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At least 19 recordsLinked to original sources
PubMed2026

Genome-wide CRISPR screen identifies a cytokine-enhancer circuit driving HIF-2α activation in renal cancer.

Resistance to HIF-2α inhibitors such as belzutifan underscores the need to better understand how HIF-2α is transcriptionally regulated in clear cell renal cell carcinoma (ccRCC). Here, we uncover a cytokine-driven enhancer mechanism that sustains HIF-2α expression through the JAK1/STAT3 signaling pathway. Using a genome-wide CRISPR screen in von Hippel-Lindau-deficient (VHL-deficient) ccRCC cells, we identified SOCS3 as a key negative regulator of HIF-2α. Mechanistically, loss of SOCS3 activates JAK1/STAT3 signaling, leading to the recruitment of STAT3 to distal enhancers upstream of endothelial PAS domain-containing protein (EPAS1) that physically loop to its promoter to drive HIF-2α transcription. This cytokine-enhancer circuit was recapitulated in samples from patients with ccRCC and functionally validated using CRISPR interference (CRISPRi), which disrupted enhancer-promoter looping and reduced tumor growth in HIF-2α-dependent models. SOCS3 overexpression or pharmacologic inhibition of JAK1/STAT3 markedly suppressed HIF-2α expression and tumor progression both in vitro and in vivo. Unlike prior studies focusing on VHL/HIF occupancy-driven enhancer activation, this work defines a trans-acting cytokine-JAK1/STAT3 pathway that transcriptionally controls EPAS1. Together, these findings reveal a targetable enhancer mechanism that sustains HIF-2α expression and suggest that combined inhibition of JAK1/STAT3 and HIF-2α may overcome therapeutic resistance in kidney cancer.

Basic Helix-Loop-Helix Proteins↗
PubMed2004

Hepatocyte growth factor-activated NF-kappaB regulates HIF-1 activity and ODC expression, implicated in survival, differently in different carcinoma cell lines.

Hepatocyte growth factor (HGF)-stimulated Met signaling influences tumor survival, growth and progression, all processes involving the transcription factor NF-kappaB. NF-kappaB plays a complex role in the control of survival due to the influence of cellular factors acting downstream. We undertook a comparative investigation of two human breast carcinoma cells with different grades of malignancy and HepG2 hepatoma cells, which present a biphasic response to HGF (proliferation followed by apoptosis). We found evidence that HGF induced gene patterns characteristic of survival rather than apoptosis depending on the cell type. The ability of NF-kappaB to regulate expression of hypoxia-inducible factor-1alpha (HIF-1alpha), a survival/anti-apoptotic gene in cancer, seemed to be critical. In the HepG2 and MCF-7 (low invasive breast carcinoma) cell lines increased transcription and translation were responsible for HIF-1alpha induction after HGF. The regulation by NF-kappaB was mainly at the level of the 5'-UTR of the HIF-1alpha message. HIF-1 (alpha/beta heterodimer) was likely to transactivate Mcl-1, another anti-apoptotic gene. Opposite results were observed in MDA-MB-231 cells (highly invasive breast carcinoma), which have high NF-kappaB activity, further inducible by HGF, because HIF-1alpha mRNA expression and HIF-1 transactivating capacity were HGF-insensitive while the alpha subunit seemed to be degraded after HGF. However, ornithine decarboxylase (ODC) and heme oxygenase mRNA expression persistently increased. By transiently transfecting two ODC gene reporters we demonstrated that ODC is a target gene of NF-kappaB in HGF-treated tumor cells. By regulating HIF-1 activity and specific gene expression downstream, NF-kappaB may influence the survival threshold, with an impact on the fate of carcinoma cells after prolonged HGF treatment.

Breast Neoplasms↗
PubMed2026

HIF-1 signaling contributes to lenvatinib resistance in patient-derived HCC organoids.

