Expression and purification of the ectodomain of erythropoietin receptor fused to mCitrine or mTFP1 fluorescent protein in Escherichia coli.

Anemia is a common complication of chronic kidney disease (CKD), particularly in patients with stage 5 disease and is associated with increased morbidity and mortality. This retrospective cohort study compared the effectiveness and short-term safety of Roxadustat versus erythropoietin (EPO) for the management of anemia among patients with CKD stage 5. Medical records of 198 adult patients were reviewed, including 99 patients treated with Roxadustat and 99 matched patients treated with EPO, matched 1:1 by age, sex and baseline hemoglobin level. Changes in hemoglobin, hematocrit, iron profile and adverse events over a three-month period were analyzed. Baseline hemoglobin levels were comparable between the Roxadustat and EPO groups (8.62±0.74 vs. 8.59±0.71 g/dL; p=0.756). At three months, mean hemoglobin increased significantly in both groups; however, the mean hemoglobin increase was greater in the Roxadustat group (2.21±0.34 g/dL) compared with the EPO group (2.04±0.37 g/dL; p=0.001). Absolute hemoglobin levels at three months did not differ significantly between groups (10.82±0.85 vs. 10.61±0.76 g/dL; p=0.071). Hematocrit at three months was slightly higher in the Roxadustat group (32.4±2.51% vs. 29.92±2.42%; p<0.001). Roxadustat-treated patients demonstrated favorable iron utilization, with higher transferrin saturation (26.0±6.2% vs. 24.0±6.1%; p<0.029) and serum ferritin levels (551±118.3 vs. 591±136 ng/mL; p=0.033) compared with the EPO group. A higher proportion of patients in the Roxadustat group achieved a hemoglobin level ≥10 g/dL (74.8% vs. 64.6%), although this difference was not statistically significant (p=0.122). The incidence of adverse events, including hypertension, electrolyte abnormalities, infections, headache, edema, thrombosis, seizure etc were comparable between the two groups (p>0.05 for all). In conclusion, Roxadustat was associated with increase in mean hemoglobin and more favorable iron metabolism parameters compared with erythropoietin, while demonstrating a similar short-term safety profile. These findings suggest that Roxadustat may represent a viable alternative to conventional erythropoiesis-stimulating agent therapy for the management of anemia in patients with CKD.

Surgical correction of craniosynostosis has historically been associated with substantial intraoperative blood loss. Given that these procedures are often performed on infants, even small amounts of blood loss can have serious clinical consequences. To mitigate this risk, patients younger than one year frequently receive perioperative blood transfusions. However, a better understanding of the risk profile of blood product transfusions in the modern era has affected indications for and rates of transfusion done in association with craniosynostosis surgery. In addition, the development of minimally invasive techniques that reduce incision size, operative time, and blood loss have facilitated a lower frequency of transfusions. Another strategy is the use of pharmacological agents such as antifibrinolytics (e.g., tranexamic acid, fibrinogen concentrate, aminocaproic acid) and recombinant erythropoietin. Blood cell salvage and autologous transfusion is yet another means of avoiding allogenic blood transfusions. This narrative review examines the most recent literature to summarize indications for and strategies to reduce blood transfusion in craniosynostosis surgery. We also provide recommendations for which areas exhibit the highest need for additional high-powered controlled studies, the results of which would be practice-changing.

