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1
* Experimental Cell Research Program, Methodist Research Institute, Indianapolis, Indiana 46202, USA;
Department of Physiology and Biophysics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA;
Department of Microbiology-Immunology and R. H. Lurie Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611, USA;
§ Department of Biochemistry, Lipid and Lipoprotein Research Group, University of Alberta, Edmonton, Alberta, T6H 5M3, Canada; and
¶ Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA
1Correspondence: Experimental Cell Research Program, Methodist Research Institute, 1701 N. Senate Ave., Indianapolis, IN 46202, USA. E-mail: dkenglish{at}msn.com
Recent studies have identified factors responsible for angiogenesis
within developing tumors, but mediators of vessel formation at sites of
trauma, injury, and wound healing are not clearly established. Here we
show that sphingosine 1-phosphate (S1P) released by platelets during
blood clotting is a potent, specific, and selective endothelial cell
chemoattractant that accounts for most of the strong endothelial cell
chemotactic activity of blood serum, an activity that is markedly
diminished in plasma. Preincubation of endothelial cells with pertussis
toxin inhibited this effect of S1P, demonstrating the involvement of a
G
i-coupled receptor. After S1P-induced
migration, endothelial cells proliferated avidly and differentiated
forming multicellular structures suggestive of early blood vessel
formation. S1P was strikingly effective in enhancing the ability of
fibroblast growth factor to induce angiogenesis in the avascular mouse
cornea. Our results show that blood coagulation initiates endothelial
cell angiogenic responses through the release of S1P, a potent
endothelial cell chemoattractant that exerts its effects by activating
a receptor-dependent process.—English, D., Welch, Z., Kovala, A. T., Harvey, K., Volpert, O. V., Brindley, D. N., Garcia,
J. G. N. Sphingosine 1-phosphate released from platelets
during clotting accounts for the potent endothelial cell chemotactic
activity of blood serum and provides a novel link between hemostasis
and angiogenesis.
Key Words: lipid mediators • vascular endothelium • angiogenesis • endothelial cell migration • hemostasis • S1P
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