Regulation of vascular permeability by sphingosine 1-phosphate

Abstract

A significant and sustained increase in vascular permeability is a hallmark of acute inflammatory diseases such as acute lung injury (ALI) and sepsis and is an essential component of tumor metastasis, angiogenesis, and atherosclerosis. Sphingosine 1-phosphate (S1P), an endogenous bioactive lipid produced in many cell types, regulates endothelial barrier function by activation of its G-protein coupled receptor S1P(1). S1P enhances vascular barrier function through a series of profound events initiated by S1P(1) ligation with subsequent downstream activation of the Rho family of small GTPases, cytoskeletal reorganization, adherens junction and tight junction assembly, and focal adhesion formation. Furthermore, recent studies have identified transactivation of S1P(1) signaling by other barrier-enhancing agents as a common mechanism for promoting endothelial barrier function. This review summarizes the state of our current knowledge about the mechanisms through which the S1P/S1P(1) axis reduces vascular permeability, which remains an area of active investigation that will hopefully produce novel therapeutic agents in the near future.

Figure 1. Biosynthesis and metabolism of S1P

Depicted are the primary cellular components responsible for S1P generation and degradation. SM, Sphingomyelin; SMase, Sphingomyelinase; Cer, Ceramide; CDase, Cermidase; Sph, Sphingosine; S1P, Sphingosine1-phosphate; SphK, Sphingosine kinase; S1Pase, Sphingosine 1-phosphate phosphatase; S1PL, S1P lyase; P-Eth, Phosphoethanolamine; Hex, Hexadecanal.

Figure 2. Regulation of Vascular Permeability by S1P/ SIP₁ signaling

Binding of S1P to the SIP₁ receptor stimulates the G_i-dependent recruitment of PI3 kinase, Tiam1 and Rac1 to lipid rafts (CEM), which serves to activate Rac1 in a G_i-PI3K-Tiam1 dependent manner. In addition, S1P induces an increase in intracellular Ca²⁺ concentration via a G_i-PLC pathway with additional activation of Rac1. After the activation of Rac1, S1P induces a series of profound events including adherens junction and tight junction assembly, cytoskeletal reorganization, and formation of focal adhesions that combine to enhance vascular barrier function. Furthermore, the transactivation of S1P₁ signaling by other barrier enhancing agents is recently recognized as a common mechanism for promoting endothelial barrier function. TJ, tight junction; AJ, adherens junction; S1P, Sphingosine-1-phosphate; SIP1, Sphingosine-1-phosphate receptor 1; PI3K, Phosphoinositide 3-kinase; Tiam 1, T-lymphoma invasion and metastasis gene 1; Rac1, Rho family of GTPase Rac1; PAK1, p21-activated protein kinase 1; LIMK, LIM kinase; PLC, Phospholipase C; ZO-1, Zona occluden protein-1; nmMLCK, non-muscle myosin light chain kinase; VE-Cad, Vascular endothelial cadherin; a-Cat, a-Catenin; ß-Cat, ß-Catenin; Vin, Vinculin; Pax, Paxillin; FAK, focal adhesion kinase; GIT2, G protein-coupled receptor kinase interactor-1; ECM, Extracellular matrix; APC, Activated protein C; LMW-HA, high molecule weight hyaluronan.

Figure 3. S1P reduces lung permeability in vivo

24 hours after mice received intratracheal LPS (2 mg/kg) or control saline, lung tissue specimens were harvested, fixed in paraformaldehyde, and histologically evaluated by hematoxylin and eosin stain. The top panel demonstrates a pronounced inflammatory cell infiltrate in response to LPS (inset: control lung for comparison). However, in mice receiving intravenous S1P (1 μM final concentration) one hour after LPS administration, the inflammatory cell infiltrate is markedly reduced (bottom panel). This effect demonstrates the potent ability of S1P to decrease vascular permeability to inflammatory cells in vivo (Peng et al., 2004).