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

Abstract

Introduction: Chronic 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.

Methods: Memory, 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.

Results: Impaired 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.

Discussion: Hippocampal 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.

Keywords: aging; angiotensin II; chronic hypertension; hippocampus; vascular cognitive impairment; vascular dementia.

FIGURE 1

Aging during chronic hypertension differentially affected memory function and long‐term memory was selectively rescued by captopril and apocynin treatments. (A) Long‐term memory function was assessed in rats in early (4 to 5 months old), mid (8 to 9 months old), and late adulthood (14 to 15 months old) using a novel object recognition task. Long‐term memory was impaired in SHR in mid and late adulthood compared to SHR and Wistar rats in early adulthood. Captopril (+Capto) and apocynin (+Apo) treatment improved memory in SHR in late adulthood. (B) The continuous Y maze test was used to assess spatial working memory. Alternation indices were lower in SHR at all stages of adulthood and was unaffected by captopril or apocynin treatment. Data are mean ± SEM; group differences were assessed using a one‐way ANOVA test with Tukey's multiple comparison test. *p < 0.05, **p < 0.01; n = 6 ‐ 8/group.

FIGURE 2

Progressive hippocampal hypoperfusion during chronic hypertension was restored by captopril treatment. (A) Schematic of hydrogen probe placement (top) and representative tracings of hydrogen clearance (bottom) are shown for each stage of adulthood studied in SHR. (B) Absolute hippocampal blood flow decreased with age in a stepwise manner in SHR and was significantly lower in SHR in late adulthood compared to SHR and Wistar rats in early adulthood. Captopril treatment (+Capto), but not apocynin (+Apo) treatment, increased hippocampal perfusion to be similar to perfusion in rats in early adulthood. Data are mean ± SEM; group differences were assessed using a one‐way ANOVA test with Tukey's multiple comparison test. *p < 0.05, **p < 0.01; n = 5 ‐ 6/group.

FIGURE 3

Hippocampal arterioles were hyperconstricted during chronic hypertension that increased with age. (A) Illustration of hippocampal vasculature and representative image of cannulated and pressurized hippocampal arteriole (HA) in arteriograph chamber used for pressure myography studies. (B) Lumen diameters of HAs remained relatively constant across the intravascular pressure range studied. HAs from SHR had smaller lumen diameters compared to Wistar rats regardless of age and/or treatment, with the smallest being in HAs from SHR in late adulthood. HAs from Late SHR+Capto had larger lumen diameters compared to HAs from untreated SHR in late adulthood. (C) Myogenic tone was increased in SHR in mid and late adulthood compared to arterioles from Wistar rats that was ameliorated by captopril treatment and apocynin treatment of SHR in late adulthood. Data are mean ± SEM; group differences were assessed using a one‐way ANOVA test with Tukey's multiple comparison test. *p < 0.05, **p < 0.01 versus Wistar; #p < 0.05 versus Late SHR+Capto; n = 5 ‐ 6/group.

FIGURE 4

Endothelial function was impaired during chronic hypertension that worsened with age and was restored by captopril and apocynin treatment. (A) Vasoreactivity of hippocampal arterioles (HAs) from SHR in early, mid, and late adulthood and Late SHR+Apo were shifted rightward at lower doses of NS309 compared to arterioles from Wistar and Late SHR+Capto rats. However, HAs from all groups vasodilated at higher concentrations of NS309. (B) Arterioles from SHR in late adulthood demonstrated little to no response to SK_Ca channel inhibition that was improved in arterioles from Late SHR+Capto and Late SHR+Apo. (C) HAs from SHR at all stages of adulthood had limited vasoconstriction in response to IK_Ca channel inhibition compared to arterioles from Wistar rats. HAs from Late SHR+Capto and Late SHR+Apo had vasoconstrictive responses similar to those of arterioles from normotensive rats. Data are mean ± SEM; group differences were assessed using a one‐way ANOVA test with Tukey's multiple comparison test. *p < 0.05, **p < 0.01; n = 5 ‐ 6/group.

FIGURE 5

Chronic hypertension impaired the vasoreactivity of hippocampal arterioles (HAs) to adenosine. (A) Representative lumen diameter traces of HAs in response to increasing doses of adenosine. (B) Reactivity of HAs from SHR at all stages of adulthood were shifted rightward and blunted compared to HAs from Wistar rats that was improved in arterioles from Late SHR+Capto and Late SHR+Apo rats. Data are mean ± SEM; group differences were assessed using a one‐way ANOVA test with Tukey's multiple comparison test. *p < 0.05, **p < 0.01 versus Wistar, Late SHR+Capto, and Late SHR+Apo; n = 5 ‐ 6/group.

FIGURE 6

Vasoreactivity of hippocampal arterioles (HAs) to nitric oxide was impaired during chronic hypertension. (A) Representative traces of lumen diameter changes of HAs in response to increasing doses of the nitric oxide (NO) donor SNP. (B) Vasoreactivity to NO was shifted rightward and blunted in arterioles from SHR at all stages of adulthood compared to HAs from Wistar rats. Vasodilation of HAs from Late SHR+Capto and Late SHR+Apo in response to increasing concentrations of NO were similar to arterioles from Wistar rats. Data are mean ± SEM; group differences were assessed using one‐way ANOVA with Tukey's multiple comparison test. *p < 0.05, **p < 0.01 versus Wistar, Late SHR+Capto and Late SHR+Apo; n = 5 ‐ 6/group.