Differential Regulation of Aortic Growth in Male and Female Rodents Is Associated With AAA Development

Abstract

Background The objective was to examine effects of gonadal hormone manipulation on aortic diameter and macrophage infiltration in rodents during abdominal aortic aneurysm (AAA) formation. Methods Experiment 1: 17-β estradiol and testosterone pellets were implanted in male (ME) and female (FT) rats. No pellet was implanted in shams (MES, FTS). Experiment 2: Testes and ovaries were removed from males (MO) and females (FO), respectively. No organs were removed from shams (MOS, FOS). Experiment 3: Male and female rats were orchiectomized and oophorectomized, respectively. Four weeks post-castration, testosterone (MOT) and 17-β estradiol (FOE) pellets were implanted. Shams underwent castration, but no pellet was implanted (MOTS, FOES). All rats underwent infrarenal aortic infusion with elastase postimplantation/postcastration. Diameters were measured on postoperative d 14. Tissue was stained for macrophages by immunohistochemistry. Results Diameter (P = 0.046) and macrophage counts (P = 0.014) decreased in ME compared with shams, but not in females treated with testosterone (FT). Diameter (P = 0.019) and macrophage infiltration (P = 0.024) decreased in MO compared with shams, but not in FO. Diameter increased in MOT compared with MOTS (P = 0.033), but decreased in FOE compared with FOES (P = 0.002). Macrophages decreased in FOE compared with FOES (P = 0.002). Conclusion This study documents a decrease in AAA diameter in males treated with estrogen or undergoing orchiectomy, but no changes in females treated with testosterone or undergoing oophorectomy; and an increase in diameter in MOT and a decrease in FOE. These data suggest that gonadal hormones differentially regulate AAA growth in association with changes in macrophages.

Sex Differences in Abdominal Aortic Aneurysm: The Role of Sex Hormones

“…In addition, they demonstrated that exogenous estrogens have prominent protective effects, as castrated females treated with 17b-estradiol presented smaller AAAs and lower macrophage counts compared to only castrated females. 69 Wu et al 70 found SMCs disorganization, inflammatory cell infiltration, partial elastic fiber degradation, larger aneurysm size, and increased MMP2 and MMP9 mRNA levels in ovariectomized female rats, illustrating also the anti-inflammatory/antiproteolytic effects of estrogen in the elastase-induced AAA model. On the other hand, Henriques et al 75 showed that murine ovariectomy failed to significantly modify neither the incidence nor the severity of the AngII-induced AAAs, indicating that the endogenous ovarian hormones are not the primary mediators of sex differences in AngII-induced AAA.…”

“…64 The protective effects of estrogens were confirmed by other studies. 69,70 Additionally, Martin-McNultry et al 71 demonstrated that infusion of AngII induced AAA in 90% of Apoe À/À mice, whereas with 17b-estradiol treatment, only 42% of mice developed AAAs. In another AAA study, tamoxifen, a selective estrogen receptor modulator, decreased neutrophil infiltration and increased catalase expression.…”

“…69 Zhang et al 74 found that the mRNA levels of angiotensin II receptor subtype 1a (Agtr1a) were increased in abdominal but not in thoracic aortas, and as a consequence, the incidence of AngII-induced AAAs was increased in adult female mice but not in adult male mice administered testosterone as neonates. In SMCs cultured from abdominal aortas of female mice, but not from male mice, testosterone promotion of Agtr1a was heritable, and the authors proposed that epigenetic mechanisms contribute to sexual dimorphism seen in the effects of testosterone.…”

“…75 Castrated male mice and rats treated with dihydrotestosterone and testosterone, respectively, showed a significant increase in the incidence of AAA compared with only castrated males. 69,76 Recently, a study by the same group showed that castration reduced the progressive lumen dilatation of established AAAs, suggesting that androgens also play a role in the progression of AAAs in male mice and that TGFb and Serpine1 may be targets of testosterone action in the progression of AAA. 77 In Vitro Studies Using Cultured SMCs Woodrum et al 78 examined sex differences of MMP2 in rat aortic SMCs (RASMCs).…”

Differential Gender And Species Specific Formation of Aneurysms Using A Novel Method Of Inducing Abdominal Aortic Aneurysms

“…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.…”