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 angiotensin II (AngII)-induced aortopathies in mice. In this study, we determined if the number of X chromosomes regulates regional development of AngII-induced aortopathies. Approach and Results: We used females with varying numbers of X chromosomes (XXF or XOF) on an C57BL/6J (ascending aortopathies) or Ldlr-/- background (descending and abdominal aortopathies) compared to XY males (XYM). To induce aortopathies, mice were infused with AngII. XOF (C57BL/6J) exhibited larger percent increases in ascending aortic lumen diameters than AngII-infused XXF or XYM. AngII-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 AngII 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 AngII-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). Conclusion: The absence of a second X chromosome promotes diffuse AngII-induced aortopathies in females.

ORGANISM(S): Mus musculus

PROVIDER: GSE154036 | GEO | 2021/06/27

REPOSITORIES: GEO