# Astrocyte regulation of the blood-brain barrier in intracerebral hemorrhage

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $386,250

## Abstract

BACKGROUND: Intracerebral hemorrhage (ICH) is the most devastating subtype of stroke, with high rates of
mortality and severe disability. A cardinal feature of ICH is dysfunction of the blood-brain barrier (BBB), which
predisposes to the formation of perihematomal edema, acts as a gateway for the entry of peripheral immune
cells, and allows entry of potentially harmful molecules into the brain. Astrocytes normally regulate the properties
of the BBB by expressing factors that act on endothelial cells to increase junctional protein expression, maintain
the basal lamina and reduce permeability, but in ICH, astrocytes that regulate the BBB acquire a new phenotype
(“reactive”) that promotes BBB opening. ICH-induced reactive astrocytes express several factors that act on
endothelium to reduce junctional proteins and increase permeability, including: chemokine (C-C motif) ligand 2
(CCL2), inducible nitric oxide 2 (NOS2), and matrix metalloproteinase 9 (MMP-9). New work from our laboratory
shows that astrocytic Sur1-Trpm4 channels may play an important, heretofore unknown, role in BBB-dysfunction
induced by ICH. New preliminary data show that: (i) after ICH, Sur1-Trpm4 channels are upregulated de novo,
predominantly in astrocytes; (ii) compared to controls, astrocyte-specific (Abcc8loxP/loxP;Gfap-Cre) deletion of
Abcc8, which encodes Sur1, reduces protein extravasation (vasogenic edema) and improves vestibulomotor
function post-ICH; (iii) salutary effects in Abcc8loxP/loxP;Gfap-Cre mice are linked to reduced expression of CCL2,
NOS2 and MMP-9 by astrocytes post-ICH. In addition, experiments with hemoglobin-activated astrocytes in
culture show that: (iv) expression of CCL2, NOS2 and MMP-9 is reduced by blockade of Sur1-Trpm4; (v)
thrombin opens Sur1-Trpm4 channels. The effect of astrocyte-specific Sur1-Trpm4 inhibition on CCL2, NOS2
and MMP-9 expression is hypothesized to reflect an effect of the Sur1-Trpm4 channel on Ca2+-dependent gene
expression, since: (i) the normal function of Sur1-Trpm4 channels is to regulate Ca2+ influx; (ii) expression of
CCL2, NOS2 and MMP-9 in other cells share the common feature of being regulated by Ca2+, including in part
by the Ca2+/calcineurin-dependent transcription factor, nuclear factor of activated T-cells (NFAT). Our
overarching hypothesis is that ICH-induced reactive astrocytes upregulate Sur1-Trpm4, in part to control Ca2+-
sensitive NFAT-mediated gene expression of factors that influence BBB permeability. Thus, modulating Sur1-
Trpm4 function in astrocytes is expected to directly impact BBB permeability.
DESCRIPTION: Here, we will evaluate this hypothesis in 3 mechanistic aims: In Aim 1, we will characterize the
effect of astrocyte-specific deletion of Abcc8/Sur1 on BBB function in ICH. In Aim 2, we will characterize the role
of astrocytic Sur1-Trpm4 in NFAT-mediated transcription of CCL2, NOS2 and MMP-9. In Aim 3, we will
characterize the signaling mechanism for thrombin-mediated opening of Sur1-Trpm4 channels in...

## Key facts

- **NIH application ID:** 10076843
- **Project number:** 5R01HL082517-14
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** J. Marc Simard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $386,250
- **Award type:** 5
- **Project period:** 2006-01-19 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10076843

## Citation

> US National Institutes of Health, RePORTER application 10076843, Astrocyte regulation of the blood-brain barrier in intracerebral hemorrhage (5R01HL082517-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10076843. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*