# SNO transport regulates endothelial adhesion of RBCs

> **NIH VA I01** · DURHAM VA MEDICAL CENTER · 2020 · —

## Abstract

PROJECT SUMMARY
Red blood cell (RBC) transfusion is costly, and is among the procedures most frequently performed in VA and
other health care settings. Growing evidence, however, suggests that many anemic patients may not benefit
from RBC transfusion, and that blood function declines even during short storage periods. We have identified a
novel mechanism whereby RBCs normally export nitric oxide (NO)-derived signals to the vasculature,
facilitating the flow of blood itself. S-nitrosothiols (SNOs) are thiol adducts formed in RBCs from precursor NO
in concert with the oxygenation-linked allosteric transition in hemoglobin. RBCs export these vasoregulatory
SNOs “on demand” in order to fine-tune regional blood flow and prevent RBC adhesion to the endothelium
(ECs). Preliminary Studies show for the first time that intercellular transport of small carrier SNOs is critical in
the prevention of RBC adhesion to ECs. These novel findings demonstrate the role of blood flow-regulating,
intercellular SNO signaling by the RBC, and impairment in this function after storage. We will test the
hypothesis that SNO transport is critical to the vasoregulatory function of RBCs, and its loss a remediable
“storage lesion” promoting post-transfusion lung morbidity, by accomplishing these Specific Aims: Aim 1:
Determine the role of RBC LAT1 in mediating SNO export by human RBCs. The specific conduit by which
RBCs export SNO groups remains undetermined, but our Preliminary Studies indicate a significant role of RBC
LAT1 in SNO export. We will use new tools and pharmacological approaches to determine the role of LAT1 in
RBC SNO export, and measures to augment this activity. We will also identify intracellular RBC molecular
targets of beneficial SNO restoration. Aim 2: Determine the role of SNO import via LAT1 in endothelial
cells in limiting the adhesivity of healthy human RBCs. We showed that SNO can be restored in banked
RBCs after storage-induced loss, and that SNO restoration limits RBC-EC adhesion. We will determine
whether LAT1-mediated SNO import by ECs is necessary for the RBC SNO-induced antiadhesive effect by
using genetic and pharmacological approaches, and test the role of alternative mechanisms. Aim 3:
Determine the role of LAT1 in the storage-sensitive effects of RBC SNOs in mouse models of human
RBC transfusion. We developed an innovative mouse model of human-RBC transfusion, recapitulating key
clinical phenotypes such as lung dysfunction. We will use intravital microscopy, a novel mouse conditionally
deficient in EC LAT1, and transfusate labeling to determine the role of RBC SNO in limiting post-transfusion
morbidity, specifically RBC adhesion and depressed blood oxygenation and tissue O2 delivery. Both naïve and
two-hit (transfusion after lipopolysaccharide), acute and chronic models will be used. Determining the role of
SNO transport in signaling from RBCs to ECs in health and disease is the next logical step toward our long-
term scientific objective: to ...

## Key facts

- **NIH application ID:** 9863989
- **Project number:** 5I01BX003478-04
- **Recipient organization:** DURHAM VA MEDICAL CENTER
- **Principal Investigator:** TIMOTHY J MCMAHON
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9863989

## Citation

> US National Institutes of Health, RePORTER application 9863989, SNO transport regulates endothelial adhesion of RBCs (5I01BX003478-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9863989. Licensed CC0.

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