Sphingosine Kinase 2 Modulates Retinal Neovascularization in the Mouse Model of Oxygen-Induced Retinopathy.

Eresch, Jeanette; Stumpf, Martin; Koch, Alexander; Vutukuri, Rajkumar; Ferreirós, Nerea; Schreiber, Yannick; Schröder, Katrin; Devraj, Kavi; Popp, Rüdiger; Huwiler, Andrea; Hattenbach, Lars-Olof; Pfeilschifter, Josef; Pfeilschifter, Waltraud (2018). Sphingosine Kinase 2 Modulates Retinal Neovascularization in the Mouse Model of Oxygen-Induced Retinopathy. Investigative ophthalmology & visual science, 59(2), pp. 653-661. Association for Research in Vision and Ophthalmology 10.1167/iovs.17-22544

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Purpose Neovascularization is a major cause of blindness in various ocular diseases. Bioactive sphingosine 1-phosphate (S1P), synthesized by two sphingosine kinases (Sphk1, Sphk2), emerged as a key player in a multitude of cellular processes, including cell survival, proliferation, inflammation, migration, and angiogenesis. We investigated the role of Sphk2, S1P, and S1P receptors (S1PR) during retinal neovascularization using the oxygen-induced retinopathy mouse model (OIR). Methods Sphk2 overexpressing (tgSphk2) and Sphk2 knockout (Sphk2-/-) mice were used in the OIR model, exposed to 75% O2 over 5 days from postnatal day (P)7 to 12 to initiate vessel regression. After returning to room air, these mice developed a marked neovascularization. Retinae recovered from untreated and treated eyes at P7, P12, P14, and P17 were used for lectin-stained retinal whole mounts, mass spectrometry, and quantitative real-time PCR. Results tgSphk2 mice showed higher retinal S1P concentrations, accelerated retinal angiogenesis, and increased neovascularization. Expression of S1PR, vascular endothelial growth factor α (VEGFα), and angiopoietin 1 and 2 was differentially regulated during the course of OIR in the different genotypes. Sphk2-/- displayed a markedly reduced retinal angiogenesis and neovascularization as well as decreased VEGFα and angiopoietin expression. Conclusions Using genetic models of Sphk2 overexpression or deletion we demonstrate a strong impact of Sphk2/S1P on retinal vasculopathy and expression of vascular growth factors like VEGF and angiopoietin in the retina. Consequently, Sphk2, S1P, and S1PR may offer attractive novel therapeutic targets for ischemic retinopathies.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Huwiler, Andrea

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0146-0404

Publisher:

Association for Research in Vision and Ophthalmology

Language:

English

Submitter:

Jana Berger

Date Deposited:

04 Jun 2018 12:46

Last Modified:

23 Oct 2019 08:41

Publisher DOI:

10.1167/iovs.17-22544

PubMed ID:

29392309

BORIS DOI:

10.7892/boris.116904

URI:

https://boris.unibe.ch/id/eprint/116904

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