ReviewIn vitro and in vivo modulation of vascular barrier integrity by sphingosine 1-phosphate: mechanistic insights
Section snippets
Introduction and historical perspective
Sphingosine 1-phosphate (S1P) is a biologically active sphingolipid produced in many cells by the phosphorylation of sphingosine, a molecule derived from the degradation of the plasma membrane component sphingomyelin (reviewed in Ref. [1]). Circulating platelets are rich in sphingosine kinase, the enzyme-catalyzing sphingosine phosphorylation, yet relatively deficient in S1P lyase [2], the enzyme primarily responsible for the degradation of S1P. Thus, activated platelets represent an important
Sphingosine as a complete angiogenic factor and barrier regulatory agent in vitro
Hla and Maciag [5] identified the Edg-1 receptor, by differential gene subtraction studies in phorbol ester-stimulated endothelium, as a gene involved in angiogenesis. When S1P was ultimately found to be the ligand for this receptor, an explosion occurred in the number of reports detailing S1P effects on endothelial cell migration and angiogenesis (reviewed in Ref. [6]). Our group was the first to demonstrate S1P to be the most potent endothelial chemoattractant present in serum and be a
Sphingosine 1-phosphate as a potent antiinflammatory and barrier regulatory agent in vivo
It is well recognized that many inflammatory disease states are characterized by increased vascular permeability and the exudation of fluid and protein across the endothelial barrier. The pulmonary vasculature is particularly susceptible to dynamic alterations in the integrity of the barrier given the marked surface area of the lung microcirculation. Disruption of this barrier, as occurs during inflammatory disease states, results in the movement of fluid and macromolecules into the
Mechanisms of sphingosine 1-phosphate-mediated human lung endothelial barrier regulation: signaling by Rho family GTPases to the cytoskeleton
The mechanisms by which S1P enhances the integrity of the endothelial barrier remain an active area of research. As vascular permeability and increases in tissue edema occur primarily via a paracellular pathway during inflammation, there has been intense focus on the forces that regulate the integrity of the paracellular junction. Mechanistic approaches to endothelial cell barrier regulation have revealed the complexity of these processes. However, one valuable paradigm has described
Mechanisms of sphingosine 1-phosphate-mediated barrier regulation: effects on adherens junctions
S1P rapidly increases trans-endothelial monolayer electrical resistance (TER) primarily through an increase in paracellular resistance, suggesting that adherens junction assembly and stabilization plays a key role in endothelial barrier integrity [51]. Alterations in cytoskeletal organization and intercellular junctional integrity interact to dynamically regulate endothelial barrier homeostasis. A number of studies have documented that adherens junction assembly is essential for the maintenance
Mechanisms of sphingosine 1-phosphate-mediated barrier regulation: effects on focal adhesions and matrix interactions
Although alterations in endothelial permeability depend largely on the function of intercellular adhesions, contacts between the endothelial cell and the underlying matrix contribute approximately 20% of resistance to permeability [51]. Focal adhesions provide additional adhesive forces in barrier regulation by forming a critical bridge for bidirectional signal transduction between the actin cytoskeleton and the cell–matrix interface. Functionally dynamic organelles, the focal adhesion (FA)
Potential mechanisms for sustained sphingosine 1-phosphate effects on vascular barrier regulation
The molecular mechanisms underlying the sustained beneficial effect of S1P are entirely unclear. The effects of S1P given intravenously would not be expected to persist beyond a few hours because its half-life in blood is relatively short (<1 hour). However, significant barrier protection was observed following a single injection of S1P administered to injured mice 6 and 23 hours earlier [22]. These data suggest the potential for an attenuating effect of S1P on key transcriptional pathways
Summary
The disruption of vascular integrity with profound increases in permeability is an essential feature of inflammatory processes and significantly contributes to the high morbidity and mortality of a number of inflammatory syndromes including acute lung injury. Although the molecular basis for EC barrier regulation remains imprecisely defined, sphingolipids are now recognized as important mediators of cellular function with in vitro and in vivo modulation of vascular barrier integrity a key
Acknowledgments
The authors gratefully acknowledge Steven M. Dudek, MD and Eddie T. Chiang for their contributions. This work was supported in part by the Center for Translational Respiratory Medicine and grant from the National Institutes of Health (HL58064).
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