Female Mice Exhibit Abdominal Aortic Aneurysm Protection in an Established Rupture Model

• Published in: The Journal of surgical research 2020-03, Vol.247, p.387-396
• Main Authors: Fashandi, Anna Z., Spinosa, Michael, Salmon, Morgan, Su, Gang, Montgomery, William, Mast, Alexis, Lu, Guanyi, Hawkins, Robert B., Cullen, J. Michael, Sharma, Ashish K., Ailawadi, Gorav, Upchurch, Gilbert R.
• Format: Article
• Language: English
• Subjects: AAA; Administration, Oral; Aminopropionitrile - administration & dosage; Aminopropionitrile - toxicity; Angiotensin II; Angiotensin II - administration & dosage; Angiotensin II - toxicity; Animals; Aorta, Abdominal - pathology; Aortic Aneurysm, Abdominal - chemically induced; Aortic Aneurysm, Abdominal - complications; Aortic Rupture - epidemiology; Aortic Rupture - etiology; B-aminopropionitrile; Disease Models, Animal; Female; Gender; Humans; Male; Mice; Mice, Knockout, ApoE; Protective Factors; Rupture model; Sex Factors
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2019.10.004

Male gender is a well-established risk factor for abdominal aortic aneurysm (AAA), whereas estrogen is hypothesized to play a protective role. Although rupture rates are higher in women, these reasons remain unknown. In the present study, we sought to determine if female mice are protected from AAA rupture. Apolipoprotein E–deficient male and female mice (aged 7 wk; n = 25 per group) were infused with angiotensin II (AngII; 2000 ng/kg/min) plus β-aminopropionitrile (BAPN) in the drinking water for 28 d to test the effects of gender on AAA rupture. Separately, a second group of male apolipoprotein E–deficient mice underwent AngII infusion + BAPN while being fed high-fat phytoestrogen free or a high-fat phytoestrogen diet to assess effects of phytoestrogens on rupture. In a third group, female mice either underwent oophorectomy or sham operation 4 wk before infusion of AngII and BAPN to further test the effects of female hormones on AA rupture. Surviving mice abdominal aorta were collected for histology, cytokine array, and gelatin zymography on postoperative day 28. Female mice had decreased AAA rupture rates (16% versus 46%; P = 0.029). Female mice expressed fewer elastin breaks (P = 0.0079) and decreased smooth muscle cell degradation (P = 0.0057). Multiple cytokines were also decreased in the female group. Gelatin zymography demonstrated significantly decreased pro-matrix metalloproteinase 2 in female mice (P = 0.001). Male mice fed a high dose phytoestrogen diet failed to decrease AAA rupture. Female mice undergoing oophorectomy did not have accelerated aortic rupture. These data are the first to attempt to tease out hormonal effects on AAA rupture and the possible role of gender in rupture.