# The Role of Pericytes in the Vascular Dysfunction of Sepsis

> **NIH NIH R35** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $377,539

## Abstract

Project Summary:
 Sepsis affects more than 19 million people each year. With improved treatment strategies, more and more
patients survive sepsis. The majority of these survivors develop cognitive impairment and mental health
problems. However, the mechanisms that promote sepsis-associated encephalopathies (SAE) remain largely
unknown, and there is a lack of SAE-targeted treatments. The long-term goals of our research program are to
understand the mechanisms that lead to cerebrovascular dysfunction and cognitive impairment post sepsis and
to develop novel targeted treatments for sepsis-induced cognitive impairment. To reach this goal, we
characterized sepsis-induced cognitive impairment using animal models. We observed that mice exhibit
hippocampus-dependent memory impairment associated with pathological neuron dysfunction. To understand
the mechanisms behind cognitive impairment post sepsis, we focused on specialized cells in the brain called
pericytes, which play a major role in regulating cerebral blood flow and maintaining blood brain barrier integrity.
Pericytes form part of the neurovascular unit to meet the energy demands of the brain and facilitate neuro-
inflammatory responses. However, the role of pericytes in sepsis-induced cognitive impairment remains
unknown. Our studies demonstrated that the transcription factor friend leukemia virus integration 1 (Fli-1)
regulates pericyte activation and viability. We also observed that brain pericyte numbers decreased after sepsis
and that pericytes underwent apoptosis after their initial activation and production of inflammatory mediators.
Pericyte loss resulted in vascular leakage and recruitment of inflammatory monocytes. We reported previously
that Fli-1 governs pericyte viability through regulating caspase 1/3 expression. In our preliminary studies, we
demonstrated that pericyte Fli-1 knockout mice exhibit decreased inflammatory mediator production in response
to LPS. More importantly, we demonstrated that Fli-1 levels were higher in the hippocampus regions of post-
mortem brain tissue from septic patients compared to controls. In this R35/MIRA application, we propose to use
newly developed, unbiased approaches such as single nucleus RNA sequencing and imaging mass cytometry
alongside inducible pericyte-specific Fli-1 knockout mice generated in our laboratory and novel antisense
oligonucleotide Gapmers targeting Fli-1 recently developed by our group to understand the role of pericytes in
vascular dysfunction and cognitive impairment post sepsis. The successful completion of the proposed studies
will lead to better understanding of the mechanisms of vascular cognitive impairment post sepsis and the
development of novel SAE-targeted treatments.

## Key facts

- **NIH application ID:** 10830385
- **Project number:** 5R35GM149203-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Hongkuan Fan
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $377,539
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830385

## Citation

> US National Institutes of Health, RePORTER application 10830385, The Role of Pericytes in the Vascular Dysfunction of Sepsis (5R35GM149203-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10830385. Licensed CC0.

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