The major implications of our findings are (i) a major contributor to abnormal retinal angiogenesis due to decreased FZD4 activity likely arises from defective vascular formation/integrity, (ii) treatment with the well-characterized S1PR2 inhibitor JTE-013 dramatically improves retinal vascularization in a well-characterized mouse model of FEVR, and (iii) this improvement by JTE-013 was recapitulated in hRMECs, suggesting this improvement is mainly at the level of endothelial cells. Here, S1PR2 is linked to Familial exudative vitreoretinopathy.