Sex Differences in the Response to Angiotensin II‐Induced Hypertension

Abstract

Hypertension impairs the structure and function of cerebral arteries. Increased plasma aldosterone or activation of the mineralocorticoid receptor (MR) are linked to cerebrovascular damage and dementia. The occurrence of dementia is higher in females than in males. We tested the hypothesis that females will experience cognitive decline in response to angiotensin II (AngII)‐induced hypertension and that this will be dependent on MR activation. Sixteen‐week‐old female C57BL/6 were treated with AngII (800 ng/kg/min via osmotic mini‐pump) ± the MR antagonist eplerenone (EPL; 100 mg/kg/day in food) for four weeks. Sham mice served as control. Blood pressure was measured by tail cuff plethysmography and tests were conducted for non‐spatial memory, spatial memory, and nesting ability. Plasma was collected at time of euthanasia. Data for the female mice are presented as mean ± SEM; n=7–8 per group. The results were compared to previously published studies using male mice. In male mice, AngII infusion resulted in elevated blood pressure and increased plasma aldosterone that was not MR‐dependent. Male mice also experienced reduced cerebral perfusion and impaired spatial and non‐spatial memory that was prevented, at least partially, by MR antagonism. In female mice, systolic blood pressure was increased after AngII infusion and was not affected by EPL treatment (Sham: 150 ± 4; AngII: 180* ± 5; AngII+EPL: 188* ± 3mmHg; *=p<0.05 vs. Sham). Cerebral perfusion was decreased after AngII infusion and was only partially improved with MR antagonism (Sham: 985 ± 14; AngII: 821* ± 24; AngII+EPL: 892*# ± 18 perfusion units; *=p<0.05 vs. Sham, #=p<0.05 vs. AngII). This reduction in cerebral perfusion was not due to artery rarefaction, shown by endothelial cell staining in the cerebral cortex with isolectin. Plasma aldosterone was increased with AngII infusion and was not affected by MR antagonism (Sham: 144 ± 5; AngII: 262* ± 4; AngII+EPL: 258* ± 5 pg/mL; *=p<0.05 vs. Sham). Novel object testing showed non‐spatial memory was not impaired in female mice treated with AngII (Sham: 48 ± 6; AngII: 53 ± 4; AngII+EPL: 57 ± 6 % novel object exploration time; p>0.05). Spatial memory, tested by Barnes maze, showed that spatial memory in female mice was also unaffected by AngII infusion (Sham: 29 ± 4; AngII: 34 ± 4; AngII+EPL: 32 ± 3 seconds spent in target quadrant; p>0.05). Nesting behavior, however, was impaired in female mice with AngII infusion and was improved with EPL treatment. (Sham: 32 ± 5; AngII 11* ± 2; AngII+EPL: 27# ± 8 % nestlet shredded; *=p<0.05 vs. Sham, #=p<0.05 vs. AngII). Interestingly, EPL treatment increased plasma 17 β‐estradiol, although not significantly (Sham: 16 ± 1; AngII: 19 ± 3; AngII+EPL: 33 ± 8 pg/mL; p=0.08). Female mice are protected from changes in cognition due to hypertension while male mice experience deficits in both spatial and non‐spatial memory. However, female mice experience a decrease in executive function, demonstrated by impaired nesting ability in response to AngII treatment.Support or Funding InformationR01‐HL‐137694‐01This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.