Sutimlimab is a monoclonal antibody against complement fraction C1s approved for the treatment of hemolytic anemia due to cold agglutinin disease (CAD). Here, we analyzed and report the largest international CAD cohort of sutimlimab-treated patients ever reported to highlight its safety and effectiveness in the real-world setting. We accrued a cohort of 57 CAD patients (median age 73.5 years, 56% females). At baseline, patients had severe to moderate anemia (median Hb 8.9 g/dL) and active hemolysis, with a substantial transfusion burden despite a median of 2 prior therapies, including corticosteroids and rituximab. After sutimlimab initiation, median Hb increased by 2 g/dL within 2 weeks and reached 12 g/dL in 4 weeks, remaining stable up to 24 months. This improvement was paralleled by an early and durable normalization of hemolytic markers. Objective responses were observed in most patients by week 2, with complete responses in approximately 50% by Week 4 and 55%-60% during long-term follow-up. Peripheral cold-induced symptoms did not improve and were associated with reduced response rates. Inadequate reticulocytosis also predicted poorer response and suggests the combination with recombinant erythropoietin. Sutimlimab was generally well tolerated. Infections were the most frequent adverse events (23%); severe infections predominantly occurred in previously rituximab-treated individuals. Hemolytic exacerbations occurred in 16% of cases, mostly due to infections. Thrombotic complications were rare. Overall, sutimlimab demonstrated rapid, durable effectiveness and a favorable safety profile in heavily pretreated real-world CAD patients.

Messenger ribonucleic acid (mRNA) therapeutics offer unprecedented potential for in vivo protein expression but raise emerging risks of misuse for gene doping. We investigated an online-available product purported to be codon-optimised, 5-methoxyuridine-substituted human erythropoietin (EPO) mRNA and developed a corresponding detection assay for equine anti-doping. Product identity was verified using a mass spectrometry (MS)-based bottom-up workflow comprising RNase 4 digestion, liquid chromatography-high-resolution tandem MS analysis, and automated sequence mapping against an mRNA database of potential doping genes. This workflow enabled direct detection of base modifications and achieved mean sequence coverage above 74%, verifying the mRNA sequence and its chemical composition. Method optimisation shows that partial RNase 4 digestion with a 10-min incubation time produced more consistent coverage by generating longer, informative oligoribonucleotides. The enhanced consistency would be advantageous for single-analysis scenarios typical of doping investigations. Building on the verified product identity, we developed a corresponding reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay for equine plasma. We explored the simple use of naked mRNA for matrix spiking as a reference material for doping control analysis. The method was validated with a limit of detection at 1250 copies/mL of EPO mRNA in equine plasma. In addition to EPO mRNA, the combined MS and RT-qPCR approach provides a practical framework that can be extended for surveillance of emerging mRNA-based agents in sport.

Erythropoietin (EPO), a glycoprotein hormone traditionally recognized for its role in erythropoiesis, has emerged as a multifaceted player in oncology. In ovarian cancer, a malignancy with high morbidity and mortality among women worldwide, EPO assumes dual relevance: as a therapeutic agent for anemia and as a potential modulator of tumor biology. Evidence suggests that erythropoietin receptors (EPOR) are expressed in ovarian cancer cells, where EPO signaling may influence proliferation, angiogenesis, apoptosis resistance, and metastatic potential. At the same time, anemia remains a frequent and debilitating complication of ovarian cancer, often resulting from chronic inflammation, myelosuppressive chemotherapy, and disease-related factors. The therapeutic use of recombinant human erythropoietin (rhEPO) in this setting has improved quality of life by reducing transfusion dependence, but concerns persist regarding its possible tumor-promoting effects. This review synthesizes current knowledge on the biological interplay between erythropoietin and ovarian cancer, evaluates clinical evidence on its use for anemia management, and discusses future directions for safely balancing symptom relief with oncologic outcomes.

Retinoic acid (RA), a bioactive metabolite of vitamin A, plays roles in early embryogenesis and hematopoietic development. However, its precise function in directing the hematopoietic lineage outcomes of human pluripotent stem cells (hPSCs) remains unclear. Here, we uncovered a distinct, stage-specific role for RA as a lineage-specifying modulator during late-stage hematopoietic differentiation, rather than as a promoter of hematopoietic progenitor generation. Using a stepwise hPSC differentiation system, we demonstrated that RA exerted minimal or inhibitory effects when applied during early mesoderm or hemogenic endothelial stages. In contrast, RA treatment during days 13-15 significantly enhanced progenitor maturation, proliferation, and functional output. Notably, RA acted cooperatively with external cytokines to modulate lineage fate. In the presence of erythropoietin (EPO), RA strongly promoted erythroid differentiation by activating EPOR signaling and upregulating erythroid transcriptional programs, including GATA1, KLF1, and globin gene expression. Conversely, under GM-CSF/M-CSF stimulation, RA biased progenitor differentiation toward macrophages, consistent with its role as an amplifier of the prevailing cytokine-directed lineage fate rather than an independent suppressor of erythropoiesis. These effects were highly dose- and context-dependent, with low-dose RA optimally enhancing lineage bias without cytotoxicity. Importantly, RA modulated the transcriptional and proliferative dynamics of committed progenitors. Taken together, our findings reveal a previously unrecognized role of RA as a versatile and tunable modulator of hematopoietic lineage fate that offers a novel strategy for in vitro blood cell engineering. This study advances approaches for lineage-specific blood production relevant to disease modeling, drug screening, and regenerative medicine.

