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.