title: Proliferative and morphological effects of endothelins in Schwann cells: roles of p38 mitogen-activated protein kinase and Ca(2+)-independent phospholipase A2.
abstract: The regulation of Schwann cell (SC) proliferation and morphology is critical to nerve homeostasis. We have previously reported that endothelins (ETs) regulate the activity of different effectors in SC including adenylyl cyclase, phospholipases C and A2 and mitogen-activated protein kinases (MAPKs). These effects imply a possible participation of ETs in the regulation of SC phenotype. We have now investigated the effects of endothelins on the proliferation and morphology of SC, and compared them with the responses to platelet-derived growth factor (PDGF), a known mitogen in these cells. Both endothelin-1 (ET-1) and PDGF increased the incorporation of [3H]thymidine and the proportion of SC in S and G2/M, with a concomitant decrease in the G0/G1 stage cells. Treatment with ET-1 produced rapid changes in the morphology of the SC, characterized by the appearance of cell spreading with shorter processes. The response to ET-1 was considered to represent a proliferative phenotype, in contrast to the effects of forskolin, which decreased [3H]thymidine incorporation in immortalized SC (iSC) and lead to a differentiated morphology with longer extensions. While both ET-1 and PDGF displayed a proliferative effect on SC, treatment with PDGF did not affect the morphology of these cells to a significant extent. A role for p38 MAPK and Ca(2+)-independent phospholipase A2 in the changes in morphology and proliferation of iSC driven by ET-1 was suggested by the effects of selective inhibitors of these pathways [SB202190 and HELSS, respectively]. The unique pattern of signaling pathways recruited by ET-1 and its combined effects on regulation of phenotype and proliferation of SC suggest an important role for this peptide during nerve degeneration/regeneration.
authors.affiliation: Division of Hypertension, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio 44106-4982, USA. lnb@po.cwru.edu
authors.forename: L N
authors.initials: LN
authors.lastname: Berti-Mattera
authors.forename: S
authors.initials: S
authors.lastname: Harwalkar
authors.forename: B
authors.initials: B
authors.lastname: Hughes
authors.forename: P L
authors.initials: PL
authors.lastname: Wilkins
authors.forename: K
authors.initials: K
authors.lastname: Almhanna
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D022081:Cell Surface Extensions / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022001:Focal Adhesions / Q000187:drug effects; D054522:Group VI Phospholipases A2; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009281:Naphthalenes / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000502:physiology*; D054467:Phospholipases A2; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology; D051381:Rats; D012583:Schwann Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction / Q000187:drug effects*; D022502:Stress Fibers / Q000187:drug effects; D016596:Vinculin / Q000032:analysis; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000199:Actins; D003994:Bucladesine; D005576:Colforsin; D016895:Culture Media, Serum-Free; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D054522:Group VI Phospholipases A2; D007093:Imidazoles; D020928:Mitogen-Activated Protein Kinases; D009281:Naphthalenes; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010741:Phospholipases A; D054467:Phospholipases A2; D010982:Platelet-Derived Growth Factor; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011753:Pyrones; D016596:Vinculin; D048051:p38 Mitogen-Activated Protein Kinases; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole