# Molecular mechanisms underlying Arteriovenous Malformations associated with HHT

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2020 · $380,000

## Abstract

PROJECT SUMMARY
Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant genetic disease that affects males
and females from all racial and ethnic groups, and is found in ~1 in every 5000 people. HHT is characterized
by inappropriate connections between arteries and veins, called arteriovenous malformations (AVMs). These
fragile connections can bleed and rupture leading to anemia, aneurysms, stroke and even death. Remarkably,
there are currently no drugs for effective treatment of AVMs in HHT patients, despite the previous identification
of the defective signaling pathway associated with HHT. Genetic causes of HHT are linked to the Transforming
Growth Factor-β (TGFβ) signaling pathway, with approximately 85% of patients showing mutations in the
Endoglin (Eng) or Activin receptor-like kinase 1 (Acvrl1) co-receptors. About 4% have defects in the
downstream transcription factor, Smad-related protein 4 (Smad4). Despite many years of HHT research mainly
focused on Eng and Acvrl1, two crucial gaps in our knowledge remain - a comprehensive understanding of the
cell morphological and biological defects of the HHT vasculature, and identification of the downstream genes
that are mechanistically responsible for the vascular defects. We have created a novel mouse model of
AVM/HHT whereby genetic ablation of Smad4 specifically in blood vessels effectively replicates the cell
biological defects associated with HHT. Using our model we have begun a detailed molecular and cellular
characterization of HHT vessels in vivo, and initial RNA-seq and ChIP-seq experiments have identified
potential novel regulators of AVM/HHT, including the vascular signaling proteins Tek and Angiopoietin 2
(Ang2), and the transcriptional co-factor Zmiz1. The central objective of this application is to answer two
fundamental questions: What are the molecular and cellular mechanisms driving AVM/HHT pathogenesis and
what are the downstream effectors of the TGFβ pathway that promote AVM/HHT? We will address these topics
by testing our hypothesis that Smad4 transcriptionally controls downstream pathway components that are
mechanistically responsible for AVM formation, via the following specific aims: 1) Identify the molecular and
cellular events causing AVM formation and the Smad4 downstream effectors associated with AVM/HHT; 2)
Examine the role of Tek/Angiopoietin signaling in generation and resolution of AVMs; and 3) Examine the role
of Zmiz1 in AVM pathogenesis. Results obtained from these studies will advance our understanding of the
mechanistic mediators of AVM pathogenesis and uncover new drug targets designed to treat the disease
mechanisms of HHT.

## Key facts

- **NIH application ID:** 9963356
- **Project number:** 5R01HL139713-03
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Stryder Medoah Meadows
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $380,000
- **Award type:** 5
- **Project period:** 2018-07-18 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963356

## Citation

> US National Institutes of Health, RePORTER application 9963356, Molecular mechanisms underlying Arteriovenous Malformations associated with HHT (5R01HL139713-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9963356. Licensed CC0.

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