Castration of male mice prevents the progression of established angiotensin II-induced abdominal aortic aneurysms.
OBJECTIVE
Male sex is a nonmodifiable risk factor for abdominal aortic aneurysm (AAA) development. Similar to humans, male mice are more susceptible to angiotensin II (AngII)-induced AAAs than female mice. Previous studies demonstrated that castration of males markedly reduced the formation of AngII-induced AAAs. Progression of AAA size is associated with increased risk of aneurysm rupture. In this study, we hypothesized that castration of male mice would reduce the progression of established AngII-induced AAAs.


METHODS
Male apolipoprotein E-deficient mice were infused with AngII for 1 month to induce AAA formation. Aortic diameters were measured by ultrasound imaging, and mice were stratified into two groups that underwent a sham operation or castration. AngII infusions were continued for a further 2 months. Ultrasound imaging was used to quantify lumen diameters, and excised aortas were processed for quantification of AAA size, volume, and tissue characteristics.


RESULTS
Sham-operated mice exhibited progressive dilation of suprarenal aortic lumen diameters during the continued AngII infusion. Aortic lumen diameters were significantly decreased in castrated mice (n = 17) compared with sham-operated mice (n = 15) at study end point (1.63 ± 0.04 vs 1.88 ± 0.05 mm; P < .05). However, maximal external AAA diameters were not significantly different between sham-operated and castrated mice. The vascular volume/lumen volume ratio of excised AAAs imaged by ultrasound was significantly increased by castration (9.5% ± 2.0%) vs sham operation (4.8% ± 0.9%; n = 11 per group; P < .05). Moreover, compared with the thin-walled AAAs of sham-operated mice, aneurysm sections from castrated mice exhibited increased smooth muscle α-actin and collagen.


CONCLUSIONS
Removal of endogenous male hormones by castration selectively reduces aortic lumen expansion while not altering the external AAA dimensions.


CONCLUSIONS
There are no therapeutics that slow the progression of abdominal aortic aneurysms (AAAs), and as the size of an AAA increases, so does the risk of rupture and death. Male sex is a nonmodifiable risk factor for AAA development, but whether male sex hormones have a similar effect on AAA progression is unclear. Removal of male sex hormones in an established mouse model of angiotensin II-induced AAAs resulted in reduced progressive lumen dilation while not altering external AAA dimensions. Therapies that limit androgen action may provide benefit against AAA progression. Alternatively, supplemental testosterone may be contraindicated in men diagnosed with an AAA.
Graduate Center for Toxicology, University of Kentucky, Lexington, Ky.
Xuan
X
Zhang
Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Ky.
Sean
S
Thatcher
Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Ky.
Congqing
C
Wu
Saha Cardiovascular Research Center, University of Kentucky, Lexington, Ky.
Alan
A
Daugherty
Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Ky. Electronic address: lcassis@uky.edu.
Lisa A
LA
Cassis
D000199:Actins / Q000378:metabolism; D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000000981:diagnostic imaging / Q000473:pathology*; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D018450:Disease Progression; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009919:Orchiectomy; D012307:Risk Factors; D012737:Sex Factors; D013739:Testosterone / Q000378:metabolism; D013997:Time Factors; D014463:Ultrasonography; D066253:Vascular Remodeling
C558396:Acta2 protein, mouse; D000199:Actins; D001057:Apolipoproteins E; D015415:Biomarkers; D000804:Angiotensin II; D013739:Testosterone; D003094:Collagen