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Molecular Mechanisms of Adaptation to Hypoxia

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 33475

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Dr. Elena Rybnikova

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Guest Editor

Pavlov Institute of Physiology, Russian Academy of Sciences, Saint Petersburg (ex Leningrad), Russia
Interests: hypoxia/ischemia; hypoxic tolerance of the brain; hypoxic signalling; neuroendocrine factors
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Prof. Dr. Ludmila D. Lukyanova

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Guest Editor

Institute of General Pathology and Pathophysiology, Baltijskaya Str. 8., 125315 Moscow, Russia
Interests: mitochondria; bioenergetics; hypoxia; adaptation; energy metabolism; succinate; HIF-1
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Impairment of the oxygen homeostasis of the body can result in the development of hypoxic/ischemic states, accompanied by multi-component multi-organ pathologies involving changes in a wide range of functional and metabolic systems. The regulation and correction of this complex process is possible through the increase of cellular and systemic resistance to oxygen insufficiency. Intensive study of the mechanisms contributing to the formation of hypoxic tolerance in cells and tissues is not only of great theoretical importance, but is also necessary to solve many problems of practical medicine. According to the modern concepts, the triggers and targets of hypoxic/ischemic states are molecular processes occurring at the cellular level. In the last two decades, significant advances have been made in their understanding; however, a number of important questions remain unresolved. For this Special Issue we would like to invite papers reporting new knowledge on the understudied questions. These include but are not limited to the following:

The mechanisms controlling and regulating the oxygen sensing of cells, their interactions, and their role in intracellular signaling in hypoxia;
The molecular mechanisms contributing to the formation of urgent and long-term cellular and systemic adaptation to hypoxia;
Variability of these processes depending on the characteristics of hypoxia (strength, duration, regime features);
Search for the optimal conditions for the induction of hypoxic tolerance;
Molecular approaches to elaborating the methods of anti-hypoxic protection which accelerate and facilitate the formation of urgent and long-term mechanisms of adaptation to oxygen deficiency.

Dr. Elena Rybnikova
Prof. Dr. Ludmila D. Lukyanova
Guest Editors

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Keywords

hypoxia\ischemia
hypoxic injury and tolerance
oxygen sensing
hypoxic signaling
hypoxia-inducible factors
HIF-1
mitochondria
succinate

Published Papers (12 papers)

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Editorial

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4 pages, 178 KiB

Open AccessEditorial

Molecular Mechanisms of Adaptation to Hypoxia

by Elena Rybnikova and Ludmila Lukyanova

Int. J. Mol. Sci. 2023, 24(5), 4563; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054563 - 26 Feb 2023

Viewed by 1120

Abstract

Oxygen is one of the most important elements, ensuring the vital activity of the body [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms of Adaptation to Hypoxia)

Research

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14 pages, 1552 KiB

Open AccessArticle

Vascular Reactions of the Diving Reflex in Men and Women Carrying Different ADRA1A Genotypes

by Tatyana Baranova, Ekaterina Podyacheva, Tatyana Zemlyanukhina, Dmitrii Berlov, Maria Danilova, Oleg Glotov and Andrey Glotov

Int. J. Mol. Sci. 2022, 23(16), 9433; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169433 - 21 Aug 2022

