on July 3, 2008
Published online before print July 3, 2008, doi: 10.1161/ATVBAHA.108.163402
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Submitted on February 7, 2008
Accepted on June 23, 2008
Retardation of Retinal Vascular Development in Apelin-Deficient Mice
Atsushi Kasai ;
From the Laboratory of Molecular Neuropharmacology (A.K., N.S., H.K., R.H., H.H., A.B.), Graduate School of Pharmaceutical Sciences, Osaka University, Japan; the Department of Pharmacotherapeutics (A.K.), Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan; and the Departments of Ophthalmology (S.M., F.G., Y.T.), and Experimental Disease Model, the Osaka-Hamamatsu Joint Research Center for Child Mental Development (H.H., M.K.), Graduate School of Medicine, Osaka University, Japan.
* To whom correspondence should be addressed. E-mail: baba{at}phs.osaka-u.ac.jp.
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.
Key words: apelin • VEGF • FGF2 • knockout mice • angiogenesis
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