Sexual Dimorphism in Brain Cellular Senescence During Angiotensin II‐Induced Hypertension

Abstract

Sex differences in the development of hypertension across the lifespan are well established. Women are at lower risk of hypertension compared to age‐matched men until menopause, when the risk of hypertension sharply rises for women. The peptide hormone angiotensin II (Ang II) is a well‐recognized contributor to hypertension, particularly through its actions in the brain. Importantly, Ang II is too large to cross into the central nervous system (CNS) and influences blood pressure regulation by acting at circumventricular nuclei located outside of the blood‐brain‐barrier, particularly the forebrain subfornical organ. For instance, in males, Ang II drives pro‐hypertensive cellular stressors in the SFO while females are resistant to Ang II‐induced hypertension. However, the underlying CNS (i.e. SFO) mechanisms that contribute to hypertension in a sexually dimorphic manner remain unclear. Intriguingly, Ang II‐induced stressors can culminate in cellular senescence. Cellular senescence is a complex cellular phenotype characterized by marked changes in cell metabolism, macromolecular damage, and a pro‐inflammatory environment known as the senescence associated secretory phenotype (SASP). The role of senescence in the CNS as related to the development of hypertension remains unclear. Based on this, we hypothesized that brain cellular senescence, particularly in the SFO, may be a novel mechanism for the sexually dimorphic nature of Ang II‐induced hypertension. To test this, 8‐week‐old male and female C57Bl/6J mice (n=7‐10/group) were implanted with subcutaneous mini‐osmotic pumps for the infusion of Ang II (600 ng/kg/min). Micropunches of the SFO were collected at baseline and following 14 days of Ang II infusion for quantitative real‐time PCR analysis. In males, infusion of Ang II resulted in a robust increase in key senescent genes including p16 (1.9±0.3 fold baseline, p<0.05) and p21 (2.5±0.5 fold baseline, p<0.05) in the SFO. In parallel with the induction of senescence, inflammatory SASP indicators were also upregulated in the SFO of males following 14 days of Ang II infusion, including interleukin‐6 (IL‐6: 2.4±0.4 fold baseline, p<0.05) and interleukin‐10 (IL‐10: 2.8±0.7 fold baseline, p<0.05). However, when examining females, clear sexual dimorphism in Ang II‐induced SFO cellular senescence was apparent. Specifically, no changes in p16 (1.1±0.4 fold baseline, p=0.9) or p21(1.2±0.2 fold baseline, p=0.2) were noted in the SFO following Ang II administration. Similarly, SASP markers that accompany senescence remained unchanged in the SFO (e.g. IL‐6: 1.3±0.5 fold baseline, p=0.8 and IL‐10: 0.98±0.2 fold baseline, p=0.6). Together, these findings indicate that: 1) Cellular senescence in the SFO is associated with Ang II‐induced hypertension in males; and 2) Females are protected against Ang II‐driven cellular senescence in the SFO. Importantly, cellular senescence increases with advancing age. Thus, our data suggests that cellular senescence may underlie the sexually dimorphic nature of hypertension at younger ages, as well as the increased hypertensive risk in women as they age.