On the possible role of reactive oxygen species in angiogenesis

Adv Exp Med Biol. 1998;454:295-310. doi: 10.1007/978-1-4615-4863-8_35.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Hypoxia / physiology*
  • Cell Respiration
  • Cells, Cultured
  • Collagen
  • Drug Combinations
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / physiology*
  • Humans
  • Kinetics
  • Laminin
  • Microcirculation / physiology*
  • NF-kappa B / metabolism
  • Neovascularization, Physiologic / physiology*
  • Oxygen Consumption
  • Protein Kinase C / metabolism
  • Proteoglycans
  • Reactive Oxygen Species / physiology*
  • Skin / blood supply


  • Drug Combinations
  • Laminin
  • NF-kappa B
  • Proteoglycans
  • Reactive Oxygen Species
  • matrigel
  • Collagen
  • Protein Kinase C