title: Activation of Prostaglandin FP and EP2 Receptors Differently Modulates Myofibroblast Transition in a Model of Adult Primary Human Trabecular Meshwork Cells.
abstract: OBJECTIVE
  Prostaglandin F2α analogues are the first-line medication for the treatment of ocular hypertension (OHT), and prostanoid EP2 receptor agonists are under clinical development for this indication. The goal of this study was to investigate the effects of F prostanoid (FP) and EP2 receptor activation on the myofibroblast transition of primary trabecular meshwork (TM) cells, which could be a causal mechanism of TM dysfunction in glaucoma.
  
  
  METHODS
  Human primary TM cells were treated with either latanoprost or butaprost and TGF-β2. Trabecular meshwork contraction was measured in a three-dimensional (3D) TM cell-populated collagen gel (CPCG) model. Expression of α-smooth muscle actin (α-SMA) and phosphorylation of myosin light chain (MLC) were determined by Western blot. Assembly of actin stress fibers and collagen deposition were evaluated by immunocytochemistry. Involvement of p38, extracellular signal-regulated kinase (ERK), and Rho-associated kinase (ROCK) pathways as well as matrix metalloproteinase activation was tested with specific inhibitors.
  
  
  RESULTS
  In one source of validated adult TM cells, latanoprost induced cell contraction as observed by CPCG surface reduction and increased actin polymerization, α-SMA expression, and MLC phosphorylation, whereas butaprost inhibited TGF-β2-induced CPCG contraction, actin polymerization, and MLC phosphorylation. Both agonists inhibited TGF-β2-dependent collagen deposition. The latanoprost effects were mediated by p38 pathway.
  
  
  CONCLUSIONS
  Latanoprost decreased TM collagen accumulation but promoted a contractile phenotype in a source of adult TM cells that could modulate the conventional outflow pathway. In contrast, butaprost attenuated both TM contraction and collagen deposition induced by TGF-β2, thereby inhibiting myofibroblast transition of TM cells. These results open new perspectives for the management of OHT.
authors.affiliation: Sorbonne Universités Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut de la Vision, Paris, France 2Sanofi Research & Development, Translational Sciences Uni.
authors.forename: Georges
authors.initials: G
authors.lastname: Kalouche
authors.affiliation: Sorbonne Universités Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut de la Vision, Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Beguier
authors.affiliation: Sorbonne Universités Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut de la Vision, Paris, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Bakria
authors.affiliation: Sorbonne Universités Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut de la Vision, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Melik-Parsadaniantz
authors.affiliation: Sanofi Research & Development, Ophthalmology, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Leriche
authors.affiliation: Sanofi Research & Development, Ophthalmology, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Debeir
authors.affiliation: Sorbonne Universités Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut de la Vision, Paris, France.
authors.forename: William
authors.initials: W
authors.lastname: Rostène
authors.affiliation: Sorbonne Universités Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut de la Vision, Paris, France 4Quinze-Vingts National Ophthalmology Hospital, Paris, Fra.
authors.forename: Christophe
authors.initials: C
authors.lastname: Baudouin
authors.affiliation: Sanofi Research & Development, Translational Sciences Unit, Chilly-Mazarin, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Vigé
mesh_terms: D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D015237:Dinoprost; D005901:Glaucoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D000077338:Latanoprost; D008297:Male; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018994:Myosin Light Chains / Q000378:metabolism; D018696:Neuroprotective Agents; D011459:Prostaglandins E, Synthetic; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology*; D012313:RNA / Q000235:genetics*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D011982:Receptors, Prostaglandin / Q000187:drug effects* / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014129:Trabecular Meshwork / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D000959:Antihypertensive Agents; D018994:Myosin Light Chains; D018696:Neuroprotective Agents; D011459:Prostaglandins E, Synthetic; D011461:Prostaglandins F, Synthetic; D011982:Receptors, Prostaglandin; D058307:Receptors, Prostaglandin E, EP2 Subtype; C034671:prostaglandin F2alpha receptor; D012313:RNA; D000077338:Latanoprost; D015237:Dinoprost; D000527:Alprostadil; C048491:butaprost