A potential role for reactive oxygen species and the HIF-1α–VEGF pathway in hypoxia-induced pulmonary vascular leak

Damian Bailey, David C. Irwin, Joe M. McCord, Eva Nozik-Grayck, Ginny Beckly, Ben Foreman, Tim Sullivan, Molly White, Joseph T. Crossno Jr, Sonia C. Flores, Susan Majka, Dwight Klemm, Martha C. TissotvanPatot

Research output: Contribution to journalArticlepeer-review


Acute hypoxia causes pulmonary vascular leak and is involved in the pathogenesis of pulmonary edema 30 associated with inflammation, acute altitude exposure, and other critical illnesses. Reactive oxygen species, 31 HIF-1, and VEGF have all been implicated in various hypoxic pathologies, yet the ROS–HIF-1–VEGF pathway 32 in pulmonary vascular leak has not been defined.We hypothesized that the ROS–HIF-1–VEGF pathway has an 33 important role in producing hypoxia-induced pulmonary vascular leak. Human pulmonary artery endothelial 34 cell (HPAEC) monolayers were exposed to either normoxia (21% O2) or acute hypoxia (3% O2) for 24 h and 35 monolayer permeability and H2O2, nuclear HIF-1a, and cytosolic VEGF levels were determined. HPAEC were 36 treated with antioxidant cocktail (AO; ascorbate, glutathione, and a-tocopherol), HIF-1 siRNA, or the VEGF 37 soluble binding protein fms-like tyrosine kinase-1 (sFlt-1) to delineate the role of the ROS–HIF-1–VEGF 38 pathway in hypoxia-induced HPAEC leak. Additionally, mice exposed to hypobaric hypoxia (18,000 ft, 10% O2) 39 were treated with the same antioxidant to determine if in vitro responses corresponded to in vivo hypoxia 40 stress. Hypoxia increased albumin permeativity, H2O2 production, and nuclear HIF-1a and cytosolic VEGF 41 concentration. Treatment with an AO lowered the hypoxia-induced HPAEC monolayer permeability as well as 42 the elevation of HIF-1a and VEGF. Treatment of hypoxia-induced HPAEC with either an siRNA designed 43 against HIF-1a or the VEGF antagonist sFlt-1 decreased monolayer permeability. Mice treated with AO and 44 exposed to hypobaric hypoxia (18,000 ft, 10% O2) had less pulmonary vascular leak than those that were 45 untreated. Our data suggest that hypoxia-induced permeability is due, in part, to the ROS–HIF-1a–VEGF
Original languageEnglish
JournalFree Radical Biology and Medicine
Publication statusPublished - 28 Mar 2009


  • vegf
  • hypoxia
  • hif
  • pulmonary edema
  • reactive oxygen species
  • free radicals


Dive into the research topics of 'A potential role for reactive oxygen species and the HIF-1α–VEGF pathway in hypoxia-induced pulmonary vascular leak'. Together they form a unique fingerprint.

Cite this