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.