Brain Cellular Senescence as a Potential Mediator of Angiotensin II‐Induced Hypertension

Abstract

Hypertension affects 1 in 3 US adults and is a leading risk factor for heart attack and stroke. The peptide hormone angiotensin II (Ang II) is a well-recognized driver of hypertension, particularly through its sympathoexcitatory actions within the central nervous system (CNS). Although a number of pro-hypertensive CNS mechanisms (i.e. neurogenic hypertension) have been elucidated, including oxidative and endoplasmic reticulum stress, how these mechanisms translate into long-term alterations in CNS circuits remains unclear. Intriguingly, stress-associated pathways can culminate in cellular senescence and the senescence-associated secretory phenotype (SASP). Chronic senescence/SASP leads to marked changes in cell metabolism, macromolecule damage, and a pro-inflammatory environment. Based on this, we hypothesized that CNS cellular senescence may be a key contributor to neurogenic hypertension. We first performed a proof-of-principle experiment to determine if CNS cellular senescence is involved in blood pressure regulation. C57Bl/6J male mice were fitted with intracerebroventricular (ICV) cannulas and underwent implantation of radiotelemeters for conscious recording of cardiovascular parameters. Following surgical recovery, the senescence inducing agent doxorubicin (0.00125 mg) or vehicle control was administered daily over three days (n=3/group). Daily ICV administration of doxorubicin resulted in marked elevations in mean arterial blood pressure within 48 hours that were sustained throughout the study (72 hours: 107±1 vs. 123±1 mmHg; ICV vehicle vs. doxorubicin, p<0.05). Relative to controls, ganglionic blockade (i.p. chlorisondamine 12 mg/kg) elicited a greater fall in blood pressure in doxorubicin-treated animals (Δ-11±4 vs. Δ-56±6 mmHg; ICV vehicle vs. doxorubicin, p<0.05). Given these findings that CNS cellular senescence is associated with a hypertensive phenotype, likely through alterations in autonomic control of blood pressure, we next profiled cellular senescence in key cardioregulatory nuclei during hypertension development. Male C57Bl/6J mice were implanted with subcutaneous osmotic minipumps for chronic infusion of Ang II (600 ng/kg/min). Brains were collected at baseline and after 14 days of Ang II infusion (n=4-5/group) and micropunches of cardiovascular and autonomic nuclei including the organum vasculosum lamina terminalis (OVLT), subfornical organ (SFO), and paraventricular nucleus of the hypothalamus (PVN) were collected. Two-week infusion of Ang II resulted in a robust increase in the key senescent gene p16 (CDKN2A) in the SFO (6.1±0.8 fold baseline, p<0.05). Interestingly, Ang II-induced hypertension was not associated with changes in p16 in the OVLT (2.2±0.7 fold baseline, p=0.2) and PVN (1.5±0.4 fold baseline, p=0.4). Additionally, Ang II-induced senescence in the SFO was paralleled by the upregulation of SASP indicators (e.g. Interleukin-1α: 6.5±1.4 fold baseline, p<0.05). Together, these findings indicate that: 1) CNS cellular senescence is pro-hypertensive; and 2) Ang II elicits cellular senescence/SASP in the SFO. Collectively, our data may point to brain cellular senescence as a novel mediator of hypertension.