# Brain Drain: In Vivo Optical Interrogation of Venular Function in Gray and White Matter

> **NIH NIH RF1** · SEATTLE CHILDREN'S HOSPITAL · 2022 · $2,459,487

## Abstract

PROJECT SUMMARY
Much of our understanding of how cerebrovascular disease contribute to dementia focuses on the pathology of
brain arterioles. However, whether pathology of cerebral venules also contribute to impairment of cerebral
perfusion remains highly understudied. Preclinical and clinical studies have demonstrated marked alterations in
venule tortuosity and vascular wall composition in small vessel diseases that underlie Vascular contributions to
Cognitive Impairment and Dementia (VCID) and Alzheimer’s disease. Yet, the fundamentals of how brain venous
networks are organized, and how their deterioration contributes to dementia, remain obscure. The goal of this
project is to leverage recent advances in multi-photon imaging to investigate age-related impairment of
venous drainage in deep gray and white matter of mouse brain in vivo. Cerebral white matter resides in
deep brain regions and is particularly sensitive to blood flow deficit in early stages of dementia. It is challenging
to access this tissue in vivo such that the etiology of white matter deficits can be better understood. Our approach
overcomes this issue by using a combination of in vivo deep two-photon imaging with long wavelength
excitation/emission and three-photon imaging to study microvasculature at the cortical gray-white matter
interface and in deeper white matter, respectively. In preliminary studies, we found that blood drainage from
deeper tissues rely exclusively on rare ascending venules, termed principle cortical venules (PCVs). PCVs
collect blood by extending massive branching networks with long, tortuous draining capillaries. Critically, deep
microvascular networks of PCVs were selectively constricted, reduced in vascular density, and more poorly
perfused in aged mice (18-24 months) compared to adult mice (6-9 months). Our over-arching hypothesis is
that deterioration of PCV structure and function is the basis for age-related blood flow impairment in deep gray
and white matter. In Aim 1 of this project, we will test the hypothesis that PCVs exhibit brain region-specific
deterioration in structure and function during aging, as white matter is more distant from arteriolar input in regions
with thicker cortex. In Aim 2, we will test the hypothesis that dysfunction of capillary pericytes contributes to
deterioration of PCV networks. In Aim 3, we will test the hypothesis that vasoconstriction and flow impairment
in PCV networks can be alleviated by fasudil, a clinically-used drug that can reduce contractile tone in capillaries
in addition to arterioles. A genetic strategy to remove fasudil’s target, rho kinase, specifically in brain capillary
pericytes will complement the pharmacological approach. This project is significant because it will: (1) Advance
novel imaging technologies to study the microvascular basis of white matter degeneration in mouse models of
VCID and Alzheimer’s disease. (2) Provide insight into the structure and function of PCVs, which are an
uncharacte...

## Key facts

- **NIH application ID:** 10463455
- **Project number:** 1RF1AG077731-01
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Andy Y Shih
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,459,487
- **Award type:** 1
- **Project period:** 2022-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463455

## Citation

> US National Institutes of Health, RePORTER application 10463455, Brain Drain: In Vivo Optical Interrogation of Venular Function in Gray and White Matter (1RF1AG077731-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10463455. Licensed CC0.

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