Smooth muscle cell estrogen receptor alpha promotes arterial stiffness in the absence of estradiol

Turner, C. G.; Matz, J.; Breton, J.; de Oliveira, K. C.; Kenney, R.; Vorn, J.; Zhao, M.; Ibarrola, J.; Lu, Q.; Martin, G.; Sun, Z.; Jaffe, I. Z.; Hill, M. A.; DuPont, J. J.

doi:10.64898/2026.03.03.709417

bioRxiv · 10.64898/2026.03.03.709417

Smooth muscle cell estrogen receptor alpha promotes arterial stiffness in the absence of estradiol

Turner, C. G.·Matz, J.·Breton, J.·de Oliveira, K. C.·Kenney, R.·Vorn, J.·Zhao, M.·Ibarrola, J.·Lu, Q.·Martin, G.·Sun, Z.·Jaffe, I. Z.·Hill, M. A.·DuPont, J. J.

View original source ↗Export metadata ↓

Abstract

BackgroundClinical evidence supports a greater impact of arterial stiffening in cardiovascular mortality in women versus men. Arterial stiffness increases across the menopausal transition, implicating a role of the loss of estrogens in arterial stiffening, but mediating mechanisms remain unclear. MethodsThe role of estradiol and smooth muscle cell (SMC) estrogen receptor alpha (ER) in arterial stiffening, by aortic pulse wave velocity (PWV), was assessed in 3 models: (1) the loss of estradiol in young, female mice comparing sham surgery or bilateral ovariectomy (OVEX) {+/-} estradiol, (2) the impact of sham versus OVEX surgery in young, female SMC-ER-intact and SMC-ER-knockout (KO) littermates, and (3) arterial stiffening during natural aging by comparing young and aged, female and male SMC-ER-intact and SMC-ER-KO littermates. Mechanistic pathways were assessed using histological assessment of aortic fibrosis and elastin degradation, aortic MMP expression, and atomic force microscopy. ResultsOVEX increased PWV and aortic medial fibrosis, with no impact on elastin integrity, in young female mice. Arterial stiffening and fibrosis were prevented in OVEX mice that were supplemented with estradiol. OVEX-induced arterial stiffening in SMC-ER-intact female mice was prevented in SMC-ER-KO littermates. In this model, OVEX was also associated with increased aortic medial fibrosis without changes in elastin integrity. Aging from 3 to 18 months significantly increased PWV in female and male SMC-ER-intact mice. Aging-induced stiffening was fully prevented in female and partially prevented in male SMC-ER-KO mice. SMC-ER contributes to aging-associated arterial stiffening by sex-specific mechanisms, including elastin degradation in females and phenotypic changes in SMC stiffness and probability to form cellular adhesions in males. Circulating estradiol was significantly decreased in serum from aged compared with young female mice. ConclusionsThese findings support that SMC-ER contributes to arterial stiffening in female and male mice in situations where the vasculature is exposed to low levels of estradiol.

Explore related subjects

physiology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Turner, C. G., Matz, J., Breton, J., de Oliveira, K. C., Kenney, R., Vorn, J., Zhao, M., Ibarrola, J., Lu, Q., Martin, G., Sun, Z., Jaffe, I. Z., Hill, M. A., DuPont, J. J.. 2026-03-05. Smooth muscle cell estrogen receptor alpha promotes arterial stiffness in the absence of estradiol. https://doi.org/10.64898/2026.03.03.709417

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Thoracoabdominal pressure transmission during prone and supine cardiopulmonary resuscitation in fresh-frozen human cadavers

