Primary endothelial cell–specific regulation of hypoxia‐inducible factor (HIF)‐1 and HIF‐2 and their target gene expression profiles during hypoxia

During hypoxia, a cellular adaptive response activates hypoxia‐inducible factors (HIFs; HIF‐1 and HIF‐2) that respond to low tissue‐oxygen levels and induce the expression of a number of genes that promote angiogenesis, energy metabolism, and cell survival. HIF‐1 and HIF‐2 regulate endothelial cell (EC) adaptation by activating genesignaling cascades that promote endothelial migration, growth, and differentiation. An HIF‐1 to HIF‐2 transition or switch governs this process from acute to prolonged hypoxia. In the present study, we evaluated the mechanisms governing the HIF switch in 10 different primary human ECs from different vascular beds during the early stages of hypoxia. The studies demonstrate that the switch from HIF‐1 to HIF‐2 constitutes a universal mechanism of cellular adaptation to hypoxic stress and that HIF1A and HIF2A mRNA stability differences contribute to HIF switch. Furthermore, using 4 genome‐wide mRNA expression arrays of HUVECs during normoxia and after 2, 8, and 16 h of hypoxia, we show using bioinformatics analyses that, although a number of genes appeared to be regulated exclusively by HIF‐1 or HIF‐2, the largest number of genes appeared to be regulated by both.—Bartoszewski, R., Moszynska, A., Serocki, M., Cabaj, A., Polten, A., Ochocka, R., Dell'Italia, L., Bartoszewska, S., Króliczewski, J., Dabrowski, M., Collawn, J. F. Primary endothelial cell–specific regulation of hypoxia‐inducible factor (HIF)‐1 and HIF‐2 and their target gene expression profiles during hypoxia. FASEB J. 33, 7929–7941 (2019). www.fasebj.org

• Publication year

  2019

• Venue

  The FASEB Journal

• Publication date

  2019-03-27

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1096/fj.201802650RRPMID 30917010PMCID PMC6593883
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• eNOS expression and NO release during hypoxia is inhibited by miR-200b in human endothelial cells

  2018cited by this paper
• miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target

  2018cited by this paper
• The Different Facades of Retinal and Choroidal Endothelial Cells in Response to Hypoxia

  2018cited by this paper
• Inherent DNA‐binding specificities of the HIF‐1α and HIF‐2α transcription factors in chromatin

  2018cited by this paper
• miR-200b downregulates CFTR during hypoxia in human lung epithelial cells

  2017cited by this paper
• Ensembl 2018

  2017cited by this paper
• miR-200b downregulates Kruppel Like Factor 2 (KLF2) during acute hypoxia in human endothelial cells.

  2017cited by this paper
• HOCOMOCO: towards a complete collection of transcription factor binding models for human and mouse via large-scale ChIP-Seq analysis

  2017cited by this paper
• Identification of HIF-2α-regulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro

  2016cited by this paper
• miR-429 regulates the transition between Hypoxia-Inducible Factor (HIF)1A and HIF3A expression in human endothelial cells

  2016cited by this paper
• Differential hypoxic response of human choroidal and retinal endothelial cells proposes tissue heterogeneity of ocular angiogenesis

  2016cited by this paper
• Genome-wide analysis of HIF-2α chromatin binding sites under normoxia in human bronchial epithelial cells (BEAS-2B) suggests its diverse functions

  2016cited by this paper
• Posttranscriptional and transcriptional regulation of endothelial nitric-oxide synthase during hypoxia: the role of microRNAs

  2016cited by this paper
• GeneAnalytics: An Integrative Gene Set Analysis Tool for Next Generation Sequencing, RNAseq and Microarray Data

  2016cited by this paper
• InteractiVenn: a web-based tool for the analysis of sets through Venn diagrams

  2015cited by this paper
• AREsite2: an enhanced database for the comprehensive investigation of AU/GU/U-rich elements

  2015cited by this paper
• The hypoxia‐inducible miR‐429 regulates hypoxia‐inducible factor‐1α expression in human endothelial cells through a negative feedback loop

  2015cited by this paper
• Extensive regulation of the non-coding transcriptome by hypoxia: role of HIF in releasing paused RNApol2

  2013cited by this paper
• Nencki Genomics Database—Ensembl funcgen enhanced with intersections, user data and genome-wide TFBS motifs

  2013cited by this paper
• miRNA-Mediated Gene Silencing by Translational Repression Followed by mRNA Deadenylation and Decay

  2012cited by this paper
• Ribosome Profiling Shows That miR-430 Reduces Translation Before Causing mRNA Decay in Zebrafish

  2012cited by this paper
• An Integrated Encyclopedia of DNA Elements in the Human Genome

  2012cited by this paper
• HIF-1 versus HIF-2--is one more important than the other?

