# Defining SMC phenotypes critical in late stage atherosclerosis pathogenesis

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $740,894

## Abstract

Atherosclerosis is a progressive disease that is a leading cause of death in the Western world.
Remarkably, despite decades of research, there remain major ambiguities regarding the role of smooth
muscle cells (SMC) in lesion pathogenesis, as well as mechanisms that control plaque stability and the
probability of plaque rupture with possible myocardial infarction (MI) or stroke. The general dogma is that
SMC are primarily involved in late not early stage lesions, and that their primary role is atheroprotective
by contributing to formation of a fibrous cap. However, recent Nature Medicine studies by our lab involving
simultaneous SMC-specific lineage tracing and knockout (KO) of the stem cell pluripotency genes, Oct4
or Klf4 provided compelling evidence that SMC play a much greater role in lesion pathogenesis than has
been generally appreciated. Key findings included our showing that: 1) >80% of SMC-derived cells within
advanced lesions of ApoE-/- mice lack detectable expression of typical SMC markers; 2) 30-40% of SMC-
derived cells within both advanced mouse and human lesions lack detectable SMC markers and have
activated markers of MФs; and 3) SMC can have major beneficial or detrimental effects on lesion
pathogenesis depending on the nature of their phenotypic transitions. Studies in this proposal will test
the hypothesis that SMC phenotypic transitions can exert dominant atheroprotective or atheropromoting
effects on late stage lesion pathogenesis and represent a novel therapeutic target for treating advanced
atherosclerosis. Aim 1 will test the hypothesis that Klf4-dependent transitions in SMC phenotype and function
exacerbate lesion pathogenesis in early and late stages of atherosclerosis, and will include defining distinct
atheroprotective SMC phenotypes induced by SMC-specific conditional KO of Klf4 based on complementary flow
cytometric and high resolution confocal analyses of unique marker panels derived from our in vivo RNAseq and
Klf4/Oct4 ChIPseq genomic analyses of advanced brachiocephalic (BCA) lesions and cross referenced to genes
linked to increased human CAD risk. We will also determine if delayed SMC specific conditional KO of Klf4 after
establishment of advanced lesions also induces favorable changes in lesion pathogenesis. Aim 2 will test the
hypothesis that Oct4-dependent transitions in SMC phenotype and function promote plaque stabilization by
enhancing investment of SMC into a protective fibrous cap and reducing their transition to a pro-inflammatory
state. We will also test if SMC phenotypes identified in our mouse studies also occur in human lesions and define
which phenotypes correlate with stable versus unstable lesions. Aim 3 will determine if SMC phenotypic changes
within advanced lesions are reversible, and if treatment SMC lineage tracing mice with advanced lesions with a
PCSK9 inhibitor promotes beneficial changes in SMC phenotype and/or overall lesion pathogenesis. Studies may
lead to identification of novel ther...

## Key facts

- **NIH application ID:** 9838248
- **Project number:** 5R01HL136314-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Gary K Owens
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $740,894
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838248

## Citation

> US National Institutes of Health, RePORTER application 9838248, Defining SMC phenotypes critical in late stage atherosclerosis pathogenesis (5R01HL136314-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9838248. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*