Rapamycin inhibits proliferation and differentiation of human endothelial progenitor cells in vitro.
Bone-marrow-derived, circulating endothelial precursor cells contribute to neoangiogenesis in various diseases. Rapamycin has recently been shown to have anti-angiogenic effects in an experimental tumor model. Our group has developed a culture system that allows expansion and endothelial differentiation of human CD133(+) precursor cells. We could show by PCR analysis that mTOR, the rapamycin-binding protein, was expressed in fresh CD133(+) cells, in expanded cells after 28 days, and in differentiated endothelial cells. Rapamycin inhibited proliferation of CD133(+) cells dose dependently at similar concentrations as hematopoietic Jurkat or HL-60 cells. Apoptosis was induced by rapamycin after 48 h of treatment, which could be reduced by preincubation with FK 506. Furthermore, the development of adherent endothelial cells from expanded CD133(+) cells was dose dependently inhibited. Expression of endothelial antigens CD144 and von Willebrand factor on differentiating endothelial precursors was reduced by rapamycin. In summary, rapamycin inhibits proliferation and differentiation of human endothelial precursor cells underlining its anti-angiogenic effects.
Butzal
Martin
M
Department of Medicine, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.
Loges
Sonja
S
Schweizer
Michaela
M
Fischer
Uta
U
Gehling
Ursula M
UM
Hossfeld
Dieter K
DK
Fiedler
Walter
W
D000071916:AC133 Antigen; D000941:Antigens / Q000187:drug effects / Q000276:immunology; D015703:Antigens, CD; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology; D018922:HL-60 Cells; D006801:Humans; D007166:Immunosuppressive Agents; D019169:Jurkat Cells; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000503:physiopathology; D010455:Peptides / Q000276:immunology; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus / Q000494:pharmacology; D014841:von Willebrand Factor / Q000276:immunology
D000071916:AC133 Antigen; D000941:Antigens; D015703:Antigens, CD; D006023:Glycoproteins; D007166:Immunosuppressive Agents; C000606023:PROM1 protein, human; D010455:Peptides; D012333:RNA, Messenger; C029417:Von Willebrand antigen; D014841:von Willebrand Factor; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D016559:Tacrolimus