Cited by 2 | Viewed by 3287

Abstract

The diving reflex is an oxygen-saving mechanism which is accompanied by apnea, reflex bradycardia development, peripheral vasoconstriction, spleen erythrocyte release, and selective redistribution of blood flow to the organs most vulnerable to lack of oxygen, such as the brain, heart, and lungs. However, this is a poorly studied form of hypoxia, with a knowledge gap on physiological and biochemical adaptation mechanisms. The reflective sympathetic constriction of the resistive vessels is realized via ADRA1A. It has been shown that ADRA1A SNP (p.Arg347Cys; rs1048101) is associated with changes in tonus in vessel walls. Moreover, the Cys347 allele has been shown to regulate systolic blood pressure. The aim of this work was to evaluate whether the ADRA1A polymorphism affected the pulmonary vascular reactions in men and women in response to the diving reflex. Men (n = 52) and women (n = 50) untrained in diving aged 18 to 25 were recruited into the study. The vascular reactions and blood flow were examined by integrated rheography and rheography of the pulmonary artery. Peripheral blood circulation was registered by plethysmography. The ADRA1A gene polymorphism (p.Arg347Cys; rs1048101) was determined by PCR-RFLP. In both men and women, reflective pulmonary vasodilation did occur in response to the diving reflex, but in women this vasodilation was more pronounced and was accompanied by a higher filling of the lungs with blood.. Additionally, ADRA1A SNP (p.Arg347Cys; rs1048101) is associated with sex. Interestingly, women with the Arg347 allele demonstrated the highest vasodilation of the lung vessels. Therefore, our data may help to indicate women with the most prominent adaptive reactions to the diving reflex. Our data also indicate that women and men with the Cys allele of the ADRA1A gene polymorphism have the highest risk of developing lung hypertension in response to the diving reflex. The diving reflex is an oxygen-saving mechanism which is accompanied by apnea, reflex bradycardia development, peripheral vasoconstriction, spleen erythrocyte release, and selective redistribution of blood flow to the organs most vulnerable to lack of oxygen, such as the brain, heart, and lungs. However, this is a poorly studied form of hypoxia, with a knowledge gap on physiological and biochemical adaptation mechanisms. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Adaptation to Hypoxia)

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15 pages, 3077 KiB

Open AccessArticle

Analysis of the Hypoxic Response in a Mouse Cortical Collecting Duct-Derived Cell Line Suggests That Esrra Is Partially Involved in Hif1α-Mediated Hypoxia-Inducible Gene Expression in mCCD_cl1 Cells

by Anna Keppner, Darko Maric, Ilaria Maria Christina Orlando, Laurent Falquet, Edith Hummler and David Hoogewijs

Int. J. Mol. Sci. 2022, 23(13), 7262; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137262 - 30 Jun 2022

Cited by 3 | Viewed by 1868

Abstract

The kidney is strongly dependent on a continuous oxygen supply, and is conversely highly sensitive to hypoxia. Controlled oxygen gradients are essential for renal control of solutes and urine-concentrating mechanisms, which also depend on various hormones including aldosterone. The cortical collecting duct (CCD) is part of the aldosterone-sensitive distal nephron and possesses a key function in fine-tuned distal salt handling. It is well known that aldosterone is consistently decreased upon hypoxia. Furthermore, a recent study reported a hypoxia-dependent down-regulation of sodium currents within CCD cells. We thus investigated the possibility that cells from the cortical collecting duct are responsive to hypoxia, using the mouse cortical collecting duct cell line mCCD_cl1 as a model. By analyzing the hypoxia-dependent transcriptome of mCCD_cl1 cells, we found a large number of differentially-expressed genes (3086 in total logFC< −1 or >1) following 24 h of hypoxic conditions (0.2% O₂). A gene ontology analysis of the differentially-regulated pathways revealed a strong decrease in oxygen-linked processes such as ATP metabolic functions, oxidative phosphorylation, and cellular and aerobic respiration, while pathways associated with hypoxic responses were robustly increased. The most pronounced regulated genes were confirmed by RT-qPCR. The low expression levels of Epas1 under both normoxic and hypoxic conditions suggest that Hif-1α, rather than Hif-2α, mediates the hypoxic response in mCCD_cl1 cells. Accordingly, we generated shRNA-mediated Hif-1α knockdown cells and found Hif-1α to be responsible for the hypoxic induction of established hypoxically-induced genes. Interestingly, we could show that following shRNA-mediated knockdown of Esrra, Hif-1α protein levels were unaffected, but the gene expression levels of Egln3 and Serpine1 were significantly reduced, indicating that Esrra might contribute to the hypoxia-mediated expression of these and possibly other genes. Collectively, mCCD_cl1 cells display a broad response to hypoxia and represent an adequate cellular model to study additional factors regulating the response to hypoxia. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Adaptation to Hypoxia)

