ApoM-bound S1P acts via endothelial S1PR1 to suppress choroidal neovascularization and vascular leakage
Neovascular age-related macular degeneration (nAMD) is a major cause of vision loss worldwide. Current standard of care is repetitive intraocular injections of vascular endothelial growth factor (VEGF) inhibitors, although responses may be partial and non-durable. We report that circulating sphingosine 1-phosphate (S1P) carried by apolipoprotein M (ApoM) acts through the endothelial S1P receptor 1 (S1PR1) to suppress choroidal neovascularization (CNV) in mouse laser-induced CNV, modeling nAMD. In humans, low plasma ApoM levels were associated with increased choroidal and retinal pathology. Additionally, endothelial S1pr1 knockout and overexpressing transgenic mice showed increased and reduced CNV lesion size, respectively. Systemic administration of ApoM-Fc, an engineered S1P chaperone protein, not only attenuated CNV to an equivalent degree as anti-VEGF antibody treatment but also suppressed pathological vascular leakage. We suggest that modulating circulating ApoM-bound S1P action on endothelial S1PR1 provides a novel therapeutic strategy to treat nAMD.
Authors
- Timothy Hla (ORCID: https://orcid.org/0000-0001-8355-4065)
- Andrew J. Dannenberg (ORCID: https://orcid.org/0000-0002-1901-6497)
- Sasha A. Singh (ORCID: https://orcid.org/0000-0003-0929-3164)
- Andrew Kuo (ORCID: https://orcid.org/0000-0002-7263-8658)
- Colin Niaudet (ORCID: https://orcid.org/0000-0001-8735-1230)
- Hitomi Yagi (ORCID: https://orcid.org/0000-0002-5199-1970)
- Tim F. Dorweiler (ORCID: https://orcid.org/0000-0003-2741-7298)
- Masanori Aikawa (ORCID: https://orcid.org/0000-0002-9275-2079)
- Taku Kasai (ORCID: https://orcid.org/0000-0002-8075-6099)
- Lois E. H. Smith (ORCID: https://orcid.org/0000-0001-7644-6410)
- B. Jung (ORCID: https://orcid.org/0000-0002-3833-938X)
- Zhongjie Fu
Institutions
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Centre National de la Recherche Scientifique (FR)
- Harvard University (US)
- Inserm (FR)
- Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers (FR)
- Io Therapeutics (United States) (US)
- Nantes Université (FR)
Publication Details
- Journal
- Angiogenesis
- Published
- 2025-04-23
- DOI
- https://doi.org/10.1007/s10456-025-09975-7
- Citations
- 6
- Primary Topic
- Protease and Inhibitor Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 5.62
Funders
- American Heart Association
- National Institutes of Health
- Genentech