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

Yasir Al Siraj, Sean E. Thatcher, Eric Blalock, Wesley N. Saintilnord, Alan Daugherty, Hong S. Lu, Wei Luo, Ying H. Shen, Scott A. Lemaire, Arthur P. Arnold, Lisa A. Cassis

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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).

Original languageEnglish
Pages (from-to)269-283
Number of pages15
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume41
Issue number1
DOIs
StatePublished - Jan 2021

Bibliographical note

Publisher Copyright:
© 2020 American Heart Association, Inc.

Keywords

  • Aneurysm
  • Angiotensin
  • Human
  • Sex chromosome
  • Turner syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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