# p16 Cellular Senescence and Vascular Dysfunction in Sleep Apnea

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2024 · $745,121

## Abstract

PROJECT SUMMARY/ABSTRACT
Obstructive Sleep Apnea (OSA) is the most severe form of Sleep-Disordered-Breathing (SDB), and is extremely
prevalent, affecting nearly a billion adults worldwide. OSA-associated morbidities affect virtually all organ
systems via activation and propagation of oxidative stress and systemic inflammatory pathways, de facto
mimicking accelerated biological aging. In particular, OSA is widely recognized as an independent cardiovascular
risk factor, associated with incident obesity, atherosclerosis, hypertension (HTN), endothelial dysfunction,
arrhythmias, stroke, coronary artery disease (CAD) and heart failure. Both epidemiologic and intervention-based
studies have provided conclusive evidence indicating a causative link between OSA and cardiovascular
morbidity. However, the physiological and molecular mechanisms of OSA-induced vascular senescence leading
to vascular dysfunction remain to be elucidated.
The cyclin dependent kinase inhibitor 2A (CDNK2A), also known as p16, is a protein that slows cell division, and
its upregulation is a hallmark of cellular senescence in both mice and humans. Recently, selective elimination of
cells highly expressing the p16 protein (commonly referred to as p16high cells) was shown to improve and reverse
aging-associated diseases. Whether targeting vascular senescence can improve vascular outcomes in OSA has
not been investigated yet. In this project, it is hypothesized that chronic exposures to Intermittent Hypoxia (IH)
and Sleep Fragmentation (SF), two main features of OSA that can be reproduced in mouse models, will induce
accelerated vascular senescence in mice manifesting as vascular dysfunction. As a corollary, it is proposed that
eliminating p16high cells may reverse or attenuate IH- and SF-mediated vascular deficits. Three different
transgenic mouse models will be used: i) containing a p16 reporter, ii) enabling systemic ablation of p16high cells,
and iii) enabling the specific ablation of p16high vascular endothelial cells (vECs). These models will be exposed
to IH, SF and the combination of both (IH+SF), to investigate the phenotypic effects and molecular mechanisms
of OSA-induced cardiovascular senescence, and their reversibility through selective elimination of senescent cells
in the vasculature. Physiological and cardiovascular changes will be assessed at predetermined time points. By
studying DNA methylation profiles at each time points, it will be determined whether such exposures will induce
an acceleration in the biological age compared with the chronological age. This is referred to as “Epigenetic Age
Acceleration” and constitutes a novel approach for quantifying aging at systemic and tissue-specific level.
Furthermore, by studying whole genome DNA methylation and RNA profiles in tissues, isolated vECs and
primary vECs cultures, the pathways, and molecular networks responsible of the OSA-induced vascular
senescence and function will be investigated. This project will create a ...

## Key facts

- **NIH application ID:** 10977909
- **Project number:** 1R01HL169266-01A1
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Rene Gabriel Cortese
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $745,121
- **Award type:** 1
- **Project period:** 2024-05-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977909

## Citation

> US National Institutes of Health, RePORTER application 10977909, p16 Cellular Senescence and Vascular Dysfunction in Sleep Apnea (1R01HL169266-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10977909. Licensed CC0.

---

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