Journal Article Ahead of print
PubMed: 41448433 DOI: 10.1016/j.jbc.2025.111107
Sphingosine-1-phosphate receptor 2 inhibition ameliorates familial exudative vitreoretinopathy models.
J Biol Chem
Authors: Hirad A Feridooni, Rachel Fody, Mahtab Tavasoli, Mariam Alkandari, Sarah van der Ende, Michel Nader, Johane M Robitaille, Christopher R McMaster
Affiliations
- Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
- Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
- Departments of Ophthalmology and Visual Sciences, Pathology, Pediatrics, and Surgery Dalhousie University/IWK Health Centre, Halifax, NS, Canada.
- Department of Pharmacology, Dalhousie University, Halifax, NS, Canada,.
Abstract
Familial exudative vitreoretinopathy (FEVR) is an inherited childhood blinding disorder with close to 85% of molecularly determined cases due to rare variants in gene encoding members of the frizzled 4 (FZD4) receptor complex. FEVR causes blindness due to complications arising from developmental peripheral non-perfusion of the retina. We sought to find a small molecule that could ameliorate FEVR models. In this study, we determine that the sphingosine1-phosphate receptor 2 (S1PR2) antagonist JTE-013 can ameliorate cellular and mouse models of FEVR. Using human primary retinal microvascular endothelial cells (hRMECs) we show that either knockdown of FZD4 expression using shRNA, or expression of a known FEVR causing dominant negative allele of FZD4, both decrease the ability of hRMECs to tubularize. The addition of JTE-013 to both hRMEC models of FEVR resulted in restoration of tubularization. In the well-established Fzd4 -/- mouse model of FEVR, dosing animals with JTE-013 ameliorated the retinal vascularization defects in these mice. The implications of these findings are (i) a major contributor to abnormal retinal angiogenesis in FEVR is likely through a decrease in vascular formation/integrity, and (ii) treatment with a well characterized S1PR2 inhibitor restores normal vascularization in cell and mouse models of FEVR. To our knowledge, this is the first study to implicate S1PR signaling in FEVR and to show that a small drug-like molecule can restore normal vascularization and prevent blinding complications.
MeSH
Sphingolipids, Cells, Genes, Sphingosine-1-Phosphate Receptors, Retina, Sphingosine, Familial Exudative Vitreoretinopathies, Endothelial Cells, Retinaldehyde