# Brain-derived neurotrophic factor: a novel regulator of cardiovascular function in the hypothalamus

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2020 · $390,000

## Abstract

The sympathetic nervous system plays a key role in the development of hypertension, and elevated sympathetic
activity is a major component of several cardiovascular risk factors, including stress. In addition, augmented
cardiovascular sensitivity to acute stressors in young normotensive individuals predicts a higher risk of becoming
hypertensive later in life, indicating that enhanced stress-responsiveness and long-term elevation of blood
pressure (BP) are linked by the same, yet unidentified, stress-related central regulatory mechanisms. Here, we
propose that brain-derived neurotrophic factor (BDNF), acting in the paraventricular nucleus of the
hypothalamus (PVN), is a multi-faceted mechanism that is uniquely suited to directly activating PVN
sympathoregulatory neurons to induce acute BP elevations to stress as well as mediating long-term
transformation of the PVN neurocircuitry to facilitate responsiveness to hypertensive stimuli leading to the
development of hypertension. Our recent publications and preliminary data suggest that BDNF exerts these
effects in the PVN via mechanisms that have traditionally been recognized to mediate plasticity, learning and
memory in hippocampal and cortical neuronal networks, but have not been explored in the PVN. These actions
include 1) intracellular Ca2+-dependent BDNF expression in PVN neurons in response to excitatory input
converging on the PVN during stress; 2) activation of the high-affinity BDNF receptor TrkB, leading to opening
of the transient receptor potential channel-3 (TRPC3) via phospholipase C (PLC) signaling; 3) differential
regulation of expression and function of N-methyl-D-aspartate (NMDA) and γ-aminobutyric acid type-A
(GABAA) receptors, shifting the excitatory-inhibitory balance toward long-term sensitization in PVN
sympathoregulatory neurons. In addition, there is evidence for important mechanisms that integrate actions of
BDNF and angiotensin II (AngII), a key regulator of BP in the PVN. These newly discovered interactions are
mediated by AngII-induced stimulation of BDNF expression; AngII-type-1 receptor (AT1R)-induced trans-
activation of TrkB; and by BDNF-induced upregulation of AT1R. We employ a comprehensive array of in vitro
patch-clamp and Ca2+-imaging techniques as well as in vivo experiments using viral vector-mediated genetic
manipulation of BDNF signaling in rats to achieve the following aims: Aim 1: To elucidate TrkB–PLC–TRPC3-
mediated mechanisms by which BDNF activates PVN sympathoregulatory neurons to acutely increase SNA and
BP; Aim 2: To characterize functional interactions between BDNF and AngII in sympathoregulatory PVN
neurons; and Aim 3: To determine how excessive activation of BDNF signaling augments excitatory and
diminishes inhibitory synaptic function in PVN sympathoregulatory neurons to promote the development of
hypertension. These studies have the strong potential to significantly advance the field by establishing BDNF as
a highly important regulator of autono...

## Key facts

- **NIH application ID:** 9903424
- **Project number:** 5R01HL133211-04
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Benedek Erdos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2017-04-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903424

## Citation

> US National Institutes of Health, RePORTER application 9903424, Brain-derived neurotrophic factor: a novel regulator of cardiovascular function in the hypothalamus (5R01HL133211-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9903424. Licensed CC0.

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