# Molecular Mechanisms of MGP; Role in AVMs

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $390,000

## Abstract

PROJECT SUMMARY:
The vascular system consists of elaborate networks that develop in combination with close regulation of
endothelial cells (ECs). An understanding of such regulation is essential for the development of new treatment
strategies aimed at vascular malformations, such as arteriovenous malformations (AVMs) and hereditary
hemorrhagic telangiectasia (HHT), caused by mutations in activin receptor-like kinase 1 (ALK1).
We previously showed that gene deletion in mice of matrix Gla protein (MGP), an inhibitor of bone
morphogenetic proteins (BMPs), causes AVMs in multiple organs similar to HHT. We showed that BMP9/ALK1
signaling induces MGP expression in ECs, where MGP plays an important role in differentiation. BMP9/ALK1
signaling also induces Crossveinless-2 (CV2) with a different induction delay, thereby creating two negative
feedback loops. Together, MGP and CV2 regulate BMP9 signaling by a previously unknown mechanism. In
cultured ECs, we found oscillations of MGP and CV2 expression that temporally coordinated transition to EC
stalk cell phenotype in ECs. This also caused markers of stalk cells to oscillate, whereas tip cell markers were
suppressed. Deletion of Mgp abolished the oscillatory behavior. In vivo, MGP and CV2 were seen as “shaping
waves” or stripes in the growing retina, and lack of MGP perturbed the vascular networks.
Our hypothesis is that MGP and CV2 are regulators of BMP9 signaling and vascular morphogenesis through
generation of oscillations or waves of expression. In Aim 1, we will characterize how MGP and CV2 orchestrate
EC differentiation in response to BMP9 using oscillations of gene expression. We will relate BMP9-induced
stalk cell phenotype to the oscillations, and explore expression profiles of ECs capable of this behavior. We will
disrupt the system by deleting the Mgp gene in vitro using established techniques of shRNA, and determine
the effect on the waves of inhibitors and stalk cell markers. We will also investigate whether waves of MGP and
CV2 can be detected in normal vasculature, with focus on the retina. In Aim 2, we will obtain key information
about the role of MGP in retinal vascular networks and AVMs by deleting Mgp, impairing MGP protein function,
and modulating the cellular origin. We will modulate potential targets for AVM treatments using the Mgp-/- mice
as an AVM model. We will start with modulation of CV2 and use approaches that include crossbreeding with
genetically altered mice and transmammary immunoblocking, and subsequently screen other factors in the
BMP9 response. Our studies will help identify targets in the BMP9 response system that might be used in
designing treatments for AVMs.

## Key facts

- **NIH application ID:** 9915958
- **Project number:** 5R01HL081397-13
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Kristina I Bostrom
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2006-04-24 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9915958

## Citation

> US National Institutes of Health, RePORTER application 9915958, Molecular Mechanisms of MGP; Role in AVMs (5R01HL081397-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9915958. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*