Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization.
Increasing evidence suggests that postnatal neovascularization involves the recruitment of circulating endothelial progenitor cells (EPCs). Hematopoietic and endothelial cell lineages share common progenitors. Cytokines formerly thought to be specific for the hematopoietic system have only recently been shown to affect several functions in endothelial cells. Accordingly, we investigated the stimulatory potential of erythropoietin (Epo) on EPC mobilization and neovascularization. The bone marrow of Epo-treated mice showed a significant increase in number and proliferation of stem and progenitor cells as well as in colony-forming units. The number of isolated EPCs and CD34+/flk-1+ precursor cells was significantly increased in spleen and peripheral blood of Epo-treated mice compared with phosphate-buffered saline-treated mice. In in vivo models of postnatal neovascularization, Epo significantly increased inflammation- and ischemia-induced neovascularization. The physiologic relevance of these findings was investigated in patients with coronary heart disease. In a multivariate regression model, serum levels of Epo and vascular endothelial growth factor were significantly associated with the number of stem and progenitor cells in the bone marrow as well as with the number and function of circulating EPCs. In conclusion, the present study suggests that Epo stimulates postnatal neovascularization at least in part by enhancing EPC mobilization from the bone marrow. Epo appears to physiologically regulate EPC mobilization in patients with ischemic heart disease. Thus, Epo serum levels may help in identifying patients with impaired EPC recruitment capacity.
Heeschen
Christopher
C
Department of Internal Medicine IV and Hematology, University of Frankfurt, Germany.
Aicher
Alexandra
A
Lehmann
Ralf
R
Fichtlscherer
Stephan
S
Vasa
Mariuca
M
Urbich
Carmen
C
Mildner-Rihm
Christiane
C
Martin
Hans
H
Zeiher
Andreas M
AM
Dimmeler
Stefanie
S
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D003327:Coronary Disease / Q000097:blood; D016228:Endothelial Growth Factors / Q000097:blood; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects*; D004921:Erythropoietin / Q000097:blood / Q000494:pharmacology* / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D007511:Ischemia / Q000139:chemically induced / Q000378:metabolism; D008222:Lymphokines / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors
D018952:Antigens, CD34; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004921:Erythropoietin; D040301:Vascular Endothelial Growth Factor Receptor-2