# Endothelial extracellular vesicles in aging

> **NIH NIH R21** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $418,000

## Abstract

Project Summary
The aging population is rapidly growing. Aging is associated with impaired organ function and repair and
increased susceptibility to various chronic diseases. Angiogenesis – the formation of new blood capillaries-
plays a key role in organ development and regeneration. Angiogenesis is impaired in aging animals and
contributes to age-related pathologies. In order to develop more efficient therapies for aging-associated
diseases, we need to understand the mechanisms by which aging impairs angiogenesis. Senescent cells
promote aging and exacerbate age-related pathologies. The levels of endothelial cell (EC) senescence are
higher in aged ECs compared to young ECs, mediating age-dependent impairment of angiogenesis.
Extracellular vesicles (EVs) serve as a messenger of signals, maintaining tissue homeostasis and function in
physiology and contributing to age-related diseases. EVs collected from lung ECs under regeneration stimulate
angiogenesis, while senescence-associated secretory phenotype factors are enriched in EVs from senescent
ECs, highlighting EC-derived EVs (EC-EVs) as a critical contributor to age-dependent decline in angiogenesis.
EVs contain and transfer a diverse cargo of proteins, lipids, and various types of nucleic acid to target cells and
control cell-cell communications. Among EV-enclosed RNAs, Y-RNAs are one of the most abundant non-
coding RNAs in EVs, and the levels of Y-RNAs correlate with age-related cardiovascular diseases, in which
angiogenesis is deregulated. The role of EV-enclosed Y-RNAs in EC senescence and age-related decline in
angiogenesis remains unclear. The overall goal of this proposal is to determine whether EV-enclosed Y-RNAs
mediate age-dependent impairment of angiogenesis. Among four human Y-RNAs (Y1, 3, 4, 5), Y5-RNA is the
most abundant Y-RNAs in EC-EVs. Our preliminary data demonstrate that: (1) conditioned media (CM) that
contains EVs, from aged human ECs induces senescence in young ECs; (2) the levels of Y5-RNA are lower in
EVs collected from CM of aged ECs; (3) overexpression of Y5-RNA 5’ fragment suppresses senescence and
restores migration in aged ECs; (4) Y5-RNA knocked down EC-EVs inhibit DNA synthesis in young ECs; and
(5) young EC-EVs restore blood vessel formation of aged ECs in the subcutaneously implanted hydrogel, while
Y5-RNA knocked down EC-EVs inhibit the effects. We hypothesize that age-dependent decreases in Y5-RNA
in EC-EVs mediate EC senescence and impairment of angiogenesis in aged ECs. In Aim 1, we will examine
whether Y5-RNA in EC-EVs mediates age-dependent induction of EC senescence. In Aim 2, we will determine
whether Y5-RNA in EC-EVs mediates age-dependent decline in angiogenesis in vitro and in the gel implanted
on mice. Our focus to investigate the effects of Y5-RNA in EC-EVs on EC senescence and age-dependent
impairment of angiogenesis is unique and conceptually innovative. If this study proves that manipulation of Y5-
RNA in aged EC-EVs reverses the age-related de...

## Key facts

- **NIH application ID:** 10984795
- **Project number:** 1R21AG084736-01A1
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** TADANORI MAMMOTO
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $418,000
- **Award type:** 1
- **Project period:** 2024-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984795

## Citation

> US National Institutes of Health, RePORTER application 10984795, Endothelial extracellular vesicles in aging (1R21AG084736-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10984795. Licensed CC0.

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