  2012cited by this paper
• Passing the baton: the HIF switch.

  2012influential reference
• Functional Importance of Dicer Protein in the Adaptive Cellular Response to Hypoxia*

  2012cited by this paper
• Hypoxia-Induced Alternative Splicing in Endothelial Cells

  2012cited by this paper
• High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq.

  2011influential reference
• CFTR expression regulation by the unfolded protein response.

  2011cited by this paper
• Hypoxia-inducible factor-1α mRNA: a new target for destabilization by tristetraprolin in endothelial cells

  2011cited by this paper
• HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression

  2011cited by this paper
• HIF-1 and HIF-2 transcription factors — Similar but not identical

  2010cited by this paper
• Tristetraprolin regulates the stability of HIF-1alpha mRNA during prolonged hypoxia.

  2010cited by this paper
• Mammalian microRNAs predominantly act to decrease target mRNA levels

  2010cited by this paper
• Concordant Regulation of Translation and mRNA Abundance for Hundreds of Targets of a Human microRNA

  2009cited by this paper
• Kruppel-like Factor 2 Inhibits Hypoxia-inducible Factor 1α Expression and Function in the Endothelium*

  2009cited by this paper
• GeneDecks: Paralog Hunting and Gene-Set Distillation with GeneCards Annotation

  2009cited by this paper
• Surviving hypoxia by modulation of mRNA translation rate

  2009cited by this paper
• Hsp70 and CHIP Selectively Mediate Ubiquitination and Degradation of Hypoxia-inducible Factor (HIF)-1α but Not HIF-2α*

  2009cited by this paper
• RNA-binding proteins HuR and PTB promote the translation of hypoxia-inducible factor 1alpha.

  2008cited by this paper
• The Mechanism of Cystic Fibrosis Transmembrane Conductance Regulator Transcriptional Repression during the Unfolded Protein Response*

  2008cited by this paper
• Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.

  2008cited by this paper
• RACK1 Competes with HSP90 for Binding to HIF-1α and is Required for O2-independent and HSP90 Inhibitor-induced Degradation of HIF-1α

  2007cited by this paper
• RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha.

  2007cited by this paper
• RACK1 vs. HSP90: Competition for HIF-1α Degradation vs. Stabilization

  2007cited by this paper
• Hypoxia-inducible Expression of a Natural cis-Antisense Transcript Inhibits Endothelial Nitric-oxide Synthase*

  2007cited by this paper
• RNA-Binding Proteins HuR and PTB Promote the Translation of Hypoxia-Inducible Factor 1α

  2007cited by this paper
• RACK1 vs. HSP90: competition for HIF-1 alpha degradation vs. stabilization.

  2007cited by this paper
• Leukemogenic Nup98-homeobox fusion proteins are targeted to a novel nuclear compartment and cause mistargeting of endogenous Nup98

  2006cited by this paper
• Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1.

  2005cited by this paper
• Proline hydroxylation and gene expression.

  2005cited by this paper
• Post-transcriptional Regulation of Endothelial Nitric-oxide Synthase by an Overlapping Antisense mRNA Transcript*

  2004cited by this paper
• Identification of a target RNA motif for RNA-binding protein HuR.

  2004cited by this paper
• Differential Function of the Prolyl Hydroxylases PHD1, PHD2, and PHD3 in the Regulation of Hypoxia-inducible Factor*

  2004cited by this paper
• Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation

  2003cited by this paper
• HIF hydroxylation and the mammalian oxygen-sensing pathway.

  2003cited by this paper
• Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation.

  2003cited by this paper
• Articles on similar topics can be found in the following Blood collections

  2002cited by this paper
• Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch

  2002cited by this paper
• A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF

  2001cited by this paper
• HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing

  2001cited by this paper
• FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity.

  2001cited by this paper
• Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

  2001cited by this paper
• Independent function of two destruction domains in hypoxia‐inducible factor‐α chains activated by prolyl hydroxylation

  2001cited by this paper
• Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation

  2001cited by this paper
• Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells

  2001influential reference
• C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation.

  2001cited by this paper
• Faculty Opinions recommendation of HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.

  2001cited by this paper
• Mechanism of regulation of the hypoxia‐inducible factor‐1α by the von Hippel‐Lindau tumor suppressor protein

  2000cited by this paper
• The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis

  1999cited by this paper
• Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.

