NEGATIVE FEEDBACK-REGULATION OF HUMAN PLATELETS VIA AUTOCRINE ACTIVATION OF THE PLATELET-DERIVED GROWTH-FACTOR ALPHA-RECEPTOR

Human platelets contain platelet-derived growth factor (PDGF) in their alpha-granules which is released during platelet exocytosis. We show by immunoprecipitation and I-125-PDGF binding experiments that human p latelets have functionally active PDGF alpha-receptors, but not beta-r eceptors. The PDGF alpha-receptor (PDGFR-alpha) was identified as a 17 0-kDa glycosylated protein-tyrosine kinase as found in other cell type s. Stimulation of platelets with 0.1 unit/ml thrombin resulted in a si gnificant increase (2-5-fold) of the tyrosine phosphorylation of the P DGFR-alpha, as determined by immunoprecipitation with phosphotyrosine antiserum as well as with PDGFR-alpha antiserum. The observed thrombin -induced autophosphorylation of the PDGFR-alpha was inhibited by the a ddition of a neutralizing monoclonal PDGF antibody. Thus, our results suggest that the platelet PDGFR-alpha is stimulated in an autocrine ma nner by PDGF secreted during platelet activation. Preincubation of pla telets with PDGF inhibited thrombin-induced platelet aggregation and s ecretion of ATP + ADP and beta-hexosaminidase. Thrombin-induced platel et aggregation was also reversed when PDGF was added 30 s after thromb in stimulation. Inhi bition of the autocrine PDGF pathway during plate let activation by the PDGF antibody led to a potentiation of thrombin- induced beta-hexosaminidase secretion. Thus, the PDGFR-alpha takes par t in a negative feedback regulation during platelet activation. Our de monstration of PDGF alpha-receptors on human platelets and its inhibit ory function during platelet activation identifies a new possible role of PDGF in the regulation of thrombosis.