# Perivascular fibroblasts, vascular fibrosis, and their contributions to cerebral amyloid angiopathy

> **NIH NIH RF1** · VANDERBILT UNIVERSITY · 2022 · $2,333,228

## Abstract

Project summary
Cerebral amyloid angiopathy (CAA) is a disease that occurs when amyloid beta (Aβ) forms deposits on brain
blood vessels. CAA frequently co-occurs with Alzheimer’s disease (AD) and is a significant risk factor for
intracranial hemorrhage and dementia. There are no approved treatments for CAA, and the molecular etiology
of the disease remains unclear, which has prevented the development of effective therapeutic interventions.
Here, we propose to study cerebral perivascular fibroblasts and vascular fibrosis signaling pathways as potential
contributors to CAA pathology. More than 20 years ago, pioneering work showed that astrocyte-specific
upregulation of transforming growth factor beta 1 (TGFβ1), a master regulator of tissue fibrosis, could specifically
induce Aβ pathology in the cerebrovasculature that was reminiscent of CAA. However, the mechanistic actions
of TGFβ1 that could drive such a response were never elucidated. In studying postmortem human brain tissue
from CAA patients, we have found that cerebral perivascular fibroblasts acquire myofibroblast markers around
vessels with Aβ deposition and fibrotic signatures—this phenotype is observed specifically in CAA but not AD or
age-matched controls. Further, this phenotype is replicated in 5xFAD mice after intracerebroventricular injections
of human vascular-derived human Aβ seeds, which yields CAA-like pathology. Hence, we hypothesize that
activation of perivascular fibroblasts and fibrotic signaling pathways in the perivascular niche leads to Aβ
deposition, vascular fibrosis, and acquisition of the CAA phenotype. In Aim 1, we will explore this hypothesis
within two complementary mouse models using three-dimensional tissue imaging techniques, single-cell RNA
sequencing, and blood flow measurements. In Aim 2, we will leverage a novel bioengineered model of human
cerebral arterioles to understand how TGFβ1 shapes the fibrotic microenvironment through multicellular
crosstalk. In Aim 3, again in mouse models, we will target cerebral perivascular fibroblasts and fibrotic signaling
pathways using gene silencing techniques and small molecule treatments and determine if CAA pathology is
lessened. Collectively, these studies will unveil and characterize how perivascular fibroblasts and vascular
fibrosis contribute to CAA pathology. Moreover, these investigations will identify potential preclinical drug
development strategies focused on targeting fibroblast activation and signaling pathways that contribute to a pro-
fibrotic microenvironment in CAA.

## Key facts

- **NIH application ID:** 10577536
- **Project number:** 1RF1NS130334-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Ethan Lippmann
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,333,228
- **Award type:** 1
- **Project period:** 2022-09-19 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10577536

## Citation

> US National Institutes of Health, RePORTER application 10577536, Perivascular fibroblasts, vascular fibrosis, and their contributions to cerebral amyloid angiopathy (1RF1NS130334-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10577536. Licensed CC0.

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