Presence of XX Sex Chromosome Complement Increases Aortic Circumferential Stiffness in Female Mice

Abstract

Elastin and collagen uniquely adapt to the mechanical demands of high pulsatile pressure in the vascular system in conjunction with the extracellular matrix (ECM). Elastic fiber networks and collagen are affected by component disorganization, leading to an array of vascular diseases and compromised mechanical behavior. It is shown that women than men have accelerated arterial stiffening. Previously, we have shown increased axial and circumferential linearized material stiffness in the carotid arteries of female than male wildtype mice. Whether sex hormones interact with sex chromosomes is unknown. Therefore, we hypothesize that sex hormones interact with sex chromosomes to increase aortic circumferential stiffening in female than male mice. In this study, we used gonadal intact 15-week-old four core genotype mice (n=4-6/group) comprising female (F) and male (M) mice with either XX or XY sex chromosome complement (SCC). Using a tissue puller, we assessed the stress-strain and displacement-force relationship of the abdominal aorta. Briefly, the aorta was cut into 3mm rings and pulled apart to a range of 1300 μm with a velocity of 35 μm/sec. To determine the load-bearing effect of collagen and elastin, collagenase type II (16 units) and elastase (5 units) were used to digest the aortic ring before pulling. Part of the aortic ring was digested for a PCR array of extracellular matrix and adhesion molecules. We observed a leftward shift of stress-strain in XXF than in XXM (P=0.03). A leftward shift of stress-strain was also indicated in XXF than in XYM mice (P=0.004). Displacement-force tests showed a similar effect with a leftward shift in XXF than XXM (P=0.01). A leftward shift of displacement force was also indicated in XXF than in XYM (P=0.004). Aorta digestion with elastase reversed the phenotype, showing a leftward shift of displacement force in XXM than in XXF (P=0.02). Collagenase digestion removed the observed sex differences in stress-strain and displacement force tests. The PCR array comparing XXF and XXM showed increased fold change in Adamts5 (4.2), Emilin (2.2), Icam1 (2.4), and Thbs2 (3). We also observed the downregulation of Cntn1 (0.4), Cntnna1 (0.5), Ecm1 (0.3), and Fbln1 (4). Our data suggested that XX sex chromosome complement, and ECM genes contribute to the structural stiffness of female mice aorta. Our study will contribute to understanding connective tissue diseases, including arterial stiffness, aortic aneurysms, Marfan and Danlos syndrome. HL105400 and HL155841. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.