Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites

Feng, Shuang; Bowden, Neil; Fragiadaki, Maria; Souilhol, Céline; Hsiao, Sarah; Mahmoud, Marwa; Allen, Simon; Pirri, Daniela; Ayllón, Blanca Tardajos; Akhtar, Shamima; Thompson, A. A. Roger; Jo, Hanjoong; Weber, Christian; Ridger, Victoria; Schober, Andreas; Evans, Paul C.

doi:10.1161/atvbaha.117.309249

Cited by 176 publications

(160 citation statements)

References 48 publications

(85 reference statements)

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“…Also, HIF-1a expression increased in the aortic arch, which is the part of the aorta most affected by disturbed flow. Disturbed flow can directly induce aortic HIF-1a expression, targeting Snai1 (45,46), the master transcription factor of EndMT, and laminar flow can even protect from TGF-binduced EndMT (14). In line with previous findings (10), we observed more matrix deposition close to the endothelium in atherosclerosis-prone areas with disturbed flow.…”

Section: The In Vivo Atherosclerotic Endmt Phenotype Is Closely Resemsupporting

confidence: 92%

Endothelial‐to‐mesenchymal transition shapes the atherosclerotic plaque and modulates macrophage function

et al. 2018

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Endothelial cells can acquire a mesenchymal phenotype upon irritation [endothelial‐to‐mesenchymal transition (EndMT)]. Macrophages accumulate in the atherosclerotic plaque. This study addressed whether macrophages modulate EndMT and delineated a reciprocal effect of EndMT on macrophage functions in atherosclerosis. In atherosclerotic murine and human aortas, endothelial cells with mesenchymal markers were elevated by confocal microscopy and flow cytometric analysis. Increased EndMT master transcription factor Snail expression and extracellular matrix are consistent with enhanced EndMT in this condition. Hypoxia was detected in individual aortic EndMT cells in vivo and rapidly induced a similar EndMT phenotype in vitro. As a novel inducer of EndMT, macrophages, which are abundant in the atherosclerotic lesions, enhance mesothelial marker expression during coculture in vitro. In the reverse relationship, EndMT altered endothelial colony‐stimulating factor expression. Functionally, EndMT cell–conditioned media attenuated macrophage proliferation, antigen‐presenting cell marker expression, and TNF‐α production in response to oxidized LDL but increased oxidized LDL uptake and scavenger receptor expression. These experiments demonstrate that macrophages promote partial EndMT. In turn, EndMT cells modulate macrophage phenotype and lipid uptake. Our data suggest that EndMT shapes macrophage and endothelial cell phenotypes, thus affecting internal atherosclerotic plaque in addition to surface structure.—Helmke, A., Casper, J., Nordlohne, J., David, S., Haller, H., Zeisberg, E. M., von Vietinghoff, S. Endothelial‐to‐mesenchymal transition shapes the atherosclerotic plaque and modulates macrophage function. FASEB J. 33, 2278–2289 (2019). http://www.fasebj.org

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Section: The In Vivo Atherosclerotic Endmt Phenotype Is Closely Resemsupporting

confidence: 92%

Endothelial‐to‐mesenchymal transition shapes the atherosclerotic plaque and modulates macrophage function

et al. 2018

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“…4 Importantly, we discovered that HIF-1α was required and sufficient for DF-induced upregulation of glycolysis and downregulation of mitochondrial respiration, which played a key role in EC activation assessed by NF-κB activation and expression of pro-inflammatory cytokines and adhesion molecules. While our conclusions about HIF-1α playing a critical role in EC activation under DF agree with those of Feng et al 1 , there are some differences between the two studies. We found that DF induced NADPH oxidase 4 (NOX4)-dependent generation of reactive oxygen species (ROS), which were required for HIF-1α stabilization and downstream effects on glycolysis and EC activation.…”

Section: To the Editorsupporting

confidence: 86%

“…1 Since atherosclerosis develops near branches or bends of arteries where endothelial cells are exposed to low shear stress, these results suggest that HIF-1α activation in endothelial cells may play a causal role in the pathogenesis of atherosclerosis.…”

Section: To the Editormentioning

confidence: 90%

Letter by Wu et al Regarding Article, “Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites”

