# Hypothalamic cytokines, glutamate receptor plasticity, and blood pressure

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

## Abstract

ABSTRACT
Hypertension is a risk factor for cardiovascular and chronic kidney diseases, as well as cerebrovascular
dysfunction and cognitive decline. Significantly, there are established sex differences in the development of
hypertension. Overcoming the insufficiency of blood pressure control and treatment resistance commonly
seen with current hypertension therapies will depend on understanding the systems, including within the brain,
that are responsible for elevated blood pressure in males and females. Provocative recent evidence points to
a critical role for brain inflammatory factors in the emergence of hypertension. Tumor necrosis factor alpha
(TNFα) is a cytokine originally characterized as a macrophage-derived signaling molecule involved in systemic
inflammation that is now known to be synthesized and released during normal, plastic, and pathological neural
function by resident brain cells. TNFα is also known to modulate hypothalamic networks that coordinate
sympathetic and neuroendocrine activity with blood pressure. TNFα signals via type 1 and type 2 receptors
(TNFR1 and TNFR2, respectively). TNFR1 receptors are the major TNFα receptor in the brain with a high
expression in the hypothalamic paraventricular nucleus (PVN). Within the brain, there is evidence that TNFR1
has key interactions with glutamate, an important substrate for neural signaling and plasticity implicated in
autonomic regulation and blood pressure control. Significantly, estrogen signaling at estrogen receptor ß
(ERß), the major estrogen receptor in the PVN, is involved in hypothalamic glutamate plasticity associated with
hypertension. However, the relationship between TNFR1, ERß, and glutamate plasticity, during hypertension
has never been established in males and females. This project will test the novel hypothesis that TNFR1
signaling in PVN neurons contributes to the glutamate receptor plasticity associated with slow-pressor AngII
administration in a sex-dependent manner. A multidisciplinary strategy combining the use of genetic/molecular,
biochemical, neurophysiological, and high-resolution neuroanatomical approaches will be used to investigate
the role of TNFR1 signaling in glutamate receptor plasticity in the PVN. Mice will be made hypertensive by a
form of angiotensin II-dependent slow onset-hypertension with clinical relevance. The following Specific Aims
will be addressed: Aim 1. TNFR1 in the PVN plays differing roles in the development of the slow-pressor
response to AngII in male and female mice. Aim 2. TNFR1 differentially modulates PVN glutamate
receptor signaling in male and female mice. Aim 3. ERß contributes to sex-differences in TNFR1-
glutamate signaling during hypertension. This project has the potential to expand our understanding of
neural-inflammatory signaling and gender differences in hypertension and offer novel insights into the neural
regulation of blood pressure control.

## Key facts

- **NIH application ID:** 9940876
- **Project number:** 5R01HL135498-04
- **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:** 2017-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940876

## Citation

> US National Institutes of Health, RePORTER application 9940876, Hypothalamic cytokines, glutamate receptor plasticity, and blood pressure (5R01HL135498-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9940876. Licensed CC0.

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