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15 pages, 6973 KiB

Open AccessArticle

Human Sarcopenic Myoblasts Can Be Rescued by Pharmacological Reactivation of HIF-1α

by Federica Cirillo, Laura Mangiavini, Paolo La Rocca, Marco Piccoli, Andrea Ghiroldi, Paola Rota, Adriana Tarantino, Barbara Canciani, Simona Coviello, Carmelo Messina, Giuseppe Ciconte, Carlo Pappone, Giuseppe Maria Peretti and Luigi Anastasia

Int. J. Mol. Sci. 2022, 23(13), 7114; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137114 - 26 Jun 2022

Cited by 4 | Viewed by 1811

Abstract

Sarcopenia, an age-related decline in muscle mass and strength, is associated with metabolic disease and increased risk of cardiovascular morbidity and mortality. It is associated with decreased tissue vascularization and muscle atrophy. In this work, we investigated the role of the hypoxia inducible factor HIF-1α in sarcopenia. To this end, we obtained skeletal muscle biopsies from elderly sarcopenic patients and compared them with those from young individuals. We found a decrease in the expression of HIF-1α and its target genes in sarcopenia, as well as of PAX7, the major stem cell marker of satellite cells, whereas the atrophy marker MURF1 was increased. We also isolated satellite cells from muscle biopsies and cultured them in vitro. We found that a pharmacological activation of HIF-1α and its target genes caused a reduction in skeletal muscle atrophy and activation of PAX7 gene expression. In conclusion, in this work we found that HIF-1α plays a role in sarcopenia and is involved in satellite cell homeostasis. These results support further studies to test whether pharmacological reactivation of HIF-1α could prevent and counteract sarcopenia. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Adaptation to Hypoxia)

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19 pages, 5780 KiB

Open AccessArticle

Functional RNA Dynamics Are Progressively Governed by RNA Destabilization during the Adaptation to Chronic Hypoxia

by Rebekka Bauer, Sofie Patrizia Meyer, Karolina Anna Kloss, Vanesa Maria Guerrero Ruiz, Samira Reuscher, You Zhou, Dominik Christian Fuhrmann, Kathi Zarnack, Tobias Schmid and Bernhard Brüne

Int. J. Mol. Sci. 2022, 23(10), 5824; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105824 - 22 May 2022

Cited by 2 | Viewed by 2439

Abstract

Previous studies towards reduced oxygen availability have mostly focused on changes in total mRNA expression, neglecting underlying transcriptional and post-transcriptional events. Therefore, we generated a comprehensive overview of hypoxia-induced changes in total mRNA expression, global de novo transcription, and mRNA stability in monocytic THP-1 cells. Since hypoxic episodes often persist for prolonged periods, we further compared the adaptation to acute and chronic hypoxia. While total mRNA changes correlated well with enhanced transcription during short-term hypoxia, mRNA destabilization gained importance under chronic conditions. Reduced mRNA stability not only added to a compensatory attenuation of immune responses, but also, most notably, to the reduction in nuclear-encoded mRNAs associated with various mitochondrial functions. These changes may prevent the futile production of new mitochondria under conditions where mitochondria cannot exert their full metabolic function and are indeed actively removed by mitophagy. The post-transcriptional mode of regulation might further allow for the rapid recovery of mitochondrial capacities upon reoxygenation. Our results provide a comprehensive resource of functional mRNA expression dynamics and underlying transcriptional and post-transcriptional regulatory principles during the adaptation to hypoxia. Furthermore, we uncover that RNA stability regulation controls mitochondrial functions in the context of hypoxia. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Adaptation to Hypoxia)

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13 pages, 2409 KiB

Open AccessArticle

From Tissue Physoxia to Cancer Hypoxia, Cost-Effective Methods to Study Tissue-Specific O₂ Levels in Cellular Biology

by Carlos H. V. Nascimento-Filho, Alexandra T. Glinos, Yeejin Jang, Eny M. Goloni-Bertollo, Rogerio M. Castilho and Cristiane H. Squarize

Int. J. Mol. Sci. 2022, 23(10), 5633; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105633 - 18 May 2022

