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S. Sakimoto, M. Kamei, H. Kidoya, H. Naito, F. Muramatsu, A. Fukamizu, N. Takakura; Apelin/apj Signaling Regulates Retinal Vascular Remodeling via Interaction Between Endothelial Cells and Astrocytes. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3350. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Apelin/APJ signaling participates in physiological retinal angiogenesis in a cooperative manner with VEGF or FGF2. However, the precise mechanisms of this signal, which involves cell-cell interaction during retinal angiogenesis, are not known. This study investigates whether apelin/APJ signaling is involved in crosstalk between vascular endothelial cells (ECs) and astrocytes, which control vascular remodeling in the developing retina.
Flat-mount triple immunostaining for CD31, apelin, and APJ was performed in P3 mouse retinas. To confirm the expression of APJ mRNA, real time PCR was performed on PDGFRα-CD31+ ECs and PDGFRα+CD31- astrocytes that were sorted from the P6 retina using flow cytometry. We analyzed postnatal vascular development of wild type (WT) and APJ knockout (KO) mouse retinas over time. ECs and astrocytes were immunohistochemically detected in P3 and P5 WT and APJ KO mice (n>=6, respectively) with the markers for CD31, PDGFRα and Pax2.
Apelin and APJ were expressed most noticeably in EC. Strong apelin expression was observed in the extending vascular network area, while APJ was less strongly expressed. In the WT P6 retina, the expression of APJ mRNA was up-regulated in PDGFRα+CD31- astrocytes by 58.5-fold more than PDGFRα-CD31- cells by real time PCR. Furthermore, APJ+PDGFRα+ astrocytes were immunohistochemically detected in the WT P3 retina. Flat-mount immunostaining for CD31 in the APJ KO retina showed excess proliferation of tip cells, which became more prominent as vascular development proceeded. Meanwhile, APJ KO mice showed an increased proliferation of retinal astrocytes coincident with the area of strong apelin expression in the vascular network.
We demonstrated that apelin/APJ signaling can control the proliferation of astrocytes which affects retinal vascular remodeling in a negative feedback mechanism.
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