clinical trials have begun enrollment to examine whether angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) are effective in the treatment of human aortic aneurysm. However, the results from these clinical trials are inconsistent and disappointing: either effective [26], no effect [27], or, even worse [28], indicating that the current understanding about the etiologies of aortic aneurysm is limited and additional unknown signaling and mechanism may underlie aortic aneurysm and account for the failure of these clinical trials.

In sharp contrast to the well-established role of Ang II in aortic aneurysm [13, 19–23], little is known about the role of aldosterone (Aldo) in aortic aneurysm. Aldo is a steroid hormone primarily synthesized and released by the adrenal glands. Aldo is a downstream effect of Ang II and is well recognized for its critical role in renal sodium reabsorption and water retention and consequently extracellular volume and blood pressure [29, 30]. Accumulated data over the last decade, however, demonstrate that Aldo not only acts on the kidney but also targets many other organelles, including those in the cardiovascular system, where it is critically involved in diverse pathophysiological processes [31–33].

Several lines of clinical study implicate Aldo signaling in aortic aneurysm. First, individual case reports demonstrated that primary hyperaldosteronism is associated with aortic dissection [34–36]. Second, a retrospective study demonstrated that

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*A New Mouse Model of Aortic Aneurysm Induced by Deoxycorticosterone Acetate or Aldosterone…*

aldosteronism is associated with high morbidity and mortality from the early onset of hemorrhagic stroke and ruptured intracranial aneurysms [37]. Third, a few small studies have shown an association between obesity and increased levels of Aldo [38] and increased AAA [39]. Finally, perhaps also the most compellingly, an analysis of drug modulation of AAA development through 25 years of surveillance in 1269 patients demonstrated a strong association between mineralocorticoid receptor (MR; also known as Aldo receptor) blockers and slowed AAA progression [40].

By incidence, we discovered that administration of deoxycorticosterone acetate (DOCA) to 10-month-old C57BL/6 male mice caused substantial animal death in the presence of high salt due to aortic aneurysmal rupture. A subsequent serial of substantial studies demonstrated that activation of MR by either implantation of DOCA pellet or infusion of Aldo in 10-month-old C57BL/6 male mice was sufficient to induce AAA and TAA formation and aneurysmal rupture in the presence of high salt [41–43]. Recently, we published the detailed methodology on how to implant DOCA pellet or Aldo pumps to induce aortic aneurysm [44]. Here, we will focus on the significant novel finding of this new AAA mouse model, highlight its unique features that mimic human aortic aneurysm, and discuss its significance and potential impact on the current understanding, diagnosis, and treatment of human aortic aneurysm.

**2. Development of a new mouse model of aortic aneurysm induced by** 

**2.1 Discovery of DOCA-salt mouse model of aortic aneurysm by accidence**

**2.2 Both DOCA and high salt are required to induce aortic aneurysm**

In an independent pilot study using 10- to 12-month-old C57BL/6 male mice to investigate DOCA-salt-induced hypertension, we unexpectedly observed that many mice died from AAA rupture. We were intrigued by this observation since it raised the possibility that activation of the MR by DOCA can cause AAA in the presence of high salt. Given that administration of DOCA and salt to mice or rats have been used extensively as an experimental model of low-renin hypertension [45], it was surprising that DOCA-salt-induced AAA has not been reported in previous studies. While the exact reasons for this discrepancy are unclear, our results suggest that the age of mice (i.e., 10-month old *vs.* 10-week old) may be critical for DOCA and salt

To verify our pilot studies and define whether DOCA, salt, or both is critical for DOCA-salt-induced aortic aneurysm, 10-month-old C57BL/6 male mice received DOCA alone (subcutaneous implantation of DOCA pellets; 50 mg, 21-day release; Innovative Research of America, USA), salt alone (drinking water containing 0.9% NaCl plus 0.2% KCl), DOCA and salt, or no treatment (controls). We used C57BL/6 mice because C57BL/6 mice are more susceptible to chemical (i.e., BAPN/ Ang II)-induced TAD, AAD, and aneurysmal rupture than other strains of mice (i.e., FVB mice) [24, 25]. We used 10-month-old rather than 10-week-old mice because we found that DOCA- or Aldo-salt-induced aortic aneurysm were aging dependent [41, 43]. We used male mice rather than female mice because DOCA- or Aldo-salt-induced aortic aneurysm has sex difference (unpublished data). All mice

We used three different approaches to quantify DOCA-salt-induced aortic aneurysm. First, the maximal intraluminal diameters of abdominal aortas were

*DOI: http://dx.doi.org/10.5772/intechopen.86477*

**DOCA- or Aldo-salt**

to induce AAA (see below).

were euthanized 3 weeks after treatment.

However, whether Aldo causes aortic aneurysm is unknown.

*A New Mouse Model of Aortic Aneurysm Induced by Deoxycorticosterone Acetate or Aldosterone… DOI: http://dx.doi.org/10.5772/intechopen.86477*

aldosteronism is associated with high morbidity and mortality from the early onset of hemorrhagic stroke and ruptured intracranial aneurysms [37]. Third, a few small studies have shown an association between obesity and increased levels of Aldo [38] and increased AAA [39]. Finally, perhaps also the most compellingly, an analysis of drug modulation of AAA development through 25 years of surveillance in 1269 patients demonstrated a strong association between mineralocorticoid receptor (MR; also known as Aldo receptor) blockers and slowed AAA progression [40]. However, whether Aldo causes aortic aneurysm is unknown.

By incidence, we discovered that administration of deoxycorticosterone acetate (DOCA) to 10-month-old C57BL/6 male mice caused substantial animal death in the presence of high salt due to aortic aneurysmal rupture. A subsequent serial of substantial studies demonstrated that activation of MR by either implantation of DOCA pellet or infusion of Aldo in 10-month-old C57BL/6 male mice was sufficient to induce AAA and TAA formation and aneurysmal rupture in the presence of high salt [41–43]. Recently, we published the detailed methodology on how to implant DOCA pellet or Aldo pumps to induce aortic aneurysm [44]. Here, we will focus on the significant novel finding of this new AAA mouse model, highlight its unique features that mimic human aortic aneurysm, and discuss its significance and potential impact on the current understanding, diagnosis, and treatment of human aortic aneurysm.
