Detrimental Roles of Hypoxia-Inducible Factor-1α in Severe Hypoxic Brain Diseases

Hypoxia stabilizes hypoxia-inducible factors (HIFs), facilitating adaptation to hypoxic conditions. Appropriate hypoxia is pivotal for neurovascular regeneration and immune cell mobilization. However, in central nervous system (CNS) injury, prolonged and severe hypoxia harms the brain by triggering neurovascular inflammation, oxidative stress, glial activation, vascular damage, mitochondrial dysfunction, and cell death. Diminished hypoxia in the brain improves cognitive function in individuals with CNS injuries. This review discusses the current evidence regarding the contribution of severe hypoxia to CNS injuries, with an emphasis on HIF-1α-mediated pathways. During severe hypoxia in the CNS, HIF-1α facilitates inflammasome formation, mitochondrial dysfunction, and cell death. This review presents the molecular mechanisms by which HIF-1α is involved in the pathogenesis of CNS injuries, such as stroke, traumatic brain injury, and Alzheimer’s disease. Deciphering the molecular mechanisms of HIF-1α will contribute to the development of therapeutic strategies for severe hypoxic brain diseases.


Introduction
Severe hypoxia affects the central nervous system (CNS) by triggering neurovascular inflammation, oxidative stress, glial activation, impaired mitochondrial function, and cell death [1].High O 2 therapy can elevate cerebral blood flow and improve cognitive behavioral performance by diminishing hypoxia involved in the pathogenesis of Alzheimer's disease (AD) [2,3].Hypoxia-inducible factors (HIF1-3) regulate transcriptional responses to reduce O 2 availability [4].HIFs are heterodimeric proteins that are composed of an O 2 -regulated HIF-α subunit and a constitutively expressed HIF-1β subunit.HIF-α subunits are subject to prolyl hydroxylation, which targets proteins for degradation under normoxic conditions [5,6].Two HIF-α proteins, HIF-1α and HIF-2α, are stabilized under low O 2 tension and dimerize with HIF-1β.Heterodimeric proteins bind to hypoxia-responsive elements in multiple target genes and regulate their transcription to facilitate adaptation to hypoxia [7].
Figure 1.The roles of hypoxia-inducible factor (HIF)-1α in different oxygen tension conditions in the central nervous system (CNS).In severe hypoxic regions of the brain, HIF-1α can induce sustained inflammation and mitochondrial dysfunction, consequently leading to cell death in the form of apoptosis, pyroptosis, and ferroptosis.HIF-1α stabilization during mild hypoxia may enhance cell regeneration (i.e., angiogenesis and neurogenesis), mitochondrial biogenesis, and cell survival in the brain.During normoxia, HIF-1α can be degraded in the CNS.

Role of HIF in Cell Damage
Several cell death pathways are associated with severe hypoxia.This section discusses the roles of HIF-1α in types of cell death in the CNS.

Apoptosis
Apoptosis refers to the process of programmed cell death, characterized by the orchestrated collapse of a cell, with membrane blebbing, cell shrinkage, chromatin condensation, and DNA fragmentation [32].While many reports have demonstrated the protective effects of HIF-1α on metabolic adaptation during mild hypoxia, activation of the HIF-1α signaling pathway during severe hypoxia is associated with cell death [15].Genetic neuronal HIF-1α and HIF-2α deficiencies triggered neuronal survival and sensorimotor function in an ischemic stroke model [8].BCL-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3), a downstream target gene of HIF-1α, is involved in apoptosis [15,33].HIF-1 is linked to oxidative stress-induced Aβ accumulation and subsequent activation of the pro-death gene BNIP3 in primary cortical neurons [34].In TBI, HIF-1α mediates tumor Narrowing or blockage of arteries can induce ischemic stroke, leading to reactive oxygen species (ROS)-mediated death of neurons, endothelial cells, and glia including oligodendrocytes [23,24].TBI is an acquired brain injury caused by a mechanical impact on the head [25].Individuals with severe ischemia or trauma are more susceptible to the development of AD [26,27].Some cases of dementia may arise from cerebral hypoperfusion after ischemic injury due to decreased beta-amyloid (Aβ) clearance or catabolism [26][27][28].A significant increase in microglia-specific thromboxane A synthase 1 was observed in the human AD brain [29].Notably, thromboxane A is a potent vasoconstrictor in the cerebral circulation and is also a target for the secondary prevention of stroke [30].Therefore, hypoxia-related diseases may share similar pathological pathways.
This review discusses the current evidence regarding the contribution of severe hypoxia to CNS injuries, with an emphasis on HIF-1α-mediated pathways.Understanding the role of these pathways in severe hypoxic CNS injuries, such as ischemic stroke, TBI, and AD, will provide clues for therapeutic strategies.HIF-1α-mediated pathways include neurovascular inflammation, oxidative stress, glial activation, vascular damage, mitochondrial dysfunction, and cell death (Figure 1) [1,14,22,31].This review describes the important actions of HIF-1α in severe hypoxic CNS injuries and their potential pathogenetic mechanisms.

