# Translational analysis of cerebrovascular dysfunction in aging

> **NIH NIH P20** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2020 · $258,193

## Abstract

ABSTRACT
 Age-related vascular cognitive impairment (VCI) and gait abnormalities are the two most common causes of
disability in older adults that lead to loss of independence and severely reduce quality of life. Recent studies
have concluded that cerebromicrovascular pathologies play an important role in the manifestation of VCI and
gait abnormalities. One of the fundamental roles of the cerebrovasculature is to match cerebral blood flow (CBF)
with energetic demands of neurons through a process known as neurovascular coupling (NVC). NVC maintains
an optimal cerebral tissue microenvironment and requires microvascular dilation induced by nitric oxide (NO)
released from cerebromicrovascular endothelial cells (CMVECs) in response to neuronal/astrocytic activation.
Recent studies demonstrate that inhibition of NO-mediated NVC responses in mice results in impaired cognitive
performance and gait abnormalities. Importantly, one of the factors that regulates NVC and cognition in animal
models is the vasoprotective hormone insulin-like growth factor-1 (IGF-1) that has been shown to decrease with
age and influences many cell-types in brain. Recent findings suggest that age-related decline of circulating IGF-
1 promotes stress and DNA damage and is associated with increased expression of markers of cellular
senescence in brain and aorta. Despite recent advances, there is a critical gap in our understanding related to
specific molecular mechanisms that promote cerebromicrovascular endothelial dysfunction in aging, and
whether the age-dependent deficiency of circulating IGF-1 is associated with impairments in NVC and higher
brain functions (including cognition and gait) in humans. Our overall hypothesis is that age-associated IGF-1
deficiency promotes endothelial dysfunction and impairments in NVC by inducing endothelial cell senescence,
which contribute to cognitive impairment and gait abnormalities in older animals and humans. The following aims
are proposed: Aim 1) Assess whether dysfunction of NVC is mediated through a specific effect of IGF-1
deficiency on CMVECs and whether endothelial cell senescence contributes to this impairment. In this aim we
will use novel model ofdisruption of IGF-1 signaling specifically in endothelial cells and a novel mouse model
(p16-3MR) which allows to specifically eliminate senescent cells. Aim 2) Determine the relationship between
age, circulating IGF-1 status, endothelial function, NVC responses, cognition and gait in human subjects.

## Key facts

- **NIH application ID:** 9857622
- **Project number:** 5P20GM125528-02
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Andriy Yabluchanskiy
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $258,193
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857622

## Citation

> US National Institutes of Health, RePORTER application 9857622, Translational analysis of cerebrovascular dysfunction in aging (5P20GM125528-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9857622. Licensed CC0.

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