# Profilin-1's Role in Atherosclerosis

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $46,036

## Abstract

PROJECT SUMMARY
Atherosclerosis is a major cause of cardiovascular-related death worldwide. Actin-binding protein Profilin-1
(Pfn1), an important regulator of actin cytoskeleton is overexpressed in atherosclerotic plaques in preclinical
models as well as in human disease. Global reduction of Pfn1 by embryonic heterozygous knockout (KO) of the
Pfn1 gene in mice displays diminished vascular infiltration of pro-atherogenic inflammatory cells (i.e.
macrophages) and plaque size in experimentally induced atherosclerosis, suggesting that Pfn1 diminution
confers partial protection against atherosclerosis. Since atherosclerosis is a disease that involves pathology of
multiple cell types (vascular endothelial cells (VEC), various types of immune cells, smooth muscle cells),
previous studies could not discern Pfn1’s contribution from specific cell types in atherosclerosis progression.
Furthermore, lack of marketed small molecule inhibitors of Pfn1 has hampered translational efforts of targeting
Pfn1 as a potential strategy to mitigate atherosclerosis development and/or progression. The goal of the
proposed study is to specifically dissect the role of endothelial Pfn1 in atherosclerosis and further explore whether
Pfn1 is an impactful pharmacological target to diminish atherosclerosis. To address this goal, a novel inducible
VEC-specific Pfn1 KO mouse model and novel small molecule investigative compounds targeting the Pfn1-actin
interaction interface will be used. Angiogenesis and vascular permeability facilitate nutrient delivery and
leukocyte invasion, promoting atherogenesis, plaque growth and eventually plaque rupture. We have shown that
endothelial Pfn1 is an important mediator of angiogenesis in physiological settings. We also found that Pfn1
depletion in VEC improves barrier function, a finding consistent with Pfn1’s ability to exacerbate agonist-induced
microvascular hyper-permeability in vivo. Thus, we hypothesize that inhibition of vascular endothelial Pfn1
function exerts an atheroprotective effect by reducing plaque angiogenesis and vascular permeability.
Aim 1A will utilize a novel EC-specific Pfn1 KO mouse to study atherosclerosis progression in Pfn1 deficient
mice. In Aim 1B, in vitro endothelial perturbation of Pfn1 expression will be used to reveal the effect of Pfn1 to
changes in leukocytic adhesion and extravasation in static and flow-based assays, as well as changes in
endothelial contractility. Aim 2 will winnow available novel Pfn1:actin interaction inhibitors to the most effective
inhibitor as determined by endothelial proliferation, migration, biochemical assays, and in vivo angiogenesis
assays. The optimal inhibitor will be used in ApoE deficient mouse model as a potential therapeutic for
atherosclerosis.

## Key facts

- **NIH application ID:** 10313442
- **Project number:** 1F31HL160118-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Abigail Elizabeth Allen Gondringer
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313442

## Citation

> US National Institutes of Health, RePORTER application 10313442, Profilin-1's Role in Atherosclerosis (1F31HL160118-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10313442. Licensed CC0.

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