Pharmacological and genetic accumulation of hypoxia-inducible factor-1alpha enhances excitatory synaptic transmission in hippocampal neurons through the production of vascular endothelial growth factor.

Abstract

Hypoxia-inducible factor-1 (HIF-1) is an important transcriptional factor in mammalian cells for coordination of adaptive responses to hypoxia. It consists of a regulatory subunit HIF-1alpha, which accumulates under hypoxic conditions, and a constitutively expressed subunit HIF-1beta. In addition to the well characterized oxygen-dependent mode of action of HIF-1, recent work has shown that various growth factors and cytokines stimulate HIF-1alpha expression, thereby triggering transcription of numerous hypoxia-inducible genes by oxygen-independent mechanisms. In this study, we examined whether accumulation of HIF-1alpha induced by insulin-like growth factor-1 (IGF-1) has a regulatory role in excitatory synaptic transmission in hippocampal neuron cultures. Our results show that IGF-1 induced a time- and dose-dependent increase in HIF-1alpha expression that was blocked by pretreatment with selective IGF-1 receptor antagonist, transcriptional inhibitor, and translational inhibitors. In addition, pharmacological blockade of the phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin signaling pathway, but not extracellular signal-regulated kinase, inhibited IGF-1-induced HIF-1alpha expression. More importantly, the increase in HIF-1alpha expression induced by IGF-1 was accompanied by increasing levels of vascular endothelial growth factor (VEGF) mRNA and protein, which enhanced excitatory synaptic transmission. In parallel, blockade of HIF-1alpha activity by echinomycin or lentiviral infection with dominant-negative mutant HIF-1alpha or short hairpin RNA targeting HIF-1alpha inhibited the increase in expression of VEGF and the enhancement of synaptic transmission induced by IGF-1. Conversely, transfection of constitutively active HIF-1alpha into neurons mimicked the effects of IGF-1 treatment. Together, these results suggest that HIF-1alpha accumulation can enhance excitatory synaptic transmission in hippocampal neurons by regulating production of VEGF.

• Authors: Yu-Fei Huang, Chih-Hao Yang, Chiung-Chun Huang, Ming-Hong Tai, Kuei-Sen Hsu
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 30 Issue 17 Pg. 6080-93 (Apr 28 2010) ISSN: 1529-2401 [Electronic] United States
• PMID: 20427666 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• HIF1A protein, human
• Hif1a protein, rat
• Hypoxia-Inducible Factor 1, alpha Subunit
• RNA, Messenger
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, rat
• Insulin-Like Growth Factor I

Topics

• Animals
• Cell Line
• Cells, Cultured
• Enzyme Inhibitors (pharmacology)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Insulin-Like Growth Factor I (metabolism)
• Neurons (drug effects, physiology)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Synapses (drug effects, physiology)
• Synaptic Transmission (drug effects, physiology)
• Time Factors
• Vascular Endothelial Growth Factor A (metabolism)