Role of HIF in Cell Damage
Several cell death pathways are associated with severe hypoxia.This section discusses the roles of HIF-1α in types of cell death in the CNS.

Apoptosis
Apoptosis refers to the process of programmed cell death, characterized by the orchestrated collapse of a cell, with membrane blebbing, cell shrinkage, chromatin condensation, and DNA fragmentation [32].While many reports have demonstrated the protective effects of HIF-1α on metabolic adaptation during mild hypoxia, activation of the HIF-1α signaling pathway during severe hypoxia is associated with cell death [15].Genetic neuronal HIF-1α and HIF-2α deficiencies triggered neuronal survival and sensorimotor function in an ischemic stroke model [8].BCL-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3), a downstream target gene of HIF-1α, is involved in apoptosis [15,33].HIF-1 is linked to oxidative stress-induced Aβ accumulation and subsequent activation of the pro-death gene BNIP3 in primary cortical neurons [34].In TBI, HIF-1α mediates tumor necrosis factor (TNF)-related apoptosis, inducing ligand-induced neuronal apoptosis [35].Pericyte cell death is related to HIF-1α-mediated caspase 3 activation during TBI [9].

Ferroptosis
Ferroptosis is an iron-dependent form of cell death that results from increased ROS and lipid peroxidation in the plasma and mitochondrial membranes [42].The Fenton reaction involves the production of ROS from the reaction between H 2 O 2 and ferrous iron (Fe 2+ ), which can trigger lipid peroxidation.HIF-1α plays a role in CNS ferroptosis.During hypoxia, HIF-1α upregulates heme oxygenase-1 (HO-1, encoded by HMOX1) gene expression [43,44].HO-1 resides within the endoplasmic reticulum, and its sustained expression in glial fibrillary acidic protein (GFAP)-expressing astrocytes exacerbates AD development [44].Transgenic mice exhibiting prolonged expression of HO-1 in astrocytes (GFAP.HMOX1 transgenic) acquire abnormal iron deposition in the mitochondria of astrocytes located in the striatum as well as neuronal deficiency and reduced cognitive ability [45][46][47][48].When GFAP.HMOX1 transgenic mice-derived astrocytes and neurons are co-cultured, active caspase-3 (an apoptotic factor) is increased in transgenic-derived neurons compared with wild-type preparations [48].These studies suggest that overexpression of HO-1 in astrocytes may give rise to neuronal dysfunction.
BNIP3 can act as the upstream regulator of the HIF-1α-mediated glycolytic program [55].In melanoma cells, BNIP3 deficiency results in increased intracellular iron levels caused by heightened nuclear receptor coactivator 4 (NCOA4)-mediated autophagic degradation of ferritin (ferritinophagy), which facilitates HIF-1α degradation [55].NCOA4 is a selective cargo receptor that mediates autophagic degradation of ferritin, a cytosolic iron-storage complex [56].Under autophagy-disrupting conditions, NCOA4 may be unable to target ferritin for lysosomal degradation, resulting in the accumulation of free iron [57].Both HIF-1α and HIF-2α upregulate NCOA4 expression in hepatic cells treated with the iron chelator deferoxamine [58].Taken together, HIF-1α may upregulate iron produc-tion and mitochondrial accumulation via HO-1.Additionally, HIF-α may be involved in ferritinophagy through the NCOA4-mediated pathway.

