Lysophosphatidic acid receptor, LPA 6, regulates endothelial blood-brain barrier function: Implication for hepatic encephalopathy

Biochem Biophys Res Commun. 2018 Jul 2;501(4):1048-1054. doi: 10.1016/j.bbrc.2018.05.106. Epub 2018 May 24.

Abstract

Cerebral edema is a life-threatening neurological condition characterized by brain swelling due to the accumulation of excess fluid both intracellularly and extracellularly. Fulminant hepatic failure (FHF) develops cerebral edema by disrupting blood-brain barrier (BBB). However, the mechanisms by which mediator induces brain edema in FHF remain to be elucidated. Here, we assessed a linkage between brain edema and lysophosphatidic acid (LPA) signaling by utilizing an animal model of FHF and in vitro BBB model. Azoxymethane-treated mice developed FHF and hepatic encephalopathy, associated with higher autotaxin (ATX) activities in serum than controls. Using in vitro BBB model, LPA disrupted the structural integrity of tight junction proteins including claudin-5, occludin, and ZO-1. Furthermore, LPA decreased transendothelial electrical resistances in in vitro BBB model, and induced cell contraction in brain endothelial monolayer cultures, both being inhibited by a Rho-associated protein kinase inhibitor, Y-27632. The brain capillary endothelial cells predominantly expressed LPA6 mRNA, whose knockdown blocked the LPA-induced endothelial cell contraction. Taken together, the up-regulation of serum ATX in hepatic encephalopathy may activate the LPA-LPA6-G12/13-Rho pathway in brain capillary endothelial cells, leading to enhancement of BBB permeability and brain edema.

Keywords: GPCR; Lipid mediator; Lysophospholipid; Neurological diseases; ROCK; p2ry5.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azoxymethane
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology
  • Brain Edema / complications
  • Brain Edema / pathology
  • Capillary Permeability / drug effects
  • Cells, Cultured
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Hepatic Encephalopathy / metabolism*
  • Hepatic Encephalopathy / pathology*
  • Liver Failure, Acute / complications
  • Liver Failure, Acute / metabolism
  • Liver Failure, Acute / pathology
  • Lysophospholipids / pharmacology
  • Male
  • Mice, Inbred C57BL
  • Models, Biological
  • Phosphoric Diester Hydrolases / metabolism
  • Rats
  • Receptors, Lysophosphatidic Acid / metabolism*
  • Signal Transduction / drug effects
  • rho GTP-Binding Proteins / metabolism
  • rho-Associated Kinases / metabolism

Substances

  • Lysophospholipids
  • Receptors, Lysophosphatidic Acid
  • rho-Associated Kinases
  • Phosphoric Diester Hydrolases
  • alkylglycerophosphoethanolamine phosphodiesterase
  • rho GTP-Binding Proteins
  • Azoxymethane
  • lysophosphatidic acid