# Understanding and targeting molecular and cellular events responsible for pulmonary arteriovenous malformation development, growth and regression

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $688,595

## Abstract

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by multiple arteriovenous
malformations (AVMs) which are direct connections between arteries and veins, bypassing the capillary bed.
Pulmonary AVMs (PAVMs) are the most common visceral AVMs in adult (10-45%) and pediatric HHT patients
(60%) and cause significant morbidity and mortality due to an increased risk for cerebral abscesses, stroke,
pulmonary hemorrhage and migraines. Current treatment for PAVMs consists of catheter mediated embolization
with a re-perfusion rate of up to 25%, necessitating frequent imaging (radiation exposure) as well as repeat
interventions. While heterozygous loss-of function mutations in ENDOGLIN, ALK1 and SMAD4 are responsible
for the development of HHT in 85% of patients, we still do not know precisely how PAVMs develop. In
particular, we do not know exactly from which vascular bed (arterial, capillary, venous) PAVMs arise, and which
downstream signaling pathway is most important for PAVM development or growth that could be harnessed as
a therapeutic target. No medical therapy exists that is able to prevent, arrest growth or even reverse
PAVMs. Furthermore, we are lacking precise animal models of PAVMs or in vitro disease models, necessary
for pre-clinical testing of therapeutic approaches. We therefore hypothesized that understanding the cellular
and molecular mechanisms governing PAVM development paired with the identification of clinically relevant,
pathological signaling abnormalities will allow us to develop and test novel therapeutic approaches that prevent
and potentially reverse disease. Our proposal has three significant parts, which are represented by our three
specific aims: First, to develop and characterize a novel mouse model of PAVM formation by deleting HHT
causing genes in different endothelial cell subpopulations and study their role in PAVM development and growth.
Second, to differentiate induced pluripotent stem cells (iPSCs) from HHT patients into arterial and venous
endothelial cells (ECs), to identify novel common or unique pathways altered in HHT as a direct consequence of
mutations in ENG, ALK1 and SMAD4, to predict repurposed drugs (in silico) and test whether they target the
newly identified pathways in iPSC-ECs and tissue culture. Third, to test whether lead candidate drugs, FK506
and Enzastaurin, and novel drugs identified in Aim 2 (ie Brivanib, see preliminary data) positively influence PAVM
formation, growth and potential regression. Our proposal is innovative because it combines a conceptionally
novel approach (understanding PAVM development by focusing on disease-causing alterations in
subpopulations of lung endothelial cells) with cutting edge techniques (multiplex single-molecule fluorescence
in situ hybridization, spatial transcriptomics, multicolor labeling and high resolution 3-D imaging of the lung) and
novel pharmacological interventions (drugs identified by High-Throughput Screening, predicting nov...

## Key facts

- **NIH application ID:** 10915604
- **Project number:** 5R01HL169787-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Edda Frauke Spiekerkoetter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $688,595
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10915604

## Citation

> US National Institutes of Health, RePORTER application 10915604, Understanding and targeting molecular and cellular events responsible for pulmonary arteriovenous malformation development, growth and regression (5R01HL169787-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10915604. Licensed CC0.

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