Role of HIF in Stroke, with a Focus on Inflammasomes
Higher HIF-1α levels have been significantly correlated with the initial stroke scale score, indicating a worse outcome [13].Necrosis is an accidental cell death that results in the uncontrolled release of inflammatory cellular contents [74].Necroptosis mimics features of both apoptosis and necrosis.Necroptosis requires related proteins, such as receptor-interacting protein kinase-3 (RIPK3) and the effector mixed lineage kinase domainlike protein (MLKL) [75].HIF-1α also regulates necroptosis-related proteins, such as RIPK3 and MLKL, in ischemic stroke [75].Enhanced HIF-1α levels after ischemic stroke appear to be involved in RIPK3/MLKL activation, leading to activation of the NLRP3 inflammasome [75].HIF-1α induces NLRP3 inflammasome-dependent pyroptotic and apoptotic cell death following ischemic stroke in adult rats [76].Treatment with an HIF-1α inhibitor reduces macrophage and neutrophil infiltration in the ipsilateral brain [76].
In a mouse model of cerebral ischemia, AIM2 and NLRC4 inflammasomes, along with ASC, contributed to the development of acute brain injury [61].Chronic cerebral hypoperfusion activates and upregulates the AIM2 and NLRP3 inflammasomes [80].The expression of NLRP3 and AIM2 is upregulated in glial cells in the brains of patients with cerebral infarction in the chronic phase, suggesting that chronic cerebral hypoperfusion induces inflammasomes [80].

Role of HIF in TBI, with a Focus on Inflammasomes
HIF-1α aggravates TBI via NLRP3-inflammasome-mediated pyroptosis and microglial activation by 3 days after TBI [22].NLRP3 is mainly expressed in microglia and has also been detected in endothelial cells, astrocytes, and oligodendrocytes [81,82].Administration of an HIF-1α inhibitor to TBI model mice reduces TBI-mediated NLRP3 protein levels and blood-brain barrier (BBB) breakdown, showing improvement of behavioral functions [22].In the TBI brain, the levels of NLRP1, NLRP3, NLRC4, and AIM2 were found to be increased in microvascular endothelial cells [82].Administration of a caspase-1 inhibitor after TBI decreases pyroptosis, as evidenced by decreased cleaved gasdermin D and IL-1β levels, and alleviates TBI-induced BBB leakage without affecting the expression of NLRP1, NLRP3, NLRC4, and AIM2 [82].Compared to wild-type mice, cortical samples of Nlrp1 − and Asc −/− mice that had been subjected to TBI showed reduced levels of proinflammatory cytokines, such as IL-1β and IL-6 [83].However, motor deficits did not change in Nlrp1 −/− and Asc −/− mice as compared to wild-type mice after TBI [83].Further studies revealing the relationship between inflammasome blockade and the improvement in behavioral function after TBI are required.

