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Biomolecules
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Hypoxia and Hypoxia-Inducible Factors in Human Endothelium
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Hypoxia and Hypoxia-Inducible Factors in Human Endothelium

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 30173

Special Issue Editor

Dr. Rafal Bartoszewski

E-Mail Website
Guest Editor
Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
Interests: HIFs; hypoxia; UPR; microRNA; miRNA; ER stress
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hypoxia is defined as the inability to meet cellular oxygen demands. During hypoxia, there are global expression changes that restore oxygen homeostasis and allow cells to survive. Despite hypoxia’s importance during normal development, it is also associated with pathological responses in the mature organism. For example, the metabolic adaptation to hypoxia and angiogenesis favors the survival and progression of many human cancers, and hypoxia also plays a role in diabetic retinopathy, macular degeneration, and glaucoma. Alternatively, it can be beneficial during hypoxia-induced angiogenesis after stroke and other ischemic events.

The activation of cellular hypoxia signaling relies on the accumulation of transcriptionally functional complexes of hypoxia-inducible factors (HIFs). HIFs, through transcriptional modulation of their specific target genes, serve as master regulators of cellular adaptation to low oxygen conditions that mediate the restoration of oxygen homeostasis. Hence, therapeutic approaches that exploit HIF-based signaling networks are certainly hot topics in current medicine, as indicated by the awarding of the 2019 Nobel Prize in Physiology or Medicine to Drs. Semenza, Ratcliffe, and Kaelin, who identified HIFs’ roles in hypoxic responses.

Despite continuous research to elucidate the extent of HIF signaling pathways, however, their utility in therapeutic approaches has been limited in scope. To date, the main research cell models for hypoxia signaling have focused on in vitro cultures of cancer cells exposed to continuous hypoxia. These cancer cells, however, have undergone specific genetic and epigenetic modifications in order to develop their pathogenic phenotypes. Furthermore, solid tumors are exposed to fluctuating oxygen levels (cyclic hypoxia) rather than chronic hypoxia and modulate endothelial angiogenesis in order to assure their survival and tumor growth. Although normal human endothelial cells provide an alternative model to study hypoxia, they still remain underappreciated, and clearly, more research is needed to distinguish between the cancer-specific and the physiological HIF signaling pathways.

For this Special Issue of Biomolecules, “Hypoxia and Hypoxia-Inducible Factors in Human Endothelium”, we encourage the submission of review and primary research articles that showcase both the molecular mechanisms of hypoxic response and HIF signaling in the human endothelium, as well as models that represent crosstalk between cancer and endothelial cells.

Dr. Rafal Bartoszewski
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • HIF-1
  • HIF-2
  • HIF-3
  • hypoxia-induced angiogenesis
  • cyclic hypoxia
  • microRNA
  • ncRNAs
  • human endothelia cells
  • HIF-switch

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Published Papers (5 papers)

