Platelets play many important roles in maintenance and formation of blood vessels. The latter is usually attributed to release of direct acting proangiogenic influences, e.g., vascular endothelial growth factor, sphingosine I phosphate, and other mediators, though their effects are normally opposed by endogenous angiogenesis inhibitors, including thrombospondin I (TSP-1/THSP1). Hence downregulation of TSP-1 is regarded as an important step in the generation of the pro-angiogenic (tumor) stroma. Here we report that platelets induce marked downregulation of TSP-1 (gene transcription and protein) in mouse dermal fibroblasts. This effect is: (i) blocked by inhibitors of sphingosine kinase, (ii) unaffected by inhibitors of G(i)-proteins (pertussis toxin), (iii) recapitulated by sphingosine, (iv) can also be induced by lysophosphatidic acid. These observations suggest a hitherto unappreciated, indirect role of platelets and their phospholipids in angiogenesis, i.e., proangiogenic conditioning of connective tissue stroma through lowering TSP-1 expression. (c) 2005 Elsevier Inc. All rights reserved.