Role of HIF in AD, Focusing on Inflammasomes
Hypoxia facilitated plaque formation in an AD transgenic mouse model, leading to memory deficits [84].Various pathogenic mechanisms of AD have been considered, including chronic hypoxia, amyloid precursor protein (APP) expression, Aβ aggregation, and hyperphosphorylated tau protein accumulation [1,2,85].Chronic hypoxia-mediated HIF-1α may upregulate the activity of β-site APP-cleaving enzyme 1, facilitate the β-cleavage of APP, increase Aβ deposition, and potentiate memory deficits in APP23 transgenic AD mice [1,84,86].In addition, HIF-1α binds to the γ-secretase subunit gene promoter and subsequently induces γ-secretase-mediated Aβ production during hypoxia [87].NLRP1 and NLRP3 are more greatly activated in monocytes obtained from patients with AD than in those from healthy controls [88].Mitochondrial ROS drive the assembly of the NLRP3 inflammasome inside microglia [89], consequently facilitating tau pathology [90].The transfer of miR-146a-5p from microglial exosomes into intermittently hypoxic neurons reduces the mRNA levels of HIF-1α, NLRP3, IL-1β, and IL-18 [91].These effects are reversed by overexpression of HIF-1α [91].Chronic intermittent hypoxia induces the formation of the neuronal NLRP3 inflammasome, which is a key regulator of neuroinflammation during cognitive impairment [91].HIF-1α and NLRP1 protein levels were markedly increased in the endothelial cells of the brain and the retinas of triple (PS1M146V, APPswe, and tauP301L) transgenic mouse models of AD aged 16 months [14].In this AD mouse model, HIF-1α protein expression was observed in the cytoplasm of endothelial cells in the brain and retina [14].Cytoplasmic accumulation of HIF-1α may have been related to apoptosis and necrosis in the cerebral cortexes of 24-month-old rats exposed to intermittent hypoxia [92].During oxygen-glucose deprivation, endothelial cells show upregulated HIF-1α and NLRP1 protein levels, while downregulation of HIF-1α reduces NLRP1 expression, and vice versa [14].Thus, HIF-1α can affect inflammasomes in sustained hypoxic injuries.

Role of HIF-1α in Mitochondrial Functions
During hypoxia, ROS are generated due to mitochondrial depolarization especially through complex I and III, activation of xanthine oxidase, and NADPH oxidases at different oxygen levels in the brain [93].Mitochondria consume O 2 for ATP production.Hypoxia elicits mitochondrial ROS accumulation due to the insufficient number of electrons supplied by O 2 , causing imbalanced electron transfer in the electron transport chain [94].Mitochondrial dysfunction is the main cause of energy failure in damaged tissues and is the basis for cell death.Activation of mitochondrial ATP-sensitive K + channels promotes HIF-1α expression in ischemic injuries [95,96].A positive feedback regulation between ROS production and the HIF pathway has also been reported [97,98].ROS and reactive nitrogen species (RNS) contribute to oxidative stress production [99].One RNS, peroxynitrite (ONOO − ), can be formed by nitric oxide (NO) and O 2 − [100].Hypoxia-induced HIF-1α can upregulate inducible nitric oxide synthase (iNOS) expression [101], leading to NO production.Uncoupling of endothelial NOS produces O 2 − during hypoxia [102].The repair strategy for hypoxic neurovascular diseases involves artificial mitochondrial transfer/transplantation by transferring healthy mitochondria into damaged cells.Mitochondrial transplantation is an emerging therapeutic approach for the treatment of hypoxic neurovascular diseases [103][104][105][106]. Transfer of healthy mitochondria ameliorates cognitive deficits and neuronal damage and increases cell viability [103][104][105][106]. Mitochondrial transfer holds great potential for maintaining homeostasis during pathological processes.

Mitochondrial DNA
The released mtDNA, cytosolic double-stranded DNA, can act as a ligand for various detrimental signal sensors, activating an innate immune response in a caspase-independent manner [107].These signal sensors include the NLRP3 inflammasome, AIM2 inflammasome, and the cytosolic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway [68,70,107].cGAS-STING signaling cascades facilitate the mtDNAmediated secretion of inflammatory cytokines and activate immune cells [70,107] (Figure 2).mtDNA can be oxidized by ROS to generate fragments [107,108].The binding of cytosolic oxidized mtDNA to the NF-κB-mediated NLRP3 inflammasome suggests a link between apoptosis and the inflammasome [109].Autophagy proteins (i.e., microtubule-associated protein 1 light chain 3B [LC3B] and beclin1) regulate the innate immune response by inhibiting NLRP3-inflammasome-mediated mtDNA release, leading to the preservation of mitochondrial integrity [110].Autophagy is an evolutionarily conserved, lysosomedependent mechanism through which eukaryotic cells eliminate potentially cytotoxic or superfluous materials from the cytoplasm, thereby maintaining homeostasis [70].Depletion of autophagic proteins promotes the accumulation of dysfunctional mtDNA in the cytosol in response to lipopolysaccharides and ATP in macrophages [110].CoCl 2 -induced hypoxia upregulates the expression of autophagy-related genes (ATGs), such as BNIP3, BECN1, LC3, ATG5, and ATG7 [111].HIF-1α inhibitors reduce hypoxic preconditioning-mediated enhancement of BNIP3 and beclin1 protein levels [112].

