Hypoxia-inducible Factor 2α Exerts Neuroprotective Effects by Promoting Angiogenesis via the VEGF/Notch Pathway after Intracerebral Hemorrhage Injury in Rats.

Abstract

Angiogenesis after intracerebral hemorrhage (ICH) injury can effectively alleviate brain damage and improve neurological function. Hypoxia-inducible factor 2α (HIF-2α) is an important angiogenic regulator and exhibits protective effects in several neurological diseases; however, its role in ICH has not yet been reported. Hence, in the present study, we explored whether HIF-2α reduces ICH injury by promoting angiogenesis. In addition, we explored the role of the vascular endothelial growth factor (VEGF)/Notch pathway in HIF-2α-mediated angiogenesis. We injected 50 μL of autologous blood taken from the femoral artery into the right striatum of healthy male adult Sprague-Dawley rats to create an autologous-blood-induced rat model of ICH. Lentiviral vectors were injected to both overexpress and knock down HIF-2α expression. VEGF receptor 2 (VEGFR2) and Notch-specific inhibitors were injected intraperitoneally to block VEGFR2- and Notch-mediated signaling after lentiviral injections. Our data showed that HIF-2α overexpression reduced neurological-damage scores and brain-water content, suggesting it had a protective effect on ICH injury. In addition, overexpression of HIF-2α promoted angiogenesis, increased focal cerebral blood flow (CBF), and reduced neuronal damage, whereas HIF-2α knockdown resulted in the opposite effects. Furthermore, we found that HIF-2α-mediated angiogenesis was blocked by a Notch-specific inhibitor. Likewise, the HIF-2α-mediated increase in phospho-VEGFR-2, cleaved-Notch1 and Notch1 expression was reversed via a VEGFR2-specific inhibitor. Taken together, our results indicate that HIF-2α promotes angiogenesis via the VEGF/Notch pathway to attenuate ICH injury. Moreover, our findings may contribute to the development of a novel strategy for alleviating ICH injury via HIF-2α-mediated upregulation of angiogenesis.

• Authors: Hui Chen, Han Xiao, Hui Gan, Li Zhang, Lu Wang, Siyu Li, Difei Wang, Tiegang Li, Xuan Zhai, Jing Zhao
• Journal: Neuroscience (Neuroscience) Vol. 448 Pg. 206-218 (11 10 2020) ISSN: 1873-7544 [Electronic] United States
• PMID: 32736070 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Hypoxia-Inducible Factor 1, alpha Subunit
• Neuroprotective Agents
• Vascular Endothelial Growth Factor A

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors
• Cerebral Hemorrhage (complications, drug therapy)
• Hypoxia
• Hypoxia-Inducible Factor 1, alpha Subunit
• Male
• Neuroprotective Agents (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Vascular Endothelial Growth Factor A