Cited by 3 | Viewed by 1992

Abstract

The human body is endowed with an extraordinary ability to maintain different oxygen levels in various tissues and organs. The maintenance of physiological levels of oxygen is known as physoxia. The development of hypoxic conditions plays an important role in the biology of several pathologies, including cancer. In vitro studies using normal and neoplastic cells require that culture conditions be carried out under appropriate oxygen levels, either physoxic or hypoxic conditions. Such requirements are difficult to widely implement in laboratory practice, mainly due to the high costs of specialized equipment. In this work, we present and characterize a cost-effective method to culture cells under a range of oxygen levels using deoxidizing pouches. Our results show that physoxic and hypoxic levels using deoxidizing absorbers can be achieved either by implementing a gradual change in oxygen levels or by a regimen of acute depletion of oxygen. This approach triggers the activation of an epithelial-mesenchymal transition in cancer cells while stimulating the expression of HIF-1α. Culturing cancer cells with deoxidizing agent pouches revealed PI3K oncogenic pathway exacerbations compared to tumor cells growing under atmospheric levels of oxygen. Similar to the PI3K signaling disturbance, we also observed augmented oxidative stress and superoxide levels and increased cell cycle arrest. Most interestingly, the culture of cancer cells under hypoxia resulted in the accumulation of cancer stem cells in a time-dependent manner. Overall, we present an attractive, cost-effective method of culturing cells under appropriate physoxic or hypoxic conditions that is easily implementable in any wet laboratory equipped with cell culture tools. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Adaptation to Hypoxia)

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20 pages, 4595 KiB

Open AccessArticle

Hypoxia Differently Affects TGF-β2-Induced Epithelial Mesenchymal Transitions in the 2D and 3D Culture of the Human Retinal Pigment Epithelium Cells

by Soma Suzuki, Tatsuya Sato, Megumi Watanabe, Megumi Higashide, Yuri Tsugeno, Araya Umetsu, Masato Furuhashi, Yosuke Ida, Fumihito Hikage and Hiroshi Ohguro

Int. J. Mol. Sci. 2022, 23(10), 5473; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105473 - 13 May 2022

Cited by 8 | Viewed by 1535

Abstract

The hypoxia associated with the transforming growth factor-β2 (TGF-β2)-induced epithelial mesenchymal transition (EMT) of human retinal pigment epithelium (HRPE) cells is well recognized as the essential underlying mechanism responsible for the development of proliferative retinal diseases. In vitro, three-dimensional (3D) models associated with spontaneous O₂ gradients can be used to recapitulate the pathological levels of hypoxia to study the effect of hypoxia on the TGF-β2-induced EMT of HRPE cells in detail, we used two-dimensional-(2D) and 3D-cultured HRPE cells. TGF-β2 and hypoxia significantly and synergistically increased the barrier function of the 2D HRPE monolayers, as evidenced by TEER measurements, the downsizing and stiffening of the 3D HRPE spheroids and the mRNA expression of most of the ECM proteins. A real-time metabolic analysis indicated that TGF-β2 caused a decrease in the maximal capacity of mitochondrial oxidative phosphorylation in the 2D HRPE cells, whereas, in the case of 3D HRPE spheroids, TGF-β2 increased proton leakage. The findings reported herein indicate that the TGF-β2-induced EMT of both the 2D and 3D cultured HRPE cells were greatly modified by hypoxia, but during these EMT processes, the metabolic plasticity was different between 2D and 3D HRPE cells, suggesting that the mechanisms responsible for the EMT of the HRPE cells may be variable during their spatial spreading. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Adaptation to Hypoxia)

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18 pages, 3100 KiB

Open AccessArticle

Chronic Intermittent Hypoxia Exposure Alternative to Exercise Alleviates High-Fat-Diet-Induced Obesity and Fatty Liver

by Yunfei Luo, Qiongfeng Chen, Junrong Zou, Jingjing Fan, Yuanjun Li and Zhijun Luo

Int. J. Mol. Sci. 2022, 23(9), 5209; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095209 - 06 May 2022