Role of HIF-1α in VDAC1-Mediated Mitochondrial Functions
Three voltage-dependent anion channel (VDAC) family members (VDAC1, VDAC2, and VDAC3) have been identified in mammalian mitochondria [127,128].Among these three, a relationship between VDAC1 and HIF-1α has been reported [129].HIF-1α and nuclear respiratory factor 1 can act as transcriptional activators of the VDAC1 promoter following serum starvation and hypoxia [129].Hypoxia induces ROS generation from the respiratory complex in the inner mitochondrial membrane [127].ROS production and the consequent mtDNA release through VDAC1 oligomerization can facilitate apoptosis and inflammation.VDAC1 oligomerization into dimers, trimers, tetramers, and higher-order oligomers induces apoptosis by increasing mitochondrial outer membrane permeability, allowing the release of mtDNA into the cytoplasmic matrix [130,131].In HeLa cells, inhibition of VDAC1 oligomerization reduced selenite-mediated cell apoptosis and mitochondrial dysfunction (i.e., cytochrome c release from the mitochondria to the cytosol, ROS levels, and decreased mitochondrial membrane potential) [132].VDAC1 forms a macromolecule-sized pore in the outer membranes of the mitochondria, and its oligomerization mediates the transport of proteins and mtDNA [133] (Figure 2).A link between VDAC1 oligomerization and inflammation in inflammatory diseases has also been reported [127].
Mitochondrial HIF-1α plays a somewhat beneficial role in cell survival.Oxidative stress induces mitochondrial translocation of endogenous HIF-1α in HeLa cells [115].Mitochondria-localized HIF-1α reduces oxidative stress and increases cell survival [115].HIF-1α associated with the outer mitochondrial membrane protects the integrity of mitochondrial membrane potential and prevents apoptosis by directly regulating VDAC1 and hexokinase 2, leading to the production of a C-terminally truncated active form of VDAC1 [114].
HIF-1α modulates cell metabolism by hypoxia, regulating glucose transporter-1 and hexokinase 2 expression in various cell types [134][135][136].Hexokinase 2 catalyzes the first stage of glycolysis and suppresses apoptosis by binding to VDAC on the mitochondrial membrane [137].HIF-1α may be associated with the regulation of mitochondrial functions via direct interactions with hexokinase 2 [137].A recent report showed that hexokinase 2 dissociation from VDAC triggers the activation of inositol triphosphate receptors, leading to the release of Ca 2+ from the endoplasmic reticulum, which is taken up by mitochondria [138].This influx of Ca 2+ into the mitochondria leads to the oligomerization of VDAC, which facilitates NLRP3 inflammasome assembly and activation [138].The relationship between Aβ-mediated toxicity and VDAC1 has been reported previously.While the VDAC1-N-terminal peptide shows protective effects against Aβ-mediated human neuroblastoma cell apoptosis, VDAC1 facilitates Aβ-mediated cell toxicity, demonstrating mitochondrial dysfunction and apoptosis induction [139].VDAC1 inhibition enhances mitochondrial function and synaptic activity [140].Hence, while mitochondrial HIF-1α may protect against oxidative stress, transcriptional activity of HIF-1α may enhance VDAC1 expression leading to VDAC1 oligomerization and consequent inflammasome formation.

