Angiogenic function of prostacyclin biosynthesis in human endothelial progenitor cells.
The role of prostaglandin production in the control of regenerative function of endothelial progenitor cells (EPCs) has not been studied. We hypothesized that activation of cyclooxygenase (COX) enzymatic activity and the subsequent production of prostacyclin (PGI(2)) is an important mechanism responsible for the regenerative function of EPCs. In the present study, we detected high levels of COX-1 protein expression and PGI(2) biosynthesis in human EPCs outgrown from blood mononuclear cells. Expression of COX-2 protein was almost undetectable under basal conditions but significantly elevated after treatment with tumor necrosis factor-alpha. Condition medium derived from EPCs hyperpolarized human coronary artery smooth muscle cells, similar to the effect of the PGI(2) analog iloprost. The proliferation and in vitro tube formation by EPCs were inhibited by the COX inhibitor indomethacin or by genetic inactivation of COX-1 or PGI(2) synthase with small interfering (si)RNA. Impaired tube formation and cell proliferation induced by inactivation of COX-1 were rescued by the treatment with iloprost or the selective peroxisome proliferator-activated receptor (PPAR)delta agonist GW501516 but not by the selective PGI(2) receptor agonist cicaprost. Downregulation of PPARdelta by siRNA also reduced angiogenic capacity of EPCs. Iloprost failed to reverse PPARdelta siRNA-induced impairment of angiogenesis. Furthermore, transfection of PGI(2) synthase siRNA, COX-1 siRNA, or PPARdelta siRNA into EPCs decreased the capillary formation in vivo after transplantation of human EPCs into the nude mice. These results suggest that activation of COX-1/PGI(2)/PPARdelta pathway is an important mechanism underlying proangiogenic function of EPCs.
He
Tongrong
T
Department of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Lu
Tong
T
d'Uscio
Livius V
LV
Lam
Chen-Fuh
CF
Lee
Hon-Chi
HC
Katusic
Zvonimir S
ZS
D000328:Adult; D049109:Cell Proliferation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000096:biosynthesis* / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D011464:Epoprostenol / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D047494:PPAR delta / Q000819:agonists; D034741:RNA, Small Interfering / Q000235:genetics; D012038:Regeneration; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology*; D013844:Thiazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D017077:Culture Media, Conditioned; D016861:Cyclooxygenase Inhibitors; C425931:GW 501516; D047494:PPAR delta; D034741:RNA, Small Interfering; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D011464:Epoprostenol; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D016285:Iloprost; D007213:Indomethacin