VEGF is upregulated by hypoxia-induced mitogenic factor via the PI-3K/Akt-NF-kappaB signaling pathway.

Abstract:

BACKGROUND:Hypoxia-induced mitogenic factor (HIMF) is developmentally regulated and plays an important role in lung pathogenesis. We initially found that HIMF promotes vascular tubule formation in a matrigel plug model. In this study, we investigated the mechanisms which HIMF enhances expression of vascular endothelial growth factor (VEGF) in lung tissues and epithelial cells. METHODS:Recombinant HIMF protein was intratracheally instilled into adult mouse lungs, VEGF expression was examined by immunohistochemical staining and Western blot. The promoter-luciferase reporter assay, RT-PCR, and Western blot were performed to examine the effects of HIMF on VEGF expression in mouse lung epithelial cell line MLE-12. The activation of NF-kappa B (NF-kappaB) and phosphorylation of Akt, IKK and IkappaBalpha were examined by luciferase assay and Western blot, respectively. RESULTS:Intratracheal instillation of HIMF protein resulted in significant increase of VEGF, mainly localized to airway epithelial and alveolar type II cells. Deletion of NF-kappaB binding sites within VEGF promoter abolished HIMF-induced VEGF expression in MLE-12 cells, suggesting that activation of NF-kappaB is essential for VEGF upregulation induced by HIMF. Stimulation of lung epithelial cells by HIMF resulted in phosphorylation of IKK and IkappaBalpha, leading to activation of NF-kappaB. In addition, HIMF strongly induced Akt phosphorylation, and suppression of Akt activation by specific inhibitors and dominant negative mutants for PI-3K, and IKK or IkappaBalpha blocked HIMF-induced NF-kappaB activation and attenuated HIMF-induced VEGF production. CONCLUSION:These results suggest that HIMF enhances VEGF production in mouse lung epithelial cells in a PI-3K/Akt-NF-kappaB signaling pathway-dependent manner, and may play critical roles in pulmonary angiogenesis.

journal_name

Respir Res

journal_title

Respiratory research

authors

Tong Q,Zheng L,Lin L,Li B,Wang D,Huang C,Li D

doi

10.1186/1465-9921-7-37

keywords:

subject

Has Abstract

pub_date

2006-03-02 00:00:00

pages

37

eissn

1465-9921

issn

1465-993X

pii

1465-9921-7-37

journal_volume

7

pub_type

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