# Vascular autophagy as a mediator of vascular aging and homeostasis

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $536,994

## Abstract

The role of autophagy in vascular homeostasis and vascular reactivity is poorly understood. In
this proposal, we characterize mice lacking autophagic flux in the endothelial or smooth muscle
cell layer. Remarkably, inhibiting autophagic flux in vascular smooth muscle cells appears to
recapitulate aspects of the rare human disease Hutchinson-Gilford Progeria Syndrome (HGPS).
This segmental progeriod condition is caused by a dominant mutation in the lamin A/C gene.
While HGPS is an accelerated aging syndrome, most of the fatalities result from vascular
complications (e.g. myocardial infarction and stroke). Analysis of human subjects, as well as
characterization of mouse models of the disease, demonstrate profound changes in the large
arteries. These changes are believed to be secondary to the vascular accumulation of progerin,
an altered form of lamin A whose production is favored in patients with HGPS. Interestingly,
progerin can also accumulate in the blood vessels of normal individuals as a function of aging.
As such, these observations suggest that the lessons learned from this rare progeriod
syndrome, HGPS, may have wider applications. In this proposal, we explore the role of
autophagy in the segmental vascular pathology of HGPS. Using a variety of novel mouse
models where autophagy has been conditionally deleted in the vessel wall, as well as human
induced pluripotent stem cells (iPSCs) in which specific genes have been deleted via CRISPR-
based strategies, we propose to study the mechanistic connection between impaired
autophagy, HGPS pathology and normal vascular aging. As such, these studies provide the first
characterization as to how endothelial and vascular smooth muscle cell autophagy regulates
vascular homeostasis.

## Key facts

- **NIH application ID:** 10186792
- **Project number:** 5R01HL142663-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** TOREN FINKEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $536,994
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186792

## Citation

> US National Institutes of Health, RePORTER application 10186792, Vascular autophagy as a mediator of vascular aging and homeostasis (5R01HL142663-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10186792. Licensed CC0.

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