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Am. J. Respir. Cell Mol. Biol., Volume 24, Number 6, June, 2001 711-719

Differential Regulation of Sphingosine-1-Phosphate- and VEGF-Induced Endothelial Cell Chemotaxis
Involvement of Gialpha 2-Linked Rho Kinase Activity

Feng Liu, Alexander D. Verin, Peiyi Wang, Regina Day, Robert P. Wersto, Francis J. Chrest, Denis K. English, and Joe G. N. Garcia

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore; National Institute of Aging, Baltimore, Maryland; Methodist Research Institute, Indianapolis, Indiana; and Tufts University, Boston, Massachusetts

We compared stimulus-coupling pathways involved in bovine pulmonary artery (PA) and lung microvascular endothelial cell migration evoked by sphingosine-1-phosphate (S1P), a potent bioactive lipid released from activated platelets, and by vascular endothelial growth factor (VEGF), a well-recognized angiogenic factor. S1P-induced endothelial cell migration was maximum at 1 µM (~ 8-fold increase with PA endothelium) and surpassed the maximal response evoked by either VEGF (10 ng/ml) (~ 2.5-fold increase) or hepatocyte growth factor (HGF) (~ 2.5-fold increase). Migration induced by S1P, but not by VEGF, was significantly inhibited by treatment with antisense oligonucleotides directed to Edg-1 and Edg-3 (endothelial differentiation gene) S1P receptors and by G protein modification. These strategies included pretreatment with pertussis toxin, or transfection with mini-genes encoding a beta gamma subunit inhibitory peptide of the beta -adrenergic receptor kinase, or an 11-amino-acid peptide that inhibits G1alpha 2 signaling. Various strategies to interrupt Rho family signaling, including C3 exotoxin, dominant/negative Rho, or the addition of Y27632, a cell-permeable Rho kinase inhibitor, significantly attenuated S1P- but not VEGF-induced migration. Conversely, pharmacologic inhibition of either myosin light chain kinase, src family tyrosine kinases, or phosphatidylinositol-3' kinase reduced basal endothelial cell migration and abolished VEGF-induced endothelial cell migration but did not inhibit the increase in S1P-induced migration. Whereas VEGF and S1P increased both p42/p44 extracellular regulated kinase and p38 mitogen-activated protein (MAP) kinase activities, only p38 MAP kinase inhibition significantly reduced VEGF- and S1P-stimulated migration. These data confirm S1P as a potent endothelial cell chemoattractant through G1alpha 2-coupled Edg receptors linked to Rho-associated kinase and p38 MAP kinase activation. The divergence in signaling pathways evoked by S1P and VEGF suggests complex and agonist-specific regulation of endothelial cell angiogenic responses.

Abbreviations: beta -adrenergic receptor kinase, beta ARK; bovine lung microvascular endothelial cell, BLMVEC; bovine pulmonary artery endothelial cell, BPAEC; Rho guanosine triphosphatase dominant/negative construct, DN Rho; endothelial differentiation gene, Edg; extracellular regulated kinase, ERK; green fluorescent protein, GFP; guanosine triphosphatase, GTPase; hepatocyte growth factor, HGF; mitogen-activated protein, MAP; MAP kinase, MAPK; myosin light chain, MLC; myosin light chain kinase, MLCK; polyacrylamide gel electrophoresis, PAGE; plasmids with enhanced green fluorescent protein, pEGFP; phosphatidylinositol-3' kinase, PI-3' kinase; pertussis toxin, PTX; Rho-associated coiled-coil forming protein serine/threonine kinases, ROCK; sphinogosine-1-phosphate, S1P; sodium dodecyl sulfate, SDS; standard error, SE; vascular endothelial growth factor, VEGF.




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