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bioRxiv · 10.1101/2025.05.21.655189

Estradiol treatment enhances neurovascular coupling independent of metabolic health status in a mouse model of menopause

Plumley, Z. M.·Calvo Iglesias, J.·Fernandez Ugidos, I.·Walker, A. B.·Pires dos Santos, I.·Taylor, H.·Mostany, R.
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Abstract

The loss of ovarian estrogen during the menopause transition has been identified as a risk factor for increased cardiometabolic and neurovascular dysfunction, age-related cognitive decline, and Alzheimers disease. A wealth of studies using rodent models of menopause have highlighted the cardio- and neuroprotective effects of 17{beta}-estradiol (E2) treatment when administered within a critical period, though these have yet to be successfully translated to human populations in clinical trials of hormone therapy. A proposed explanation for this mismatch in results is the "healthy cell bias," where estrogen is only beneficial when initiated in physiologically intact systems. Our study investigates whether pre-existing metabolic dysfunction attenuates the effects of E2 on neurovascular coupling (NVC) in a rodent model of menopause. Female mice were fed a high-fat diet (HFD) or control diet (CD) for 11 weeks to induce metabolic dysfunction, followed by ovariectomy (OVX) and subsequent E2 or vehicle (Veh) treatment. NVC was assessed in awake mice using two-photon laser scanning microscopy of penetrating arterioles (PAs) in the somatosensory cortex, barrel field. Mice developed glucose intolerance and increased adiposity yet displayed intact NVC following 11 weeks of HFD exposure. Following ovariectomy, E2 treatment enhanced NVC responses regardless of diet. Interestingly, in HFD-fed mice, E2 appeared to reduce basal PA diameter relative to Veh, suggesting health status-specific mechanisms of action. These results indicate that PAs retain functional sensitivity to estrogen treatment in the face of metabolic impairment, which has implications for the use of hormone therapy in women that arrive at the menopause transition with varied pre-existing cardiometabolic disorders.

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Plumley, Z. M., Calvo Iglesias, J., Fernandez Ugidos, I., Walker, A. B., Pires dos Santos, I., Taylor, H., Mostany, R.. 2025-05-21. Estradiol treatment enhances neurovascular coupling independent of metabolic health status in a mouse model of menopause. https://doi.org/10.1101/2025.05.21.655189

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