Resistance to lenvatinib remains an important limitation in hepatocellular carcinoma treatment. Six patient-derived organoid lines were established and classified as sensitive or resistant according to ex vivo drug responses, retaining histological and immunophenotypic features of matched parental tumors. Resistant organoids showed unchanged ATP activity, whereas sensitive ones exhibited pronounced morphological changes and reduced ATP activity at higher concentrations. Transcriptome sequencing identified 408 upregulated and 269 downregulated genes in resistant versus sensitive organoids, with HIF-1 signaling among altered pathways. In resistant organoids, lenvatinib increased HIF-1α, ANGPT2, and HK3 mRNA, whereas comparable changes were not detected in sensitive organoids. KC7F2 reduced these transcripts and further decreased ATP activity when combined with lenvatinib. In organoid-derived xenografts, this combination suppressed tumor growth and HIF-1 target expression more than lenvatinib alone, indicating HIF-1 signaling contributes to the resistant phenotype and its inhibition may enhance response.

Drug resistance↗
PubMed1975

[The effect of human leukocyte interteron (HIF) on experimental viral keratitis in monkeys (author's transl)].

12 african green monkeys were inoculated in both eyes with herpes simplex virus typ 1 and 16 rhesus monkeys with vaccinia virus. The right eyes were treated with human leukocyte interferon (HIF) while the left eyes served as controls and showed the typical keratitis, 7 out of 8 herpes eyes and all 9 vaccinia eyes which were treated prophylactically or simultaneiously with HIF showed no signs of disease. When HIF was given later in the course of the infection the keratitis was either little influenced or not modified at all. The reasons are discussed.

Animals↗
PubMed2026

Enhanced HIF-1α cooperation by a human RORγt mutant potentiates Th17 pathogenicity.

T helper 17 (Th17) cells are pivotal in mucosal defense and autoimmune pathology, with their function governed by the transcription factor retinoic acid receptor-related orphan receptor gamma t (RORγt). Although genome-wide association studies link RORC variants to inflammatory diseases, their functional consequences remain poorly understood. We identify a pathogenic RORγt mutation N277D (mouse homolog N275D) that amplifies Th17 pathogenicity through cooperation with hypoxia-inducible factor HIF-1α. This mutation enhances IFN-γ and other Th1-type cytokine production by Th17 cells, exacerbating colitis without disrupting T cell development or homeostasis. Integrated transcriptomic and metabolomic profiling reveals activation of glycolytic and hypoxia-associated pathways, consistent with increased RORγtN275D recruitment by HIF-1α to the Pdk1 locus. Notably, silencing Pdk1 normalizes the excessive IFN-γ production in RORγtN275D Th17 cells. Together, these findings define a regulatory axis linking RORγt and HIF-1α that coordinates transcriptional and metabolic programs in pathogenic Th17 cells, providing a framework for dissecting the functional impact of autoimmune risk variants.

CP: immunology↗
PubMed2026

The Triad of NF-κB, HIF-1α, and Oxidative Stress in Hepatocellular Carcinoma: Pathogenesis, Clinical Challenges, and Therapeutic Potential of CIGB-552 in Liver Transplantation.

Hepatocellular carcinoma (HCC) represents a formidable oncological challenge characterized by complex molecular pathogenesis and limited therapeutic outcomes, particularly in the context of liver transplantation. As the sixth most commonly diagnosed cancer and the third leading cause of cancer-related mortality worldwide, HCC poses significant clinical challenges that demand innovative therapeutic approaches. Central to HCC development and progression is a pathogenic triad comprising nuclear factor-kappa B (NF-κB), hypoxia-inducible factor-1α (HIF-1α), and oxidative stress-three interconnected pathways that drive inflammation, angiogenesis, metabolic reprogramming, and cell survival. This comprehensive review examines the molecular mechanisms underlying this triad in HCC pathogenesis across different etiological contexts, including viral hepatitis and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). We critically analyse the unique clinical challenges posed by HCC in liver transplantation recipients, particularly the paradoxical requirement for immunosuppression alongside antitumor immunity, and constraints surrounding immunotherapy application. Furthermore, we present CIGB-552, a novel peptide therapeutic targeting COMMD1 (Copper Metabolism MURR1 Domain-containing protein 1), as a promising dual-function agent capable of simultaneously disrupting the pathogenic triad through NF-κB inhibition, HIF-1α suppression, and strategic modulation of oxidative stress via SOD1 regulation. The multimodal mechanism of CIGB-552 offers a theoretically rational therapeutic approach for HCC management in both pre-transplant and post-transplant settings. Clinical validation in the transplantation setting is required.

