Erythropoietin promotes endothelial progenitor cell proliferative and adhesive properties in a PI 3-kinase-dependent manner.
OBJECTIVE
Patients with congestive heart failure (CHF) suffer considerable morbidity and mortality despite advances in therapy. Treatment with erythropoietin (Epo) has shown promise in CHF patients, yet its mechanisms of action remain elusive. Endothelial progenitor cells (EPC) contribute to postnatal angiogenesis and vasculogenesis, and Epo was shown to promote EPC mobilization. We explored the effect of chronic treatment with Epo on the numbers and functional properties of EPC in CHF patients.


RESULTS
Twenty-eight patients with CHF treated with Epo for a mean period of 28 months were compared to a matched group (n = 28) with regard to the number of circulating hematopoietic and endothelial stem cells (either CD34+, CD34+/CD45+, CD34+/CD133+, CD34+/VEGF-R2+ or CD34+/CD133+/VEGF-R2+) as well as their proliferative and adhesive capacity. In vitro, Epo was added to cultured EPC from healthy subjects to test proliferation and adhesion. No differences were observed in circulating numbers of hematopoietic and endothelial stem cells between CHF patients chronically treated with Epo or untreated. EPC from Epo-treated patients exhibited enhanced proliferation as well as a trend towards adhesion to cultured endothelial cells prior to and following stimulation with TNF-alpha. Addition of Epo to EPC from healthy subjects dose-dependently increased their proliferation and adhesion to fibronectin, cultured endothelial cells, and cardiomyocytes. These effects were significantly reduced in the presence of phosphatidylinositol (PI) 3-kinase inhibitors.


CONCLUSIONS
Chronic Epo treatment is associated with an increase in the adhesive and proliferative properties of circulating EPC in patients with CHF.
George
Jacob
J
The Department of Cardiology, Tel Aviv Sourasky Medical Center, Tel Aviv University, Israel. jacobg@post.tau.ac.il
Goldstein
Emil
E
Abashidze
Anastasia
A
Wexler
Dov
D
Hamed
Saher
S
Shmilovich
Haim
H
Deutsch
Varda
V
Miller
Hylton
H
Keren
Gad
G
Roth
Arie
A
D000368:Aged; D000704:Analysis of Variance; D016022:Case-Control Studies; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004921:Erythropoietin / Q000378:metabolism / Q000627:therapeutic use*; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D005353:Fibronectins / Q000494:pharmacology; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology*; D013268:Stimulation, Chemical
D005353:Fibronectins; D004921:Erythropoietin; D019869:Phosphatidylinositol 3-Kinases