ABSTRACTBackground and AimEndogenous erythropoietin (EPO) deficiency has been associated with anemia in patients with type 2 diabetes mellitus (T2DM) and renal injury. The purpose of this study was to characterize EPO levels and anemia in Vietnamese patients with T2DM and chronic kidney disease (CKD).MethodsA prospective observational study was conducted with 219 patients who were selected: 129 with T2DM and CKD, 51 with T2DM without CKD, and 49 healthy controls. Kruskal–Wallis, Chi‐square tests, and univariate ROC curve analysis were conducted to evaluate the predictive value of variables for anemia and reduced EPO levels.ResultsMedian EPO levels were significant lower in patients with T2DM and CKD (35.83 IU/L), compared with patients without CKD and healthy controls (p < 0.001). The reduction in EPO was 41.9% in patients with CKD, compared to 17.6% in those without CKD (p < 0.01). Patients with CKD exhibited significant decreases in red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin concentration compared with patients without CKD (p < 0.001). Moderate and severe anemia were observed in 31.8% and 4.6% of CKD patients, respectively, whereas only 5.9% of patients without CKD had moderate anemia (p < 0.001). EPO levels and rates of reduction did not differ significantly between types of kidney injury but varied markly across stages of renal failure (p < 0.001). A decreased glomerular filtration rate (GFR) was the strongest predictor of lower EPO levels (AUC = 0.661), p < 0.01), while both albumin and GFR were the strongest predictors of anemia (AUC = 0.787 and 0.786, p < 0.001).ConclusionVietnamese patients with T2DM and CKD exhibited a 3.16‐fold decrease in EPO concentration compared to healthy people. GFR was significantly associated with reduced EPO levels, while both albumin and GFR were the most reliable predictors of anemia in these patients.

A patient with metastasized prostate adenocarcinoma underwent 18F-PSMA-11 PET/CT restaging following 177Lu-PSMA-617 treatment and rising PSA-level. The maximum intensity projection image (right-side of the figure) demonstrated an intense homogenous tracer uptake throughout the bone marrow containing skeleton, whereas CT images showed specific bone metastases but no diffuse involvement, and previously known lymph node and liver metastases exhibited significantly reduced or absent uptake (see also left-side of the image, 18F-PSMA-11 MIP prior to 177Lu-PSMA-617 therapy). None of the patients that underwent imaging with the same tracer-batch demonstrated similar findings excluding free 18F as a potential cause for the imaging findings. Furthermore, the patient did not suffer from any bone marrow disorder previously reported to present with diffuse bone marrow uptake on PSMA-targeting PET/CT imaging [1, 2]. Of interest, the patient had received recombinant human erythropoietin, 100µg of Aranesp, 24h prior to imaging to treat his renal failure associated anemia. At this dose, Aranesp reaches a nanomolar concentration in the bone marrow resulting in stimulation of the Tissue Protective Receptor on endothelial cells leading to the creation of a massive systemic reservoir of PSMA-positive neovasculature that outcompetes PSMA-expressing prostate carcinoma lesions for radiotracer availability [3, 4]. This may explain the diffuse marrow uptake and the decreased visibility of known metastases [4]. The effect of erythropoietin on bone marrow mobilization and neovascularization can persist for 7-10 days [5]. This should be taken into consideration in order to avoid erroneous interpretation of 18F-PMSA-11 PET/CT imaging and unnecessary bone marrow toxicity of 177Lu-PSMA-617 treatment.

