S1P₂ receptor regulation of sphingosine-1-phosphate effects on conventional outflow physiology

Abstract

Elevated intraocular pressure is the main risk factor in primary open-angle glaucoma, involving an increased resistance to aqueous humor outflow in the juxtacanalicular region of the conventional outflow pathway which includes the trabecular meshwork (TM) and the inner wall of Schlemm's canal (SC). Previously, sphingosine-1-phosphate (S1P) was shown to decrease outflow facility in porcine and human eyes, thus increasing outflow resistance and intraocular pressure. Owing to S1P's known effect of increasing barrier function in endothelial cells and the robust expression of the S1P₁ receptor on the inner wall of SC, we hypothesized that S1P₁ receptor activation promotes junction formation and decreases outflow facility. The effects of subtype-specific S1P receptor compounds were tested in human and porcine whole-eye perfusions and human primary cultures of SC and TM cells to determine the receptor responsible for S1P effects on outflow resistance. The S1P₁-specific agonist SEW2871 failed to both mimic S1P effects in paired human eye perfusions, as well as increase myosin light chain (MLC) phosphorylation in cell culture, a prominent outcome in S1P-treated SC and TM cells. In contrast, the S1P₂ antagonist JTE-013, but not the S1P₁ or S1P₁,₃ antagonists, blocked the S1P-promoted increase in MLC phosphorylation. Moreover, JTE-013 prevented S1P-induced decrease in outflow facility in perfused human eyes (P < 0.05, n = 6 pairs). Similarly, porcine eyes perfused with JTE-013 + S1P did not differ from eyes with JTE-013 alone (P = 0.53, n = 3). These results demonstrate that S1P₂ , and not S1P₁ or S1P₃, receptor activation increases conventional outflow resistance and is a potential target to regulate intraocular pressure.

A Comparison of Trabecular Meshwork Sphingolipids and Ceramides of Ocular Normotensive and Hypertensive States of DBA/2J Mice

“…36,37 Subsequent experimental findings support their role in aqueous humor drainage. 37,38 As identified here, there are several different sphingoid base-1-phosphate species differing by acyl chain length, which are present in the TM (Table 3). Toward transition to hypertensive from the normotensive …”

Bioactive Lysophospholipids: Role in Regulation of Aqueous Humor Outflow and Intraocular Pressure in the Context of Pathobiology and Therapy of Glaucoma

“…42,112,114 Interestingly, an antagonist of S1P2 receptor but not S1P1 or S1P3 receptors was reported to suppress S1P-induced decrease in AH outflow facility in human eyes. 44 These different observations offer definitive evidence for the importance of S1P in the regulation of AH outflow and IOP. However, little is known about S1P levels, expression profiles of S1P kinases, S1P phosphatases, and receptors in the glaucomatous human eye.…”

“…45,51,79 In the context of AH outflow and IOP, both LPA and S1P have been demonstrated to activate Rho and Rac GTPase signaling and to regulate actin cytoskeletal organization, cell adhesive interactions, cell-cell junctions, permeability, and contraction in the cells of AH outflow pathway, including the TM and SC. 42,44,80 In addition, enzymes generating these lysolipids were found to influence AH outflow and IOP. 43,81 There is also some evidence of dysregulation of LPA production in the AH and optic nerve head of glaucoma patients.…”

“…40,41 In addition to growth factors, steroids, and ECM molecules, various fatty acids, including eicosanoids, prostaglandins, and other lipids such as lysophospholipids, are recognized to influence cell contractile and cell adhesive properties of TM and SC cells. 42,44 From this point onward, the discussion will be focused on the known effects of lysophospholipids in TM and SC cells and in AH outflow and IOP.…”

“…10 As a part of recent efforts to explore and unravel additional cellular mechanisms regulating AH outflow via the TM and SC, we and others have identified that certain bioactive lipids, especially lysophospholipids, influence the TM cell contractile and cell adhesive properties, AH outflow, and IOP, highlighting a significant role for these molecules in both normal and aberrant regulation of outflow dynamics. [42][43][44] In the rest of this review, I will be focusing my discussion primarily on the role and mechanism of action of lysophospholipids [eg, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P)] in AH outflow and IOP, lysophospholipid metabolism, and receptors, and will be addressing the significance of the targeting of certain key molecules in the lysophospholipid signaling pathways to lower IOP and treatment of glaucoma. Importantly, dysregulation of these signaling pathways is implicated in various disease processes and is considered a viable therapeutic target for the treatment of several diseases.…”