Role of HIF-1α in Cellular Activation
HIF-1α is closely related to glial activation and consequent release of proinflammatory factors (Figure 3).Inflammatory factors induce BBB leakage by changing the structures of tight junction proteins [141,142].Endothelial damage, pericyte apoptosis, reactive glial activation (gliosis), and inflammatory cytokines exacerbate CNS neurodegeneration by uncoupling normal cell-cell communication [9].The infiltration of immune cells through leaky vessels further stimulates various brain cells located in the neurovascular unit.
HIF-1α is closely related to glial activation and consequent release of proinflamma tory factors (Figure 3).Inflammatory factors induce BBB leakage by changing the struc tures of tight junction proteins [141,142].Endothelial damage, pericyte apoptosis, reactive glial activation (gliosis), and inflammatory cytokines exacerbate CNS neurodegeneration by uncoupling normal cell-cell communication [9].The infiltration of immune cells through leaky vessels further stimulates various brain cells located in the neurovascular unit.

Astrocyte Activation
Inactivation of astrocytic VEGFA expression reduces BBB leakage in inflammatory CNS diseases [143].In the acute phase of stroke, excessive VEGF acts as a potent vascular permeability factor [17,141,144].Ischemia/reperfusion-injury-mediated release of proin flammatory cytokines and other soluble mediators triggers paracellular permeability and tight junction disruption [145][146][147].Tight junctions are disrupted during neuroinflamma tory diseases, which results in the infiltration of monocytes into the brain parenchyma where they become activated macrophages [147,148].
Cortical astrocytes located in the penumbra of an ischemic stroke rat model show enhanced levels of high mobility group box 1 (HMGB1) and its receptor TLR4 [149].Ad ministration of recombinant HMGB1 to the normal rat cortex triggers the expression o TLR4 and its downstream mediator, iNOS, in astrocytes [149].HIF-1α-mediated human iNOS expression is seen in primary human astrocytes under cytokine-stimulated

Astrocyte Activation
Inactivation of astrocytic VEGFA expression reduces BBB leakage in inflammatory CNS diseases [143].In the acute phase of stroke, excessive VEGF acts as a potent vascular permeability factor [17,141,144].Ischemia/reperfusion-injury-mediated release of proinflammatory cytokines and other soluble mediators triggers paracellular permeability and tight junction disruption [145][146][147].Tight junctions are disrupted during neuroinflammatory diseases, which results in the infiltration of monocytes into the brain parenchyma, where they become activated macrophages [147,148].
Cortical astrocytes located in the penumbra of an ischemic stroke rat model show enhanced levels of high mobility group box 1 (HMGB1) and its receptor TLR4 [149].Administration of recombinant HMGB1 to the normal rat cortex triggers the expression of TLR4 and its downstream mediator, iNOS, in astrocytes [149].HIF-1α-mediated human iNOS expression is seen in primary human astrocytes under cytokine-stimulated conditions [101].HMGB1 is upregulated in human astrocytoma tissues.Moreover, hypoxiainduced HIF-1α is an upstream regulator of HMGB1 in human glioma stem cell lines [150].iNOS-derived NO triggers the post-translational S-nitrosylation of HMGB1, leading to HMGB1 secretion and proinflammatory responses [151].Secreted HMGB1 acts in a damageassociated molecular pattern (DAMP), activating the NLRP3 inflammasome [152,153].Multiple inflammasome-related complications affect immune system homeostasis in patients with severe TBI [154].

Oligodendrocyte Activation
In the brain, oligodendrocytes produce myelin, which is a lipid-rich membrane.Oligodendrocytes in the white matter have a high metabolic demand that requires mitochondrial ATP production during remyelination processes [155].White matter degeneration has been correlated with decreased cognitive function during normal brain aging [156].Hypoxic oligodendrocyte precursor cell (OPC)-derived VEGF is associated with BBB impairment [157].HIF-1α activates a unique set of genes in OPCs through interaction with the OPC-specific transcription factor OLIG2, which results in impaired oligodendrocyte formation [158].The receptors for HMGB1 in OPCs include TLR2, TLR4, TLR9, and the re-ceptor for advanced glycation end-product (RAGE) [159].Treatment of OPCs with HMGB1 blocks OPC maturation into oligodendrocytes and triggers nuclear translocation of NF-κB through a TLR2-dependent pathway [159].RAGE expression is influenced by hypoxia via nuclear translocation of NF-κB and HIF-1α [160].

