# mTOR and VEGFR2 pathways in HHT pathogenesis

> **NIH NIH R01** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2022 · $418,750

## Abstract

PROJECT SUMMARY/ABSTRACT (DESCRIPTION)
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder characterized by the
development of systemic and potentially life-threatening vascular anomalies called arteriovenous malformations
(AVMs). HHT mutations are mostly found in the ALK1 and ENG genes and lead to a loss-of-function of BMP9/10-
ALK1-ENG signaling in endothelial cells (ECs). Recent evidence suggests that HHT pathogenesis and AVM
development require the aberrant overactivation of the endothelial mTOR and VEGFR2 pathways. The overall
goal of this program is to characterize the precise mechanisms of mTOR and VEGFR2 overactivations upon
ALK1-ENG loss-of-function, and determine whether targeting of these mechanisms has disease-modifying
properties and therapeutic potential in cell and mouse models of HHT. Using whole-transcriptome interrogation,
our preliminary investigation has shown that combined pharmacological inhibition of mTOR and VEGFR2
demonstrated a remarkable synergy and efficacy in correcting a pathological gene expression signature in the
BMP9/10-immunoblocked (BMP9/10ib) mouse model of HHT. Strikingly, dual mTOR-VEGFR2 inhibition blocked
vascular pathology and AVMs in the retina, liver, lungs, and mucosa to avert bleeding and anemia in BMP9/10ib
mice. Mechanistically, our preliminary data revealed that, downstream of ALK1-ENG inhibition, changes in
angiopoietin-2 (ANG2)/Tie2 receptor signaling were important triggers for mTOR-VEGFR2 activation and AVM
development in HHT mice. Therefore, our data support the working model that HHT pathogenesis is caused by
defective ANG2-mTOR-VEGFR2 pathways, and that interventions targeting these mechanistic defects might
provide therapeutic benefit in HHT. Based on these results, we propose in Aim 1 to assess whether endothelial
mTOR and VEGFR2 are independently activated and whether they are both required for AVM development in
HHT mice. To this end, pharmacological and gene deletion approaches independently targeting mTOR and
VEGFR2 will be employed in two HHT mouse models: the BMP9/10ib mice and a newly generated knockin (KI)
mouse expressing a HHT-causing ALK1 mutation. In Aim 2, we will delineate the precise mechanism of mTOR
and VEGFR2 overactivation by ANG2/Tie2 signaling, both in vivo in HHT mice and in vitro in primary ECs,
including in HHT patient blood outgrowth ECs. Lastly in Aim 3, we will determine whether Tie2 derepression
blocks vascular pathology in HHT mice.

## Key facts

- **NIH application ID:** 10434787
- **Project number:** 5R01HL150040-03
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** PHILIPPE MARAMBAUD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2020-08-05 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434787

## Citation

> US National Institutes of Health, RePORTER application 10434787, mTOR and VEGFR2 pathways in HHT pathogenesis (5R01HL150040-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10434787. Licensed CC0.

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