Interplay between VEGF and Nrf2 regulates angiogenesis due to intracranial venous hypertension.

Abstract

Venous hypertension(VH) plays an important role in the pathogenesis of cerebral arteriovenous malformations (AVMs) and is closely associated with the HIF-1α/VEGF signaling pathway. Nuclear factor erythroid 2-related factor 2(Nrf2) significantly influences angiogenesis; however, the interplay between Nrf2 and VEGF under VH in brain AVMs remains unclear. Therefore, our study aimed to investigate the interplay between Nrf2 and VEGF due to VH in brain AVMs. Immunohistochemistry indicated that Nrf2 and VEGF were highly expressed in human brain AVM tissues. In vivo, we established a VH model in both wild-type (WT) and siRNA-mediated Nrf2 knockdown rats. VH significantly increased the expression of Nrf2 and VEGF. Loss of Nrf2 markedly inhibited the upregulation of VEGF, as determined by Western blot analysis and qRT-PCR. In vitro, primary brain microvascular endothelial cells (BMECs) were isolated from WT and Nrf2-/- mice, and a VEGF-Nrf2 positive feed-back loop was observed in BMECs. By trans well assay and angiogenesis assay, Nrf2 knockout significantly inhibited the migration and vascular tube formation of BMECs. These findings suggest that the interplay between Nrf2 and VEGF can contribute to VH-induced angiogenesis in brain AVMs pathogenesis.

• Authors: Liwen Li, Hao Pan, Handong Wang, Xiang Li, Xiaomin Bu, Qiang Wang, Yongyue Gao, Guodao Wen, Yali Zhou, Zixiang Cong, Youqing Yang, Chao Tang, Zhengwei Liu
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 37338 (11 21 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27869147 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hif1a protein, rat
• Hypoxia-Inducible Factor 1, alpha Subunit
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Vascular Endothelial Growth Factor A
• Heme Oxygenase-1

Topics

• Animals
• Cell Movement
• Cells, Cultured
• Cerebrovascular Circulation
• Endothelial Cells (physiology)
• Heme Oxygenase-1 (metabolism)
• Humans
• Hypertension (complications, metabolism, physiopathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Intracranial Arteriovenous Malformations (etiology, metabolism, physiopathology)
• MAP Kinase Signaling System
• Male
• Mice, Inbred ICR
• Microvessels (pathology, physiopathology)
• NF-E2-Related Factor 2 (metabolism)
• Neovascularization, Pathologic (metabolism)
• Rats, Sprague-Dawley
• Vascular Endothelial Growth Factor A (metabolism)