Retardation of Retinal Vascular Development in Apelin-Deficient Mice

OBJECTIVE—Apelin is an endogenous ligand for the G protein–coupled receptor, APJ, and participates in multiple physiological processes. To identify the roles of endogenous apelin, we investigated the phenotype of apelin-deficient (apelin-KO) mice. METHODS AND RESULTS—Apelin-KO mice showed impaired retinal vascularization and ocular development, which were analyzed by histology, immunohistochemistry, real-time polymerase chain reaction, and the mouse corneal micropocket assay. Apelin-KO mice showed significantly impaired retinal vascularization in the early postnatal period. Retinal apelin/APJ mRNAs were transiently upregulated during the first 2 postnatal weeks but were undetectable in adults. There were no differences in VEGF or FGF2 mRNA expression, or in the morphology and localization of GFAP-positive astrocytes, in the apelin-KO retinas at P5. The corneal pocket assay showed that angiogenic responses to VEGF and FGF2 were remarkably decreased in apelin-KO mice. The reduced responses to VEGF and FGF2 in apelin-KO mice were partially restored by apelin, but apelin alone did not induce angiogenesis. CONCLUSIONS—Our results suggest that spatiotemporally regulated apelin/APJ signaling participates in retinal vascularization in a cooperative manner with VEGF or FGF2, and contributes to normal ocular development.