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

Irwin DC, McCord JM, Nozik-Grayck E, Beckly G, Foreman B, Sullivan T, White M, T Crossno J, Bailey D, Flores SC, Majka S, Klemm D, van Patot MC
Free Radic Biol Med. 2009 47 (1): 55-61

PMID: 19358884 · PMCID: PMC2689923 · DOI:10.1016/j.freeradbiomed.2009.03.027

Acute hypoxia causes pulmonary vascular leak and is involved in the pathogenesis of pulmonary edema associated with inflammation, acute altitude exposure, and other critical illnesses. Reactive oxygen species, HIF-1, and VEGF have all been implicated in various hypoxic pathologies, yet the ROS-HIF-1-VEGF pathway in pulmonary vascular leak has not been defined. We hypothesized that the ROS-HIF-1-VEGF pathway has an important role in producing hypoxia-induced pulmonary vascular leak. Human pulmonary artery endothelial cell (HPAEC) monolayers were exposed to either normoxia (21% O(2)) or acute hypoxia (3% O(2)) for 24 h and monolayer permeability and H(2)O(2), nuclear HIF-1alpha, and cytosolic VEGF levels were determined. HPAEC were treated with antioxidant cocktail (AO; ascorbate, glutathione, and alpha-tocopherol), HIF-1 siRNA, or the VEGF soluble binding protein fms-like tyrosine kinase-1 (sFlt-1) to delineate the role of the ROS-HIF-1-VEGF pathway in hypoxia-induced HPAEC leak. Additionally, mice exposed to hypobaric hypoxia (18,000 ft, 10% O(2)) were treated with the same antioxidant to determine if in vitro responses corresponded to in vivo hypoxia stress. Hypoxia increased albumin permeativity, H(2)O(2) production, and nuclear HIF-1alpha and cytosolic VEGF concentration. Treatment with an AO lowered the hypoxia-induced HPAEC monolayer permeability as well as the elevation of HIF-1alpha and VEGF. Treatment of hypoxia-induced HPAEC with either an siRNA designed against HIF-1alpha or the VEGF antagonist sFlt-1 decreased monolayer permeability. Mice treated with AO and exposed to hypobaric hypoxia (18,000 ft, 10% O(2)) had less pulmonary vascular leak than those that were untreated. Our data suggest that hypoxia-induced permeability is due, in part, to the ROS-HIF-1alpha-VEGF pathway.

MeSH Terms (18)

Active Transport, Cell Nucleus Animals Antioxidants Capillary Permeability Cell Nucleus Cells, Cultured Endothelium, Vascular Hypoxia Hypoxia-Inducible Factor 1, alpha Subunit Male Mice Mice, Inbred C57BL Pulmonary Artery Reactive Oxygen Species RNA, Small Interfering Signal Transduction Transcriptional Activation Vascular Endothelial Growth Factor A

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