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Khayyam Durrani, Timothy Hla; Sphingosine 1-Phosphate Receptor Modulation as a Therapeutic Target in Retinal Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3116.
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Sphingosine 1-phosphate (S1P) is a powerful modulator of angiogenesis in selected tissues. We have shown that the S1P receptor 2 (S1P2) plays an essential role in pathologic angiogenesis in a mouse model of OIR. We hypothesized that the novel S1P receptor modulators JTE013, an S1P2 antagonist, VPC44116, an S1P1 antagonist, and FTY720, a functional S1P1 antagonist at high concentrations, may inhibit retinopathy in this model.
C57BL/6 WT mice were exposed to 75% oxygen from P7 to P12. On return to room air, systemic S1P receptor modulators were administered from P12 to P17. Retinal flat mounts were analyzed at P17. Agents were administered as follows: JTE: 1 mg/kg/day, 3 mg/kg/day; VPC: 1 mg/kg/day; VPC+JTE: 1 mg/kg/day each; FTY: 0.5 mg/kg/day, 1 mg/kg/day, and 5 mg/kg/day.
Mice treated with JTE 1 mg/kg/day did not have a significant difference in avascular or total tuft area compared to controls (avascular area: 15.7+/-0.8 vs. 17.7+/-1.0%, p=0.1; tuft area: 3.9+/-0.6 vs. 3.4+/-0.5%, p=0.6). No increase in effect was observed at a dose of 3 mg/kg/day (avascular: 12.5+/-0.8 vs. 11.2+/-0.5, p=0.3; tuft: 2.0+/-0.1 vs. 2.0+/-0.4, p=0.8). Mice treated with VPC 1 mg/kg/day alone or in combination with JTE also showed no significant difference in these parameters (VPC alone, avascular: 19.1+/-2.3 vs. 19.4+/-1.9, p=0.4; tuft: 3.0+/- 0.6 vs. 3.8+/-0.9, p=0.6; for VPC+JTE, avascular: 23.6+/-1.1 vs. 22.7+/-2.0, p=0.2; tuft: 6.8+/-1.4 vs. 9.0+/-0.8, p=0.4). FTY similarly did not show a significant effect or variation in response when administered at escalating doses (0.5 mg/kg, avascular: 12.1+/-0.9 vs. 11.9+/-0.8, p=0.9, tuft: 3.2+/-0.3 vs. 4.0+/-0.5, p=0.2; at 1 mg/kg, avascular: 13.7+/-1.3 vs. 15.2+/-0.8, p=0.4, tuft: 3.2+/-0.3 vs. 3.4+/-0.4, p=0.8, and at 5 mg/kg, avascular: 13.0+/-0.8 vs. 15.4+/-0.5, p=0.1, tuft: 3.0+/-0.4 vs. 4.1+/-0.7, p=0.1).
Systemic administration of the S1P receptor modulators JTE013, VPC44116 and FTY720 do not inhibit retinopathy in mouse OIR at the doses studied. This may result from variable G-protein coupling, opposing effects of S1P receptors in different effector cells, and homo- or heterodimerization of S1P receptors. This data further supports prior evidence that these agents have differing effects in selected organs.
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