# Progressive degenerative role of Nox and thrombospondin-1 in the aging vasculature

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $577,109

## Abstract

PROJECT SUMMARY
Aging is a recognized risk factor in peripheral vascular disease (PVD). A hallmark of aging in humans is loss of
vascular function reflected, in part, by inhibited self-renewal of endothelial cells (EC). An unmet need is the
emergence of therapies that stop or reverse endothelial senescence (decreased capacity for cellular division,
self-renewal) and vascular insufficiency. A second pathognomonic feature of aging is increased reactive
oxygen species (ROS). Pathologic ROS impair vascular flow, but the mechanisms responsible for these
maladaptive age-related changes in the endothelium remain unknown. Thrombospondin-1 (TSP1) is increased
in the plasma, arterial walls and interstitial fluid of peripheral vascular disease (PVD) patients and is linked to
disease severity and loss of vascularity. We have found that with aging, wild type (WT) mice show induction of
TSP1 and its cognate cell membrane receptor CD47 and this was associated with decreased vasodilator-
mediated changes in blood flow, an effect not observed in TSP1-/- and CD47-/- mice. We also reported that
TSP1, via CD47, potently stimulates NADPH oxidase 1 (Nox1)-derived ROS and impedes hind-limb blood flow.
Preliminary data by our group show that TSP1 is upregulated in older adults, and it inhibits endothelial self-
replication and promotes endothelial senescence in peripheral vessels. These findings led us to propose the
overarching hypothesis that TSP1, via CD47 engagement and Nox1 activation, impairs self-renewal through
exacerbated ROS production culminating in EC senescence and vasculopathy. Three specific aims will be
pursued to: (1) test in vitro that with aging TSP1 induces Nox1-mediated suppression of key self-
renewal genes and promotes endothelial cell (EC) senescence; (2) explore in vivo that inhibition of the
TSP1-CD47 axis as well as attenuating its downstream Nox1 effector restores self-renewal,
angiogenesis and perfusion in aged animals; and (3) investigate that perturbing the TSP1-CD47-Nox1
axis in aged human tissue ameliorates age-related endothelial and vascular dysfunction. The proposal
will employ multiple molecular and genetic tools to interrogate mechanisms into TSP1-CD47-mediated
activation of Nox1 in aging human and mouse vessel function, self-renewal and angiogenesis, as well as
generate two EC-specific knockout mice to test our hypotheses. These studies will also provide robust pre-
clinical data towards rational development of new and effective treatments for EC senescence and
vasculopathy.

## Key facts

- **NIH application ID:** 10349498
- **Project number:** 5R01HL142248-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Patrick J Pagano
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $577,109
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10349498

## Citation

> US National Institutes of Health, RePORTER application 10349498, Progressive degenerative role of Nox and thrombospondin-1 in the aging vasculature (5R01HL142248-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10349498. Licensed CC0.

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