# Interaction between blood flow and ALK1 signaling in AVM development

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $434,652

## Abstract

PROJECT SUMMARY
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder with a prevalence of
1 in 5000 that is caused by ENG, ALK1, or SMAD4 haploinsufficiency. These genes encode proteins important
in endothelial bone morphogenetic protein (BMP) signaling, which is required to prevent development of
fragile, direct connections between arteries and veins, or arteriovenous malformations (AVMs). In HHT
patients, AVMs develop throughout life in skin, nasal mucosa, gastrointestinal (GI) tract, and liver and can lead
to epistaxis, hemorrhage, anemia, and high-output heart failure. Congenital lesions in lung and brain may lead
to brain abscess or stroke. Currently available medications for HHT patients block angiogenesis or enhance
clotting. These therapeutics are not ideal: they decrease epistaxis and GI bleeds in some but not all patients
and are ineffective against potentially life-threatening congenital lesions in the brain and lung. Furthermore,
these agents may delay wound healing and enhance risk of severe hemorrhage and thrombotic events.
Therefore, the goal of our research program is to understand HHT disease mechanism to support development
of targeted medical therapies for this disease. Using a zebrafish alk1 mutant as an HHT2 model, we uncovered
a two-step mechanism of AVM development. In Step 1, loss of flow-dependent Alk1 signaling enhances
endothelial cell migration in the direction of flow within lumenized arteries. This aberrant migration skews
endothelial cell distribution toward and enlarges caliber of more distal arterial segments. In Step 2, normally
transient artery-vein connections downstream of enlarged arterial segments are retained in a flow-dependent
manner, resulting in high-flow AVMs. In this work, we will explore the mechanisms that underlie these two
independent flow-based signaling pathways, the first of which is abrogated with Alk1 loss, and the second of
which is intact with Alk1 loss. In Aim 1, we will combine developmental biology and biomechanics approaches
to determine whether flow-dependent Alk1 signaling governs arterial endothelial cell migration via control of
planar cell polarity or generation of endothelial tension in live zebrafish embryos. In Aim 2, we will use
zebrafish embryos and a novel microfluidic platform seeded with human endothelial cells to dissect the roles of
two components of blood flow—the heart-derived circulating ALK1 ligand, BMP10, and the mechanical force of
shear stress—in flow- and Alk1-dependent retrograde arterial endothelial cell migration. In Aim 3, we will test
the hypothesis that AVMs represent an adaptive response to altered hemodynamic force and address the
signaling mechanisms that underlie flow-dependent AVM development. These studies will shed new light on
two distinct flow-dependent pathways important for HHT-associated AVM development. Mechanistic
information gleaned from this work can be used to develop targeted therapeutics that 1) stop devel...

## Key facts

- **NIH application ID:** 9900858
- **Project number:** 5R01HL136566-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** BETH L ROMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $434,652
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9900858

## Citation

> US National Institutes of Health, RePORTER application 9900858, Interaction between blood flow and ALK1 signaling in AVM development (5R01HL136566-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9900858. Licensed CC0.

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