Humans↗
PubMed2026

Hypoxia-inducible factor-1α promotes the malignant progression of cervical cancer cells by regulating lactate dehydrogenase A-mediated glycolysis.

BACKGROUND: Enhanced glycolysis is a hallmark of metabolic reprogramming in cervical cancer and plays a key role in tumor progression. Hypoxia-inducible factor-1α (HIF-1α), a core regulator of glycolytic metabolism, remains incompletely characterized in cervical cancer. This study aimed to investigate the expression pattern and clinical significance of HIF-1α in cervical cancer, and to explore its association with malignant biological behavior and lactate dehydrogenase A (LDHA)-related glycolytic metabolism in cervical cancer cells. METHODS: The expression level, clinicopathological features, immune infiltration correlation, and prognostic value of HIF-1α in cervical cancer were analyzed based on the The Cancer Genome Atlas (TCGA) database. HIF-1α overexpression and knockdown models were established in HeLa and Caski cells. Cell viability and invasive ability were assessed by Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to detect changes in LDHA expression. Lactate production was measured using a lactate assay kit, and intracellular reactive oxygen species (ROS) levels were determined by flow cytometry. RESULTS: Bioinformatics analysis showed that HIF-1α was highly expressed in cervical cancer and was closely associated with patient age, menopausal status, immune cell infiltration, and poor prognosis. Kaplan-Meier survival analysis demonstrated that patients with high HIF-1α expression had significantly worse overall survival (OS) than those with low expression. In vitro functional experiments further confirmed that HIF-1α overexpression significantly enhanced the viability and invasive ability of HeLa and Caski cells, whereas HIF-1α knockdown produced the opposite effects. HIF-1α overexpression was associated with increased messenger RNA (mRNA) and protein expression levels of LDHA, a key glycolytic molecule, along with increased lactate production and elevated intracellular ROS levels. CONCLUSIONS: HIF-1α is aberrantly highly expressed in cervical cancer and may enhance glycolytic activity by upregulating LDHA expression, thereby promoting the proliferation and invasion of cervical cancer cells. These findings suggest that HIF-1α could serve as a potential diagnostic, prognostic, and therapeutic target biomarker for cervical cancer.

Hypoxia-inducible factor-1α (HIF-1α)↗
PubMed1979

Intramuscular and/or intralumbar postexposure treatment of rabies virus-infected cynomolgus monkeys with human interferon.

From 9 to 10 of 10 cynomolgus monkeys infected with rabies street virus died of rabies about 20 days postinfection (pI). Symptoms of illness appeared 1 to 4 days before death. In an attempt to protect infected animals from the disease, human leukocyte interferon (HIF) was administered intramuscularly (i.m.) near the site of infection or into the cerebrospinal fluid between the first and second lumbar vertebrae (i.e., intralumbarly [i.l.]). Multiple HIF doses given over a period of several days proved more effective than a single HIF dose. In every experiment, i.m. HIF treatment was started 1 day pI. The best result obtained was a survival rate of 7 of 10 monkeys. The i.l. HIF administration schedules, consisting of multiple doses given over a period of at least 8 days, were started on day 3, 7, or 11 pI. Here the best result noted was the protection of 5 of 10 treated monkeys. The latest successful postexposure i.l. HIF treatment began on day 11 pI. The highest protection rate, 8 survivors of 10 treated monkeys, was achieved by a combined i.m. and i.l. HIF treatment. From these results we conclude that human patients severely bitten by rabid animals should in addition to an active immunization be i.m. and i.l. treated with HIF. Particularly, i.l. HIF administration could be effective, even when given several days pI. Whether an HIF administration starting after the appearance of clinical symptoms of rabies can help cannot be decided upon from the studies made in this monkey model. The most obvious difference between rabies in humans and cynomolgus monkeys is the duration of illness between the outbreak of the disease and death (1 to 4 days only in this animal model). It might have been due to this short period of illness that i.l. and i.m. HIF treatment at the appearance of clinical symptoms failed to help any of the monkeys treated.

Animals↗
PubMed2004

Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans.

