# Autophagy maintains vascular function through a novel glycolysis-linked pathway regulating eNOS.

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $396,868

## Abstract

SUMMARY
One report indicates endothelial cell (EC) autophagy is compromised in aged humans. We showed that genetic
repression of autophagy in ECs negates shear-stress induced EC nitric oxide (NO) synthase (eNOS) activation
and NO generation. It is unknown whether disruption of autophagy specifically in ECs has functional relevance
in vivo, and the mechanism whereby repressed EC autophagy compromises NO generation is not known. In
Aim 1 we will test the hypothesis that conditional deletion of autophagy in ECs from adult mice (iecAtg3KO
mice) phenocopies arterial dysfunction that is present in old mice. Further, based on compelling preliminary
data, we will test the hypothesis that repressed EC autophagy in mutant mice and old mice evokes a p53-
mediated block in glycolysis, leading to decreased signaling by extracellular ATP via the P2Y1-R and PKCδ to
eNOS, resulting in arterial dysfunction. Aim 2 will explore the translational potential of this novel pathway in the
context of human aging. In immortalized human arterial endothelial cells (HAECs) we hypothesize that genetic
autophagy suppression prevents shear-stress induced purinergic signaling to eNOS. Next, this pathway will be
evaluated in primary arterial ECs obtained from old (> 60 y) and adult (18-30 y) subjects before and following
rhythmic handgrip exercise that elevates brachial artery shear-rate similarly in both groups. ECs will be used to
quantify EC autophagy, eNOS activation, and NO generation. Importantly, pharmacological and genetic
approaches that restore purinergic mediated signaling to eNOS will be used in these models of genetic and
aging-associated autophagy repression in human ECs. Aim 3 will use adult and aged mutant mice to
determine whether exercise-training attenuates the aging-associated decline in EC autophagy, and whether
intact autophagy is required for training-induced vascular improvements. To evaluate translational potential, we
will discern whether one-limb rhythmic handgrip exercise training by old (> 60 y) human subjects is sufficient to
elevate basal and shear-induced EC autophagy initiation, eNOS activation, and NO generation vs. the
contralateral sedentary limb. Results from this work have tremendous potential to reveal a new therapeutic
target and approach for restoring / maintaining vascular function in the aging population.

## Key facts

- **NIH application ID:** 10166904
- **Project number:** 5R01HL141540-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** John David SYMONS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $396,868
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166904

## Citation

> US National Institutes of Health, RePORTER application 10166904, Autophagy maintains vascular function through a novel glycolysis-linked pathway regulating eNOS. (5R01HL141540-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10166904. Licensed CC0.

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