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Oxygen sensing is of paramount importance for maintaining cellular and systemic homeostasis. In response to diminished oxygen levels, the hypoxia-inducible factors (HIFs) orchestrate various biological processes. These pivotal transcription factors have been identified as key regulators of several biological events. Notably, extensive research from our group and others has demonstrated that HIF1α exerts an inverse regulatory effect on steroidogenesis, leading to the suppression of crucial steroidogenic enzyme expression and a subsequent decrease in steroid levels. These steroid hormones occupy pivotal roles in governing a myriad of physiological processes. Substantial or prolonged fluctuations in steroid levels carry detrimental consequences across multiple organ systems and underlie various pathological conditions, including metabolic and immune disorders. MicroRNAs serve as potent mediators of multifaceted gene regulatory mechanisms, acting as influential epigenetic regulators that modulate a broad spectrum of gene expressions. Concomitantly, phosphodiesterases (PDEs) play a crucial role in governing signal transduction. PDEs meticulously manage intracellular levels of both cAMP and cGMP, along with their respective signaling pathways and downstream targets. Intriguingly, an intricate interplay seems to exist between hypoxia signaling, microRNAs, and PDEs in the regulation of steroidogenesis. This review highlights recent advances in our understanding of the role of microRNAs during hypoxia-driven processes, including steroidogenesis, as well as the possibilities that exist in the application of HIF prolyl hydroxylase (PHD) inhibitors for the modulation of steroidogenesis. [ABSTRACT FROM AUTHOR]

Embryonic neurogenesis can be defined as a period of prenatal development during which divisions of neural stem and progenitor cells give rise to neurons. In the central nervous system of most mammals, including humans, the majority of neocortical neurogenesis occurs before birth. It is a highly spatiotemporally organized process whose perturbations lead to cortical malformations and dysfunctions underlying neurological and psychiatric pathologies, and in which oxygen availability plays a critical role. In case of deprived oxygen conditions, known as hypoxia, the hypoxia-inducible factor (HIF) signaling pathway is activated, resulting in the selective expression of a group of genes that regulate homeostatic adaptations, including cell differentiation and survival, metabolism and angiogenesis. While a physiological degree of hypoxia is essential for proper brain development, imbalanced oxygen levels can adversely affect this process, as observed in common obstetrical pathologies such as prematurity. This review comprehensively explores and discusses the current body of knowledge regarding the role of hypoxia and the HIF pathway in embryonic neurogenesis of the mammalian cortex. Additionally, it highlights existing gaps in our understanding, presents unanswered questions, and provides avenues for future research. [ABSTRACT FROM AUTHOR]

Endogenous steroid hormones, especially glucocorticoids and mineralocorticoids, derive from the adrenal cortex, and drastic or sustained changes in their circulatory levels affect multiple organ systems. Although hypoxia signaling in steroidogenesis has been suggested, knowledge on the true impact of the HIFs (Hypoxia-Inducible Factors) in the adrenocortical cells of vertebrates is scant. By creating a unique set of transgenic mouse lines, we reveal a prominent role for HIF1α in the synthesis of virtually all steroids in vivo. Specifically, mice deficient in HIF1α in adrenocortical cells displayed enhanced levels of enzymes responsible for steroidogenesis and a cognate increase in circulatory steroid levels. These changes resulted in cytokine alterations and changes in the profile of circulatory mature hematopoietic cells. Conversely, HIF1α overexpression resulted in the opposite phenotype of insufficient steroid production due to impaired transcription of necessary enzymes. Based on these results, we propose HIF1α to be a vital regulator of steroidogenesis as its modulation in adrenocortical cells dramatically impacts hormone synthesis with systemic consequences. In addition, these mice can have potential clinical significances as they may serve as essential tools to understand the pathophysiology of hormone modulations in a number of diseases associated with metabolic syndrome, auto-immunity or even cancer. [ABSTRACT FROM AUTHOR]

Skin wound healing in mammals is a complex, multicellular process that depends on the precise supply of oxygen. Hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2) serves as a crucial oxygen sensor and may therefore play an important role during reepithelialization. Hence, this study was aimed at understanding the role of PHD2 in cutaneous wound healing using different lines of conditionally deficient mice specifically lacking PHD2 in inflammatory, vascular, or epidermal cells. Interestingly, PHD2 deficiency only in keratinocytes and not in myeloid or endothelial cells was found to lead to faster wound closure, which involved enhanced migration of the hyperproliferating epithelium. We demonstrate that this effect relies on the unique expression of β3-integrin in the keratinocytes around the tip of the migrating tongue in an HIF 1α-dependent manner. Furthermore, we show enhanced proliferation of these cells in the stratum basale, which is directly related to their attenuated transforming growth factor β signaling. Thus, loss of the central oxygen sensor PHD2 in keratinocytes stimulates wound closure by prompting skin epithelial cells to migrate and proliferate. Inhibition of PHD2 could therefore offer novel therapeutic opportunities for the local treatment of cutaneous wounds. [ABSTRACT FROM AUTHOR]

Erythropoiesis is a complex process driving the production of red blood cells. During homeostasis, adult erythropoiesis takes place in the bone marrow and is tightly controlled by erythropoietin (EPO), a central hormone mainly produced in renal EPO-producing cells. The expression of EPO is strictly regulated by local changes in oxygen partial pressure (pO2) as under-deprived oxygen (hypoxia); the transcription factor hypoxia-inducible factor-2 induces EPO. However, erythropoiesis regulation extends beyond the well-established hypoxia-inducible factor (HIF)–EPO axis and involves processes modulated by other hypoxia pathway proteins (HPPs), including proteins involved in iron metabolism. The importance of a number of these factors is evident as their altered expression has been associated with various anemia-related disorders, including chronic kidney disease. Eventually, our emerging understanding of HPPs and their regulatory feedback will be instrumental in developing specific therapies for anemic patients and beyond. [ABSTRACT FROM AUTHOR]

