Regulation of endothelial progenitor cells by prostaglandin E1 via inhibition of apoptosis.
Bone marrow derived endothelial progenitor cells (EPC) improve endothelial function and neoangiogenesis. Prostaglandin E1 (PGE1) is used for the treatment of patients with peripheral artery disease (PAD). However, the molecular effects are only partially understood. Treatment of C57/Bl6 mice with PGE1, 10 microg/kg BW increased the number of circulating Sca-1/VEGFR-2 positive EPC in the blood compared to vehicle (122+/-7% and 119+/-6% after 10 and 20 days). EPC in the bone marrow were upregulated to 125+/-11% (10 days) and 142+/-15% (20 days). PGE1 increased DiLDL/Lectin positive spleen-derived EPC to 170+/-20% and 174+/-14% after 10 and 20 days. Treatment with PGE1 enhanced in-vivo neoangiogenesis by 2-fold (disk assay, 218+/-27%). PGE1 enhanced the SDF-1 induced migratory capacity per number of EPC to 140+/-11%, 146+/-22% and 160+/-16% after 10, 14 and 20 days. Greater migratory capacity was associated with upregulation of expression of telomere repeat-binding factor (TRF2). EPC of PGE1-treated mice were characterized by reduced apoptosis. Similarly, PGE1 prevented H(2)O(2)-induced apoptosis in cultured human EPC. The effect is mediated by PI3-kinase. The effects of PGE1 on EPC were completely prevented by co-treatment with the NO-inhibitor L-NAME, 50 mg kg(-1) p.o. Treatment with the prostaglandin I2 derivative iloprost (10 microg/kg BW, 20 days) did not alter EPC numbers or function. Physical exercise is the basis of the treatment of patients with PAD. Voluntary running increased EPC numbers in mice. Treatment with PGE1 resulted in an additional increase of Sca-1/VEGFR-2- and DiLDL/lectin positive EPC as well as migration. n=10-24 for all groups, all effects p<0.05. In summary, prostaglandin E1 increases the number of EPC in the blood and the bone marrow in mice. The effect is additive to physical exercise, depends on nitric oxide and is characterized by reduction of PI3-kinase mediated apoptosis. PGE1-mediated upregulation of EPC is associated with improved EPC function and enhanced angiogenesis.
Gensch
Christoph
C
Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, 66421 Homburg, Saar, Germany.
Clever
Yvonne
Y
Werner
Christian
C
Hanhoun
Milad
M
Böhm
Michael
M
Laufs
Ulrich
U
D000527:Alprostadil / Q000494:pharmacology*; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2; D000527:Alprostadil