Deferoxamine accelerates endothelial progenitor cell senescence and compromises angiogenesis

Abstract

Senescence reduces the circulating number and angiogenic activity of endothelial progenitor cells (EPCs), and is associated with aging-related vascular diseases. However, it is very time-consuming to obtain aged cells (~1 month of repeated replication) or animals (~2 years) for senescence studies. Here, we established an accelerated senescence model by treating EPCs with deferoxamine (DFO), an FDA-approved iron chelator. Four days of low-dose (3 μM) DFO induced senescent phenotypes in EPCs, including a senescent pattern of protein expression, impaired mitochondrial bioenergetics, altered mitochondrial protein levels and compromised angiogenic activity. DFO-treated early EPCs from young and old donors (< 35 vs. > 70 years old) displayed similar senescent phenotypes, including elevated senescence-associated β-galactosidase activity and reduced relative telomere lengths, colony-forming units and adenosine triphosphate levels. To validate this accelerated senescence model in vivo , we intraperitoneally injected Sprague-Dawley rats with DFO for 4 weeks. Early EPCs from DFO-treated rats displayed profoundly senescent phenotypes compared to those from control rats. Additionally, in hind-limb ischemic mice, DFO pretreatment compromised EPC angiogenesis by reducing both blood perfusion and capillary density. DFO thus accelerates EPC senescence and appears to hasten model development for cellular senescence studies.

CCL4 contributes to aging related angiogenic insufficiency through activating oxidative stress and endothelial inflammation

“…On the other hand, EPCs can be mobilized from the bone marrow for vascular repair and neovascularization when vascular injury and tissue ischemia occur [24]. However, senescence reduces circulating numbers of EPCs-and their angiogenic activity-and is associated with aging-associated vascular diseases [25]. Kallistatin could decrease TNF-α-induced cellular senescence in EPCs, as indicated by decreased senescenceassociated β-galactosidase activity [26].…”

Pannexin 1 Modulates Angiogenic Activities of Human Endothelial Colony-Forming Cells Through IGF-1 Mechanism and Is a Marker of Senescence

“…23 In addition, telomere length (telomere repeat copy number [T]/single-copy gene 36B4 copy number [S] ratio) of senescent ECFCs was about 40% shorter, compared with young ECFCs, similar to previous reports (Figure S2B). 23,27 In parallel, compared with young ECFCs, the expression of senescence-associated indicators in senescent ECFCs, including p16 INK4a , p21, acetyl-p53, and SA-β-Gal activity were also enhanced (Figure S2C and S2D). In subsequent experiments, phospho-histone H2A.X (phosphor-H2A.X, a DNA damage marker), MnSOD, and IL-6 were also enhanced in senescent ECFCs, whereas SirT1 and lamin B1 were decreased but GPx remained steady.…”

Senescence induces miR‐409 to down‐regulate CCL5 and impairs angiogenesis in endothelial progenitor cells

“…Eighty millilitre of peripheral bloods of healthy donors were collectted to isolate the peripheral blood mononuclear cells (PBMCs). 7 PBMCs were fractioned from other components of bloods by Ficoll‐Paque™ plus (GE Healthcare, USA) gradient centrifugation. EPCs were isolated further using a CD34 MicroBead kit and MACS Cell Separation System (all from Miltenyi Biotec).…”

“… 2 , 3 , 4 Ageing results in a decline in progenitor cell angiogenic activities, including proliferation, migration and vessel tube formation. 5 , 6 , 7 Ageing also impairs EPC recruitment and vascular incorporation. 8 The available data indicate that ageing may affect the availability and angiogenic activity of EPCs.…”