2575-P: Mice with Targeted Deletion of Erythropoietin Receptor in Adipose Tissue Exhibit Increased Adiposity, Elevated Glucose, and Impaired Glucose Tolerance

A challenge in preclinical neonatal neuroprotection research is the implementation of study designs that enable direct comparison of multiple potentially effective drugs. We used adaptive design to test four FDA-approved drugs (azithromycin, erythropoietin, caffeine, and melatonin) concurrently and determine which best combined safety and efficacy. Seven-day-old (P7) rats underwent hypoxia-ischemia (HI; right carotid ligation + timed 8% O2 exposure); some experiments included pre-treatment with agents that induced inflammation, and some included post-HI brief moderate hypothermia. Sensorimotor and neuropathology measures were incorporated into a Composite Score that also accounted for deaths. Outcome was initially evaluated at P21 and in confirmatory studies at P35. A pre-specified Bayesian algorithm with futility and efficacy stopping rules was devised to analyze emerging data and adjust subsequent animal allocation among drug groups. In all models, either azithromycin or erythropoietin (EPO) offered superior neuroprotection at P21, and the other was "runner-up". Caffeine and melatonin conferred modest neuroprotection in pure HI but were quickly eliminated in hypothermia-treated HI. At P35, azithromycin and EPO outcomes were generally similar. These results support azithromycin as a candidate neuroprotective agent that warrants future studies in large animal neonatal cerebral hypoxia-ischemia models. We used adaptive design to compare four repurposed drugs (azithromycin, caffeine, erythropoietin, and melatonin) in neonatal rodent brain injury. Key factors differentiating our approach from existing reports were within-litter comparisons, evaluation in multiple models, and measurement of both function and neuropathology. Either azithromycin or erythropoietin was the most neuroprotective in any given model, with the other a close "runner-up". Melatonin and caffeine were neuroprotective in pure HI, but less effective than azithromycin. In other models, they were less effective and eliminated early by the Bayesian algorithm. This supports azithromycin as a candidate neuroprotectant and supports future studies in large animal models.

Osteoporotic bone defects present formidable clinical challenges due to the limited capacity for natural bone repair. Erythropoietin (EPO) and Selenium (Se) have both demonstrated significant efficacy in enhancing bone regeneration; however, it remains unclear whether the combination of EPO and Se can further augment bone repair in the context of estrogen deficiency-induced osteoporosis. We undertook a study aimed at exploring the potential effects of localized implantation of materials incorporating EPO and/or Se on bone regeneration in rats subjected to osteoporosis via bilateral ovariectomy. Our observations revealed that local administration of EPO and Se over a period of 12 weeks effectively accelerated the healing process of osteoporotic bone defects, as evidenced by Micro-CT imaging and hematoxylin-eosin (HE) pathological staining. In addition, our findings from immunofluorescence assays, immunohistochemical analyses, and PCR testing indicate that local treatment with Se/EPO led to heightened expression levels of skeletal osteocalcin (OC), nuclear factor erythroid 2-related factor 2 (NRF2), and vascular endothelial growth factor (VEGF), alongside reduced expression levels of tartrate-resistant acid phosphatase (TRAP) in osteoporotic rats. Furthermore, this topical treatment exhibited conspicuous alterations in the expression profiles of key genes including osteoprotegerin (OPG), Runt-related transcription factor 2 (RUNX2), receptor activator of nuclear factor kappa-B ligand (RANKL), and sclerostin (SOST). Our results substantiate that localized administration utilizing Se/EPO holds considerable promise as an effective strategy for expediting the healing process associated with bone defects in cases of postmenopausal osteoporosis.

