title: Plasticity-related gene-1 inhibits lysophosphatidic acid-induced vascular smooth muscle cell migration and proliferation and prevents neointima formation.
abstract: Plasticity-related gene-1 (PRG-1) protects neuronal cells from lysophosphatidic acid (LPA) effects. In vascular smooth muscle cells (VSMCs), LPA was shown to induce phenotypic modulation in vitro and vascular remodeling in vivo. Thus we explored the role of PRG-1 in modulating VSMC response to LPA. PCR, Western blot, and immunofluorescence experiments showed that PRG-1 is expressed in rat and human vascular media. PRG-1 expression was strongly inhibited in proliferating compared with quiescent VSMCs both in vitro and in vivo (medial vs. neointimal VSMCs), suggesting that PRG-1 expression is dependent on the cell phenotype. In vitro, adenovirus-mediated overexpression of PRG-1 specifically inhibited LPA-induced rat VSMC proliferation and migration but not platelet-derived growth factor-induced proliferation. This effect was abolished by mutation of a conserved histidine in the lipid phosphate phosphatase family that is essential for interaction with lipid phosphates. In vivo, balloon-induced neointimal formation in rat carotid was significantly decreased in vessels infected with PRG-1 adenovirus compared with β-galactosidase adenovirus (-71%; P < 0.05). PRG-1 overexpression abolished the activation of the p42/p44 signaling pathway in LPA-stimulated rat VSMCs in culture and in balloon-injured rat carotids. Taken together, these findings provide the first evidence of a protective role of PRG-1 in the vascular media under pathophysiological conditions.
authors.affiliation: INSERM, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche UMR_S 956, Faculté de Médecine Pitié-Salpétrière, Paris, France.
authors.forename: Amira
authors.initials: A
authors.lastname: Gaaya
authors.forename: Odette
authors.initials: O
authors.lastname: Poirier
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mougenot
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Hery
authors.forename: Fabrice
authors.initials: F
authors.lastname: Atassi
authors.forename: Alexandre
authors.initials: A
authors.lastname: Marchand
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Saulnier-Blache
authors.forename: Julien
authors.initials: J
authors.lastname: Amour
authors.forename: Johannes
authors.initials: J
authors.lastname: Vogt
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lompré
authors.forename: Florent
authors.initials: F
authors.lastname: Soubrier
authors.forename: Sophie
authors.initials: S
authors.lastname: Nadaud
mesh_terms: D000256:Adenoviridae; D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D005822:Genetic Vectors; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D058426:Neointima / Q000139:chemically induced; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002148:Calmodulin-Binding Proteins; D008246:Lysophospholipids; C476330:Plppr4 protein, rat; D010744:Phosphoric Monoester Hydrolases; C032881:lysophosphatidic acid