Inhibition of Endothelial Cell Proliferation by Platelet Factor-4 Involves a Unique Action on S Phase Progression

• Published in: The Journal of cell biology Vol. 127; no. 4; pp. 1121 - 1127
• Main Authors: Gupta, Shalley K., Singh, Jai Pal
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 01-11-1994; The Rockefeller University Press
• Subjects: Animals; Aorta; Biochemistry; Capillaries; Cattle; Cell culture techniques; Cell cycle; Cell Cycle - drug effects; Cell Division - drug effects; Cell growth; Cell lines; Cells; Cells, Cultured; Cellular biology; Cultured cells; DNA - biosynthesis; Endothelial cells; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Fetus; Flow Cytometry; Heart; Heparin; Heparin - pharmacology; Humans; Hydroxyurea - pharmacology; Interphase; Kinetics; Platelet Factor 4 - pharmacology; Proteins; Rabbits; Retinal Vessels; T lymphocytes; Thymidine - metabolism
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.127.4.1121

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 [3 H]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.