Microglia/Macrophage Activation
The levels of mitochondrial DAMPs (i.e., mtDNA) in patients are often associated with the severity and prognosis of human diseases.Mitochondrial DAMPs are released into the extracellular space, causing immune responses [161].Immune cells such as macrophages and microglia are activated under hypoxic conditions, leading to increased mobilization [162].In human AD brains, endothelial cells upregulate genes involved in cytokine secretion and immune responses [29].AD microglia downregulate homeostatic genes [29].Inhibition of autophagy in microglia and macrophages exacerbates the innate immune responses and worsens brain injury outcomes [163].Autophagic flux can be disrupted in brain cells following TBI in mice.Macrophage-/microglia-specific knockout of the essential autophagy gene beclin1 leads to an overall increase in neuroinflammation after TBI [163].Increasing autophagy following rapamycin treatment decreases inflammation and improves the outcomes in wild-type mice after TBI [163].
Depending on the disease stage and chronicity, microglia are stimulated differently, leading to particular activation states (M1 and M2), which correspond to altered microglial morphology, gene expression, and function [166].Ramified microglial morphology (M2 phenotype) is associated with normal surveillance activity, while a more rounded phagocytic appearance (M1 phenotype) is observed in the damaged brain [166].Macrophage-specific HIF-1α-deficient mice show suppressed wire-induced neointimal thickening and decreased infiltration of inflammatory cells as compared to wild-type mice [167].This result implies that decreasing HIF-1α activity in macrophages may prevent the progression of vascular remodeling [167].Additionally, HIF-1α-deficient macrophages are positively correlated with the phenotypic profile of M2 macrophages and negatively correlated with that of M1 macrophages [167].

Vascular Cells
When mice were exposed to chronic mild hypoxia (8% O 2 ), leaky blood vessels were noted [168].Prolonged hypoxia has deleterious effects on AD pathogenesis [1,14,169,170].Microvessels obtained from the brains of patients with AD express higher levels of HIF-1α protein than do those in controls [171].Plasma levels of HMGB1 increase within 30 min of severe trauma in humans, which correlates with tissue hypoperfusion [172].
In spinal cord injury models, primary mouse brain microvascular endothelial cells engulf myelin debris through immunoglobulin G opsonization [173].Myelin debris in endothelial cells can then be delivered to the lysosomal degradation system via the autophagy pathway [173].Autophagic degradation of myelin debris is required for endothelial cell proliferation, via VEGF [173].The uptake of myelin debris by endothelial cells stimulates macrophage recruitment by upregulating monocyte chemoattractant protein-1 (MCP-1), inflammatory responses, and glial activation [173].

Conclusions and Future Directions
This review has revealed the molecular mechanisms of a key molecule, HIF-1α, during severe hypoxic conditions, such as those in brain diseases.Severe and chronic hypoxia exacerbates inflammation, mitochondrial malfunction, excessive oxidative stress, and cell death, partly due to the disproportionate accumulation of HIF-1α.
Developing techniques to diminish HIF-1α during severe hypoxia is valuable, creating a new direction for brain disease treatment.Proper inactivation of HIF-1α may contribute to the reduction in inflammasomes and cell damage and to enhanced mitochondrial function through the transcriptional regulations and post-modification of target molecules in neurodegenerative diseases, such as stroke, TBI, and AD.

Figure 1 .
Figure 1.The roles of hypoxia-inducible factor (HIF)-1α in different oxygen tension conditions in the central nervous system (CNS).In severe hypoxic regions of the brain, HIF-1α can induce sustained inflammation and mitochondrial dysfunction, consequently leading to cell death in the form of apoptosis, pyroptosis, and ferroptosis.HIF-1α stabilization during mild hypoxia may enhance cell regeneration (i.e., angiogenesis and neurogenesis), mitochondrial biogenesis, and cell survival in the brain.During normoxia, HIF-1α can be degraded in the CNS.