XX Sex Chromosome Complement Promotes Arterial Stiffening and High Blood Pressure in Female Mice

Arterial stiffness measured by pulse wave velocity (PWV) increases precipitously during menopausal transition due to estradiol decline. Longitudinal studies show a steep increase in PWV of postmenopausal women compared to age-matched men. Previously, we have demonstrated increased PWV in ovariectomized and middle-aged female mice. Additionally, we showed increased oxidative stress in female than male vascular cells treated with angiotensin II in hormone-free charcoal-stripped media. We hypothesize that a decline in estradiol unleashes the female sex chromosomes effect that promotes arterial stiffening. In this study, we used the four core genotype mice (n=6-10/group) comprising females with either XX or XY sex chromosome complement that were left intact or ovariectomized for 8 weeks. Arterial stiffening was assessed with pulse wave Doppler and 24-hour blood pressure by radiotelemetry. Carotid artery passive myography and vascular reactivity of 2 nd order mesenteric artery were assessed by pressure myography. To induce hypertension, ovariectomized XX and XY mice were treated with deoxycorticosterone acetate (DOCA; 50 mg/pellet) for 21 days and 1% saline as drinking water. PWV was significantly increased in ovariectomized than in gonadal intact XX and XY mice (main effect: p<0.001). However, an interaction effect was indicated with higher PWV in XX than XY ovariectomized mice (4.9±0.1 vs. 4.2±0.2 m/s; p<0.001), indicating a sex chromosome effect. Carotid artery stress-strain curves showed a leftward shift of XX than XY ovariectomized mice, suggesting increased structural stiffness. Masson’s trichrome staining of the aorta showed increased collagen in the adventitia of XX than XY ovariectomized mice (30±0.01 vs. 26±0.02 %; P=0.005). Higher systolic blood pressure (SBP) was indicated in ovariectomized XX than in XY mice (Baseline; 123±3 vs. 116±4 mmHg; P=0.02). DOCA-induced hypertension blunted the PWV difference between OVX XX and XY mice; however, SBP was higher in XX than in XY mice (Week 1: 135±13 vs.127±3 mmHg; P=0.3), (Week 2: 148±4 vs.140±1 mmHg; P=0.08), and (Week 3: 137±9 vs.127±4 mmHg; P=0.4). We observed impaired acetylcholine-mediated relaxation in mesenteric arteries of hypertensive ovariectomized XX than XY mice (47±6 % vs. 24±6 %; P=0.03). Our data suggested that ovariectomized female mice with XX sex chromosome complement promote arterial stiffening and blood pressure. However, DOCA-induced hypertension promotes endothelial dysfunction and blunts PWV in ovariectomized XX and XY mice. Future studies will identify elements in the XX sex chromosome complement contributing to arterial stiffening and high blood pressure. R00HL155841 and R25HL105400. 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.