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.