Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement

J Clin Invest. 2001 Sep;108(5):689-701. doi: 10.1172/JCI12450.

Abstract

Substances released by platelets during blood clotting are essential participants in events that link hemostasis and angiogenesis and ensure adequate wound healing and tissue injury repair. We assessed the participation of sphingosine 1-phosphate (Sph-1-P), a biologically active phosphorylated lipid growth factor released from activated platelets, in the regulation of endothelial monolayer barrier integrity, which is key to both angiogenesis and vascular homeostasis. Sph-1-P produced rapid, sustained, and dose-dependent increases in transmonolayer electrical resistance (TER) across both human and bovine pulmonary artery and lung microvascular endothelial cells. This substance also reversed barrier dysfunction elicited by the edemagenic agent thrombin. Sph-1-P-mediated barrier enhancement was dependent upon G(ialpha)-receptor coupling to specific members of the endothelial differentiation gene (Edg) family of receptors (Edg-1 and Edg-3), Rho kinase and tyrosine kinase-dependent activation, and actin filament rearrangement. Sph-1-P-enhanced TER occurred in conjunction with Rac GTPase- and p21-associated kinase-dependent endothelial cortical actin assembly with recruitment of the actin filament regulatory protein, cofilin. Platelet-released Sph-1-P, linked to Rac- and Rho-dependent cytoskeletal rearrangement, may act late in angiogenesis to stabilize newly formed vessels, which often display abnormally increased vascular permeability.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actin Depolymerizing Factors
  • Actins / metabolism
  • Animals
  • Capillary Permeability* / drug effects
  • Cattle
  • Cells, Cultured
  • Cytoskeleton / metabolism
  • Cytoskeleton / ultrastructure*
  • DNA-Binding Proteins / physiology*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiology*
  • Endothelium, Vascular / ultrastructure
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Humans
  • I-kappa B Proteins*
  • Immediate-Early Proteins / physiology*
  • Lysophospholipids*
  • MAP Kinase Signaling System
  • Microfilament Proteins / metabolism
  • NF-KappaB Inhibitor alpha
  • Neovascularization, Physiologic
  • Protein-Serine-Threonine Kinases / physiology
  • Receptors, Cell Surface*
  • Receptors, G-Protein-Coupled*
  • Receptors, Lysophospholipid
  • Sphingosine / analogs & derivatives
  • Sphingosine / pharmacology*
  • p21-Activated Kinases
  • rac GTP-Binding Proteins / physiology

Substances

  • Actin Depolymerizing Factors
  • Actins
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Immediate-Early Proteins
  • Lysophospholipids
  • Microfilament Proteins
  • NFKBIA protein, human
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Receptors, Lysophospholipid
  • NF-KappaB Inhibitor alpha
  • sphingosine 1-phosphate
  • PAK1 protein, human
  • Protein-Serine-Threonine Kinases
  • p21-Activated Kinases
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • rac GTP-Binding Proteins
  • Sphingosine