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Cited by 199Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerErythropoietin and Anemia Treatment

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

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Bartoszewski, Rafal, Moszyńska, Adrianna, Serocki, Marcin, Cabaj, Aleksandra, Polten, Andreas, Ochocka, Renata, Dell'Italia, Louis, Bartoszewska, Sylwia +3 more·2019·The FASEB Journal
DOI 10.1096/fj.201802650rrPMC PMC6593883
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Abstract

ABSTRACT 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

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  • In primary human endothelial cells, our analyses uncovered over 150 hypoxia-responsive genes involved in metabolic control and angiogenic regulation, erythropoiesis, autophagy, and pro-survival signaling.

    “In primary human endothelial cells, our analyses uncovered over 150 hypoxia-responsive genes involved in metabolic control and angiogenic regulation erythropoiesis, autophagy, and pro-survival signaling [7]”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [7]

    The Results (page unavailable) report 280 genes affected after 16 hours of hypoxia, with gene-ontology signals for angiogenesis, glycolysis, and antiapoptotic responses. The paper also discusses erythropoietin expression, but the retrieved passages do not establish erythropoiesis or autophagy as functions of the genes identified in its analysis. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Diversity in HIF complex composition contributes to cell type-specific hypoxic transcriptional responses.

    “This diversity in HIF complex composition contributes to cell type–specific hypoxic transcriptional responses”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [7]

    The Results report differences in HIF-1α timing among endothelial cells from different vascular beds, and the Discussion links the HIF-1-to-HIF-2 switch to transcriptional consequences in endothelial cells. But the paper does not establish that differences in HIF complex composition cause distinct transcriptional responses across cell types; its gene-expression analysis concerns endothelial cells during hypoxia. The indexed passages provide section labels but no page numbers. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The global architecture of HIF-1- and HIF-2-dependent target gene networks remains largely conserved across different cell types.

    “Notwithstanding these distinctions, the global architecture of HIF-1- and HIF-2-dependent target gene networks remains largely conserved across different cell types [7,66,68,70]”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [7]

    The Discussion (page unavailable) says the paper’s HIF-binding-motif analysis agrees well with results from cancer cell lines, despite the different cell types. It also reports overlapping HIF-1 and HIF-2 targets in endothelial cells. These findings support some cross-cell-type similarity, but do not establish that the global architecture of their target-gene networks is largely conserved across different cell types. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Genes governed by overlapping HIF-1- and HIF-2-dependent regulatory inputs exhibited the strongest induction during hypoxia, including classical targets such as VEGFA and GLUT1.

    “Genes governed by overlapping HIF-1- and HIF-2-dependent regulatory inputs exhibited the strongest induction during hypoxia [7], including classical targets such as VEGFA and GLUT1 [60,96]”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [7]

  • Genes induced exclusively during prolonged hypoxia were enriched for HIF-2 motifs.

    “Whereas genes induced exclusively during prolonged hypoxia were enriched for HIF-2 motifs”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [7]

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References 71 · Cited by 199

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Authors
Bartoszewski, R., Moszyńska, A., Serocki, M., Cabaj, A., Polten, A., Ochocka, R., Dell'Italia, L., Bartoszewska, S., Króliczewski, J., Dąbrowski, M., & Collawn, J. F.
Affiliations
  • Department of Biology and Pharmaceutical Botany Medical University of Gdansk Gdansk Poland
  • Gdańsk Medical University (PL)
  • Instytut Biologii Doświadczalnej im. Marcelego Nenckiego (PL)
  • Agilent Technologies (Germany) (DE)
  • Department of Medicine Birmingham Veterans Affairs (VA) Medical Center Birmingham Alabama USA
  • University of Alabama at Birmingham (US)
ORCID
Venue
The FASEB Journal
Publisher
Wiley
Published
2019-03-27
Volume
33
Issue
7
Pages
7929-7941
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
DOI
10.1096/fj.201802650rr
PMC
PMC6593883
OpenAlex
W2923377894
Cited by
199
References
71
Citations by year
2026: 22 · 2025: 17 · 2024: 39 · 2023: 40 · 2022: 33 · 2021: 27 · 2020: 17 · 2019: 4
FWCI
6.41
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The FASEB Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Narodowym Centrum Nauki (UMO-2015/18/E/NZ3/00687)
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK072482)
  • Cystic Fibrosis Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Keywords
HIF-1, HIF-2, endothelial cells, hypoxia, mRNA stability, HIF1A, HIF-2α, target gene expression, human umbilical vein endothelial cells, vascular bed
MeSH terms
Endothelial PAS Domain-Containing Protein 1, Adaptation, Physiological, Aorta, Cells, Cultured, Female, Gene Expression Regulation, Half-Life, Humans, Iliac Artery, Organ Specificity, Pulmonary Artery, RNA, Messenger, Skin, Uterus, Cell Hypoxia, Gene Expression Profiling, RNA Stability, Endothelial Cells, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Real-Time Polymerase Chain Reaction, Primary Cell Culture, Human Umbilical Vein Endothelial Cells

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