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Research

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14 pages, 3217 KiB  
Article
IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells
by Adrianna Moszyńska, James F. Collawn and Rafal Bartoszewski
Biomolecules 2020, 10(6), 895; https://doi.org/10.3390/biom10060895 - 11 Jun 2020
Cited by 22 | Viewed by 4914
Abstract
While the role of hypoxia and the induction of the hypoxia inducible factors (HIFs) and the unfolded protein response (UPR) pathways in the cancer microenvironment are well characterized, their roles and relationship in normal human endothelium are less clear. Here, we examined the [...] Read more.
While the role of hypoxia and the induction of the hypoxia inducible factors (HIFs) and the unfolded protein response (UPR) pathways in the cancer microenvironment are well characterized, their roles and relationship in normal human endothelium are less clear. Here, we examined the effects of IRE1 on HIF-1α protein levels during hypoxia in primary human umbilical vein endothelial cells (HUVECs). The results demonstrated that HIF-1α levels peaked at 6 h of hypoxia along with two of their target genes, GLUT1 and VEGFA, whereas at up to 12 h of hypoxia the mRNA levels of markers of the UPR, IRE1, XBP1s, BiP, and CHOP, did not increase, suggesting that the UPR was not activated. Interestingly, the siRNA knockdown of IRE1 or inhibition of IRE1 endonuclease activity with 4µ8C during hypoxia significantly reduced HIF-1α protein without affecting HIF1A mRNA expression. The inhibition of the endonuclease activity with 4µ8C in two other primary endothelial cells during hypoxia, human cardiac microvascular endothelial cells and human aortic endothelial cells showed the same reduction in the HIF-1α protein. Surprisingly, the siRNA knockdown of XBP1s during hypoxia did not decrease the HIF1α protein levels, indicating that the IRE1-mediated effect on stabilizing the HIF1α protein levels was XBP1s-independent. The studies presented here, therefore, provide evidence that IRE1 activity during hypoxia increases the protein levels of HIF1α in an XBP1s-independent manner. Full article
(This article belongs to the Special Issue Hypoxia and Hypoxia-Inducible Factors in Human Endothelium)
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17 pages, 1518 KiB  
Article
Ticagrelor Prevents Endothelial Cell Apoptosis through the Adenosine Signalling Pathway in the Early Stages of Hypoxia
by Catherine Feliu, Hélène Peyret, Sylvie Brassart-Pasco, Floriane Oszust, Gaël Poitevin, Philippe Nguyen, Hervé Millart and Zoubir Djerada
Biomolecules 2020, 10(5), 740; https://doi.org/10.3390/biom10050740 - 9 May 2020
Cited by 13 | Viewed by 3598
Abstract
Background: Several studies have reported the beneficial effects of anti-platelet drugs in cardioprotection against ischaemia–reperfusion injuries. To date, no studies have focused on the indirect cytoprotective effects of ticagrelor via adenosine receptor on the endothelium. Method: By evaluating cell viability and cleaved caspase [...] Read more.
Background: Several studies have reported the beneficial effects of anti-platelet drugs in cardioprotection against ischaemia–reperfusion injuries. To date, no studies have focused on the indirect cytoprotective effects of ticagrelor via adenosine receptor on the endothelium. Method: By evaluating cell viability and cleaved caspase 3 expression, we validated a model of endothelial cell apoptosis induced by hypoxia. In hypoxic endothelial cells treated with ticagrelor, we quantified the extracellular concentration of adenosine, and then we studied the involvement of adenosine pathways in the cytoprotective effect of ticagrelor. Results: Our results showed that 10 µM ticagrelor induced an anti-apoptotic effect in our model associated with an increase of extracellular adenosine concentration. Similar experiments were conducted with cangrelor but did not demonstrate an anti-apoptotic effect. We also found that A2B and A3 adenosine receptors were involved in the anti-apoptotic effect of ticagrelor in endothelial cells exposed to 2 h of hypoxia stress. Conclusion: we described an endothelial cytoprotective mechanism of ticagrelor against hypoxia stress, independent of blood elements. We highlighted a mechanism triggered mainly by the increased extracellular bioavailability of adenosine, which activates A2B and A3 receptors on the endothelium. Full article
(This article belongs to the Special Issue Hypoxia and Hypoxia-Inducible Factors in Human Endothelium)
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Review

