Essential role of sphingosine 1–phosphate receptor 2 in pathological angiogenesis of the mouse retina
Athanasia Skoura, … , Richard L. Proia, Timothy Hla
Athanasia Skoura, … , Richard L. Proia, Timothy Hla
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2506-2516. https://doi.org/10.1172/JCI31123.
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Research Article Ophthalmology

Essential role of sphingosine 1–phosphate receptor 2 in pathological angiogenesis of the mouse retina

Abstract

Sphingosine 1–phosphate (S1P), a multifunctional lipid mediator that signals via the S1P family of G protein–coupled receptors (S1PR), regulates vascular maturation, permeability, and angiogenesis. In this study, we explored the role of S1P 2 receptor (S1P2R) in normal vascularization and hypoxia-triggered pathological angiogenesis of the mouse retina. S1P2R is strongly induced in ECs during hypoxic stress. When neonatal mice were subjected to ischemia-driven retinopathy, pathologic neovascularization in the vitreous chamber was suppressed in S1p2–/– mice concomitant with reduction in endothelial gaps and inflammatory cell infiltration. In addition, EC patterning and normal revascularization into the avascular zones of the retina were augmented. Reduced expression of the proinflammatory enzyme cyclooxygenase-2 (COX-2) and increased expression of eNOS were observed in the S1p2–/– mouse retina. S1P2R activation in ECs induced COX-2 expression and suppressed the expression of eNOS. These data identify the S1P2R-driven inflammatory process as an important molecular event in pathological retinal angiogenesis. We propose that antagonism of the S1P2R may be a novel therapeutic approach for the prevention and/or treatment of pathologic ocular neovascularization.

Authors

Athanasia Skoura, Teresa Sanchez, Kevin Claffey, Suzanne M. Mandala, Richard L. Proia, Timothy Hla

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Figure 1

S1P2R expression in the course of ischemia-induced pathologic retinal angiogenesis.

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S1P2R expression in the course of ischemia-induced pathologic retinal an...
(A) Schematic representation of hypoxia-induced mouse model of ROP. (B) S1P1, S1P2, and S1P3 mRNA expression at P12 (“Hypoxia,” day 0) was determined by quantitative RT-PCR analysis (n = 3). S1P2R expression was upregulated by 3-fold at P13 (24 hours of hypoxia; *P < 0.035) compared with P12 and was further increased by 5-fold at P17 (5 days of hypoxia; *P < 0.035). S1P1 expression was upregulated by 3-fold at P14 (2 days of hypoxia; #P < 0.01). S1P3 expression was induced by 3-fold at P16 (4 days of hypoxia; **P < 0.03). (C) Ang-2 and VEGF mRNA in the course of hypoxia (n = 3). Ang-2 expression was 14-fold higher at P16 (4 days of hypoxia; *P < 0.015). VEGF expression was induced by 3-fold at P16 (4 days of hypoxia; #P < 0.0015). (D) Immunohistochemical localization of S1P2R in P17 hypoxic retinal cross sections. S1P2R was detected in the GCL, showing a vessel-like distribution pattern (arrow) and in the INL (arrowhead). Scale bar: 100 μm. At a higher magnification (right panel), S1P2R immunodetection revealed a strong signal in the INL (arrowhead) as well as in vascular tufts (VT; arrow); scale bar: 10 μm. Nuclear counterstaining was with methyl green.