# Integrative Mechanisms of Vascular Aging

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $459,678

## Abstract

Arterial aging is characterized by diminished endothelium dependent dilation (EDD) and large artery stiffening.
The endothelium is a critical modulator of arterial function participating in the control of vascular tone, nitric
oxide production and bioavailability, large artery stiffening, inflammation, and barrier function. Deterioration of
the glycocalyx, a gel-like structure bound to the luminal surface of the endothelium, is accompanied by age-
associated vascular dysfunction by altering these functions of the vascular endothelium. Although the
glycocalyx is primarily known for its role in the microvasculature, it also impacts central cardiovascular
features, and deterioration or phenotypic changes in the glycocalyx with advancing age that likely impair larger
arterial function. The thickness of the glycocalyx decreases in the microvasculature of both mice and humans
with advancing age and this appears to be accompanied by alterations in its constituent molecules. Although
there is no consensus on whether the content of hyaluronan (HA), one of the primary glycosaminoglycan
components of the endothelial glycocalyx, decreases across the lifespan, there is evidence of a phenotypic
shift from high (HMW-HA) to low molecular weight. The importance of maintaining a youthful, HMW-HA, profile
is demonstrated by observations that HMW-HA has anti-aging, vasoprotective properties. Among the three HA
synthase (HAS) enzymes, HAS2 produces the majority of HMW-HA. However, although reductions in HAS2
gene expression have been reported in non-vascular tissues with aging, arterial data concerning the effects of
aging on HAS2 expression are limited. Thus, despite evidence suggesting that alterations in the glycocalyx; its
constituent, HA; and the enzyme responsible for its production, HAS2, are coincident with age-related arterial
dysfunction, their causal role remains elusive. Here, we will utilize endothelial specific, loss and gain of function
mouse models to elucidate the role of HAS2 and HA phenotype in alterations in the glycocalyx, arterial
function, inflammation, and permeability across the lifespan of mice. We will also interrogate the role of a HA
receptor, CD44, in these effects. Last, we will assess the efficacy of dietary supplementation with HMW-HA to
improve these aspects of arterial function in advancing age and explore underlying mechanisms. The results
will elucidate novel mechanisms of age-related vascular dysfunction as well as demonstrate proof-of-concept
for a new therapeutic to ameliorate age-associated arterial dysfunction that is easily translatable to humans.

## Key facts

- **NIH application ID:** 10828851
- **Project number:** 5R01AG077751-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Anthony John Donato
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $459,678
- **Award type:** 5
- **Project period:** 2023-04-15 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828851

## Citation

> US National Institutes of Health, RePORTER application 10828851, Integrative Mechanisms of Vascular Aging (5R01AG077751-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10828851. Licensed CC0.

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