%0 Journal Article
%T Impairment of hypoxia-induced angiogenesis by LDL involves a HIF-centered signaling network linking inflammatory TNF¦Á and angiogenic VEGF
%A Dirk M. Hermann
%A Fengyan Jin
%A Gang Yao
%A Long Ye
%A Thorsten R. Doeppner
%A Xiangyu Zheng
%A Yanping Yang
%A Yun Dai
%J Archive of "Aging (Albany NY)".
%D 2019
%R 10.18632/aging.101726
%X 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 TNF¦Á by endothelial cells (ECs), suggesting an autocrine loop that in turn activated HIFs via an NF-¦ÊB-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 TNF¦Á, while knockdown of either HIF-1¦Á or HIF-2¦Á 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 TNF¦Á/NF-¦ÊB/HIF/VEGF signaling cascade via down-regulation of the TNF receptor TNF-R1, rather than TNF¦Á itself, and multiple key components of both canonical and non-canonical NF-¦ÊB 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 TNF¦Á/NF-¦ÊB/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
%K low-density lipoprotein
%K hypoxia-inducible factor
%K tumor necrosis factor-¦Á
%K vascular endothelial growth factor
%K nuclear factor-kappaB
%K angiogenesis
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366960/