# Regulation of brain endothelial integrity by angiotensin receptors as treatment for cerebral malaria

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $326,701

## Abstract

Summary. Cerebral malaria (CM) remains the most virulent and deadliest manifestation of malaria. It is
caused by Plasmodium falciparum infected erythrocytes (iRBC) adhering to host brain endothelial cells and
compromising the blood brain barrier. While available anti-malarial drugs are effective at clearing parasites
from the blood, they do not have specific effects against CM.
We have found that P. falciparum-iRBC induced disruption of human brain microvascular endothelial cell
junctions was prevented by the activation of the angiotensin (Ang) II receptor type 2 (AT2), achieving
protection of endothelial integrity. We also found that AT2 agonists are protective against experimental CM,
and mice deficient in the AT2 receptor are more susceptible to this syndrome. However, over the last years, we
have expanded the renin-angiotensin system by identifying additional receptors (Mas and MrgD) that are
activated by agonists similar or equal to AT2 agonists, such as C21, Ang-(1-7) and Ang-(1-9). We could also
show that these compounds are protective against P. falciparum-induced disruption of endothelial integrity.
Thus, we hypothesize that activation of one, two, or all three receptors of the beneficial arm of the renin-
angiotensin system protects brain endothelial cells from parasite-induced disruption of their barrier function.
To identify which receptor(s) are key in the protection of endothelial integrity, we will first quantify the effect of
Ang-(1-9), Ang-(1-7) and C21 in receptor-transfected HEK293 cells and in human and murine brain endothelial
cells on intracellular signaling molecules, known to be regulated by the agonists and important in the
maintenance of endothelial barrier integrity. Receptor blockers targeting different angiotensin receptors will be
tested for their ability to block the intracellular signaling induced by the protective Ang peptides/analogues.
Primary endothelial cells will be also targeted with siRNA against AT2 and/or Mas and/or MrgD to identify the
responsible receptor(s) for the signaling effects. Finally, primary brain endothelial cells isolated from mice
deficient in one, two or three receptors will be used as a genetic model to confirm the conclusions made from
the pharmacological and siRNA experiments. We will then identify the receptors involved in the protection
mediated by Ang-(1-9), Ang-(1-7), and C21 of brain endothelial cells from P. falciparum-induced endothelial
disruption. We will use a pharmacological approach with the receptor antagonists and siRNA against the
receptors to determine their effects on endothelial activation and junction integrity and on selected second
messengers. Finally, we will test how treatment with Ang-(1-9), Ang-(1-7) and C21 affects the outcome of CM
in wild-type and genetically deficient mice in one of the three receptors as well as double and triple knockouts.
The main goal of this project is to identify the angiotensin receptor(s) that mediate protection of endothelial
integr...

## Key facts

- **NIH application ID:** 9875482
- **Project number:** 5R01NS105910-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** ANA RODRIGUEZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $326,701
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875482

## Citation

> US National Institutes of Health, RePORTER application 9875482, Regulation of brain endothelial integrity by angiotensin receptors as treatment for cerebral malaria (5R01NS105910-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9875482. Licensed CC0.

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