Clonogenic endothelial progenitor cells are sensitive to oxidative stress.
Endothelial progenitor cells (EPCs) circulate in the peripheral blood and reside in blood vessel walls. A hierarchy of EPCs exists where progenitors can be discriminated based on their clonogenic potential. EPCs are exposed to oxidative stress during vascular injury as residents of blood vessel walls or as circulating cells homing to sites of neovascularization. Given the links between oxidative injury, endothelial cell dysfunction, and vascular disease, we tested whether EPCs were sensitive to oxidative stress using newly developed clonogenic assays. Strikingly, in contrast to previous reports, we demonstrate that the most proliferative EPCs (high proliferative potential-endothelial colony-forming cells and low proliferative potential-endothelial colony-forming cells) had decreased clonogenic capacity after oxidant treatment. In addition, EPCs exhibited increased apoptosis and diminished tube-forming ability in vitro and in vivo in response to oxidative stress, which was directly linked to activation of a redox-dependent stress-induced kinase pathway. Thus, this study provides novel insights into the effect of oxidative stress on EPCs. Furthermore, this report outlines a framework for understanding how oxidative injury leads to vascular disease and potentially limits the efficacy of transplantation of EPCs into ischemic tissues enriched for reactive oxygen species and oxidized metabolites.
Ingram
David A
DA
Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana 46202, USA.
Krier
Theresa R
TR
Mead
Laura E
LE
McGuire
Colleen
C
Prater
Daniel N
DN
Bhavsar
Janak
J
Saadatzadeh
M Reza
MR
Bijangi-Vishehsaraei
Khadijeh
K
Li
Fang
F
Yoder
Mervin C
MC
Haneline
Laura S
LS
D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002384:Catalysis / Q000187:drug effects; D002999:Clone Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D003114:Colony-Forming Units Assay; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007231:Infant, Newborn; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D018919:Neovascularization, Physiologic / Q000187:drug effects; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*
D016877:Oxidants; D006861:Hydrogen Peroxide; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human