The von Hippel-Lindau (VHL) tumor suppressor functions as a ubiquitin ligase that mediates proteolytic inactivation of hydroxylated alpha subunits of hypoxia-inducible factor (HIF). Although studies of VHL-defective renal carcinoma cells suggest the existence of other VHL tumor suppressor pathways, dysregulation of the HIF transcriptional cascade has extensive effects that make it difficult to distinguish whether, and to what extent, observed abnormalities in these cells represent effects on pathways that are distinct from HIF. Here, we report on a genetic analysis of HIF-dependent and -independent effects of VHL inactivation by studying gene expression patterns in Caenorhabditis elegans. We show tight conservation of the HIF-1/VHL-1/EGL-9 hydroxylase pathway. However, persisting differential gene expression in hif-1 versus hif-1; vhl-1 double mutant worms clearly distinguished HIF-1-independent effects of VHL-1 inactivation. Genomic clustering, predicted functional similarities, and a common pattern of dysregulation in both vhl-1 worms and a set of mutants (dpy-18, let-268, gon-1, mig-17, and unc-6), with different defects in extracellular matrix formation, suggest that dysregulation of these genes reflects a discrete HIF-1-independent function of VHL-1 that is connected with extracellular matrix function.

Animals↗
PubMed1975

Effect of human leukocyte interferon on vaccinia-and herpes virus-infected cell cultures and monkey corneas.

Pretreatment of human fibroblast cultures with human leukocyte interferon (HIF, 1,000 IU/ml) resulted in a 24-h delay of virus replication after infection with vaccinia virus and herpes simplex virus type 1 and type 2. Additional HIF treatment 24 h after infection effectively lowered the maximum yield of viral infectivity. Equal results were obtained in simian cells with 3,000 IU of HIF per ml. The spread of two cell-bound herpesviruses, varicella zoster virus and Medical Lake macaque herpesvirus, was inhibited by 2,000 IU of HIF per ml in human fibroblasts and Vero cells, respectively. Varicella zoster virus infectivity was notably reduced by HIF, whereas the latter system showed a low sensitivity. To study the effect of HIF in the infected cornea, keratitis was induced experimentally in both eyes of 12 rhesus monkeys and 12 African green monkeys by inoculation with vaccinia virus and herpes simplex virus, respectively. In each monkey one eye served as a control for the full cycle of disease. In the other eye HIF treatment was initiated prophylactically 15 h before or simultaneously with the challenge virus infection or 6 to 20 h postinfectionally or therapeutically after onset of the disease, and the treatment was continued for 2 to 7 days. Prophylactic and simultaneous administration equally resulted in inhibition of both vaccinia and herpes keratitis. Postinfectional and therapeutic administration of interferon moderated the course of keratitis slightly and shortened the period of virus shedding.

Animals↗
PubMed1975

[Sensitivity of various primate cells and animal viruses to the antiviral activity of human leukocyte interferon (author's transl)].

U cells (a permanent, human amnion cell line) were protected against infection with Semliki Forest Virus (SFV) by human interferon (HIF) from peripheral leukocytes. Despite the usual genus-specific action of interferons, mouse L929 cultures (a permanent mouse fibroblast cell line) were also protected by HIF. The antiviral action of HIF in six other primate cell cultures was also examined. It is of interest that two lymphoblastoid cell lines, RPMI1788 and Kaplan, were insensitive to HIF. The sensitivity of ten different viruses against HIF in primary African green monkey kidney cell cultures was compared. Among the viruses tested SFV was the most sensitive whereas two strains of vaccinia virus were barely inhibited. In contrast, type 1 herpes simplex virus was relatively sensitive to the action of HIF.

Amnion↗
PubMed2001

Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation.

Oxygen-dependent proteolytic destruction of hypoxia-inducible factor-alpha (HIF-alpha) subunits plays a central role in regulating transcriptional responses to hypoxia. Recent studies have defined a key function for the von Hippel-Lindau tumour suppressor E3 ubiquitin ligase (VHLE3) in this process, and have defined an interaction with HIF-1 alpha that is regulated by prolyl hydroxylation. Here we show that two independent regions within the HIF-alpha oxygen-dependent degradation domain (ODDD) are targeted for ubiquitylation by VHLE3 in a manner dependent upon prolyl hydroxylation. In a series of in vitro and in vivo assays, we demonstrate the independent and non-redundant operation of each site in regulation of the HIF system. Both sites contain a common core motif, but differ both in overall sequence and in the conditions under which they bind to the VHLE3 ligase complex. The definition of two independent destruction domains implicates a more complex system of pVHL-HIF-alpha interactions, but reinforces the role of prolyl hydroxylation as an oxygen-dependent destruction signal.

