# Determining the pathophysiology of pediatric arteriovenous malformation

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $708,558

## Abstract

The goal of this project is to understand the mechanisms by which arteriovenous malformation (AVM)
forms and progresses. This will inform us about the fundamental process of vascular morphogenesis
and, importantly, identify specific genes/pathways for which targeted therapies can be developed to
improve the lives of patients affected by AVM and other vascular diseases. AVM is present at birth
and undergoes significant progression over time. The lesion enlarges, bleeds, ulcerates, and causes
pain and deformity. Vital structures can be threatened and congestive heart failure may occur.
Currently, there is no cure for AVM and drug treatment does not exist.
We recently found that most human AVMs contain somatic mutations in MAP2K1, and that this
mutation is exclusive to the endothelial cell. We now aim to: (1) identify other somatic mutations in
human AVMs, (2) determine how MAP2K1 mutations affect endothelial cell function, and (3) develop
animal models of AVM to further study its pathophysiology as well as to test pharmacotherapy. We
will perform molecular inversion probe, RNA, whole-exome, and whole genome sequencing on AVM
tissues and isolated endothelial cells to find additional mutations in human AVMs. Mutant endothelial
cells containing the MAP2K1 mutation will be studied to determine how the mutation affects signaling
pathways, protein production, and the ability of the cells to interact with pericytes to form blood
vessels. An animal model of AVM will be developed by inserting mutant MAP2K1 endothelial cells
into immunodeficient mice, as we have successfully done with other types of vascular anomalies.
FDA-approved inhibitors of MAP2K1 will be tested in vitro and in vivo to understand the
pathophysiology of how the mutation affects cell behavior and to determine the efficacy of the drugs.
These experiments will be high impact when we succeed in identifying the pathophysiology
responsible for AVM formation and enlargement. For the first time we would be able to pursue a
targeted approach for treating this lesion. For example, pathway specific topical, intralesional, and/or
systemic pharmacologic agents could be developed to prevent AVM progression or recurrence.
Discoveries into the pathophysiology of AVM also will help us to understand the mechanisms that
underlie other pediatric vascular lesions, and will improve our ability to manipulate vascular growth in
a broad range of diseases.

## Key facts

- **NIH application ID:** 9939593
- **Project number:** 5R01HD093735-03
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Arin K. Greene
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $708,558
- **Award type:** 5
- **Project period:** 2018-09-10 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939593

## Citation

> US National Institutes of Health, RePORTER application 9939593, Determining the pathophysiology of pediatric arteriovenous malformation (5R01HD093735-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9939593. Licensed CC0.

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