Abstract

Chronic hypertension causes cerebrovascular disease and accelerates age-related cognitive decline. However, little is known about how hypertension and age impact the arterioles supplying deep brain regions involved in memory and cognition, such as the hippocampus, that may contribute to vascular dementia. The aim of the current study was to investigate age-related hippocampal vascular dysfunction during chronic hypertension and its relationship to cognitive decline. We hypothesized that vasodilation of hippocampal arterioles (HAs) to mediators of neurovascular coupling would be impaired during chronic hypertension and worsen with age. We further hypothesized that hypertension-induced HA dysfunction would be associated with impaired memory function. HAs were studied isolated and pressurized from 4 mo. male Wistar rats and compared to male spontaneously hypertensive rats (SHR) at 4, 6 and 12 months of age (n=6/group). Reactivity to mediators of neurovascular coupling were determined, including nitric oxide (NO) and adenosine, and structural remodeling measured under fully relaxed conditions. A novel object recognition task was used and recognition index calculated to assess long-term memory function. Data are mean±SEM. Differences between groups were determined by one-way analysis of variance (ANOVA) with a post-hoc Tukey test. Chronic hypertension impaired vasodilation of HAs to a NO donor regardless of age, as vasoreactivity was similarly blunted in HAs from SHR at 4 mo. (13±3%), 6 mo. (24±4%), and 12 mo. (9±4%) compared to arterioles from Wistar rats (43±7%; p<0.05). Vasodilation to adenosine was also significantly impaired during chronic hypertension at all ages studied, with HA reactivity being ~35-45% in HAs from SHR compared to 70±3% in HAs from normotensive rats. Fully relaxed HAs from Wistar rats had lumen diameters of 65±2 μm at 120mmHg intravascular pressure. Lumen diameters were smaller in HAs from SHR at 4 mo. (54±2 μm) and 6 mo. (53±4 μm), and smallest in arterioles from 12 mo. SHR (46±3 μm; p<0.01). Long-term memory function was similar between 4 mo. SHR and Wistar rats that had recognition indices > 0.70. However, memory was impaired in older SHR, with recognition index being 0.52±0.02 in 6 mo. SHR and 0.47±0.05 in 12 mo. SHR (p<0.01). Overall, chronic hypertension caused inward remodeling and impaired vasoreactivity of HAs to mediators of neurovascular coupling that may disrupt basal and/or activity-dependent changes in blood flow in the hippocampus. Importantly, HA dysfunction was present at an age prior to the onset of memory dysfunction in SHR. These findings suggest these arterioles have a causal role in hypertension- and age-related cognitive decline, and represent a therapeutic target to slow memory loss and reduce vascular contributions to cognitive impairment and dementia. NIH NINDS 1R01 NS127284 and AHA 20CDA35310239 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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