# Proangiogenic M2-type macrophages and choroidal neovascularization

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $423,758

## Abstract

SUMMARY
Macrophages infiltrate the site of inflammation and polarize to either antiangiogenic M1-type macrophages or
proangiogenic M2-type macrophages, depending on the presence of various cytokines and other external
factors. Proangiogenic M2-type macrophages are major contributors to inflammatory angiogenesis in many
common diseases, in part by secreting proangiogenic factors, such as VEGF-A or IL-1b. Notably, M2-type
macrophages accumulate in areas of choroidal neovascularization (CNV) in patients with neovascular AMD. The
increase in M2-type macrophage-derived cytokines in eyes of patients with neovascular AMD has implicated this
cell population as a major driver of CNV pathogenesis. This hypothesis is further supported by the observation
of an accumulation of M2-type macrophages in laser-induced CNV or in a genetic VEGF-A-induced mouse
model of neovascular AMD. Ablation of macrophages in laser-induced CNV, which are predominantly M2-type
macrophages, blocked CNV, whereas administration of M2-type macrophages in the eye promoted CNV. Based
on these findings we propose that pharmacologic therapies that prevent M2-type polarization of macrophages
can serve as a novel approach to potently inhibit CNV progression in patients with neovascular AMD. The limited
understanding of the signaling mechanisms that are regulating M1- versus M2-type polarization of macrophages
has hindered the identification of molecular targets and pharmacologic inhibitors to selectively block M2-type
macrophage polarization. To address this unmet need, we have performed global quantitative time-course
proteomics and phosphoproteomics and identified kinase activation events that are associated with M1- versus
M2-type macrophage polarization. Furthermore, we identified in chemical screens pharmacologic inhibitors of
M2-type polarization that selectively block M2- but not M1-type polarization. Thus, the combination of these two
approaches provides us now with a unique resource to establish novel therapies that selectively block
proangiogenic M2- but not antiangiogenic M1-type macrophages in CNV. In proof-of-principle experiments we
can show that two of the identified inhibitors, the MEK inhibitor trametinib and the HDAC inhibitor panobinostat,
blocked M2-type macrophage polarization in CNV lesions and potently inhibited CNV lesion formation in laser-
induced CNV experiments. Our proposed experiments will test identified kinase and non-kinase inhibitors in a
systematic manner for their ability to selectively block M2-type polarization in detailed in vitro experiments as
well as in three well-established mouse models of neovascular AMD. Our proposal is based on extensive
preliminary data that provide a strong scientific premise. The proposed experiments have high rigor and
important clinical relevance and will likely lead to novel therapeutic approaches for neovascular AMD.

## Key facts

- **NIH application ID:** 10515809
- **Project number:** 1R01EY033360-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Alexander Georg Marneros
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,758
- **Award type:** 1
- **Project period:** 2022-09-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10515809

## Citation

> US National Institutes of Health, RePORTER application 10515809, Proangiogenic M2-type macrophages and choroidal neovascularization (1R01EY033360-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10515809. Licensed CC0.

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