# BMP and Notch crosstalk in cerebral arteriovenous malformations

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $336,875

## Abstract

ABSTRACT
Therapeutic advances in vascular disease may have far-reaching public benefits. Bone morphogenetic
proteins (BMPs) and Notch signaling are emerging as essential regulators of the vasculature, and important in
disorders such as arteriovenous malformations (AVMs). Our previous studies have demonstrated that excess
BMP induces Notch signaling causing cerebral AVMs. In preliminary studies, we demonstrate a strong
endothelial induction of Sox2 in human cerebral AVMs, and a dramatic improvement of cerebral AVMs after
limiting Sox2 in ECs. We find that excess transcriptional activity of Sox2 disrupts cerebral EC differentiation to
cause lumen disorder in AVMs. Sox2 is regulated by crosstalk of BMP and Notch signaling. In vitro, we show
that BMP-induced Notch ligands Jagged 1 and 2 upregulate Sox2, and knockdown of Notch1 receptor
diminishes Sox2 induction. In vivo, Jagged 1 and 2 and Notch1 are increased and directly targeted Sox2 in
MGP-deficient cerebral ECs, in which a decrease of Jagged 1 or 2 reduces Sox2 expression. In contrast, we
find no induction or significant changes of transcriptional effects of Sox2 in pulmonary AVMs, where instead
the expression of VEGF is increased. Limiting endothelial Sox2 does not improve pulmonary AVMs. To induce
Sox2, Notch requires ski-interacting protein (Skip), which is active in brain ECs but inactive in pulmonary ECs.
Furthermore, we have created a high throughput-screening model and aim to identify chemical compounds
that suppress Sox2 expression in brain ECs. We hypothesize that regulation of Sox2 and its transcriptional
activity is important in the maintenance of EC differentiation and lumen formation in normal cerebral
vasculature. Specific Aim 1 will determine how Sox2 is regulated by BMP and Notch signaling and affects the
differentiation of brain endothelial cells. Specific Aim 2 will determine if Sox2 is induced to contribute to human
cerebral AVMs. Specific Aim 3 will determine how regulation of Sox2 differs in cerebral versus pulmonary
AVMs and identify the chemical compounds that suppress Sox2 expression. If successful, the obtained
information may translate into strategies for using Sox2 inhibitors in the treatment of cerebral AVMs. The study
may also provide significant insights of tissue-specific formation of AVMs, and lead to different treatment
strategies for AVMs.

## Key facts

- **NIH application ID:** 9927680
- **Project number:** 5R01NS079353-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Yucheng Yao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $336,875
- **Award type:** 5
- **Project period:** 2012-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927680

## Citation

> US National Institutes of Health, RePORTER application 9927680, BMP and Notch crosstalk in cerebral arteriovenous malformations (5R01NS079353-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9927680. Licensed CC0.

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