# Shear stress Regulation of Endothelial Glycolysis via METTL3-mediated RNA m6A Modification

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $840,873

## Abstract

Project Summary
Shear stresses resulting from distinct blood flow patterns impact endothelial cell (EC) functions.
ECs under atheroprone flow exhibit increased proliferation, inflammation, and glycolysis,
compared to those under atheroprotective flow. Our recent studies have uncovered a novel role
of epitranscriptional regulation (i.e., functional changes to RNAs without altered nucleotide
sequence) in EC mechanobiology. Thus, atheroprone flow induces METTL3, a methyltransferase
that catalyzes N6-methyladenosine (m6A) to result in the most abundant RNA modification found
in eukaryotes. Our newly conducted preliminary studies indicate that METTL3 inhibition in ECs
suppresses the atheroprone flow-induced pro-inflammatory response and glycolysis. Through
transcriptome and epitranscriptome mapping, we found that METTL3 caused hypermethylation
of the mRNAs encoding the key enzymes involved in glycolysis and pentose phosphate pathway
(PPP, a branch of glycolysis). These findings led to the guiding hypothesis that atheroprone flow
upregulates METTL3 to modulate m6A epitranscriptomes and hence promote glycolysis and PPP
in ECs, thus contributing to EC dysfunction and atherosclerosis. The four specific aims proposed
to test this hypothesis are: Aim 1. To delineate the dynamics of METTL3-regulated
epitranscriptomes in ECs under atheroprone vs. atheroprotective flow patterns; Aim 2. To identify
the METTL3-modulated m6A RNA targets that drive the atheroprone flow enhancement of EC
glycolysis and PPP; Aim 3. To elucidate the effects of the flow-regulated EC m6A
epitranscriptomes on the phenotypic changes of co-cultured SMCs and EC glycolysis by SRS
imaging; Aim 4. To validate flow regulation of METTL3 and m6A epitranscriptomes in mouse
atherosclerosis models. This interdisciplinary research will unveil novel epitranscriptional
mechanisms underlying EC mechanobiology and atherosclerotic diseases.

## Key facts

- **NIH application ID:** 10990943
- **Project number:** 1R01HL170107-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** SHU CHIEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $840,873
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990943

## Citation

> US National Institutes of Health, RePORTER application 10990943, Shear stress Regulation of Endothelial Glycolysis via METTL3-mediated RNA m6A Modification (1R01HL170107-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10990943. Licensed CC0.

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