Hypertensive female BPH/2J mice have increased renal Xist expression and vascular dysfunction

Women experience a later onset of cardiovascular disease (CVD) risk factors, including hypertension and arterial stiffening. The kidney plays a crucial role in maintaining blood pressure homeostasis. The underlying mechanisms behind hypertension and arterial stiffening are complex and not well understood in women. Women have XX chromosomes, whereas men have XY chromosomes. The Xist gene is essential for inactivating one of the female X chromosomes to achieve gene dosage balance. The role of Xist beyond X chromosome inactivation is not well understood in relation to CVD. We hypothesize that elevated Xist levels in the kidney promote neurogenic hypertension in female mice. In this study, we utilized the 12- to 13-week-old (N=5-10/group) BPH/2J model of neurogenic hypertension and compared it with female BPN/3J mice. Blood pressure was measured by tail-cuff plethysmography, and arterial stiffening by Pulse Wave Doppler. Body composition was assessed by nuclear magnetic resonance, and an advanced metabolic cage system was used to measure oxygen, carbon dioxide, and heat production. Aortic vasoreactivity was assessed by wire myography, and arterial structural changes were analyzed using a pressure myograph. Gene expression was analyzed via RT-PCR. GraphPad Prism was used for data analysis, which included multiple t-tests; P-values < 0.05 between standard error means were considered significant. Mean arterial pressure was notably higher in BPH mice compared to BPN mice (130 mmHg vs. 143 mmHg). No significant differences were observed in aortic stiffness measured by PWV (2.5 m/s vs. 2.4 m/s) or Phenylephrine (PE)-induced aortic constriction (PE 10^-6 M: 84% vs. 91%; P=0.3) between BPN and BPH mice. However, in PE-preconstricted aorta, BPH mice showed a significant reduction in Acetylcholine (Ach)-induced relaxation (Ach 10^-6 M: 88% vs. 43%; P< 0.01) and sodium nitroprusside (SNP)-mediated relaxation (SNP 10^-6 M: 105% vs. 66%; P< 0.01). Carotid arteries from BPN mice had increased cross-sectional area (P< 0.05) and wall thickness (P< 0.05) compared to BPH mice. When compared to BPH, BPN mice had decreased oxygen consumption (1711 ml/Kg/hr vs. 4775 ml/Kg/hr; P< 0.001), carbon dioxide production (1471 ml/Kg/hr vs. 4366 ml/Kg/hr; P< 0.001), respiratory exchange ratio (0.8 vs. 0.9; P< 0.01), and heat generation (8 kcal/hr/Kg vs. 22 kcal/hr/Kg; P< 0.001). BPH mice, relative to BPN, exhibited lower body weight (20 g vs. 17 g; P< 0.05) and a higher fat-to-lean mass ratio (34% vs. 22%). Conversely, BPH mice showed a higher heart-to-body weight ratio (7 mg/g vs. 5 mg/g; P< 0.05). Gene expression analysis revealed increased Xist expression in the kidney (P< 0.01), aortic fat (P< 0.05), and abdominal fat (P< 0.01). Our findings suggest that, compared with BPN, BPH mice exhibit vascular dysfunction, consistent with impaired endothelium- and smooth muscle-mediated vasodilatation via the nitric oxide pathway. Because BPH mice have lower fat mass than BPN mice, they exhibit increased heat production, consistent with lean thermogenesis and hypertension, which are linked to cardiac hypertrophy. We propose that increased Xist expression worsens neurogenic hypertension by downregulating renal sympathetic nerve activity and impairs nitric oxide signaling in the aorta. Our findings could inform new strategies for addressing the genetic underpinnings of hypertension, especially in females. This study was supported by the American Physiological Society’s Summer Undergraduate Research Fellowship, KUH PRIME, HL155841, and HL169191. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.