# Quantifying the Influence of Pathological Hemodynamics on Cerebral Microvascular Dysfunction and Neuronal Injury

> **NIH NIH P20** · UNIVERSITY OF DELAWARE · 2021 · $320,515

## Abstract

PROJECT SUMMARY
Dementia is a debilitating syndrome with many incapacitating symptoms requiring dependent care that is
emotionally and financially burdensome for patients and their families. Dementia is the 6th leading cause of
death in the United States with 47.5 million people worldwide currently living with dementia which is projected to
reach 75.6 million by 2030 and 135.5 million by 2050. Unfortunately, no therapies to treat dementia exist,
indicating a critical and urgent need for a better understanding of how dementia is initiated and progresses so
that new therapeutic approaches can be developed. Age-related stiffening of the large elastic arteries is a major
contributor to dementia but the mechanism(s) by which this occurs remain unknown. In healthy individuals,
pulsatile flow in large vessels is converted to continuous flow in cerebral µvasculature via pulsatility dampening
by large arteries. Repeated cycles of distension and relaxation over time induce irreversible elastin fragmentation
in large arteries which is replaced by stiffer collagen thereby diminishing compliance and dampening. This results
in the conversion from continuous to pulsatile flow in cerebral microvasculature accompanied by increases in
pulse pressure and pulse wave velocity. These pathological hemodynamics have been linked to cognitive decline
via neuronal injury, synaptic dysfunction, and neurodegeneration. While most hypotheses focus on shear-
induced injury mechanisms, endothelial cells and neurons are also sensitive to strain. We hypothesize that
induction of cyclic strain, in the microvessel wall and adjacent tissue, due to the conversion to pulsatile flow,
exacerbates shear-induced brain microvascular endothelial cell (BMEC) dysfunction and is the primary cause of
neuronal injury. We will test our hypotheses via fulfillment of two aims. (1) Investigate the independent, and
combined influences of, conversion to, and increases in, cyclic shear stress and cyclic strain on BMEC
dysfunction and inflammation. We hypothesize that conversion from continuous to pulsatile flow, and an increase
in pulse wave velocity, induce BMEC dysfunction and inflammation via exposure to increased cyclic shear stress.
We further hypothesize that cyclic strain in the microvascular wall, and increase in strain magnitude due to
increased pulse pressure, exacerbate shear-induced BMEC dysfunction. (2) Investigate the influence of cyclic
strain on neuronal injury. We hypothesize that as pulse pressure increases, the associated increase in strain will
induce neuronal injury via strain propagation into tissue and neurons adjacent to the vessel and that this process
worsens with age-related brain softening. The results of this proposal will provide significant insight into how
pathological hemodynamics induced by arterial stiffening lead to BMEC and neuronal injury.

## Key facts

- **NIH application ID:** 10271701
- **Project number:** 2P20GM113125-06
- **Recipient organization:** UNIVERSITY OF DELAWARE
- **Principal Investigator:** John Hundley Slater
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $320,515
- **Award type:** 2
- **Project period:** 2016-05-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271701

## Citation

> US National Institutes of Health, RePORTER application 10271701, Quantifying the Influence of Pathological Hemodynamics on Cerebral Microvascular Dysfunction and Neuronal Injury (2P20GM113125-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10271701. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*