# Telomerase Reverse Transcriptase in Vascular Homeostasis

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $594,673

## Abstract

The vascular endothelium plays an essential role in coordinating diverse circulatory 
functions such as blood flow, thrombosis, leukocyte trafficking, and even metabolism. Normal 
endothelial function is characterized by a quiescent cell phenotype that is non-proliferative, 
non-migratory, and exhibits a cell surface that prevents thrombosis, inflammation, and lipid 
deposition, thereby resisting atherosclerosis and vascular disease. A key stabilizing 
stimulus for endothelial quiescence is laminar fluid shear stress (FSS) on the cell 
surface that is a feature of straight vascular segments. In contrast, curved and 
branching arteries experience chaotic FSS, called disturbed flow, that dictates a less 
stable, activated, endothelial phenotype that is more susceptible to atherosclerosis. The 
mechanisms governing endothelial phenotype in response to fluid shear stress are 
incompletely understood. In this application, we present data that peroxisome proliferator 
gamma coactivator-1α (PGC1α), is a fluid shear stress-responsive factor in endothelium that is 
upregulated with laminar, but not oscillatory FSS. Upregulation of PGC1α is important for the 
activation of key pathways linked to normal vascular homeostasis such as Klf2, Notch, and 
eNOS that promote a stable anti-atherosclerotic endothelial phenotype. Exciting pilot data 
 links this effect to upregulation of telomerase reverse transcriptase (TERT) and its 
extra-nuclear, telomere length-independent, function to stabilize maintain 
mitochondrial homeostasis in response to laminar FSS. Endothelium lacking TERT activity 
shows mitochondrial fragmentation and fails to align with flow, a key function needed 
to resist atherosclerosis. Collectively, these data prompt our central hypothesis that 
endothelial PGC1α-TERT signaling is required for endothelial and vascular adaptation to 
shear and normal vascular homeostasis. To investigate this hypothesis, we propose to first 
determine how PGC1α influences endothelial responses to FSS in vivo using a 
tamoxifen-inducible Cre/Lox system producing endothelial specific PGC1α-gene excision, in 
situ confocal microscopy, single-cell RNA-seq, Network Medicine, and the ApoE-/- atherosclerosis 
model. Similarly, we will use the same strategy with inducible endothelial TERT gene excision. 
Finally, using cell culture of cells lacking either PGC1α or TERT, we will dissect the 
mechanisms whereby PGC1α-TERT signaling impacts endothelial FSS responsiveness with a 
particular focus on FSS-induced PGC1α genome occupancy, mitochondrial and cellular metabolism, 
endothelial cell flow alignment, and TERT localization to the nucleus vs. mitochondria.
Collectively, these studies will provide insight into a new paradigm of endothelial cell 
responsiveness to FSS and the requirements to maintain a quiescent endothelial monolayer that 
resists vascular disease. With this information, we should have the requisite insight to design new 
therapies to alleviate morbidity a...

## Key facts

- **NIH application ID:** 10412985
- **Project number:** 5R01HL151626-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** John Francis Keaney
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $594,673
- **Award type:** 5
- **Project period:** 2020-05-06 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412985

## Citation

> US National Institutes of Health, RePORTER application 10412985, Telomerase Reverse Transcriptase in Vascular Homeostasis (5R01HL151626-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10412985. Licensed CC0.

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