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

Abstract

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% O 2 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 a (VEGFa), and angiopoietin 1 and 2 was differentially regulated during the course of OIR in the different genotypes. Sphk2À/À displayed a markedly reduced retinal angiogenesis and neovascularization as well as decreased VEGFa 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.

Angiogenesis and Blood-Brain Barrier Permeability in Vascular Remodeling after Stroke

“…Activation of S1PR 1 was found to increase endothelial barrier integrity by modulating EC cytoskeletal forces [ 154 , 160 ] via the PI3K/Akt/Rac signaling pathway [ 161 - 164 ]. S1PR 1 promotes the expression of TJPs and AJPs in ECs and ACs, enhances BBB integrity [ 151 ], reduces vascular leakage, limits leukocyte infiltration, and inhibits astrogliosis [ 154 , 160 , 165 , 166 ]. S1PR 3 cooperates with S1PR 1 in stimulating migration of EC progenitors and EC proliferation, thereby contributing to vasculogenesis and angiogenesis [ 167 ].…”

Sphingolipids as Emerging Mediators in Retina Degeneration

“…Abnormal retina blood vessel growth and macular edema are major complications leading to vision loss in diabetes retinopathy and S1P emerges as a key signal in the induction of neovascularization and in the preservation of retina endothelial barrier integrity (Allende and Proia, 2002; McGuire et al, 2011). In transgenic mice that overexpress SphK2, higher retinal S1P concentration accelerates retinal angiogenesis and increases neovascularization (Eresch et al, 2018). In turn, downregulation of S1P signaling with anti-S1P monoclonal antibodies and in S1P2 null mice in an ischemia-driven retinopathy markedly reduces pathologic neovascularization (Skoura et al, 2007; Caballero et al, 2009).…”

Characterizing Sphingosine Kinases and Sphingosine 1-Phosphate Receptors in the Mammalian Eye and Retina

“…SPHK1 and SPHK2 single knockout animals generally have no phenotype and are thought to compensate with the remaining kinase. However, knocking out SPHK2 is sufficient to reduce resilience to oxygen-induced retinopathy [17]. Meanwhile, the S1P produced by the two kinases has shown myriad roles in retinal development and function.…”