Hypertensive stimuli promote neuroinflammation and cognitive impairment in a pressure-dependent manner

Objective: Hypertension greatly increases the risk for cognitive impairment, and is associated with inflammation of the brain. However, it is unclear to what extent there is neuroinflammation during hypertension and whether this promotes cognitive impairment. This study aimed to quantify neuroinflammatory and cognitive changes caused by administration of angiotensin II, and determine whether this is blood pressure-dependent. Design and method: Male C57Bl/6 mice were administered vehicle (saline; n = 33) or angiotensin II (0.7 mg/kg/d, n = 34) for 14 d via an osmotic minipump. A subset of mice also received hydralazine hydrochloride (50 mg/kg; n = 38) in their drinking water for 14 d after minipump implantation. Systolic blood pressure (SBP) was measured using tail-cuff; inflammation was assessed using flow cytometry and RNA sequencing; and recognition memory was evaluated using the novel object recognition test. Results: Angiotensin II infusion increased SBP and promoted accumulation of neutrophils, monocytes, T cells and B cells in the brain compared to vehicle infusion which was blunted by co-administration of hydralazine (n = 7–8, P < 0.05). Angiotensin II infusion also impaired recognition memory and this effect could be prevented by co-treatment with hydralazine (n = 11–12, P < 0.05). Angiotensin II infusion promoted differential expression of 1194 genes in whole brain hemisphere and 634 genes in hippocampus compared to vehicle infusion. Out of these genes, 295 in whole brain hemisphere and 125 in hippocampus were inflammation/immune-related (n = 6, P-adjusted < 0.05). Angiotensin II caused downregulation of genes involved in cognitive function and memory consolidation ( Dusp1, Arc ) and upregulation of genes involved in immune cell function, regulation and migration ( H2-Ab1, H2-Q6, Il17rc, Fcrlb, Ltb, Ccl8, Itga9 ) in whole brain hemisphere (n = 6, P-adjusted < 0.05). In the hippocampus, a key region in learning and memory, angiotensin II promoted upregulation of genes involved in immune cell proliferation and differentiation ( Il12rb2, Acvr1b, Sema3c ) and apoptosis ( Plxna3, Anxa11, Hyal1, Axin1 ) (n = 6, P-adjusted < 0.05). Co-treatment with hydralazine altered expression of all of these genes suggesting possible reversal of the transcriptomic changes induced by angiotensin II infusion (n = 6, P-adjusted < 0.05). Conclusion: Angiotensin II promotes neuroinflammation and cognitive impairment in a blood pressure-dependent manner. Co-treatment with hydralazine may reverse some of the transcriptomic changes induced by angiotensin II. Chronic neuroinflammation may be a contributing factor to cognitive impairment during hypertension and could be modulated by blood pressure reduction.