INTRODUCTION
Hypertension is a prevalent condition affecting at least 30% of the global adult population (Mills et al., 2016). The impact of uncontrolled hypertension is particularly pronounced in the brain and cerebral circulation, where end-organ disease manifests earlier than in other parts of the body (Jennings & Zanstra, 2009). Hypertension is a major risk factor for two of the most important conditions that impact the brain: stroke and cognitive impairment (Iadecola et al., 2016). However, the underlying mechanisms by which hypertension promotes brain disease are not clear. Importantly, the incidence of cognitive impairment is rapidly increasing and even mild cognitive decline increases the risk of developing dementia (Bozoki, Giordani, Heidebrink, Berent, & Foster, 2001). Patients on anti-hypertensives have a lower risk of cognitive impairment and dementia (Ou et al., 2020) but it is not conclusive from clinical trials whether anti-hypertensive therapy reverses established cognitive dysfunction (Iadecola et al., 2016; Rapp et al., 2020).
Inflammation plays a central role in the pathophysiology of hypertension (Drummond, Vinh, Guzik, & Sobey, 2019). For example, mice that lack T cells have reduced pressor responses (Dinh et al., 2021; Guzik et al., 2007) and preventing T cell activation attenuates hypertension (Dinh et al., 2021; Vinh et al., 2010). Hypertension is strongly associated with inflammation and leukocyte infiltration into the systemic vasculature and kidneys. While T cells and microglia are upregulated in the brain during hypertension, it remains unclear whether other leukocyte subtypes are similarly upregulated. Angiotensin II infusion has been shown to stimulate tumour necrosis factor (TNF)-α production in the hippocampus (Iulita et al., 2018), a key brain region for regulating aspects of cognitive function, particularly memory, and brain inflammation is associated with cognitive impairment (Faraco et al., 2016). Interestingly, evidence is accumulating to suggest that immune cells may directly contribute to cognitive impairment. For example, T cell infiltration in white matter is associated with cognitive decline in aged monkeys (Batterman, Cabrera, Moore, & Rosene, 2021), and T cell depletion in a mouse model of Alzheimer’s disease improves spatial memory (Laurent et al., 2017). Further, in the setting of hypertension, depletion of perivascular macrophages inhibits angiotensin II-induced cognitive impairment (Faraco et al., 2016).
Here, we have infused mice with angiotensin II or aldosterone to test if hypertension can promote brain immune cell infiltration, transcriptomic changes and cognitive impairment. Using hydralazine hydrochloride, we also studied whether development of these effects on the brain following angiotensin II infusion are blood pressure-dependent and reversible.