Research Paper Volume 11, Issue 2 pp 328—349
Impairment of hypoxia-induced angiogenesis by LDL involves a HIF-centered signaling network linking inflammatory TNFα and angiogenic VEGF
- 1 Department of Hematology, Cancer Center, the First Hospital of Jilin University, Changchun, Jilin, China
- 2 Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin, China
- 3 Department of Neurology, the Second Affiliated Hospital of Jilin University, Changchun, Jilin, China
- 4 Laboratory of Cancer Precision Medicine, the First Hospital of Jilin University, Changchun, Jilin, China
- 5 Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
- 6 Department of Neurology, University Duisburg-Essen Medical School, Essen, Germany
- 7 Department of Neurosurgery, the First Hospital of Jilin University, Changchun, Jilin, China
Received: November 19, 2018 Accepted: December 12, 2018 Published: January 18, 2019
https://doi.org/10.18632/aging.101726How to Cite
Abstract
Hypoxia inducible factors (HIFs) mediate angiogenesis via up-regulation of various pro-angiogenic factors (particularly VEGF) in response to hypoxia. Here, we report that hypoxia unexpectedly induced robust production of the pro-inflammatory factor TNFα by endothelial cells (ECs), suggesting an autocrine loop that in turn activated HIFs via an NF-κB-dependent process, resulting in production of VEGF and thereby promotion of angiogenesis. In contrast, low-density lipoprotein (LDL) prevented expression of HIFs in ECs exposed to either hypoxia or TNFα, while knockdown of either HIF-1α or HIF-2α strikingly attenuated hypoxia-induced production of VEGF by ECs as well as EC colony formation and tube formation. Significantly, LDL attenuated hypoxia-induced angiogenesis by disrupting the TNFα/NF-κB/HIF/VEGF signaling cascade via down-regulation of the TNF receptor TNF-R1, rather than TNFα itself, and multiple key components of both canonical and non-canonical NF-κB pathways. By doing so, LDL was able to either inhibit or down-regulate a wide spectrum of HIF-dependent pro-angiogenic downstream targets and signals. Together, these findings argue existence of a self-regulatory TNFα/NF-κB/HIF/VEGF signaling network in ECs, which mediates and fine-tones angiogenesis, at least in response to hypoxia. They also suggest that LDL impairs angiogenesis by disrupting this network, which might represent a novel mechanism underlying anti-angiogenic property of LDL.