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, 2019https://doi.org/10.18632/aging.101726
How to Cite
Copyright: Jin et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.