Abstract Body: Introduction: Xist is a long noncoding RNA that recruits polycomb repressive complexes and forms a heterochromatin structure on the inactive X chromosome in female cells during embryogenesis. However, the post-developmental role of Xist and X-linked genes in arterial stiffening, endothelial dysfunction, and cardiometabolic disease remains to be established.
Hypothesis: We hypothesize that an increase in visceral adiposity promotes downregulation of Xist in the aorta and adipose tissue, leading to arterial stiffness and endothelial dysfunction.
Methods: Women between 23 and 56 years old were recruited and divided into two groups: premenopausal (N=41) and postmenopausal (N=21). We measured arterial stiffening by pulse wave velocity (PWV), blood pressure (BP), brachial artery flow-mediated (FMD) endothelial function by ultrasound, body mass index (BMI), and % fat by dual energy X-ray absorptiometry.
Results: Postmenopausal compared to premenopausal women had increased BP (112 vs. 124 mmHg; P<0.05), PWV (5.6 vs. 8.9 m/s; P<0.01), BMI (25 vs. 29 kg/m; P<0.001), and trunk fat (34% vs. 43%; P<0.01). Additionally, postmenopausal women had impaired FMD (9.6% vs. 5.6%; P<0.01). To mimic obesogenic conditions, we assessed vascular and cardiometabolic parameters in leptin-deficient (N=7) versus wild-type lean (N=5) female mice. Obese mice had increased PWV (2.6 vs. 4.8 m/s; P<0.01) but no significant differences in BP. Body (21 vs. 48 g; P<0.01) and fat (2 vs. 27 g; P<0.001) mass were significantly increased in obese versus lean mice. Mesenteric artery vasoreactivity indicated increased phenylephrine-mediated constriction and impaired acetylcholine-mediated endothelial relaxation in obese compared to lean mice. Arterial wall parameters assessed by pressure myography indicated decreased outer diameter, wall thickness, and cross-sectional area in obese compared to lean mice. The stress-strain curve was reduced in obese compared to lean mice. Oxygen consumption, carbon dioxide released, heat production, and wheel activity were significantly decreased in obese compared to lean mice. RT-qPCR indicated a significant reduction in Xist expression in the aorta, peri-aortic, and visceral fat in obese compared to lean mice.
Conclusion: Our data suggest that increased fat deposition promotes vascular dysfunction in postmenopausal women. In obese mice, leptin deficiency and Xist downregulation promote vascular dysfunction, arterial remodeling, and impaired metabolic activity.