Role of Lysophospholipid Growth Factors in the Modulation of Aqueous Humor Outflow Facility

Abstract

These studies demonstrate that LPA and S1P, the physiological agonists of Edg receptors, decrease outflow facility in perfused porcine eyes in association with increased MLC phosphorylation and Rho guanosine triphosphatase (GTPase) activation. These data provide evidence for a novel mechanism for negative regulation of outflow facility, which may contribute to overall physiological homeostasis of aqueous humor outflow facility.

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

“…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.…”

“…87 There is, however, overwhelming evidence that LPA influences cell adhesive, actin cytoskeletal organization, and contractile properties of TM cells derived from different species, including human and porcine. 42,80,84,88 Moreover, both TM cells and TM tissue derived from human eyes have been shown to express various LPA-specific GPCR receptors that are specific to LPA. 42 In serum-starved TM and SC cells, LPA has been shown to induce a robust increase in actin stress fibers, focal adhesions (vinculin and paxillin based), and contraction in association with increased myosin light chain (MLC) phosphorylation.…”

“…42,80,84,88 Moreover, both TM cells and TM tissue derived from human eyes have been shown to express various LPA-specific GPCR receptors that are specific to LPA. 42 In serum-starved TM and SC cells, LPA has been shown to induce a robust increase in actin stress fibers, focal adhesions (vinculin and paxillin based), and contraction in association with increased myosin light chain (MLC) phosphorylation. 42 These effects were found to be mediated predominantly by LPA-induced activation of Rho GTPase signaling.…”

“…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.…”