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Updated: Jul 19, 2026
A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
Published on: June 8, 2022
Pharmacologic manipulation of sphingosine kinase in retinal endothelial cells: implications for angiogenic ocular
Lynn W Maines1, Kevin J French, Ellen B Wolpert
1Apogee Biotechnology Corporation, Hershey, Pennsylvania, USA.
Purpose:
The increased vascular permeability and pathogenic angiogenesis observed in diabetic retinopathy are induced, at least in part, by local inflammation and vascular endothelial growth factor (VEGF). Therefore, inhibition of signaling from VEGF and tumor necrosis factor-alpha (TNFalpha) is a promising approach to the treatment of this disease, as well as ocular diseases with similar etiologies, including age-related macular degeneration. A growing body of evidence demonstrates that sphingosine kinase (SK) plays an important role in cellular proliferation and angiogenesis. This study was undertaken to examine the effects of SK inhibitors on the responses of retinal endothelial cells (RECs) to VEGF and TNFalpha and their therapeutic efficacy in a diabetic retinopathy model.
Methods:
The expression and function of SK in bovine and human RECs were examined by immunoblot analysis. The involvement of SK in mediating responses to VEGF and TNFalpha was examined by using pharmacologic inhibitors of SK in cellular and in vivo assays, including a 3-month streptozotocin-induced diabetic retinopathy model in rats.
Results:
SK was present and active in human and bovine RECs, and SK activity in these cells was stimulated by VEGF. Inhibitors of SK blocked VEGF-induced production of sphingosine 1-phosphate and markedly attenuated VEGF-induced proliferation and migration of RECs. In addition, SK inhibitors were shown to block TNFalpha-induced expression of adhesion proteins, suppress VEGF-induced vascular leakage in an in vivo mouse model, and reduce retinal vascular leakage in the rat diabetic retinopathy model.
Conclusions:
Overall, these studies demonstrate that inhibitors of SK attenuate the effects of proliferative and inflammatory stimuli on RECs both in vitro and in vivo, and so could be significant therapeutics in the treatment of diabetic retinopathy.
Insights
Sphingosine kinase (SK) inhibitors reduce inflammation and vascular leakage in diabetic retinopathy models. These findings suggest SK inhibitors are promising therapeutics for treating diabetic retinopathy and similar ocular diseases.
Area of Science:
- Ophthalmology
- Cell Biology
- Pharmacology
Background:
- Diabetic retinopathy involves increased vascular permeability and angiogenesis, driven by vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNFα).
- Sphingosine kinase (SK) is implicated in cellular proliferation and angiogenesis, making it a potential therapeutic target.
Purpose of the Study:
- To investigate the effects of SK inhibitors on retinal endothelial cells (RECs) responses to VEGF and TNFα.
- To evaluate the therapeutic efficacy of SK inhibitors in a diabetic retinopathy model.
Main Methods:
- Examined SK expression and function in human and bovine RECs using immunoblot analysis.
- Utilized pharmacologic SK inhibitors in cellular assays and a rat model of streptozotocin-induced diabetic retinopathy.
Main Results:
- SK was present and active in RECs, with activity stimulated by VEGF.
- SK inhibitors attenuated VEGF-induced REC proliferation and migration, and blocked TNFα-induced adhesion protein expression.
- SK inhibitors reduced vascular leakage in vivo, including in the rat diabetic retinopathy model.
Conclusions:
- SK inhibitors effectively reduce the impact of proliferative and inflammatory stimuli on RECs.
- SK inhibitors demonstrate potential as significant therapeutics for diabetic retinopathy and related ocular conditions.
