# Lesions and loss of smooth muscle cells in brain underlies small vessel disease

> **NIH NIH RF1** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2022 · $1,989,320

## Abstract

In response to the FOA, PAR-22-026, we propose an integrated and technologically/conceptually innovative approach to
advance our mechanistic understanding of how dysfunction of small brain vessels can have long-term impacts on the brain
parenchyma and cause cognitive impairment. Cerebral small vessel disease (cSVD) accounts for up to 25% of ischemic
strokes and more than 90% of spontaneous intracerebral hemorrhages (ICHs), and as such is a major driver of dementia.
Recent studies have shown that there are at least four types of mural cells defining four major microvascular zones:
smooth muscle cells (SMCs) on arterioles, contractile pericytes (PCs) on the post-arteriole region of the capillary bed (i.e.,
transition zone), non-contractile PCs on distal capillaries and venular PCs on venules. Loss of arteriolar SMCs in human
post-mortem brains is a feature shared by both multifactorial and inherited cSVD, whether associated with ischemic
strokes or ICHs. We have provided compelling evidence that loss of SMCs on arterioles coupled with enhanced function
of contractile PCs on the transition zone mutually reinforce each other to cause ICHs, and recently discovered that
arteriolar SMCs and contractile PCs in the transition zone are lost early in the brain and retina of clinically relevant mouse
models of ischemic cSVDs with gain- or loss-of-function mutations in the NOTCH3 receptor. On the basis of these and
other observations, we propose that loss of SMCs specifically in brain arterioles is a common factor underlying the
development of cSVDs and that changes in the properties/density of contractile PCs in the post-arteriole transition zone
modify disease presentation. To test this, we will explore the causal relationship between the loss of SMCs/PCs and cSVD-
related brain pathologies and cognitive symptoms (Aim 1) and determine how loss of SMCs/contractile PCs compromises
integrative vascular functions (Aim 2). To this end, we will employ existing and novel mouse models with conditional
inactivation of Notch3 in specific mural cell populations and deploy a powerful array of new techniques, including 1) a
novel coordinate-based object analysis methodology capable of simultaneously quantifying all imageable parameters,
including small vessel pathology, in massive 4D (3D over time) imaging datasets from high-resolution sections of the entire
brain; 2) a novel pressurized retina preparation in conjunction with labeled red blood cells and microspheres for
quantitatively assessing the impact of small vessel pathology on intravascular pressure and flow across different
microvascular segments; and 3) ultrafast functional ultrasound imaging, an emerging technology that can non-invasively
sample cerebral blood volume changes in vivo in a complete coronal section of a mouse brain with a high spatiotemporal
resolution, for elucidating how small brain vessel pathologies affect cerebral blood flow regulation in deep parts of the
brain. We expect that the proposed ...

## Key facts

- **NIH application ID:** 10527075
- **Project number:** 1RF1NS128963-01
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** ANNE JOUTEL
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,989,320
- **Award type:** 1
- **Project period:** 2022-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10527075

## Citation

> US National Institutes of Health, RePORTER application 10527075, Lesions and loss of smooth muscle cells in brain underlies small vessel disease (1RF1NS128963-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10527075. Licensed CC0.

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