Amino Acid Motifs↗
PubMed1976

Growth inhibition of human lymphoblastoid Daudi cells in vitro by interferon preparations.

Human interferon (HIF) preparations inhibited the propagation of Daudi cells in stationary suspension cultures, while a control preparation showed no such effect. The growth inhibition (= anticellular) activity of differently pretreated HIF preparations was determined by the reduction of 14C-labelled thymidine (14C-TDR) uptake in a microassay system. These studies demonstrated that the degree of anticellular activity is directly proportional to the antiviral activity of different HIF preparations. These preparations were obtained from peripheral leukocytes (lHIF) or diploid fibroblasts (fHIF). Together with gel chromatography results, and the sensitivity of the anticellular activity to tryptic digestion and heat inactivation, these results suggest that the anticellularly active substance is a protein which is very similar to, or identical with, interferon.

Burkitt Lymphoma↗
PubMed2002

Control of the hypoxic response in Drosophila melanogaster by the basic helix-loop-helix PAS protein similar.

In mammalian systems, the heterodimeric basic helix-loop-helix (bHLH)-PAS transcription hypoxia-inducible factor (HIF) has emerged as the key regulator of responses to hypoxia. Here we define a homologous system in Drosophila melanogaster, and we characterize its activity in vivo during development. By using transcriptional reporters in developing transgenic flies, we show that hypoxia-inducible activity rises to a peak in late embryogenesis and is most pronounced in tracheal cells. We show that the bHLH-PAS proteins Similar (Sima) and Tango (Tgo) function as HIF-alpha and HIF-beta homologues, respectively, and demonstrate a conserved mode of regulation for Sima by oxygen. Sima protein, but not its mRNA, was upregulated in hypoxia. Time course experiments following pulsed ectopic expression demonstrated that Sima is stabilized in hypoxia and that degradation relies on a central domain encompassing amino acids 692 to 863. Continuous ectopic expression overrode Sima degradation, which remained cytoplasmic in normoxia, and translocated to the nucleus only in hypoxia, revealing a second oxygen-regulated activation step. Abrogation of the Drosophila Egl-9 prolyl hydroxylase homologue, CG1114, caused both stabilization and nuclear localization of Sima, indicating a central involvement in both processes. Tight conservation of the HIF/prolyl hydroxylase system in Drosophila provides a new focus for understanding oxygen homeostasis in intact multicellular organisms.

Active Transport, Cell Nucleus↗
PubMed2026

Hypoxia-Induced ADAM23 Drives Neuron-Tumor Crosstalk and Therapeutic Resistance in Hepatocellular Carcinoma.

Hypoxia and nutrient deprivation are fundamental drivers of tumor aggressiveness and therapeutic resistance in hepatocellular carcinoma (HCC). While the involvement of neural components in the tumor microenvironment (TME) is increasingly recognized, the molecular transducers linking metabolic stress to neuron-tumor crosstalk remain elusive. Here, we identify ADAM23 (A disintegrin and metalloproteinase 23) as a hypoxia-responsive mediator that mediates communication between HCC cells and neuronal cells. ADAM23 expression was markedly upregulated in HCC cells under both chemical (CoCl2) and physical hypoxia (1% O2), a process further amplified by glucose deprivation and directly modulated by HIF-1α. Functional assays revealed that ADAM23 overexpression promotes epithelial-mesenchymal transition (EMT) and enhances cell viability under metabolic stress. Notably, sorafenib-resistant HCC cells (Huh7SR) exhibited high levels of ADAM23 secretion, which triggered proliferative and metabolic activation in neuronal SH-SY5Y cells. In 3D co-culture spheroid models, Huh7SR cells mixed with SH-SY5Y cells displayed significantly larger spheroid volumes and enhanced neuronal fluorescence compared with parental controls, suggesting that ADAM23-mediated interactions facilitate a supportive neural niche. Analysis of The Cancer Genome Atlas (TCGA) datasets and patient microarrays confirmed that ADAM23 is significantly overexpressed in HCC and positively correlates with HIF-1α expression. Moreover, elevated expression of ADAM23 was significantly correlated with poor overall survival. Collectively, our findings underscore ADAM23 as a critical metabolic-neural linker that promotes HCC progression and drug resistance. These findings suggest that the ADAM23-mediated neuron-tumor axis may represent a potential therapeutic target in aggressive HCC.

