TUMOR-NECROSIS-FACTOR ALPHA-INDUCED ANGIOGENESIS DEPENDS ON IN-SITU PLATELET-ACTIVATING-FACTOR BIOSYNTHESIS

Tumor necrosis factor (TNF) alpha, a potent inhibitor of endothelial c ell growth in vitro, is angiogenic in vivo. Therefore, it was suggeste d that the angiogenic properties of this agent might be consequent to the production of secondary mediators. Since TNF-alpha stimulates the synthesis of platelet-activating factor (PAF) by monocytes and endothe lial cells, we investigated the possible involvement of PBF in the ang iogenic effect of TNF-alpha. Angiogenesis was studied in a murine mode l in which Matrigel was used as a vehicle for the delivery of mediator s. In this model the angiogenesis induced by TNF-alpha was shown to be inhibited by WEB 2170, a specific PAF receptor antagonist. Moreover, in mice injected with TNF-alpha, PAF was detected within the Matrigel, 6 and 24 h after TNF-alpha injection. The synthesis of PAF within the Matrigel was concomitant with the early migration of endothelial cell s and infiltration of monocytes. No infiltration of lymphocytes or pol ymorphonuclear leukocytes was observed. Synthetic PAF as well as PAF e xtracted and purified from mice challenged with TNF-alpha induced a ra pid angiogenic response, inhibited by WEB 2170. These results suggest that the angiogenic effect of TNF-alpha is, at least in part, mediated by PAF synthesized from monocytes and/or endothelial cells infiltrati ng the Matrigel plug.