Vascular Smooth Muscle Specific Deletion of Xist Regulates Blood Pressure and Arterial Stiffening in Female Mice

Compared to men, women are disproportionately affected by hypertension with a significant rise in blood pressure after middle age. Xist is a female-specific gene that plays an essential role in X chromosome inactivation during embryonic development. Beyond embryonic development, the role of Xist remains poorly understood. Xist plays a vital role in autoimmune disease, including lupus, which is usually confounded by hypertension. However, the functional role of Xist in vascular cells during hypertension remains unknown. We hypothesize that vascular smooth muscle-specific deletion of Xist promotes Angiotensin II (Ang II)-induced hypertension and arterial stiffening. We used Sm22-Cre mice to delete Xist (KO) in vascular smooth muscle cells (VSMC). Age-matched female mice (N=8-10/group) were ovariectomized to remove confounding endogenous sex steroid effects. Ang II (490 ng/kg/min) was infused for two weeks to induce hypertension. Day- and night time blood pressure (BP) was measured by radiotelemetry, and arterial stiffness by pulse wave velocity (PWV). Vascular reactivity was assessed by wire myography, while arterial structural remodeling was assessed using pressure myography. Echocardiography was performed to evaluate cardiac function. RT-PCR and immunoblots were used to assess gene expression. GraphPad Prism was used for Multiple t-tests, and P< 0.05 was considered significant. At baseline, systolic BP was higher in floxed mice than in Xist KO mice (120 mmHg vs. 113 mmHg; P< 0.05). We also observed significant decreases in PWV (3.6 m/s vs. 1.8 m/s) and pulse pressure (31 mmHg vs. 22 mmHg) in Xist KO mice compared with floxed mice. Cardiac function indicated decreased ejection fraction in Xist KO mice compared with floxed mice (80% vs 66%). Phenylephrine (PE)-mediated constriction was reduced in Xist KO mice relative to floxed mice (PE 10^-5: 203% vs. 148%; P< 0.01). Aortic stress-strain curves shifted to the right in Xist KO mice compared with floxed mice. Aortic gene expression showed significant downregulation of Xist in both the aorta and the heart. Aortic VSMC contractile genes, including Cnn1, Myh11, and Acta2, were also significantly decreased in Xist KO mice compared with floxed mice. Ren1 mRNA and immunohistology were reduced in the kidney sections of Xist KO mice compared with floxed mice. To determine the impact of Xist deletion on hypertension, we used Ang II infusion. We observed that Ang II hypertension increased systolic BP in Xist KO mice compared to floxed mice (145 mmHg vs. 136 mmHg) and eliminated the differences in PWV, pulse pressure, and PE-mediated vasoconstriction. Ang II hypertension increased fibrosis in the heart and kidney cross-sections in Xist KO mice compared with floxed mice. Our data suggest that VSMC-specific Xist KO is vasoprotective in the absence of hypertension. However, Xist KO and Ang II-induced hypertension promote detrimental effects in cardiac and renal fibrosis compared to floxed mice. 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.