  1995cited by this paper
• Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms.

  1994cited by this paper
• General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia.

  1993cited by this paper

• Advances in Proteolysis Targeting Chimeras

  2026cites this paper
• Long non-coding RNA LINC00607 epigenetically regulates endothelial TSPAN18 to promote hypoxia-induced thromboinflammation.

  2026cites this paper
• Ginsenoside potential targeting hypoxia-inducible factor-1α as promising therapeutics for cancer: a review

  2026cites this paper
• Emerging regulators of endothelial lipid metabolism in atherosclerosis.

  2026cites this paper
• Challenges in mimicking hypoxia: insights into HIF-regulated MiRNA expression induced by DMOG and CoCl2

  2025influential citation
• The Role of Growth Factors and Signaling Pathways in Ovarian Angiogenesis

  2025cites this paper
• HIF-1α: a bridge connecting sepsis and acute respiratory distress syndrome

  2025cites this paper
• A dynamic model of gene activation in response to hypoxia accounting for both HIF-1 and HIF-2

  2025cites this paper
• The Role of the Vascular Niche in Regulating Kidney Tubulo-Interstitial Fibrosis.

  2025cites this paper
• LACK OF OXYGEN AND/OR GLUCOSE DIFFERENTIALLY POTENTIATES Aβ40E22Q- AND Aβ42-INDUCED CEREBRAL ENDOTHELIAL CELL DEATH, BARRIER DYSFUNCTION AND ANGIOGENESIS IMPAIRMENT

  2025cites this paper
• A mechanistic computational model of HGF-VEGF-mediated endothelial cell proliferation and vascular permeability

  2025cites this paper
• Prolyl hydroxylase-2 (EGLN1) mediates TGF-β1 pathway regulated epithelial-mesenchymal transition in yak kidneys.

  2025cites this paper
• Hypoxia promotes the generation of a versican-rich extracellular matrix by human coronary artery endothelial cells

  2025cites this paper
• Multiomics Analysis Reveals Role of ncRNA in Hypoxia of Mouse Brain Microvascular Endothelial Cells

  2025cites this paper
• Differential roles of the type I and II secretion systems for the intracellular ABC141 Acinetobacter baumannii infection, which elicits an atypical hypoxia response in endothelial cells

  2025cites this paper
• Comparative transcriptomics of iPSC-derived cardiomyocytes in a high and a low altitude population

  2025cites this paper
• Role of Ischemia/Reperfusion and Oxidative Stress in Shock State

  2025cites this paper
• Hypoxia-Induced Changes in Endothelial Cell Phenotype and Function

  2025cites this paper
• Transcriptomic analysis of iPSC-derived endothelium reveals adaptations to high altitude hypoxia in energy metabolism and inflammation

  2025cites this paper
• A Case Study of Combined Treatment of Whiplash Injury with Traditional Chinese and Western Medicine

  2025cites this paper
• A novel multiplex RNAi therapy simultaneously targets Hif1a and Hif2a to defy retinal degeneration in two models of AMD

  2025cites this paper
• The role of hypoxia-inducible factors 1 and 2 in the pathogenesis of diabetic kidney disease

  2024cites this paper
• Placental and immune cell DNA methylation reference panel for bulk tissue cell composition estimation in epidemiological studies

  2024cites this paper
• Functional EPAS1/HIF2A missense variant is associated with hematocrit in Andean highlanders

  2024cites this paper
• Metabolic disruption exacerbates intestinal damage during sleep deprivation by abolishing HIF1α-mediated repair.

  2024cites this paper
• A mechanistic systems biology model of brain microvascular endothelial cell signaling reveals dynamic pathway-based therapeutic targets for brain ischemia

  2024cites this paper
• Branched-chain α-ketoacids aerobically activate HIF1α signalling in vascular cells

  2024cites this paper
• Impact of Hypoxia and the Levels of Transcription Factor HIF-1α and JMJD1A on Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma Cell Lines

  2024cites this paper
• Hypoxia-Induced Inflammation in In Vitro Model of Human Blood–Brain Barrier: Modulatory Effects of the Olfactory Ensheathing Cell-Conditioned Medium

  2024cites this paper
• NADPH Oxidase 4: Crucial for Endothelial Function under Hypoxia—Complementing Prostacyclin

  2024cites this paper
• Impact of Metal Ions on Cellular Functions: A Focus on Mesenchymal Stem/Stromal Cell Differentiation

  2024cites this paper
• Deciphering the Protective Role of HIF-1α Downregulation on HIBD through the MALAT1/miR-140-5p/TGFBR1/NF-κB Signaling Pathway

  2024cites this paper
• Senotherapy preserves resilience in aging

  2024cites this paper
• Therapeutic efficacy of ECs Foxp1 targeting Hif1α-Hk2 glycolysis signal to restrict angiogenesis

  2024cites this paper
• Exploring the pathogenesis of pulmonary vascular disease

  2024cites this paper
• Cathepsins L and B target HIF1α for oxygen-independent proteolytic cleavage

  2024cites this paper
• Regulation of the HIF switch in human endothelial and cancer cells.

