Erythropoietin regulates endothelial progenitor cells

Abstract

Circulating bone marrow-derived endothelial progenitor cells (EPCs) promote vascular reparative processes and neoangiogenesis, and their number in peripheral blood correlates with endothelial function and cardiovascular risk. We tested the hypothesis that the cytokine erythropoietin (EPO) stimulates EPCs in humans. We studied 11 patients with renal anemia and 4 healthy subjects who received standard doses of recombinant human EPO (rhEPO). Treatment with rhEPO caused a significant mobilization of CD34 ؉ /CD45 ؉ circulating progenitor cells in peripheral blood (measured by flow cytometry), and increased the number of functionally active EPCs (measured by in vitro assay) in patients (week 2, 312% ؎ 31%; week 8, 308% ؎ 40%; both P < .01 versus baseline) as well as in healthy subjects (week 8, 194% ؎ 15%; P < .05 versus baseline). IntroductionStem cell therapy emerges as a promising approach in cardiovascular medicine. Current research focuses on bone marrow-derived endothelial progenitor cells (EPCs), which promote vascular reparative processes. [1][2][3] EPCs are considered to originate from CD34-positive (CD34 ϩ ) stem cells. 3 These cells differentiate via separate pathways into erythrocytes, thrombocytes, various lineages of leukocytes, and also endothelial cells. EPCs are found mainly in the bone marrow, but may also circulate in the vasculature where they home and incorporate into sites of active neovascularization. 1,[4][5][6][7] In experimental studies, increased neovascularization by these cells improves cardiac function after myocardial ischemia. [8][9][10] In patients with myocardial infarction, the clinical outcome is strongly correlated to the number of mobilized EPCs from the bone marrow. 11 Thus, the search for substances that modulate the number and/or function of EPCs is a matter of considerable interest. For example, vascular endothelial growth factor (VEGF) has been shown to regulate EPC proliferation and differentiation. 12 Erythropoietin (EPO) is a cytokine stimulating erythrocyte differentiation. It is produced mainly in the renal interstitium in response to hypoxic stimuli. Currently the main indication for use of recombinant human EPO (rhEPO) is treatment of anemia due to EPO deficiency in patients with chronic renal failure. EPO also appears to have direct biologic effects on endothelial cells. 13,14 Furthermore, both VEGF and EPO share important activities with respect to neoangiogenesis. 12,15 The main target of both cytokines seems to be the vasculature. 16 Thus, EPO could affect EPC proliferation and differentiation as well.We tested the hypothesis that EPO modulates the number of functionally active EPCs in humans. For this purpose, we assessed circulating CD34 ϩ cells in whole blood using flow cytometry, and the number of functionally active EPCs in an in vitro assay during 8 weeks of treatment with standard rhEPO doses in 11 patients with renal anemia and in 4 healthy subjects. Patients and methods Study participants and protocolThe study protocols were approved by the Hannover Medic...

Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesisin a mouse model

“…In contrast, when EPO was used as a proangiogenic agent (recently, EPO has also been found to promote mobilization of EPCs) (23,24), accelerated formation of neovasculature was accompanied by enhanced neurogenesis after stroke in our murine model. Our data provide the first direct link between therapeutic neovascularization after stroke and enhanced neurogenesis; formation of neovasculature after stroke supported neurogenesis.…”

“…EPO, well known for its essential role in regulating proliferation and differentiation of erythroid cells, has recently been found to promote mobilization of EPCs (23) and to have angiogenic potential (24). On day 4 after stroke, a significant increase in circulating CD34 + cells was observed with EPO injection (5,244 ± 1,267 and 1,333 ± 389 cells/ml in the EPO and PBS groups, respectively; n = 6 per group, P < 0.05).…”

Prolyl hydroxylase inhibition during hyperoxia prevents oxygen-induced retinopathy

“…Critically, the use of small molecules like DMOG enhances the opportunity to regulate therapeutic angiogenesis in the absence of conventional gene therapy (23)(24)(25) or stem cell therapy (26). In fact, the overwhelming induction of Epo protein synthesis by DMOG and the reported effects of Epo on mobilization of erythroid precursor cells (27)(28)(29) suggest that targeting HIF activation by small-molecule inhibition of HIF-␣ subunit degradation could be a novel therapeutic approach for the treatment of ROP and other ischemia-induced proliferative retinopathies. nursing mothers were exposed to hyperoxic conditions (75% oxygen) for 5 days in a Plexiglas incubator with an adjustable oxygen sensor and feedback system (Pro-Ox).…”

Flow cytometric measurement of circulating endothelial cells: The effect of age and peripheral arterial disease on baseline levels of mature and progenitor populations

“…Also, the number of risk factors in their study was significantly correlated with a reduction of EPC levels (R ¼ À0.394, P ¼ 0.002) and CD34-/KDR-positive cells (R ¼ À0.537, P < 0.001) thus indicating individual confounding variables exist among patients. Pharmaceutical compounds also appear to stimulate (21) and perhaps inhibit EPC mobilization from the bone marrow (22,23). The purpose of our study was to design and test a strategy of measuring multiple populations of cells using multiparameter flow cytometry and not to clinically evaluate the effects of risk factors or medications on EPC number.…”