# Role of Metabolic Reprogramming in Formation and Maintenance of the Acta2+ Atherosclerotic Lesion Protective Fibrous Cap

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $747,576

## Abstract

Atherothrombosis, resulting from rupture or erosion of unstable atherosclerotic plaques, is the leading cause of
death worldwide. However, the mechanisms that regulate the stability of late stage atherosclerotic lesions remain
poorly understood. Recent studies from our lab showed that smooth muscle cell (SMC) conditional knockout of the
platelet-derived growth factor receptor-β (PdgfrbSMC-Δ/Δ) in ApoE-/- mice was associated with nearly complete failure
of SMC to invest into lesions or the fibrous cap. However, surprisingly we observed no changes in lesion size or
indices of plaque stability, including the thickness of the Acta2+ fibrous cap, following 18 weeks of Western diet (WD)
feeding. Further investigation provided novel insights regarding the mechanisms underlying these changes. Key
findings included: 1) contrary to long-standing dogma that Acta2+ fibrous cap cells are derived almost exclusively
from SMC, we showed that they account for only 60-70% of Acta2+ cells in advanced ApoE-/- brachiocephalic (BCA)
or human coronary artery lesions with the remainder coming from endothelial cell-to-mesenchymal-to-myofibroblast
transitions (EndoMT-MFT, 20-25%) and macrophage-to-myofibroblast transitions (MMFT), 10-15%) respectively; 2)
loss of SMC investment into lesions with SMC PDGFRB KO was associated with large adaptive increases in
EndoMT-MFT and MMFT; 3) increased EndoMT-MFT, and MMFT did not sustain indices of stability when WD
feeding was extended to 26 weeks suggesting there may be qualitative differences in Acta2+ fibrous cap cells
depending on their origin; 4) RNA-seq analysis on the BCA of 18-week WD-fed PdgfrbSMC-Δ/Δ ApoE-/- mice versus
control littermate mice showed that energy metabolism pathways were the top ten upregulated pathways suggesting
that metabolic reprogramming may be required for SMC-MF, EndoMT-MF, and MMF transitions; and 5) inhibition of
aerobic glycolysis in cultured SMC prevented their transition to a MF state following treatment with PDGF and TGFβ.
Studies in this proposal will test the hypothesis that SMC, EC, and macrophage adaptive responses for maintaining
plaque stability require major shifts in energy metabolism and that the metabolic state of these cells can be
manipulated to stimulate beneficial changes in the phenotype of lesion cells and overall increases in plaque stability.
Aim 1 will determine if genetic knockout or pharmacologic inhibition of aerobic glycolysis in SMC and EC lineage
tracing ApoE-/- mice with advanced atherosclerosis is associated with evidence of reduced plaque stability. Aim 2 will
determine if genetic or pharmacologic promotion of aerobic glycolysis in SMC and EC lineage tracing ApoE-/- lineage
tracing mice with advanced atherosclerosis is associated with increased plaque stability. Studies for both aims will
include human validation studies using scRNAseq and histological data from stable asymptomatic versus unstable
symptomatic carotid endarterectomy samples. All studies will assess se...

## Key facts

- **NIH application ID:** 10292012
- **Project number:** 1R01HL155165-01A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Gary K Owens
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $747,576
- **Award type:** 1
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10292012

## Citation

> US National Institutes of Health, RePORTER application 10292012, Role of Metabolic Reprogramming in Formation and Maintenance of the Acta2+ Atherosclerotic Lesion Protective Fibrous Cap (1R01HL155165-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10292012. Licensed CC0.

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