Angiotensin II differentially affects hippocampal glial inflammatory markers in young adult male and female mice

Hypertension is a risk factor for neurodegenerative disorders involving inflammation and inflammatory cytokine-producing brain cells (microglia and astrocytes) in the hippocampus and medial prefrontal cortex (mPFC). Here we investigated the effect of slow-pressor angiotensin II (AngII) on gliosis in the hippocampus and mPFC of young adult (2-mo-old) male and female mice. In males, AngII induced hypertension, and this resulted in an increase in the density of the astrocyte marker glial fibrillary acidic protein (GFAP) in the subgranular hilus and a decrease in the density of the microglial marker ionized calcium binding adapter molecule (Iba-1) in the CA1 region. Females infused with AngII did not show hypertension but, significantly, showed alterations in hippocampal glial activation. Compared with vehicle, AngII-infused female mice had an increased density of Iba-1 in the dentate gyrus and CA2/3a region. Like males, females infused with AngII exhibited decreased Iba-1 in the CA1 region. Neither male nor female mice showed differences in GFAP or Iba-1 in the mPFC following AngII infusion. These results demonstrate that the hippocampus is particularly vulnerable to AngII in young adulthood. Differences in gonadal hormones or the sensitivity to AngII hypertension may account for divergences in GFAP and Iba-1 in males and females.

Hypertension is a significant risk factor for neurological disorders such as Alzheimer''s disease (AD) that are associated with neurodegeneration and cognitive decline (Daugherty 2021). Hypertension can develop during the life span yet is often studied at middle and late life. There is emerging evidence that hypertension is becoming more common in late adolescence and early adulthood (Azegami et al. 2021; Hamrahian and Falkner 2022). In addition, there is increasing awareness that the duration of hypertension can impact the onset of neural degeneration (Schaare et al. 2019; Yang et al. 2021) and cognitive dysfunction (Yaffe et al. 2014, 2021; Mahinrad et al. 2020; Zhou et al. 2022). Although the age of onset of hypertension may influence the trajectory of degenerative disease in later life, the effect of hypertension on brain health in young adult subjects is relatively underinvestigated.Hippocampal and medial prefrontal cortical pathology are commonly present in neurodegenerative diseases like AD (Belonwu et al. 2021). Structurally and functionally, both the hippocampus and mPFC also are compromised during hypertension (Raz et al. 2007; Gonzalez et al. 2015; Bu et al. 2018). In the hippocampus, hypertension is known to disrupt cerebrovascular function, promote inflammatory processes, and contribute to neuronal impairment and cognitive decline (Iulita et al. 2018). Although less studied than the hippocampus, the PFC is also compromised by hypertension (Raz et al. 2007; Bu et al. 2018; Wang et al. 2020).Microglia, the resident macrophages in the brain, have been implicated in inflammatory states, cognitive function (Cornell et al. 2022), and the brain''s response to hypertension (Calvillo et al. 2019; Li et al. 2020). An increase in the density of ionized calcium binding adapter molecule (Iba-1), a protein constitutively expressed in microglia and up-regulated when microglia enter an activated stage (Imai et al. 1996; Sasaki et al. 2001), is commonly reported in models of cognitive and neurodegenerative disorders (Prinz et al. 2021).In addition to microglia, astrocytes also have been implicated in the emergence of hippocampal and cortical dysfunction. Astrocytes play critical roles in blood–brain barrier (BBB) formation; brain metabolic, ion, and water homeostasis; neurotransmitter recycling; synapse formation; and neuroimmune signaling (Matias et al. 2019). In the context of insult, pathogen infection, or neurological disease, astrocytes undergo functionally complex reactive responses (Chiu et al. 2014; Giovannoni and Quintana 2020) that are associated with an increase in glial fibrillary acidic protein (GFAP) gene and protein expression (Crespo-Castrillo et al. 2020; Sofroniew 2020).To better understand the consequences of elevated blood pressure on the young adult brain, we conducted an exploratory investigation of the impact of hypertension on the expression of microglia and astrocyte markers—Iba-1 and GFAP, respectively—in the hippocampus and mPFC of male mice. Mice were exposed to angiotensin II (AngII) using the “slow-pressor” model (Dickinson and Lawrence 1963), which in males mimics the gradual rise in blood pressure and increase in sympathetic activation (Grassi and Ram 2016; Lerman et al. 2019) characteristic of essential hypertension (Lerman et al. 2019). Significantly, there is an important sex dimorphism in the risk for hypertension. Compared with men, women are protected from hypertension before middle age but become increasingly affected as they reach perimenopause, and intact young female rodents show a reduced sensitivity to AngII hypertension (Van Kempen et al. 2016). Similarly, there are sex differences in the incidence, progression, and severity of hypertension-associated neurodegenerative disease (Lopez-Lee et al. 2021). Furthermore, sex differences in glial function have also been documented within the context of neurodegenerative diseases (Kodama and Gan 2019; Biechele et al. 2020). Given this evidence, the effect of AngII on hippocampal and medial prefrontal cortical glial markers also was investigated in young intact female mice.