# The Role of Brain Cellular Senescence in the Sexual Dimorphism of Hypertension.

> **NIH NIH F31** · GEORGE WASHINGTON UNIVERSITY · 2023 · $40,679

## Abstract

PROJECT SUMMARY
It is estimated that about 10 million deaths worldwide each year are associated with hypertension, but
unfortunately, the etiology is unknown in 95% of cases. Furthermore, the risk of hypertension is greater in men
than pre-menopausal women. However, post-menopause, the female risk of hypertension exceeds that of age-
matched males, pointing to the hormone estrogen as protective against hypertension. In contrast to the
cardiovascular protective effects of estrogen, the hormone angiotensin II (Ang II) is well-recognized as a driver
of hypertension. Ang II acts within the brain to elevate sympathetic nervous system outflow, which subsequently
leads to increases in blood pressure. Indeed, hypertensive patients display elevated levels of Ang II and
sympathetic overactivity. As a peptide hormone, Ang II is too large to cross the blood-brain-barrier and influences
cardiovascular regulation at specialized circumventricular nuclei that lack a blood-brain-barrier, particularly the
subfornical organ (SFO). Ang II-induced cellular stressors including oxidative stress and endoplasmic reticulum
dysfunction within the SFO are strongly implicated in Ang II-induced hypertension. However, the integrative
downstream cellular mechanisms by which these alterations in the SFO lead to chronic changes in neuronal
function remains unclear. Interestingly, these stressors have been shown to induce cellular senescence - a
complex cellular phenotype characterized by marked changes in cell metabolism, macromolecular damage, and
a secretory pro-inflammatory environment known as the senescence associated secretory phenotype (SASP).
Our key preliminary data in murine models reveals that central nervous system senescence contributes to
hypertension. Additional exciting evidence indicates that Ang II drives senescence and SASP activation in the
SFO of males, but not in females. Building upon this, the current proposal will test the hypothesis that estrogen
is protective against SFO cellular senescence/SASP and subsequently hypertension development. To address
this hypothesis, we will comprehensively characterize SFO cellular senescence/SASP in male versus female
mice during Ang II-induced hypertension development using molecular, histological, and innovative in vivo
imaging techniques. We will further determine the functional consequence of cellular senescence on SFO
neurons and how the sexual dimorphism of hypertension is driven by the interplay between SFO Ang II-mediated
senescence and estrogen. Findings from this proposal have the potential to advance our understanding of
sexually dimorphic brain mechanisms in hypertension pathology, which may spur novel therapeutic treatments
for hypertension in both sexes.

## Key facts

- **NIH application ID:** 10656211
- **Project number:** 5F31HL164059-02
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Samantha Annie Dow
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $40,679
- **Award type:** 5
- **Project period:** 2022-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10656211

## Citation

> US National Institutes of Health, RePORTER application 10656211, The Role of Brain Cellular Senescence in the Sexual Dimorphism of Hypertension. (5F31HL164059-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10656211. Licensed CC0.

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