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

Abstract

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 monolayers (HPAEC) were exposed to either normoxia (21% O2) or acute hypoxia (3% O2) for 24 h and monolayer permeability, H2O2, nuclear HIF-1α, and cytosolic VEGF were determined. HPAEC were treated with antioxidant cocktail (AO: ascorbate, glutathione, and α-tocopherol), HIF-1 siRNA, or VEGF soluble binding protein (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% O2) were treated with the same antioxidant to determine if in-vitro responses corresponded to in-vivo hypoxia stress. Hypoxia increased albumin permeability, H2O2 production, nuclear HIF-1α, and cytosolic VEGF concentration. Treatment with an AO lowered the hypoxia-induced HPAEC monolayer permeability as well as elevation of HIF-1α and VEGF. Treatment of hypoxia-induced HPAEC with either a siRNA designed against HIF-1α or VEGF antagonist soluble fms-like tyrosine kinase (sFlt)-1 decreased monolayer permeability. Mice treated with AO and exposed to hypobaric hypoxia (18,000 ft, 10% O2) 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-1α-VEGF pathway.

Hemoglobin-Induced Endothelial Cell Permeability Is Controlled, in Part, via a Myeloid Differentiation Primary Response Gene–88–Dependent Signaling Mechanism

“…Uncontrolled HIF activity can lead to endothelial cell dysfunction and pulmonary vascular leakage in vivo and in vitro (8,26,27). Our data showed that the knockdown of HIF-1a exerted a minimal effect on attenuating Hb-induced endothelial cell permeability.…”

“…NF-kB is known to up-regulate HIF-1a and HIF-2a mRNA mechanistically (7,8). An increased abundance of cytosolic HIF protein may also account for increased HIF activity.…”

“…In vascular endothelial cells, NF-kB can control the regulation of hypoxia-inducible factor (HIF) (6,7), and once activated, these two transcription factors together induce chronic inflammation, vasoconstriction, and endothelial permeability (7)(8)(9). To date, few studies have investigated whether Hb alters the endothelial activity of NF-kB (5,10,11) or HIF-1a (12)(13)(14).…”

The Effects ofPortulaca oleraceaon Hypoxia-Induced Pulmonary Edema in Mice

“…This research did not measure pulmonary artery pressure in mice, so we could not observe the change of hypoxic pulmonary vasoconstric- tion. Some studies reported that ROS and HIF-a signaling pathway could result in ET-1 and VEGF overexpression in hypoxia (Irwin et al, 2009). In addition, ET-1 receptor antagonist proved to be efficacious against pulmonary hypertension (Modesti et al, 2006), and many molecules, such as hypoxia inducible factor-1 (HIF-1), vascular endothelial growth factor (VEGF), and endothelin-1 (ET-1), participated in the mechanism of pulmonary edema induced by hypobaric hypoxia.…”

Reactive Oxygen Species/Hypoxia-Inducible Factor-1α/Platelet-Derived Growth Factor-BB Autocrine Loop Contributes to Cocaine-Mediated Alveolar Epithelial Barrier Damage

“…Previous studies have indicated that vascular endothelial growth factor (VEGF)-and platelet-derived growth factor (PDGF-BB)-mediated impairment of barrier integrity is directly associated with their direct effects on redistribution and down-regulation of the tight junction proteins (TJPs), including zonula occludens-1 (Zo-1) and occludin (20,21). Interestingly, the expression of both VEGF and PDGF-BB can be regulated by HIF-1a in response to ROS, and both of the growth factors have also been implicated in triggering pulmonary barrier dysfunction (22,23). Importantly, significant increases in expression of PDGF-BB and VEGF have been reported in lung tissues from cocaine abusers (24,25), suggesting, thereby, their potential role in cocainemediated pulmonary impairment.…”