Monosomy X in Female Mice Influences the Regional Formation and Augments the Severity of Angiotensin II–Induced Aortopathies

Abstract

Objective: Turner syndrome women (monosomy X) have high risk of aortopathies consistent with a role for sex chromosomes in disease development. We demonstrated that sex chromosomes influence regional development of Ang II (angiotensin II)–induced aortopathies in mice. In this study, we determined if the number of X chromosomes regulates regional development of Ang II–induced aortopathies. Approach and Results: We used females with varying numbers of X chromosomes (XX female mice [XXF] or XO female mice [XOF]) on an C57BL/6J (ascending aortopathies) or low-density lipoprotein receptor deficient ( Ldlr −/− ) background (descending and abdominal aortopathies) compared with XY males (XYM). To induce aortopathies, mice were infused with Ang II. XOF (C57BL/6J) exhibited larger percent increases in ascending aortic lumen diameters than Ang II–infused XXF or XYM. Ang II–infused XOF ( Ldlr −/− ) exhibited similar incidences of thoracic (XOF, 50%; XYM, 71%) and abdominal aortopathies (XOF, 83%; XYM, 71%) as XYM, which were greater than XXF (XXF, 0%). Abdominal aortic lumen diameters and maximal external diameters were similar between XOF and XYM but greater than XXF, and these effects persisted with extended Ang II infusions. Larger aortic lumen diameters, abdominal aortopathy incidence (XXF, 20%; XOF, 75%), and maximal aneurysm diameters (XXF, 1.02±0.17; XOF, 1.96±0.32 mm; P =0.027) persisted in ovariectomized Ang II–infused XOF mice. Data from RNA-seq demonstrated that X chromosome genes that escape X-inactivation (histone lysine demethylases Kdm5c and Kdm6a ) exhibited lower mRNA abundance in aortas of XOF than XXF ( P =0.033 and 0.024, respectively). Conversely, DNA methylation was higher in aortas of XOF than XXF ( P =0.038). Conclusions: The absence of a second X chromosome promotes diffuse Ang II–induced aortopathies in females.

Illuminating the Mechanisms Underlying Sex Differences in Cardiovascular Disease

“…LDL receptor-deficient mice with one X chromosome (XO) had higher incidence of aneurysms than XX mice in both the descending and abdominal aorta. 75 The aneurysm incidence for XO mice was either similar to or higher than XY mice, and gonadectomy of XO mice had no impact on the incidence rate. This is consistent with the ≈6-fold higher rate of aortic dissections that occur in Turner syndrome women (XO) compared with XX women in the general population.…”

Imaging Techniques for Aortic Aneurysms and Dissections in Mice: Comparisons of Ex Vivo, In Situ, and Ultrasound Approaches

“…In 20 articles investigating TAAs, 13 studies (65%) performed ultrasonography as the primary approach for aortic measurements ( Figure 1 C) [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. Direct measurements using ex vivo or in situ images were performed in four studies (20%) [ 28 , 29 , 30 , 31 ].…”

“…Three studies (15%) evaluated aortic diameters histologically [ 32 , 33 , 34 ]. Conversely, direct imaging using ex vivo or in situ approach was the most common mode for AAA determination (38 articles, 68%) [ 28 , 29 , 30 , 31 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ], and ultrasonography was the second most common approach (16 articles, 28%, Figure 1 D) [ 25 , 26 , 27 , 69 , 70 , 71 , 72 …”

Gonadal Sex and Sex-Chromosome Complement Interact to Affect Ethanol Consumption in Adolescent Four Core Genotypes Mice

“…It escapes X-inactivation in mice and humans and thus is expressed at higher levels in XX relative to XY cells of many tissues, including brain [177][178][179][180]. Accordingly, it is a candidate gene for causing sex differences in disease phenotypes that are sensitive to the number of X chromosomes [181][182][183][184].…”