Hypoxia Modulates Epithelial Permeability via Regulation of Vascular Endothelial Growth Factor in Airway Epithelia

Abstract

Hypoxia resulting from occlusion of the sinus ostium is known to be one of the major pathogenic mechanisms of sinusitis. Hypoxia-inducible factor (HIF)-1 is a widely known transcription factor that induces the cellular response to hypoxic conditions and activates the transcription of several genes, including vascular endothelial growth factor (VEGF). We hypothesized that induced permeability caused by hypoxia is a major pathophysiologic mechanism of upper airway diseases, such as sinusitis. The aim of this study was to investigate the mechanism of hypoxia-induced hyperpermeability, which mediates increased paracellular permeability and enhanced microbial invasiveness in the airway epithelium. We show that expression of VEGF mRNA and protein and HIF-1α protein increased as a function of time under hypoxia in normal human nasal epithelial cells. Our results also indicate that VEGF expression was induced by transfection with a mammalian expression vector encoding HIF-1 but down-regulated by transfection with small interfering RNA specific for HIF-1α under hypoxic conditions. Results of a transepithelial permeability assay measuring transepithelial electrical resistance indicated that permeability was increased as a function of time under hypoxia and was rescued by anti-VEGF monoclonal antibody (bevacizumab) and small interfering RNA specific for HIF-1α. We detected up-regulated HIF-1α and VEGF expression in mucosal epithelium samples from patients with sinusitis compared with normal mucosal epithelium using Western blotting and immunohistochemical staining. In conclusion, we suggest that the hypoxia-HIF-1α-VEGF axis plays an important role in hyperpermeability of airway epithelial cells, implying a role in the pathophysiology of upper respiratory tract diseases, such as sinusitis.

Association between Upper-airway Surgery and Ameliorative Risk Markers of Endothelial Function in Obstructive Sleep Apnea

“…Our findings are consistent with results of experimental studies reporting vascular hyperpermeability, hypercoagulability, and unbalance of the steady endovascular environment in response to chronic intermittent hypoxia 46,47 and impaired sleep architecture 48 . Potential physiological pathways may include oxidative stress, inflammation, and sympathetic activation 49–51 .…”

The Effect of TNF and VEGF on the Properties of Ea.hy926 Endothelial Cells in a Model of Multi-Cellular Spheroids

“…[ 1 , 2 ]. Both the inflammatory process and tumor growth are accompanied by tissue hypoxia, which leads to the formation of new blood vessels under the influence of the vascular endothelial growth factor (VEGF), which is secreted by epithelial cells in conditions of hypoxia [ 3 , 4 ]. The expression level of αvβ3-integrin in endothelial cells is known to be significantly increased in tumor vessels [ 5 ].…”

Interleukin 13 (IL‐13) alters hypoxia‐associated genes and upregulates CD73

“…AMP = adenosine monophosphate; HIF = hypoxia-inducible factor; IL = interleukin. findings, 10,11,17 we observed that the major hypoxia-related gene, HIF1A, was upregulated in the sinonasal epithelial tissue from CRSwNP patients compared to control subjects. However, to the best of our knowledge, this is the first report of expression of all known HIFα (HIF1A, EPAS1, HIF3A) and HIFβ (ARNT, ARNT2) genes.…”

“…Hypoxia can develop in chronic airway diseases such as sinusitis and asthma due to alterations in microvascular structures and increased metabolism. 9 Published literature demonstrates local activation of the hypoxia signaling pathway with effects such as mucus hypersecretion, 10 increased vascular permeability through VEGF expression, 11 and reduced expression of junction proteins. 12 Other studies have demonstrated an impact of hypoxia on immune cells.…”