# Contribution of estrogen receptor beta to changes in hypothalamic plasticity and hypertension susceptibility in mice with accelerated ovarian failure

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $423,750

## Abstract

ABSTRACT
Hypertension is more prevalent in men than in young women, but as women progress towards
menopause this relationship is reversed. Unfortunately, compared to men, menopausal women are less
likely to receive optimal diagnostic evaluation and therapeutic intervention. In women, the increased
incidence of hypertension begins at “perimenopause”, a transitional phase preceding and extending
through menopause beginning at ~45-54 years of age. The perimenopausal period is accompanied by
irregular estrous cycles and erratically fluctuating estrogen levels; it may also be a critical period for the
emergence of brain plasticity that may contribute to the development of hypertension. The reversal of
hypertension liability in young and older women may be phylogenetically conserved: aged female mice,
but not young female mice, show increased sympathetic tone and blood pressure following slow-pressor
angiotensin II (AngII) administration. To better understand the role of ovarian hormones in female
hypertension, we have utilized a mouse model of accelerated ovarian failure (AOF) that uniquely
recapitulates hormone fluctuations seen in human menopause. Using AOF mice, we made the novel
finding that the susceptibility to hypertension begins at “peri-AOF”, which is a stage marked by irregular
and extended estrous cycles similar to human perimenopause. In addition, peri-AOF hypertension was
associated with a unique profile of N-methyl-D-aspartic acid (NMDA) receptor plasticity in estrogen
receptor β (ERβ) containing neurons in the hypothalamic paraventricular nucleus (PVN) not seen in pre- or
post-AOF females, or in males. These findings define peri-AOF as a critical period when hypertension and
adaptations in neuro-cardiovascular regulatory systems emerge. In the current proposal, we will
investigate the role of ERβ in the emergence of hypertension and PVN NMDA receptor plasticity during
peri-AOF. For this, we will test the central hypothesis that ERβ influences the susceptibility to
hypertension and NMDA receptor plasticity in select populations of PVN neurons in peri-AOF mice
following slow-pressor AngII administration. Two aims will test this hypothesis. Aim 1 will test the sub-
hypothesis that ERβ in the PVN is critically involved in the susceptibility of peri-AOF females to
hypertension and potentiated NMDA receptor-mediated excitatory signaling in CRF-expressing neurons.
Aim 2 will test the sub-hypothesis that cyclic administration of ERβ agonists during peri-AOF reduces both
hypertension susceptibility and NMDA-mediated excitatory signaling selectively in CRF-containing PVN
neurons. These studies will be achieved using a multidisciplinary approach including spatio-temporal
deletion of the ERβ gene, electron microscopic immunocytochemistry, molecular and biochemical assays
and neurophysiological methods.

## Key facts

- **NIH application ID:** 9858422
- **Project number:** 5R01HL136520-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** MICHAEL J GLASS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858422

## Citation

> US National Institutes of Health, RePORTER application 9858422, Contribution of estrogen receptor beta to changes in hypothalamic plasticity and hypertension susceptibility in mice with accelerated ovarian failure (5R01HL136520-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9858422. Licensed CC0.

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