Inhibition of endothelial cell proliferation by platelet factor-4 involves a unique action on S phase progression.
Modulation of endothelial cell proliferation and cell cycle progression by the "chemokine" platelet factor-4 (PF-4) was investigated. PF-4 inhibited DNA synthesis, as well as proliferation of endothelial cells derived from large and small blood vessels. Inhibition by PF-4 was independent of the type and the concentration of stimuli used for the induction of endothelial cell proliferation. Inhibition of cell growth by PF-4 was reversible. The effects of PF-4 were antagonized by heparin. Cell cycle analysis using [3H]thymidine pulse labeling during traverse of synchronous cells from G0/G1 to S phase revealed that addition of PF-4 during G1 phase completely abolished the entry of cells into S phase. In addition, PF-4 also inhibited DNA synthesis in cells that were already in S phase. In exponentially growing cells, addition of PF-4 resulted in an accumulation of > 70% of the cells in early S phase, as determined by FACS (Becton-Dickinson Immunocytometry Systems, Mountain View, CA). In cells synchronized in S phase by hydroxyurea and then released, addition of PF-4 promptly blocked further progression of DNA synthesis. These results demonstrate that in G0/G1-arrested cells, PF-4 inhibited entry of endothelial cells into S phase. More strikingly, our studies have revealed a unique mode of endothelial cell growth inhibition whereby PF-4 effectively blocked cell cycle progression during S phase.
Gupta
S K
SK
Lilly Research Laboratories, Indianapolis, Indiana 46285.
Singh
J P
JP
D000818:Animals; D001011:Aorta; D002196:Capillaries; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D005333:Fetus; D005434:Flow Cytometry; D006321:Heart; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D007700:Kinetics; D010978:Platelet Factor 4 / Q000494:pharmacology*; D011817:Rabbits; D012171:Retinal Vessels; D013936:Thymidine / Q000378:metabolism
D010978:Platelet Factor 4; D006493:Heparin; D004247:DNA; D013936:Thymidine; D006918:Hydroxyurea