# Erasing ill features of arterial endothelial cells in hereditary hemorrhagic telangiectasia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $390,000

## Abstract

PROJECT SUMMARY
Therapeutic advances in vascular disease may have far-reaching public benefits. Arteriovenous malformations
(AVMs) are the common feature of hereditary hemorrhagic telangiectasia (HHT) and cause the high risk of life-
threatening complications. Advanced studies have shown that loss function of mutations in activin receptor-like
kinase 1 (ALK1) are linked to HHT type 2 (HHT2) and ALK1 gene deletion in mice causes AVMs. Previous
studies also reveal that ALK1 is predominantly expressed in arterial endothelial cells (ECs). However, it is
unknown if ALK1 deficiency allows arterial ECs to acquire ill characteristics resulting in AVMs. In present
proposal, we have obtained preliminary data to suggest that the emerging lymphatic endothelial characteristics
in arterial ECs through the induction of mouse double minute 2 (MDM2) is previously unknown mechanism of
AVMs in endothelial ALK1 deficiency, and we show that the approaches of erasing these undesired
characteristics reduce AVMs. Therefore, we hypothesize that ALK1 deficiency elevates MDM2 to cause AVMs
through the induction of lymphatic endothelial characteristics in arterial ECs, and MDM2 inhibition abolishes
these characteristics to reduce AVMs. In specific Aim 1, we will elucidate the mechanism underlying arterial
MDM2 induction as a causative factor of AVMs in endothelial ALK1 deficiency. In specific Aim 2, we will
determine the contribution of arterial MDM2 induction to human HHT2. In specific Aim 3, we will determine if
limiting MDM2 reduces AVMs in endothelial ALK1-deficient mice. There is no primary medical treatment to
prevent or reduce the AVMs of HHT2 patients. In this proposal, we discover a novel mechanism that reveals the
unwanted characteristics emerging in arterial ECs driven by ALK1 deficiency, and arterial ECs with these
characteristics cause AVMs. We identify a compound and propose a novel treatment paradigm aiming to
ameliorate AVMs by erasing these ill characteristics from arterial ECs. If succussed, our proposed studies would
reveal the mechanistic underpinnings of alterations in arterial ECs of HHT2 and provide insight into new
opportunities for therapeutic interventions.

## Key facts

- **NIH application ID:** 10413737
- **Project number:** 1R01HL162643-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Yucheng Yao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,000
- **Award type:** 1
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10413737

## Citation

> US National Institutes of Health, RePORTER application 10413737, Erasing ill features of arterial endothelial cells in hereditary hemorrhagic telangiectasia (1R01HL162643-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10413737. Licensed CC0.

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