Background: Prone cardiopulmonary resuscitation (CPR) may be necessary when turning a prone patient supine would delay chest compressions. Although prone compressions can generate arterial pressures comparable with or greater than supine CPR, the pathway of pressure transmission is uncertain. We examined synchronized intrathoracic, intra-abdominal, and central arterial pressures in both supine and prone positions. Methods: Two thawed fresh-frozen adult cadavers underwent three, 2-minute mechanical CPR trials per position in a counterbalanced crossover sequence. Solid-state catheters recorded pleural, peritoneal, and central arterial pressures simultaneously. Trial-level outcomes included peak pressure, mean pressure, pressure-time area, and the mean peritoneal-to-pleural pressure gradient. Exploratory fixed-effects models included position, cadaver, and their interaction. Results: Prone CPR increased peak intrathoracic pressure by 7.04 mmHg, peak intra-abdominal pressure by 21.69 mmHg, and peak arterial pressure by 15.40 mmHg. Mean intra-abdominal and arterial pressures increased by 16.22 and 9.90 mmHg, respectively. The mean peritoneal-to-pleural gradient reversed direction from -8.46 mmHg supine to 4.85 mmHg prone. Intrathoracic pressure-time area increased 3.4-fold, from 1.62 to 5.46 mmHg{middle dot}s, and arterial pressure-time area increased 2.2-fold, from 2.96 to 6.42 mmHg{middle dot}s. Conclusions: Compared to supine, prone mechanical CPR generated higher arterial pressures and reversed the pressure relationship across the thoracoabdominal boundary in both cadavers. Higher abdominal pressure coincided with a larger intrathoracic pressure-time area, a pattern compatible with reduced caudal pressure dissipation.

physiology↗

bioRxiv2026

Hypothalamic Farnesoid X Receptor deficiency alters energy balance by modulating hepatic glucose production and adipose tissue metabolism through central insulin signaling.

Objectives: The bile acid nuclear receptor Farnesoid X Receptor (FXR, NR1H4) is a major regulator of metabolism and energy homeostasis in peripheral organs. It modulates bile acid, glucose, and lipid metabolism, as well as fat mass and body weight. However, FXR is also expressed in the brain, particularly in the hypothalamus, a key center for the regulation of energy homeostasis. Although one study has demonstrated a role for brain FXR activation in energy balance, its specific hypothalamic role is still unknown. Here, we examined the role of FXR in the mediobasal hypothalamus in the regulation of energy balance. Methods: We used a genetic approach combined with metabolic phenotyping to determine the effect of FXR invalidation in the mediobasal hypothalamus on metabolic parameters involved in the central regulation of energy homeostasis. Results: Our results demonstrate that hypothalamic FXR deficiency induces a positive energy balance, resulting in a reduction in energy expenditure due to alterations in glucose metabolism accompanied by structural changes in white adipose tissues. Conclusion: This study uncovers a previously unrecognized role for hypothalamic FXR in the central homeostatic control of energy balance, providing new insights into its contribution to peripheral glucose metabolism and adipose tissue structural remodeling.

physiology↗

bioRxiv2026

Rad and Phospholamban are Key Drivers of the Ventricular Adrenergic Response and Stress-Induced Arrhythmia

The adrenergic response is a fundamental mechanism that regulates heart rate (chronotropy), cardiac contractility (inotropy) and relaxation (lusitropy). Adrenergic stress is also a recognized trigger of arrhythmia in disease. Yet, our understanding of the underlying molecular basis remains incomplete. Protein kinase A (PKA) and the calcium/calmodulin-dependent kinase II (CaMKII) phosphorylate multiple targets proposed to participate in the adrenergic response, including the GTP-binding protein Rad, phospholamban (PLB) and ryanodine receptor 2 (RyR2). Here we demonstrate that phosphorylation of both Rad and PLB is necessary for inotropy and lusitropy. We show that changes in cardiac contractility and relaxation are primarily dependent on intracellular calcium handling. Finally, we report that Rad and PLB control stress-induced arrhythmogenesis, despite the phosphorylation of other pro-arrhythmic targets. We have identified the essential molecular components of the adrenergic response, resolving a long-standing debate in cardiac excitation-contraction coupling and refining current models of sympathetic regulation in health and disease.

physiology↗