ADAM23↗
PubMed2026

Integrative Genomic and Transcriptomic Insights into High-Altitude Adaptation in Changthangi Goats.

The Changthangi goat, native to the high-altitude Ladakh Plateau in northern India, thrives in oxygen-deficient environments above 4,000 m. This study investigated the genetic basis of high-altitude adaptation in Changthangi goats by integrating comparative genomics and transcriptomics, using the tropical lowland Jamunapari goat as a comparative model. Whole-genome sequence data from 15 individuals per breed were analyzed using complementary selection sweep metrics, including nucleotide diversity, Tajima's D, iHS, CLR, XP-EHH, and FST. These analyses identified candidate genomic regions under strong selective pressure, encompassing genes involved in hypoxia sensing (HIF-1α, HIF-2α/EPAS1, EGLN1), angiogenesis (VEGFA, AGGF1, ZEB1), cardiovascular regulation (PRKCB, ESR1, RYR2), mitochondrial and energy metabolism (ACADSB, ACSS3, ACSL1), cellular stress tolerance (BCL2, ATM), and thermogenesis (UCP1, FGF21). Unlike previous caprine studies that primarily infer hypoxia adaptation from genomic signals alone, our study integrates cardiac transcriptomics to demonstrate that genomic selection in Changthangi goats is accompanied by coordinated transcriptional remodeling across interconnected physiological systems in a physiologically relevant tissue. Comparative cardiac transcriptomic profiling revealed concordant expression divergence in genes associated with oxygen transport, vascular remodeling, mitochondrial function, substrate utilization, redox balance, and genome maintenance. This integrative multi-omics framework provides a mechanistic view of caprine high-altitude adaptation and highlights the value of combining genomic selection analyses with tissue-specific transcriptional profiling to resolve complex adaptive traits.

Animals↗
PubMed2026

Hypoxia reprograms VEGF signaling to differentially control ADAMTS2 and ADAMTS3 expression in endothelial cells.

ADAMTS2/-3, key metalloproteinases involved in collagen processing and extracellular matrix dynamics, remain insufficiently characterized in terms of their transcriptional regulation under hypoxic and pro-angiogenic conditions. In this study, we demonstrate that VEGF₁₆₅ robustly enhances ADAMTS2/-3 expression in endothelial cells, with hypoxia providing a striking amplification of this response. Bioinformatic analyses revealed that hypoxia and VEGF induced HIF-mediated and time-varying expression responses in ADAMTS2/-3. Using HUVECs exposed to CoCl₂-induced hypoxia, VEGF stimulation led to substantial increases in ADAMTS2 (approximately 19-fold at 3 h) and ADAMTS3 (approximately 46-fold at 3 h) mRNA levels, accompanied by concordant protein upregulation. Promoter-reporter assays revealed strong VEGF responsiveness in defined ADAMTS2 (-658/+112) and ADAMTS3 (-131/+40; -1340/+40) promoter fragments, particularly under hypoxic conditions. Pharmacological inhibition showed that JNK, MAPK/ERK, p38, and PI3K pathways each contributed partially to VEGF-mediated transcription, indicating multi-pathway convergence rather than single-pathway dependency. This finding is consistent with RNA-seq analyses showing that VEGF-related signaling is extensively re-regulated under hypoxic conditions. Extension of these analyses to MG-63 and SAOS-2 cell lines revealed modest but consistent VEGF-induced upregulation, supporting a tissue-independent regulatory axis. Collectively, these findings position ADAMTS2/-3 as potent hypoxia- and VEGF-responsive genes, uncovering their integration into HIF-1α-dependent transcriptional networks and VEGF-activated signaling cascades. This work highlights the relevance of ADAMTS2/-3 in angiogenesis-associated extracellular matrix remodeling and identifies them as promising biomarkers and potential therapeutic targets in hypoxia-driven vascular pathology.

Humans↗