On the possible role of reactive oxygen species in angiogenesis.
Human microvascular endothelial cells grown on a 3-D reconstituted extracellular matrix (Matrigel) spontaneously and rapidly form a capillary network of tubular structures, thus modeling part of the angiogenic cascade. Exposure of the cells at the time of plating onto Matrigel to a brief episode of hypoxia (40-60) min and subsequent reoxygenation, significantly accelerated (up to 3-fold) the rate of tubular morphogenesis, as determined by computer-aided morphometry. This effect was not dependent on activation of PKC or upregulation/release of angiogenic growth factors. Rather, hypoxia/reoxygenation (H/R), but not hypoxia alone, caused the formation of reactive oxygen species (ROS) and the activation of the nuclear transcription factor NF kappa B, both of which were inhibited by ROS-scavengers, such as pyrollidine dithiocarbamate. Tube formation was inhibited, also under normoxic conditions, by diverse ROS antagonists in a dose-dependent fashion. Our results indicate that angiogenesis is accompanied by and/or requires generation of ROS. We hypothesize that in the clinical setting of hypoxia/reoxygenation during ischemic pre-conditioning, enhanced activation of ROS-dependent intracellular signaling may accelerate the rate of neovascularization also in vivo, thus contributing to the alleviation of certain ischemic lesions.
Lelkes
P I
PI
Laboratory of Cell Biology, University of Wisconsin Medical School, Milwaukee 53201-0342, USA. pilelkes@facstaff.wisc.edu
Hahn
K L
KL
Sukovich
D A
DA
Karmiol
S
S
Schmidt
D H
DH
D015687:Cell Hypoxia / Q000502:physiology*; D019069:Cell Respiration; D002478:Cells, Cultured; D003094:Collagen; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D007797:Laminin; D008833:Microcirculation / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010101:Oxygen Consumption; D011493:Protein Kinase C / Q000378:metabolism; D011509:Proteoglycans; D017382:Reactive Oxygen Species / Q000502:physiology*; D012867:Skin / Q000098:blood supply
D004338:Drug Combinations; D007797:Laminin; D016328:NF-kappa B; D011509:Proteoglycans; D017382:Reactive Oxygen Species; C059485:matrigel; D003094:Collagen; D011493:Protein Kinase C