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 4

S1P2R modulates retinal vascular patterning.

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S1P2R modulates retinal vascular patterning. (A and C) A...
(A and C) At P14, S1p2+/– and S1p2–/– retinas optically sectioned at the GCL showed similar distribution of proliferative cells (BrdU staining). At P17, S1p2+/+ retinas (B) optically sectioned at the GCL showed an increased number of proliferative cells (BrdU staining) colocalizing with ECs (E, GS-lectin, white arrowhead) in the vascular tuft areas, while in S1p2–/– retinas (D), mitogenic cells were incorporated into the central vascular bed (F, ECs–GS-lectin, white arrowhead). (G) Quantification of fluorescent pixels representing BrdU-positive cells per retina at P14: S1p2+/– retinas showed 0.05 ± 0.006 (n = 5), whereas S1p2–/– retinas showed 0.05 ± 0.011 (n = 5; *P = 0.47) fluorescent pixels/total retinal area. At P15, S1p2+/+ retinas favored excessive growth of neovascular tufts into the vitreous (H), whereas S1p2–/– retinas favored vascular sprouts directed into the central retina (tip cells, arrows) (I). At P17, S1p2–/– retinas optically sectioned at the GCL presented enhanced normal revascularization with endothelial tip cells (inset) redirected into the ischemic retina area (K), whereas S1p2+/+ retinas formed abnormal vascular buds directed toward the vitreous chamber (J, inset). (L) At the early stage of retina pathogenesis (P15), S1p2+/– retinas developed 23.122 ± 5.73 tip cells/field (n = 9), whereas S1p2–/– retinas developed 34.34 ± 6.3 tip cells/field (n = 7; †P < 0.0025). Values represent mean ± SD. Scale bars: 200 μm (A–D, H, and I), 20 μm (E and F), and 50 μm (J and K).