  2024cites this paper
• Prolonged Hypoxic Exposure Impairs Endothelial Functions: Possible Mechanism of HIF-1α Signaling

  2024cites this paper
• The cellular-centered view of hypoxia tumor microenvironment: Molecular mechanisms and therapeutic interventions.

  2024cites this paper
• Branched chain α-ketoacids aerobically activate HIF1α signaling in vascular cells

  2024influential citation
• Fish gill chemosensing: knowledge gaps and inconsistencies

  2024cites this paper
• Transcriptomic analysis of the effect of remote ischaemic conditioning in an animal model of necrotising enterocolitis

  2024cites this paper
• Placental and Immune Cell DNA Methylation Reference Panel for Bulk Tissue Cell Composition Estimation in Epidemiological Studies

  2024influential citation
• Targeting hypoxia signaling pathways in angiogenesis

  2024cites this paper
• Hypoxia, hypoxia-inducible factors and inflammatory bowel diseases

  2024cites this paper
• Endothelial cells signaling and patterning under hypoxia: a mechanistic integrative computational model including the Notch-Dll4 pathway

  2024cites this paper
• Prevention of Cerebral Malaria Hypoxia through administration of Neem leaves extract (Azadirachta indica) in Mice C57BL

  2024cites this paper
• ARF6 as a novel activator of HIF-2α in pulmonary arterial hypertension

  2023cites this paper
• Endotyping COPD: hypoxia-inducible factor-2 as a molecular “switch” between the vascular and airway phenotypes?

  2023cites this paper
• The Underexplored Landscape of Hypoxia-Inducible Factor 2 Alpha and Potential Roles in Tumor Macrophages: A Review

  2023influential citation
• Hypoxia‐Inducible Factor‐2α Signaling in the Skeletal System

  2023influential citation
• Long noncoding RNA GATA2-AS1 augments endothelial hypoxia inducible factor 1-α induction and regulates hypoxic signaling

  2023cites this paper
• Transcriptional Response to Hypoxia: The Role of HIF-1-Associated Co-Regulators

  2023cites this paper
• Manipulation of iron status on cerebral blood flow at high altitude in lowlanders and adapted highlanders

  2023cites this paper
• EPAS1 resistance to miRNA-based regulation contributes to prolonged expression of HIF-2 during hypoxia in human endothelial cells.

  2023cites this paper
• Comparative analysis of hypoxic response of human microvascular and umbilical vein endothelial cells in 2D and 3D cell culture systems

  2023cites this paper
• Overexpression of hypoxia-inducible factor-1α in hidradenitis suppurativa: the link between deviated immunity and metabolism

  2023cites this paper
• Investigation of the Role of Carcinoembryonic Antigen-Related Cell Adhesion Molecule-1 in Diabetic Retinopathy

  2023cites this paper
• Hypoxia‐inducible lncRNA MIR210HG promotes HIF1α expression by inhibiting miR‐93‐5p in renal tubular cells

  2023cites this paper
• A novel OSA-related model of intermittent hypoxia in endothelial cells under flow reveals pronounced inflammatory pathway activation

  2023cites this paper
• Proteolysis targeting chimeras in non-small cell lung cancer.

  2023cites this paper
• Endothelial cells signaling and patterning under hypoxia: a mechanistic integrative computational model including the Notch-Dll4 pathway

  2023cites this paper
• HIF-1-Induced hsa-miR-429: Understanding Its Direct Targets as the Key to Developing Cancer Diagnostics and Therapies

  2023cites this paper
• Effects of Zinc on the Right Cardiovascular Circuit in Long-Term Hypobaric Hypoxia in Wistar Rats

  2023cites this paper
• Long-term treatment of chronic kidney disease patients with anemia using hypoxia-inducible factor prolyl hydroxylase inhibitors: potential concerns

  2023cites this paper
• Impact of High-Flow Nasal Cannula Use in Subjects With COVID-19 ARDS at High Altitudes: Clinical Presentation and Prognostic Factors

