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

Abstract

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 Galphai-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.

Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720

“…The lower S1P levels in plasma relative to serum (Fig. 2D, inset) are consistent with S1P release by platelets during blood clotting (42,43).…”

Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer

“…The influence of PMV on chemotaxis, for example, may be attributed to the presence of S1P or AA. 13,20,52 Unsaturated acids, however, have been found to induce apoptosis and inhibit proliferation in several other experimental systems. 13,52 Our previous studies have demonstrated that the biologic activity of PMV is associated with high-molecular-weight proteins and is only partly affected by protein digest and/or heat inactivation.…”

“…13,20,52 Unsaturated acids, however, have been found to induce apoptosis and inhibit proliferation in several other experimental systems. 13,52 Our previous studies have demonstrated that the biologic activity of PMV is associated with high-molecular-weight proteins and is only partly affected by protein digest and/or heat inactivation. 12 We suggested that it could be related partly to high-molecular-weight, relatively temperature-stable proteins and partly to bioactive lipids conjugated with high-molecular-weight proteins.…”

“…7,8 Recently, we and others have postulated that MV are important signaling molecules in intercellular crosstalk. [11][12][13][14] This communication between cells may perhaps have developed very early in the course of eukaryocytic evolution, before soluble mediators emerged.…”

Involvement of Endothelial Nitric Oxide in Sphingosine-1-Phosphate–Induced Angiogenesis

“…It seems likely that S1P, which is known to be abundantly stored in platelets and released on their activation, 17 may contribute to plateletinduced angiogenesis in wound repair, because it was demonstrated that S1P is the major EC chemoattractant released into serum by platelets during blood clotting. 18 Therefore, it is suggested that the angiogenic activity of S1P may account for the important role of platelet interaction with ECs in angiogenesis at sites of injury. Interestingly, previous studies have demonstrated the crucial role of NO in wound healing, as wound healing is accelerated by systemic administration of L-arginine, a substrate of NOS, but delayed by NOS inhibitors.…”