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29 pages, 1626 KiB  
Review
Nitric Oxide-Dependent Pathways as Critical Factors in the Consequences and Recovery after Brain Ischemic Hypoxia
by Joanna M Wierońska, Paulina Cieślik and Leszek Kalinowski
Biomolecules 2021, 11(8), 1097; https://doi.org/10.3390/biom11081097 - 26 Jul 2021
Cited by 58 | Viewed by 6730
Abstract
Brain ischemia is one of the leading causes of disability and mortality worldwide. Nitric oxide (NO•), a molecule that is involved in the regulation of proper blood flow, vasodilation, neuronal and glial activity constitutes the crucial factor that contributes to the [...] Read more.
Brain ischemia is one of the leading causes of disability and mortality worldwide. Nitric oxide (NO•), a molecule that is involved in the regulation of proper blood flow, vasodilation, neuronal and glial activity constitutes the crucial factor that contributes to the development of pathological changes after stroke. One of the early consequences of a sudden interruption in the cerebral blood flow is the massive production of reactive oxygen and nitrogen species (ROS/RNS) in neurons due to NO• synthase uncoupling, which leads to neurotoxicity. Progression of apoptotic or necrotic neuronal damage activates reactive astrocytes and attracts microglia or lymphocytes to migrate to place of inflammation. Those inflammatory cells start to produce large amounts of inflammatory proteins, including pathological, inducible form of NOS (iNOS), which generates nitrosative stress that further contributes to brain tissue damage, forming vicious circle of detrimental processes in the late stage of ischemia. S-nitrosylation, hypoxia-inducible factor 1α (HIF-1α) and HIF-1α-dependent genes activated in reactive astrocytes play essential roles in this process. The review summarizes the roles of NO•-dependent pathways in the early and late aftermath of stroke and treatments based on the stimulation or inhibition of particular NO• synthases and the stabilization of HIF-1α activity. Full article
(This article belongs to the Special Issue Hypoxia and Hypoxia-Inducible Factors in Human Endothelium)
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21 pages, 1685 KiB  
Review
Endothelial Dysfunction Driven by Hypoxia—The Influence of Oxygen Deficiency on NO Bioavailability
by Anna Janaszak-Jasiecka, Anna Siekierzycka, Agata Płoska, Iwona T. Dobrucki and Leszek Kalinowski
Biomolecules 2021, 11(7), 982; https://doi.org/10.3390/biom11070982 - 3 Jul 2021
Cited by 86 | Viewed by 7320
Abstract
Cardiovascular diseases (CVDs) are the leading cause of death worldwide. The initial stage of CVDs is characterized by endothelial dysfunction, defined as the limited bioavailability of nitric oxide (NO). Thus, any factors that interfere with the synthesis or metabolism of NO in endothelial [...] Read more.
Cardiovascular diseases (CVDs) are the leading cause of death worldwide. The initial stage of CVDs is characterized by endothelial dysfunction, defined as the limited bioavailability of nitric oxide (NO). Thus, any factors that interfere with the synthesis or metabolism of NO in endothelial cells are involved in CVD pathogenesis. It is well established that hypoxia is both the triggering factor as well as the accompanying factor in cardiovascular disease, and diminished tissue oxygen levels have been reported to influence endothelial NO bioavailability. In endothelial cells, NO is produced by endothelial nitric oxide synthase (eNOS) from L-Arg, with tetrahydrobiopterin (BH4) as an essential cofactor. Here, we discuss the mechanisms by which hypoxia affects NO bioavailability, including regulation of eNOS expression and activity. What is particularly important is the fact that hypoxia contributes to the depletion of cofactor BH4 and deficiency of substrate L-Arg, and thus elicits eNOS uncoupling—a state in which the enzyme produces superoxide instead of NO. eNOS uncoupling and the resulting oxidative stress is the major driver of endothelial dysfunction and atherogenesis. Moreover, hypoxia induces impairment in mitochondrial respiration and endothelial cell activation; thus, oxidative stress and inflammation, along with the hypoxic response, contribute to the development of endothelial dysfunction. Full article
(This article belongs to the Special Issue Hypoxia and Hypoxia-Inducible Factors in Human Endothelium)
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30 pages, 5094 KiB  
Review
Hypoxia as a Driving Force of Pluripotent Stem Cell Reprogramming and Differentiation to Endothelial Cells
by Paulina Podkalicka, Jacek Stępniewski, Olga Mucha, Neli Kachamakova-Trojanowska, Józef Dulak and Agnieszka Łoboda
Biomolecules 2020, 10(12), 1614; https://doi.org/10.3390/biom10121614 - 29 Nov 2020
Cited by 32 | Viewed by 6491
Abstract
Inadequate supply of oxygen (O2) is a hallmark of many diseases, in particular those related to the cardiovascular system. On the other hand, tissue hypoxia is an important factor regulating (normal) embryogenesis and differentiation of stem cells at the early stages [...] Read more.
Inadequate supply of oxygen (O2) is a hallmark of many diseases, in particular those related to the cardiovascular system. On the other hand, tissue hypoxia is an important factor regulating (normal) embryogenesis and differentiation of stem cells at the early stages of embryonic development. In culture, hypoxic conditions may facilitate the derivation of embryonic stem cells (ESCs) and the generation of induced pluripotent stem cells (iPSCs), which may serve as a valuable tool for disease modeling. Endothelial cells (ECs), multifunctional components of vascular structures, may be obtained from iPSCs and subsequently used in various (hypoxia-related) disease models to investigate vascular dysfunctions. Although iPSC-ECs demonstrated functionality in vitro and in vivo, ongoing studies are conducted to increase the efficiency of differentiation and to establish the most productive protocols for the application of patient-derived cells in clinics. In this review, we highlight recent discoveries on the role of hypoxia in the derivation of ESCs and the generation of iPSCs. We also summarize the existing protocols of hypoxia-driven differentiation of iPSCs toward ECs and discuss their possible applications in disease modeling and treatment of hypoxia-related disorders. Full article
(This article belongs to the Special Issue Hypoxia and Hypoxia-Inducible Factors in Human Endothelium)
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