Cited by 8 | Viewed by 3050

Abstract

Obesity often concurs with nonalcoholic fatty liver disease (NAFLD), both of which are detrimental to human health. Thus far, exercise appears to be an effective treatment approach. However, its effects cannot last long and, moreover, it is difficult to achieve for many obese people. Thus, it is necessary to look into alternative remedies. The present study explored a noninvasive, easy, tolerable physical alternative. In our experiment, C57BL/6 mice were fed with a high-fat diet (HFD) to induce overweight/obesity and were exposed to 10% oxygen for one hour every day. We found that hypoxia exerted protective effects. First, it offset HFD-induced bodyweight gain and insulin resistance. Secondly, hypoxia reversed the HFD-induced enlargement of white and brown adipocytes and fatty liver, and protected liver function. Thirdly, HFD downregulated the expression of genes required for lipolysis and thermogenesis, such as UCP1, ADR3(beta3-adrenergic receptor), CPT1A, ATGL, PPARα, and PGC1α, M2 macrophage markers arginase and CD206 in the liver, and UCP1 and PPARγ in brown fat, while these molecules were upregulated by hypoxia. Furthermore, hypoxia induced the activation of AMPK, an energy sensing enzyme. Fourthly, our results showed that hypoxia increased serum levels of epinephrine. Indeed, the effects of hypoxia on bodyweight, fatty liver, and associated changes in gene expression ever tested were reproduced by injection of epinephrine and prevented by propranolol at varying degrees. Altogether, our data suggest that hypoxia triggers stress responses where epinephrine plays important roles. Therefore, our study sheds light on the hope to use hypoxia to treat the daunting disorders, obesity and NAFLD. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Adaptation to Hypoxia)

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Review

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19 pages, 905 KiB

Open AccessReview

Adaptation to Hypoxia May Promote Therapeutic Resistance to Androgen Receptor Inhibition in Triple-Negative Breast Cancer

by Nikita Jinna, Padmashree Rida, Max Smart, Mark LaBarge, Tijana Jovanovic-Talisman, Rama Natarajan and Victoria Seewaldt

Int. J. Mol. Sci. 2022, 23(16), 8844; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23168844 - 09 Aug 2022

Cited by 4 | Viewed by 2714

Abstract

Triple-negative breast cancer (TNBC) surpasses other BC subtypes as the most challenging to treat due to its lack of traditional BC biomarkers. Nearly 30% of TNBC patients express the androgen receptor (AR), and the blockade of androgen production and AR signaling have been the cornerstones of therapies for AR-positive TNBC. However, the majority of women are resistant to AR-targeted therapy, which is a major impediment to improving outcomes for the AR-positive TNBC subpopulation. The hypoxia signaling cascade is frequently activated in the tumor microenvironment in response to low oxygen levels; activation of the hypoxia signaling cascade allows tumors to survive despite hypoxia-mediated interference with cellular metabolism. The activation of hypoxia signaling networks in TNBC promotes resistance to most anticancer drugs including AR inhibitors. The activation of hypoxia network signaling occurs more frequently in TNBC compared to other BC subtypes. Herein, we examine the (1) interplay between hypoxia signaling networks and AR and (2) whether hypoxia and hypoxic stress adaptive pathways promote the emergence of resistance to therapies that target AR. We also pose the well-supported question, “Can the efficacy of androgen-/AR-targeted treatments be enhanced by co-targeting hypoxia?” By critically examining the evidence and the complex entwinement of these two oncogenic pathways, we argue that the simultaneous targeting of androgen biosynthesis/AR signaling and hypoxia may enhance the sensitivity of AR-positive TNBCs to AR-targeted treatments, derail the emergence of therapy resistance, and improve patient outcomes. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Adaptation to Hypoxia)

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16 pages, 1059 KiB

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Ferroptosis: A Promising Therapeutic Target for Neonatal Hypoxic-Ischemic Brain Injury

by Eric S. Peeples and Thiago C. Genaro-Mattos

Int. J. Mol. Sci. 2022, 23(13), 7420; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137420 - 04 Jul 2022

