Platelet-released phospholipids link haemostasis and angiogenesis

Considerable attention has focused on identifying mediators of neovasculari zation at sites of growth and abnormal tissue development. By contrast, med iators of angiogenesis at sites of injury and wound repair are not well def ined but factors generated during blood coagulation (haemostasis) are attra ctive candidates. In addition to proteins generated, activated and released during the activation of clotting cascades, platelet-derived lipid mediato rs are now known to play a key role in many aspects of the angiogenic respo nse. The first indication of lipid mediator involvement in angiogenesis was the discovery that lysophosphatidate (LPA), phosphatidic acid (PA) and sph ingosine 1-phosphate (SPP) are high affinity agonists for G-protein coupled EDG (endothelial differentiation gene) receptors. The prototype for this f amily, EDG-1, was cloned from genes expressed when endothelial cells were a ctivated to assume an angiogenic phenotype in vitro. The subsequent finding that SPP is a high affinity ligand for EDG-1 led Spiegel, Hla and associat es (Lee et al,, Science 1998;279:1552-1555) to hypothesize that platelet-re leased phospholipids play an important role in angiogenesis. These investig ators and others demonstrated that SPP, LPA and phosphatidate (PA) induce m any important endothelial cell responses associated with angiogenesis, incl uding liberation of endothelial cells from established monolayers, chemotac tic migration, proliferation, adherens junction assembly and morphogenesis into capillary-like structures. Although these studies indicated the potent ial involvement of platelet-derived phospholipids in angiogenesis, their ph ysiological importance was not established However, recent work demonstrate s that >80% of the potent endothelial cell chemoattractive activity generat ed in human serum during clotting - an activity necessary for optimal angio genesis - results from platelet-derived SPP. Other factors released from pl atelets during clotting, including LPA and PA, exert profound effects on en dothelial cells that contribute unique aspects to the angiogenic response. These combined studies establish that SPP and other platelet-derived lipid mediators provide a novel link between haemostasis and angiogenesis. (C) 20 01 Elsevier Science B.V. All rights reserved.