Hamanaka

Fang

et al. 2017

ATVB

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“…7 The molecular mechanisms downstream from NOX4 were not identified by Wu et al 2 ; however, they speculate that reactive oxygen species (ROS) may stabilize HIF1α by inhibiting the activity of PHD and VHL (von Hippel-Lindau) enzymes. Although we observed that the expression of PHD and VHL was not reduced by disturbed flow, 1 further work is necessary to investigate whether flow alters the activity of these enzymes. It should be noted that effects of flow on PHD, VHL, and Cezanne are not mutually exclusive; it is plausible that disturbed flow promotes HIF1α stability by simultaneously enhancing deubiquitination and reducing ubiquitination.…”

mentioning

confidence: 73%

“…In both studies, unbiased transcriptome-based methods identified enriched expression of HIF1α, and its target genes, in endothelial cells exposed to disturbed flow. 1,2 It was also demonstrated, by both studies, that HIF1α-dependent glycolysis promotes vascular inflammation at atheroprone sites via induction of adhesion molecules and other inflammatory mediators. In contrast to Wu et al, 2 our study revealed that HIF1α additionally induces excessive rates of endothelial cell proliferation 1 -a phenotype that has been previously linked with vascular leakiness and atherogenesis.…”

mentioning

confidence: 92%

Response by Feng et al to Letter Regarding Article, “Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites”

Feng

Fragiadaki

Souilhol

et al. 2017

ATVB

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In Response:We welcome the letter from Wu et al on our recent study, which showed that disturbed flow can activate hypoxia-inducible factor (HIF1α) leading to enhanced endothelial glycolysis, proliferation, and vascular inflammation 1 . It is notable that Wu et al 2 independently recapitulated our observation in a series of elegant experiments. In both studies, unbiased transcriptome-based methods identified enriched expression of HIF1α, and its target genes, in endothelial cells exposed to disturbed flow. 1,2 It was also demonstrated, by both studies, that HIF1α-dependent glycolysis promotes vascular inflammation at atheroprone sites via induction of adhesion molecules and other inflammatory mediators. In contrast to Wu et al, 2 our study revealed that HIF1α additionally induces excessive rates of endothelial cell proliferation 1 -a phenotype that has been previously linked with vascular leakiness and atherogenesis. Taken together, the effects of HIF1α on inflammation and proliferation represent a plausible dual mechanism to explain its previously described proatherogenic effects. 3 We performed detailed biochemical studies to define the underlying molecular mechanism for HIF1α stabilization in the presence of oxygen in endothelial cells exposed to disturbed flow; dual regulation of HIF1α at both transcriptional and protein levels was identified. Evidence from multiple experiments led us to conclude that transcriptional upregulation of HIF1α mRNA in response to disturbed flow is under the control of NF-κB because (1) HIF1α expression was significantly reduced by overexpression of IκBα (an inhibitor of NF-κB), (2) silencing of RelA NF-κB subunits using siRNA reduced HIF1α expression, and (3) chromatin immunoprecipitation revealed that NF-κB interacts directly with HIF1α promoter sequences. Moreover, our results are in agreement with previous studies demonstrating that NF-κB can induce HIF1α in other contexts. 4 Wu et al 2 questioned our observation because they found that a peptide inhibitor of NF-κB did not alter HIF1α expression; however, we are uncertain of their conclusion because it seems to be based on data from a single Western blot that was not quantified. On the contrary, Wu et al 2 show convincingly that HIF1α can activate NF-κB in endothelium exposed to disturbed flow. Considering the data from both studies, we posit that NF-κB is positioned both upstream and downstream from HIF1α in cells exposed to disturbed flow, thereby forming a positive feedback loop in HIF1α activation.HIF1α is tightly regulated by enzymes that control the attachment of Lys48-linked polyubiquitin chains-a modification that targets proteins for degradation. In the presence of oxygen, HIF1α is modified with hydroxyl groups by prolyl hydroxylase domain (PHD) enzymes, and this modification is subsequently recognized by von Hippel-Lindau E3 ubiquitin ligase, which targets HIF1α for Lys48 polyubiquitination.5 However, in some situations, this process can be reversed by Cezanne-a deubiquitinating cysteine protease that can remove poly...

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Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites

Abstract: Supplemental Digital Content is available in the text.

Cited by 176 publications

References 48 publications

Endothelial‐to‐mesenchymal transition shapes the atherosclerotic plaque and modulates macrophage function

Endothelial‐to‐mesenchymal transition shapes the atherosclerotic plaque and modulates macrophage function

Letter by Wu et al Regarding Article, “Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites”

Response by Feng et al to Letter Regarding Article, “Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites”

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