Angiotensin II‐mediated hippocampal hypoperfusion and vascular dysfunction contribute to vascular cognitive impairment in aged hypertensive rats

Abstract

IntroductionChronic hypertension increases the risk of vascular cognitive impairment (VCI) by ∼60%; however, how hypertension affects the vasculature of the hippocampus remains unclear but could contribute to VCI.MethodsMemory, hippocampal perfusion, and hippocampal arteriole (HA) function were investigated in male Wistar rats or spontaneously hypertensive rats (SHR) in early (4 to 5 months old), mid (8 to 9 months old), or late adulthood (14 to 15 months old). SHR in late adulthood were chronically treated with captopril (angiotensin converting enzyme inhibitor) or apocynin (antioxidant) to investigate the mechanisms by which hypertension contributes to VCI.ResultsImpaired memory in SHR in late adulthood was associated with HA endothelial dysfunction, hyperconstriction, and ∼50% reduction in hippocampal blood flow. Captopril, but not apocynin, improved HA function, restored perfusion, and rescued memory function in aged SHR.DiscussionHippocampal vascular dysfunction contributes to hypertension‐induced memory decline through angiotensin II signaling, highlighting the therapeutic potential of HAs in protecting neurocognitive health later in life.Highlights Vascular dysfunction in the hippocampus contributes to vascular cognitive impairment. Memory declines with age during chronic hypertension. Angiotensin II causes endothelial dysfunction in the hippocampus in hypertension. Angiotensin II‐mediated hippocampal arteriole dysfunction reduces blood flow. Vascular dysfunction in the hippocampus impairs perfusion and memory function.

Onset of α5GABA-A Receptor Dependent Hippocampal Trisynaptic Circuit Dysfunction Is Associated Increased Age and Blood Pressure

“…These findings support the hypothesis that untreated age-associated increased MAP disrupts functional hippocampal circuitry that would likely underly performance deficits in aspects of spatial memory function. Some behavioral observations such as impaired performance on the delayed recognition trial of the Novel Object Recognition Test (NORT) are consistent with this reasoning (Dunnett et al, 1988; Johnson et al, 2020; Gannon et al, 2024). Additionally, age-associated increased MAP, either directly or as a comorbidity, disrupts high-frequency neural network oscillations in the ripple frequency band.…”

“…The effects of chronic hypertension on neural network activity underlying memory have not, to the best of our knowledge, been previously investigated. The male Sprague Dawley (SD) rat develops increased MAP and impairments in memory function with aging, making it an excellent animal model for probing the role of hypertension in age-related amnestic mild-cognitive impairment (aMCI) (Dunnett et al, 1988; Johnson et al, 2020; Gannon et al, 2024). Synchronous high frequency activity in the ripple band (140 to 200 Hz) or sharp wave ripples (SPW-Rs) recorded from the CA1 hippocampal subregion is an established functional correlate of memory replay and consolidation during sleep and awake immobility in rodents, non-human primates, and humans (Buszaki et al, 1992 & 2015; Jadhav et al, 2012; Liu et al, 2022).…”