# The role of Angiopoietin-TEK signaling in polypoidal choroidal vasculopathy

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $389,853

## Abstract

PROJECT SUMMARY
Age-dependent macular degeneration (AMD) is a leading cause of vision loss. Late stage AMD is divided into
two types, neovascular or exudative (wet) and atrophic (dry). Wet AMD is increasingly recognized as a group of
diseases with differential presentations in patients of different ethnic backgrounds. In patients of European
ancestry, it is typically characterized by large drusen and progression to choroidal neovascularization caused by
excessive production of vascular endothelial growth factor (VEGF), which is central to disease progression. Wet
AMD is therefore treated with intravitreal VEGF inhibitors which have transformed disease prognosis. However,
in patients of Asian or African ancestry exudative AMD is most associated with a paucity of drusen and polypoidal
choroidal vasculopathy (PCV), a member of the pachychoroid disease spectrum. Despite the prevalence of PCV,
this disease remains poorly understood and anti-VEGF therapy is often less effective for these eyes than for
those with typical neovascular AMD, leaving a critical need for new therapeutic targets and treatments
specifically targeted at this disease. Pachychoroid diseases are characterized by the formation of dilated
“pachyvessels” which originate from the choroid and are accompanied by aneurysmal polyps in PCV. Recent
genetic studies have linked members of the angiopoietin (Angpt)-TEK endothelial signaling system with PCV
and central serous chorioretinopathy, another member of the pachychoroid spectrum. Directly testing this
association, we discovered that neural crest specific Angpt1 knockout mice exhibit choriocapillaris attenuation
and encroachment of dilated pachyvessels characteristic of pachychoroid and PCV, representing a new genetic
model of these poorly understood diseases and a key tool for understanding the role of angiopoietin signaling in
disease progression and as a therapeutic target. To further characterize ANGPT1 signaling in the choroidal
vasculature, we performed preliminary single cell transcriptomics analysis which revealed that ANGPT1 is
essential for maintenance of the differentiated choriocapillaris phenotype. Angpt1 knockout mice exhibited
markedly reduced expression of key choriocapillaris functional genes, including the VEGF receptor encoded by
Kdr. In contrast, Kdr expression was elevated in other vascular beds, providing a potential mechanism by which
ANGPT1 deficiency leads to choriocapillaris dysfunction and pachyvessel formation through dilation of choroidal
vessels. In this proposal, we will leverage these findings and our new mouse model to (1) fully characterize the
role of angiopoietin signaling in the choriocapillaris and identify unique markers differentiating pachyvessels from
the healthy choroid, (2) Understand the respective role(s) of choriocapillaris dysfunction and direct ANGPT1
signaling in pachyvessel formation and (3) investigate the potential of a new ANGPT1 mimetic drug as a targeted
therapeutic in pachychoroid d...

## Key facts

- **NIH application ID:** 10412011
- **Project number:** 5R01EY032609-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Benjamin R. Thomson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $389,853
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412011

## Citation

> US National Institutes of Health, RePORTER application 10412011, The role of Angiopoietin-TEK signaling in polypoidal choroidal vasculopathy (5R01EY032609-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10412011. Licensed CC0.

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