  2023cites this paper
• The association of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α protein expression with clinicopathological characteristics in papillary thyroid carcinoma: A meta-analysis

  2023influential citation
• Regulatory Functions of Hypoxia in Host–Parasite Interactions: A Focus on Enteric, Tissue, and Blood Protozoa

  2023cites this paper
• IRE1-mediated degradation of pre-miR-301a promotes apoptosis through upregulation of GADD45A

  2023cites this paper
• The influence of redox modulation on hypoxic endothelial cell metabolic and proteomic profiles through a small thiol‐based compound tuning glutathione and thioredoxin systems

  2023cites this paper
• Multimerization of HIF enhances transcription of target genes containing the hypoxia ancillary sequence.

  2023cites this paper
• Hub genes identification and association of key pathways with hypoxia in cancer cells: A bioinformatics analysis

  2023cites this paper
• Efficient targeting of HIF-1α mediated by YC-1 and PX-12 encapsulated niosomes: potential application in colon cancer therapy

  2023cites this paper
• NADH elevation during chronic hypoxia leads to VHL-mediated HIF-1α degradation via SIRT1 inhibition

  2023cites this paper
• Hypoxia-Induced miR-101 Impairs Endothelial Barrier Integrity Through Altering VE-Cadherin and Claudin-5

  2023cites this paper
• The association of Hypoxia-Inducible Factor-2α (HIF-2α) overexpression score with Germinal Center B-Cell Like (GCB) and Non-Germinal Center B-Cell Like (Non-GCB) subtypes of Diffuse Large B-cell Lymphoma (DLBCL)

  2023cites this paper
• Transcriptomic Analysis of the Effect of Remote Ischaemic Conditioning in an Animal Model of Necrotising Enterocolitis

  2023cites this paper
• RasGRP2 Attenuates Oxygen Deprivation-Induced Autophagy in Vascular Endothelial Cells.

  2023cites this paper
• Identifying key genes related to the peritubular capillary rarefaction in renal interstitial fibrosis by bioinformatics

  2023cites this paper
• EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake

  2023cites this paper
• Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis

  2023cites this paper
• Marein Ameliorates Myocardial Fibrosis by Inhibiting HIF-1α and TGF-β1/Smad2/3 Signaling Pathway in Isoproterenol-stimulated Mice and TGF-β1-stimulated Cardiac Fibroblasts.

  2023cites this paper
• Super Enhancer-Associated Circular RNA-CircKrt4 Regulates Hypoxic Pulmonary Artery Endothelial Cell Dysfunction in Mice

  2023cites this paper
• Escape From Cisplatin-Induced Senescence of Hypoxic Lung Cancer Cells Can Be Overcome by Hydroxychloroquine

  2022cites this paper
• CircRNA–miRNA interactions in atherogenesis

  2022cites this paper
• Adaptive exhaustion during prolonged intermittent hypoxia causes dysregulated skeletal muscle protein homeostasis

  2022cites this paper
• The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability

  2022cites this paper
• The vascular gene Apold1 is dispensable for normal development but controls angiogenesis under pathological conditions

  2022cites this paper
• A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans

  2022cites this paper
• Short-term hypoxia triggers ROS and SAFB mediated nuclear matrix and mRNA splicing remodeling

  2022cites this paper
• Metabolic reprogramming of pulmonary fibrosis

  2022cites this paper
• The Role of Hypoxia-Inducible Factor-1 Alpha in Renal Disease

  2022cites this paper
• AURKB, in concert with REST, acts as an oxygen-sensitive epigenetic regulator of the hypoxic induction of MDM2

  2022cites this paper
• Hypoxia-Inducible Factor-1: A Novel Therapeutic Target for the Management of Cancer, Drug Resistance, and Cancer-Related Pain

  2022cites this paper
• The Role of the Hypoxia-Related Unfolded Protein Response (UPR) in the Tumor Microenvironment

  2022cites this paper
• Hypoxia-inducible factor (HIF)-3a2 serves as an endothelial cell fate executor during chronic hypoxia

  2022cites this paper
• Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy

  2022cites this paper
• Shuxie-1 Decoction Alleviated CUMS -Induced Liver Injury via IL-6/JAK2/STAT3 Signaling

  2022cites this paper
• Molecular mechanisms of skin wound healing in non-diabetic and diabetic mice in excision and pressure experimental wounds

  2022cites this paper
• Acute hypoxia changes the gene expression profiles and alternative splicing landscape in gills of spotted sea bass (Lateolabrax maculatus)

  2022cites this paper