# Defining the role of endothelial Piezo1, a mechanosensitive ion channel, in providing resilience to vascular contributions to cognitive impairment and dementia (VCID)

> **NIH NIH R56** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $620,183

## Abstract

Cerebrovascular dysfunction is a contributing factor to the development of cognitive impairment and dementia
in both Alzheimer’s disease (AD) and in non-AD pathologies. Vascular contributions to cognitive impairment and
dementia (VCID) is an evolving field of study which covers the overlap and interrelationship between vascular
disorders and disorders leading to dementia. More basic science research investigating the impact of aging, AD
pathology, and cerebrovascular function is currently needed.
 Piezo1 is a recently identified mechanosensitive ion channel that gates calcium influx in response to membrane
stretch or increased shear forces. It is expressed in multiple tissues, but plays a critical role in cardiovascular health
and disease. In the peripheral vasculature, activation of this ion channel by luminal shear or by a selective agonist
promotes increased endothelial intracellular calcium and vasodilation. Our significant preliminary data provide
the first demonstration that endothelial Piezo1 plays an important role in regulating cerebral blood flow (CBF) and
contributes to microvascular stability. We also demonstrate that CBF can be enhanced by delivery of a selective
Piezo1 agonist (Yoda1) at doses that do not alter systemic blood pressure.
 An intriguing recent study showed that shear-mediated Ca2+ influx in cells exogenously expressing human PIEZO1
was potently inhibited by amyloid beta (Ab) monomers (Ab40>Ab42). If these findings are similarly valid with
endogenously-expressed Piezo1 within the cerebral vasculature, it would suggest a new mechanism by which
elevated Ab contributes to impaired CBF regulation and the eventual development of VCID. We tested this
possibility with mouse brain microvascular endothelial cells (BMVECs). We found that exposure to human Ab40
indeed abolished the flow-mediated Ca2+ response, but that responsiveness to direct pharmacological Piezo1
activation remained intact. We further demonstrated that the in vivo CBF response to Yoda1 was also intact in
TgSwDI mice which express elevated levels of soluble Ab40 and Ab42. These provocative findings suggest that
while flow/shear-dependent function of cerebral endothelium may indeed be impaired by elevated Ab peptides,
this dysfunction may be “bypassed” by direct pharmacological activation of Piezo1.
 In this proposal, we will test the overall hypothesis that loss of endothelial Piezo1 function (such as in conditions
of chronically reduced flow or elevated soluble Ab) leads to cerebrovascular dysregulation and the development
of VCID. In addition, we seek to establish proof-of-concept for a strategy to provide resilience to VCID by
pharmacologically “mimicking” flow-mediated endothelial activation with selective Piezo1 agonists.
 Completion of these studies will establish a vital role of EC Piezo1 in the regulation of cerebral blood flow and
the pathological consequences of its functional loss in the development of VCID. These studies will further
establish the sc...

## Key facts

- **NIH application ID:** 10419669
- **Project number:** 1R56NS120709-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Sean P Marrelli
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $620,183
- **Award type:** 1
- **Project period:** 2021-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10419669

## Citation

> US National Institutes of Health, RePORTER application 10419669, Defining the role of endothelial Piezo1, a mechanosensitive ion channel, in providing resilience to vascular contributions to cognitive impairment and dementia (VCID) (1R56NS120709-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10419669. Licensed CC0.

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