Cited by 17 | Viewed by 3213

Abstract

Ferroptosis is a type of programmed cell death caused by phospholipid peroxidation that has been implicated as a mechanism in several diseases resulting from ischemic-reperfusion injury. Most recently, ferroptosis has been identified as a possible key injury mechanism in neonatal hypoxic-ischemic brain injury (HIBI). This review summarizes the current literature regarding the different ferroptotic pathways, how they may be activated after neonatal HIBI, and which current or investigative interventions may attenuate ferroptotic cell death associated with neonatal HIBI. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Adaptation to Hypoxia)

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16 pages, 1649 KiB

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Impact of Zinc on Oxidative Signaling Pathways in the Development of Pulmonary Vasoconstriction Induced by Hypobaric Hypoxia

by Karem Arriaza, Constanza Cuevas, Eduardo Pena, Patricia Siques and Julio Brito

Int. J. Mol. Sci. 2022, 23(13), 6974; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23136974 - 23 Jun 2022

Cited by 4 | Viewed by 2509

Abstract

Hypobaric hypoxia is a condition that occurs at high altitudes (>2500 m) where the partial pressure of gases, particularly oxygen (PO₂), decreases. This condition triggers several physiological and molecular responses. One of the principal responses is pulmonary vascular contraction, which seeks to optimize gas exchange under this condition, known as hypoxic pulmonary vasoconstriction (HPV); however, when this physiological response is exacerbated, it contributes to the development of high-altitude pulmonary hypertension (HAPH). Increased levels of zinc (Zn²⁺) and oxidative stress (known as the “ROS hypothesis”) have been demonstrated in the vasoconstriction process. Therefore, the aim of this review is to determine the relationship between molecular pathways associated with altered Zn²⁺ levels and oxidative stress in HPV in hypobaric hypoxic conditions. The results indicate an increased level of Zn²⁺, which is related to increasing mitochondrial ROS (mtROS), alterations in nitric oxide (NO), metallothionein (MT), zinc-regulated, iron-regulated transporter-like protein (ZIP), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-induced protein kinase C epsilon (PKCε) activation in the development of HPV. In conclusion, there is an association between elevated Zn²⁺ levels and oxidative stress in HPV under different models of hypoxia, which contribute to understanding the molecular mechanism involved in HPV to prevent the development of HAPH. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Adaptation to Hypoxia)

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30 pages, 1123 KiB

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Prenatal Hypoxia Affects Foetal Cardiovascular Regulatory Mechanisms in a Sex- and Circadian-Dependent Manner: A Review

by Hana Sutovska, Katarina Babarikova, Michal Zeman and Lubos Molcan

Int. J. Mol. Sci. 2022, 23(5), 2885; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052885 - 07 Mar 2022

Cited by 11 | Viewed by 5765

Abstract

Prenatal hypoxia during the prenatal period can interfere with the developmental trajectory and lead to developing hypertension in adulthood. Prenatal hypoxia is often associated with intrauterine growth restriction that interferes with metabolism and can lead to multilevel changes. Therefore, we analysed the effects of prenatal hypoxia predominantly not associated with intrauterine growth restriction using publications up to September 2021. We focused on: (1) The response of cardiovascular regulatory mechanisms, such as the chemoreflex, adenosine, nitric oxide, and angiotensin II on prenatal hypoxia. (2) The role of the placenta in causing and attenuating the effects of hypoxia. (3) Environmental conditions and the mother’s health contribution to the development of prenatal hypoxia. (4) The sex-dependent effects of prenatal hypoxia on cardiovascular regulatory mechanisms and the connection between hypoxia-inducible factors and circadian variability. We identified that the possible relationship between the effects of prenatal hypoxia on the cardiovascular regulatory mechanism may vary depending on circadian variability and phase of the days. In summary, even short-term prenatal hypoxia significantly affects cardiovascular regulatory mechanisms and programs hypertension in adulthood, while prenatal programming effects are not only dependent on the critical period, and sensitivity can change within circadian oscillations. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Adaptation to Hypoxia)

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