Impairment of hypoxia-induced angiogenesis by LDL involves a HIF-centered signaling network linking inflammatory TNFα and angiogenic VEGF.

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.

• Authors: Fengyan Jin, Xiangyu Zheng, Yanping Yang, Gang Yao, Long Ye, Thorsten R Doeppner, Dirk M Hermann, Haifeng Wang, Yun Dai
• Journal: Aging (Aging (Albany NY)) Vol. 11 Issue 2 Pg. 328-349 (01 18 2019) ISSN: 1945-4589 [Electronic] United States
• PMID: 30659163 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Lipoproteins, LDL
• Tumor Necrosis Factor-alpha
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• oxidized low density lipoprotein

Topics

• Cell Movement
• Cell Proliferation
• Gene Expression Regulation (drug effects)
• Human Umbilical Vein Endothelial Cells
• Humans
• Hypoxia
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Inflammation (metabolism)
• Lipoproteins, LDL (pharmacology)
• Neovascularization, Physiologic
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (metabolism)
• Vascular Endothelial Growth Factor A (genetics, metabolism)