# Regulation of Flt 1 Splicing by Fibronectin and Integrin Signaling During Aging

> **NIH NIH RF1** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2023 · $1,583,383

## Abstract

Abstract
Risk factors for cognitive impairment and dementia target the vasculature, a condition known as
Vascular contributions to Cognitive Impairment & Dementia (VCID). However, the molecular
mechanisms that result in reduced vascular function, density and perfusion in disease are
poorly understood. Recent work has focused on vascular endothelial growth factor (VEGF),
which signals through VEGF receptor 2, and is a major contributor to endothelial cell survival
and vessel maintenance. VEGF bioavailability declines with age, leading to vascular dysfunction
and reduced vessel density in the brain and other organs. This effect is due to increased levels
of a VEGF antagonist, an alternatively spliced soluble form of the decoy receptor VEGFR1,
termed soluble Flt1 (sFlt1), primarily expressed in the endothelium. Interestingly, the above risk
factors for vascular disease – age, diabetes, hypertension and vascular injury – are linked to
increased subendothelial accumulation of the extracellular matrix protein fibronectin (FN) in
vascular basement membrane. FN contributes to vessel repair and integrity but in disease
settings can drive inflammation and dysfunction. Preliminary data show that, under conditions of
high substrate stiffness, cell adhesion to FN through integrin α5β1 induces alternative splicing of
the Flt1 transcript to increase sFlt1 production These findings lead us to propose the novel
hypothesis that FN accumulation and vessel stiffening with age drives increased production of
sFlt1, which mediates vascular rarefaction in the brain and impairs cognitive function. In the first
Aim, we will determine how mechanical strain on integrin α5β1 leads to Flt1 splicing and
premature polyadenylation, identifying the RNA-binding proteins (RBPs) responsible for the
change in splicing and elucidating mechanisms of regulation. In the second Aim, we will test the
above hypothesis in mouse models and identify therapeutic targets whose blockade prevents
sFlt1 production and protects from cognitive impairment. Together, the completion of these aims
will provide new molecular insights into VCID by linking the increased vascular accumulation of
FN to the production of sFlt1, determining molecular mechanisms, and identifying ways to inhibit
this pathway to limit vascular rarefaction and cognitive decline associated with VCID risk factors.

## Key facts

- **NIH application ID:** 10777172
- **Project number:** 1RF1NS135026-01
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Patrick Andries Murphy
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,583,383
- **Award type:** 1
- **Project period:** 2023-09-19 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10777172

## Citation

> US National Institutes of Health, RePORTER application 10777172, Regulation of Flt 1 Splicing by Fibronectin and Integrin Signaling During Aging (1RF1NS135026-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10777172. Licensed CC0.

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