Arterial levels of oxygen stimulate intimal hyperplasia in human saphenous veins via a ROS-dependent mechanism

PLoS One. 2015 Mar 23;10(3):e0120301. doi: 10.1371/journal.pone.0120301. eCollection 2015.


Saphenous veins used as arterial grafts are exposed to arterial levels of oxygen partial pressure (pO2), which are much greater than what they experience in their native environment. The object of this study is to determine the impact of exposing human saphenous veins to arterial pO2. Saphenous veins and left internal mammary arteries from consenting patients undergoing coronary artery bypass grafting were cultured ex vivo for 2 weeks in the presence of arterial or venous pO2 using an established organ culture model. Saphenous veins cultured with arterial pO2 developed intimal hyperplasia as evidenced by 2.8-fold greater intimal area and 5.8-fold increase in cell proliferation compared to those freshly isolated. Saphenous veins cultured at venous pO2 or internal mammary arteries cultured at arterial pO2 did not develop intimal hyperplasia. Intimal hyperplasia was accompanied by two markers of elevated reactive oxygen species (ROS): increased dihydroethidium associated fluorescence (4-fold, p<0.05) and increased levels of the lipid peroxidation product, 4-hydroxynonenal (10-fold, p<0.05). A functional role of the increased ROS saphenous veins exposed to arterial pO2 is suggested by the observation that chronic exposure to tiron, a ROS scavenger, during the two-week culture period, blocked intimal hyperplasia. Electron paramagnetic resonance based oximetry revealed that the pO2 in the wall of the vessel tracked that of the atmosphere with a ~30 mmHg offset, thus the cells in the vessel wall were directly exposed to variations in pO2. Monolayer cultures of smooth muscle cells isolated from saphenous veins exhibited increased proliferation when exposed to arterial pO2 relative to those cultured at venous pO2. This increased proliferation was blocked by tiron. Taken together, these data suggest that exposure of human SV to arterial pO2 stimulates IH via a ROS-dependent pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / pharmacology
  • Aldehydes / metabolism
  • Arteries / metabolism
  • Free Radical Scavengers / pharmacology
  • Humans
  • Hyperplasia / metabolism
  • Lipid Peroxidation
  • Oxygen / blood*
  • Reactive Oxygen Species / metabolism*
  • Saphenous Vein / metabolism
  • Saphenous Vein / pathology*
  • Tunica Intima / drug effects
  • Tunica Intima / metabolism*
  • Tunica Intima / pathology


  • Aldehydes
  • Free Radical Scavengers
  • Reactive Oxygen Species
  • 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt
  • 4-hydroxy-2-nonenal
  • Oxygen