Bernstein, G. A. | bioRxiv Science

bioRxiv2026

Mechanisms of impaired cerebral hemodynamics and memory resilience differ by sex: A role for mineralocorticoid receptors in VCID

INTRODUCTION: Chronic hypertension is associated with cerebral hypoperfusion and is a primary risk factor for vascular contributions to cognitive impairment and dementia (VCID). Aldosterone, a key mediator of hypertension, causes cerebrovascular dysfunction via its mineralocorticoid receptor (MR). METHODS: The effects of MR signaling during hypertension on hemodynamics in two cognition-centric brain regions were determined in both sexes using an established model of VCID (spontaneously hypertensive rat, SHR) and MR antagonist eplerenone. Long-term and spatial working memory were tested, and absolute brain blood flow and brain oxygenation were measured in vivo in CA1 of dorsal hippocampus and medial prefrontal cortex (mPFC). RESULTS: Hypertension differentially impaired hemodynamics in a sex- and region-dependent manner. Female SHR had more pervasive hypoperfusion than males that did not affect flow-metabolism coupling. Eplerenone treatment in females restored perfusion in mPFC and hippocampus, improved working memory, but did not protect hippocampal-dependent memory. Eplerenone had no effect in male SHR, indicating the MR-dependent mechanism of VCID is sex-specific. DISCUSSION: This study advances our understanding of how chronic hypertension compromises brain blood flow, suggests that resilience of memory function differs by domain, and that efficacy of interventions depend upon sex.

neuroscience↗

bioRxiv2026

Chronic hypertension disrupts the blood-brain barrier in the ventral hippocampus in females but not males in a rat model of vascular cognitive impairment

Background: Chronic hypertension is a leading cause of cerebrovascular disease, ischemic stroke, and cognitive impairment. In addition, anxiety and hypertension often co-exist, however, little is known about the relationship between the two. Understanding how chronic hypertension impacts limbic brain regions such as the ventral hippocampus may provide insight into how cerebrovascular contributes to altered emotional behavior. Methods: An open field task was used to quantify locomotion, exploratory behavior, thigmotaxis, rearing and risk assessment behaviors in adult (7-month-old) male and female normotensive Wistar rats and spontaneously hypertensive rats (SHR; n=8/group). Blood-brain barrier (BBB) permeability was assessed by measuring extravasation of sodium fluorescein, 3 kDa Texas red dextran and 10 kDa cascade blue into the ventral hippocampus. Enzyme-linked immunosorbent assays were used to measure markers of vascular signaling, inflammation, and central nervous system-specific proteins indicative of neuroaxonal and glial injury in serum from separate groups of male and female SHR (n=6/group). Main effects and interactions between two independent variables (sex and hypertension) were determined using two-way analysis of variance (ANOVA) with Tukey's post-hoc tests. Circulating factors were compared using a Welch's t-test. Relationships between BBB permeability and anxiety-like behavior were determined using Pearson's correlations. Results: Chronic hypertension increased circulating inflammatory factors and BBB permeability in female but not male rats. BBB permeability did not differ by sex in male and female normotensive rats. There was an anxiolytic effect of chronic hypertension on exploratory-related anxiety-like behavior, including less thigmotaxis, lower latency to cross through the center of the arena, and increased unsupported rearing. Risk assessment behavior, quantified as stretch-attend posture, was increased in female SHR. BBB permeability in the ventral hippocampus was correlated with anxiety-like behavior in females, but not in males, suggesting sex-dependent mechanisms of hypertension-induced changes in emotional behavior. Conclusions: These findings implicate a role for chronic hypertension-induced BBB disruption in neuropsychiatric disorders in the female sex and advances our understanding of cerebrovascular vulnerability in deep limbic brain regions.

neuroscience↗