The regulation of oxygen (O2) levels is crucial in embryogenesis and adult life, as O2 controls a multitude of key cellular functions. Low oxygen levels (hypoxia) are relevant for tissue physiology as they are integral to adequate metabolism regulation and cell fate. Hence, the hypoxia response is of utmost importance for cell, organ and organism function and is dependent on the hypoxia-inducible factor (HIF) pathway. HIF pathway activity is strictly regulated by the family of oxygen-sensitive HIF prolyl hydroxylase domain (PHD) proteins. Physiologic hypoxia is a hallmark of the hematopoietic stem cell (HSC) niche in the bone marrow. This niche facilitates HSC quiescence and survival. The present review focuses on current knowledge and the many open questions regarding the impact of PHDs/HIFs and other proteins of the hypoxia pathway on the HSC niche and on normal and malignant hematopoiesis. [ABSTRACT FROM AUTHOR]

The key players of the hypoxic response are the hypoxia-inducible factors (Hif), whose α-subunits are tightly regulated by Prolyl-4-hydroxylases (PHD), predominantly by PHD2. Monocytes/Macrophages are involved in atherosclerosis but also restenosis and were found at hypoxic and sites of the lesion. Little is known about the role of the myeloid PHD2 in atherosclerosis and neointima formation. The study aimed to investigate the consequences of a myeloid deficiency of PHD2 in the process of neointima formation using an arterial denudation model. LysM-cre mice were crossed with PHD2fl/fl, PHD2fl/fl/Hif1αfl/fl and PHD2fl/fl/Hif2αfl/fl to get myeloid specific knockout of PHD2 and the Hif-α subunits. Denudation of the femoral artery was performed and animals were fed a western type diet afterwards with analysis of neointima formation 5 and 35 days after denudation. Increased neointima formation in myeloid PHD2 knockouts was observed, which was blunted by double-knockout of PHD2 and Hif1α whereas double knockout of PHD2 and Hif-2α showed comparable lesions to the PHD2 knockouts. Macrophage infiltration was comparable to the neointima formation, suggesting a more inflammatory reaction, and was accompanied by increased intimal VEGF-A expression. Collagen-content inversely correlated to the extent of neointima formation suggesting a destabilization of the plaque. This effect might be triggered by macrophage polarization. Therefore, in vitro results showed a distinct expression pattern in differentially polarized macrophages with high expression of Hif-1α, VEGF and MMP-1 in proinflammatory M1 macrophages. In conclusion, the results show that myeloid Hif-1α is involved in neointima hyperplasia. Our in vivo and in vitro data reveal a central role for this transcription factor in driving plaque-vascularization accompanied by matrix-degradation leading to plaque destabilization. • Myeloid knockout of PHD2 increases neointima formation after denudation. • Myeloid PHD2/Hif1α knockout reverses the proatherogenic effect of PHD2. • Myeloid PHD2 knockout lead to increased macrophage plaque content. • Macrophage content inversely correlates with collagen content. • Macrophage polarization modulates Hif-α and target gene expression. [ABSTRACT FROM AUTHOR]

AbstractSingh, Rashim Pal, Kristin Franke, and Ben Wielockx, Hypoxia-mediated regulation of stem cell fate. High Alt Med Biol.13:162–168, 2012.—Hypoxia-mediated regulation of stem cell fate, or reduced oxygen availability, is a prominent feature during mammalian development and under physiological and pathological conditions in adults. Oxygen-sensing is therefore indispensable as it enables the cells to adapt instantaneously to an inappropriate pO2. This machinery relies primarily on hypoxia inducible factor (HIF). Moreover, a growing body of evidence proposes that different types of stem cells exist in a very hypoxic microenvironment, which may be beneficial for the maintenance of these cells and ensures continuous replenishment of dead or damaged cells in virtually all tissues of the body. Recent reports have shown that HIF is a critical player in these responses. However, a better understanding of the different HIF-related mechanisms is of utmost importance for the improvement of therapeutic strategies for tissue regeneration as well as hematological malignancies. [ABSTRACT FROM AUTHOR]

Hypoxia is a prominent feature in the maintenance of hematopoietic stem cell (HSC) quiescence and multipotency. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain proteins (PHDs) serve as oxygen sensors and may therefore regulate this system. Here, we describe a mouse line with conditional loss of HIF prolyl hydroxylase 2 (PHD2) in very early hematopoietic precursors that results in self-renewal of multipotent progenitors under steady-state conditions in a HlFlα- and SMAD7-dependent manner. Competitive bone marrow (BM) transplantations show decreased peripheral and central chimerism of PHD2-deficient cells but not of the most primitive progenitors. Conversely, in whole BM transfer, PHD2-deficient HSCs replenish the entire hematopoietic system and display an enhanced self-renewal capacity reliant on HIF1α. Taken together, our results demonstrate that loss of PHD2 controls the maintenance of the HSC compartment under physiological conditions and causes the outcompetition of PHD2-deficient hematopoietic cells by their wild-type counterparts during stress while promoting the self-renewal of very early hematopoletic progenitors. [ABSTRACT FROM AUTHOR]