# Uncover the Pathogenesis of Brain Arteriovenous Malformation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $525,423

## Abstract

PROJECT ABSTRACT:
Patients with brain arteriovenous malformation (bAVM) are at risk of intracranial hemorrhage (ICH). Overall,
bAVM account for 25% of hemorrhagic strokes in adults <50 years of age. The treatment of unruptured lesions
has become controversial, because the natural history of these patients may be less morbid than invasive
therapies. The mechanism of bAVM formation is not fully understood. There are no specific medical therapies
to treat bAVMs. We are among a few groups that have mouse models with bAVM in the brain parenchyma.
Using these model, we have identified key factors that are crucial for bAVM formation and progression. We
found that the presence of angiogenesis and gene mutation in endothelial cells are essential for bAVM
formation. Inflammation may promote bAVM progression. We have also found that bAVM vessels have less
mural cell coverage, which is associated with vessel leakage and hemorrhage in mouse bAVMs and in human
sporadic bAVMs. Reduction of platelet derived growth factor B (PDGFB) expression in mutant endothelial cells
(ECs) might be responsible to the reduction of mural cell coverage. We showed that inhibition of vascular
endothelial growth factor (VEGF) signaling through bevacizumab (an anti-VEGF antibody) treatment or
intravenous injection of an adeno-associated viral vector (AAV) expressing soluble FMS-related tyrosine
kinase 1 (sFLT1) containing the extracellular domain of VEGF receptor 1 inhibits bAVM formation and
progression. Increase pericyte coverage by thalidomide treatment reduced the number of abnormal vessels
and micro-hemorrhage. The most interesting finding is that homozygous mutation of Alk1 or Eng in a portion of
somatic ECs or in bone marrow-derived EC alone is sufficient to trigger de novo bAVM phenotype in the
presence of angiogenic stimulation in adult mice. Coincidently, recent studies conducted by others shown that
sporadic bAVM and extra-neural AVM harbor somatic mutations in a small number of ECs. It is not clear how a
few mutant ECs can cause bAVM formation. In this proposal, we will test our hypothesis that mutant ECs
cause bAVM formation and progression through stimulating excessive angiogenesis (Aim 1), impairing
pericyte function (Aim 2) and induction of inflammation (Aim 3). In Aim 1, we will show that mutant ECs
undergo clonal expansion and release angiogenic factors to stimulate the proliferation of adjacent normal ECs.
In Aim 2, we will show that mutant EC impair pericyte function through reduction of PDGFB mediated ANG1,
TGFb1 and PDGFRb expression in pericytes. In Aim 3, we will show that mutant EC drives microglia
activation, macrophage and lymphocyte infiltration through induction of EC-inflammation. The overarching goal
of this project is to identify new therapeutic targets.

## Key facts

- **NIH application ID:** 9832203
- **Project number:** 5R01NS027713-29
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** HUA SU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $525,423
- **Award type:** 5
- **Project period:** 1990-08-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9832203

## Citation

> US National Institutes of Health, RePORTER application 9832203, Uncover the Pathogenesis of Brain Arteriovenous Malformation (5R01NS027713-29). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9832203. Licensed CC0.

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