VEGF and S-1P Signaling
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VEGF and S-1P Signaling
Angiogenesis is important in embryonic development as well as in physiological events and dysregulated angiogenesis is involved in various pathological conditions, like solid tumor growth, Rheumatoid Arthritis, and Diabetic Retinopathy. Angiogenesis is initiated by vascular endothelial cells and involves their orderly proliferation, migration, and morphogenesis into new capillary networks. Such events are precisely regulated by soluble growth factors as well as endothelial cell-derived signals. Recently, S-1P (Sphingosine 1-Phosphate), a bioactive lipid released by activated platelets, has emerged as an important mediator of angiogenesis. S-1P induces migration, proliferation, and cytoskeletal changes of endothelial cell by binding to the EDG (Endothelial Differentiation Gene), a family of GPCR (G-Protein Coupled Receptors). In the EDG family, EDG1, EDG3, EDG5, EDG6, and EDG8 work as S-1P Receptors. Among them, EDG1 plays a major role in endothelial cell and smooth muscle cell function. Activation of EDG1 Receptor triggers several signaling pathways via G-Proteins (Ref.1).

S-1P is unusual in that it can function both as an extracellular signaling molecule and as an intracellular second messenger. A number of growth factors activate SphK1 (Sphingosine Kinase-1), which converts Sph (Sphingosine) to S-1P, including PDGF (Platelet-Derived Growth Factor), VEGF (Vascular Endothelial Growth Factor), NGF (Nerve Growth Factor), TNF (Tumor Necrosis Factor), and basic FGF (Fibroblast Growth Factor). VEGF is one of the most important growth factors involved in angiogenesis. After binding VEGF, VEGFR2 (VEGF Receptor-2) activates stimulates endothelial cell growth through PKC (Protein Kinase-C) and subsequent ERK1/2 (Extracellular-Signal-Regulated Kinase) activation (Ref.2), which stimulates the SphK1. This increases S-1P levels with concomitant decreases in Sphingosine and inhibition of the GTPase-activating protein, RasGAP. Activation of Ras, in turn lead to activation of Raf, MEK (MAPK/ERK Kinase) and, eventually, to DNA synthesis. S-1P can also activate VEGFR2 in the absence of added VEGF by receptor crosstalk. Ligation of the S-1P receptor EDG1/S1P2 and activation of G-Alpha, G-Beta and G-Gamma, in turn, lead to the activation of components such as Src that result in the phosphorylation of VEGFR2. This transactivation of VEGFR2 causes activation of two signaling cascades that are important for movement and vascular remodeling: first, activation of Src-family tyrosine kinases, the adaptor protein CrkII and CAS (Crk-associated substrate); and second, activation of PI3K-Alpha (Phosphatidylinositol 3-Kinase-Alpha), Akt Pathway and eNOS (endothelial Nitric Oxide Synthase), and the formation of NO (Nitric Oxide). In endothelial cell the predominant VEGFR2 that mediates eNOS phosphorylation is Flk1/KDR (Fetal Liver Kinase-1/Kinase-insert Domain-containing Receptor) leading to phosphorylation and stimulation of the PI3K-Akt1-eNOS pathway. VEGF receptor Flk1/KDR localizes to caveolae, while EDG1 receptor exists in both non-caveolae and caveolae membranes. After stimulation EDG1 translocates and concentrates in caveolae. Upon G-AlphaI protein-mediated activation of PLC (Phospholipase-C), intracellular Ca2+ levels increase and Ca2+ complexes with Calm (Calmodulin). The Ca2+/Calm complex then activates eNOS. Simultaneously, Ca2+ and Src family kinase-dependent transactivation of Flk1/KDR occurs, which stimulates Src family kinase and PI3K causing Akt1 and eNOS to be phosphorylated and activated (Ref.3).

Several Sphingolipids are now recognised as second messengers and they play an important role in the regulation of cell proliferation, survival, and cell death. Sphingosine usually inhibits proliferation and promotes apoptosis, while the further metabolite S-1P stimulates growth and suppresses apoptosis. Furthermore, S-1P can act in an autocrine and/or paracrine fashion to regulate blood vessel formation. SphK1 not only protects tumors from apoptosis, it may also increase their vascularization, further enhancing growth. The cytoprotective effects of SphK/S-1P may also be important for clinical benefit, as S-1P protects oocytes from radiation-induced cell death (Ref.4).