Erythropoietin (EPO) is classically viewed as a kidney-derived hormone essential for erythropoiesis, yet accumulating evidence places it at the center of complex interactions between the kidney and the immune system. The kidney is both a frequent target of immune-mediated injury and an organ with distinctive tolerogenic properties, capable in experimental models of inducing acceptance of otherwise rejection-prone allografts. Herein, we review experimental and clinical data showing that EPO, through its homodimeric EPO receptor (EPOR) or heterodimer EPOR/CD131 receptors, shapes both adaptive and innate immunity in ways that are directly relevant to tolerance and rejection. EPO selectively restrains effector T cells while preserving and expanding regulatory T cells through a macrophage-mediated production of active transforming growth factor β. EPO inhibits TH17 differentiation and skews the T follicular helper/T follicular regulatory (TFH/TFR) balance toward regulation, resulting in reduced germinal center B-cell activity and diminished allo- and autoantibody production. In macrophages, EPO signaling limits proinflammatory cytokine production, promotes an M2-like phenotype, enhances clearance of apoptotic cells, and counteracts trained immunity programs that otherwise accelerate allograft rejection. Studies in posttransplant erythrocytosis and lupus models support a nonredundant role for endogenous EPO as a physiological mechanism of peripheral immune tolerance. Similarly, the activation of the EPO-EPOR axis in tumor-associated macrophages drives immune suppression and resistance to immune checkpoint inhibitors. Integrating these insights, we propose that EPO functions as a key rheostat of renal and systemic immunity, and discuss how harnessing this pathway may offer novel strategies to promote transplant tolerance while minimizing oncologic risk.

Erythropoietin (EPO) is a glycoprotein hormone primarily known for its central role in red blood cell production, but it is now also recognized for its immunomodulatory effects on a range of immune effectors. Several studies indicate that EPO helps regulate intestinal barrier integrity, although its effect on intraepithelial lymphocytes (IELs) is still unknown. Using multiparameter flow cytometry and both conventional and unsupervised analyses, we conducted an in-depth phenotypic assessment of IELs from the murine duodenum, jejunum, ileum and colon. Our results revealed that in EPO-treated C57BL/6 mice, the absolute IEL count in the colonic epithelium was more than twice that observed in control mice without changes in the frequencies of the various subpopulations, indicating a global increase. This was accompanied by integrin α4β7 overexpression. Furthermore, EPO treatment alters the intestinal microbiota, increasing bacterial load while reducing diversity, with a notable decrease in Muribaculaceae, a taxon involved in microbial cross-feeding. This alteration may contribute to epithelial imbalance and indirectly to the observed increase in IEL density. Importantly, EPO treatment did not trigger colonic mucosal inflammation, although the affected IELs show a microbiota-dependent decrease in CD8αα expression (known to downregulate IEL activity). The present study is the first to provide a phenotypic mapping of IEL populations in the digestive tract of C57BL/6 mice and highlighted a novel regulatory role of EPO on colonic IELs. These results raise important questions about the impact of exogenous EPO supplementation and endogenous EPO fluctuations on intestinal immune responses - particularly in the context of inflammatory diseases.

An inflammation-targeted lipid nanoparticle inhibiting ferroptosis for spinal cord injury repair.

High‑altitude polycythemia (HAP) is classically attributed to erythropoietin (EPO)‑driven erythrocytosis, yet epidemiological and mechanistic evidence increasingly challenges this monocular view. Field data have demonstrated that up to 40% of individuals with a hematocrit level >68% circulate EPO within the sea‑level reference range, whereas multi‑omics studies have revealed sustained HIF activity, mitochondrial oxidative stress, iron dysregulation, gut dysbiosis and epigenetic reprogramming as parallel, EPO‑independent drivers. Hypoxia‑inducible microRNAs, hepcidin suppression, TLR4‑IL‑6 signaling and defective mitophagy converge to lock erythroid precursors into a survival‑plus‑proliferation state even after ambient oxygen levels normalize. The purpose of the present review is to integrate these disparate pathways into a unified molecular framework and to outline a phased, biomarker‑guided therapeutic roadmap for the precise prevention of maladaptive polycythemia at high altitudes.

Bone marrow and peripheral blood HLA-G in hematologic diseases presenting with impaired erythropoiesis: HLA-G in disorders with impaired erythropoiesis.

Composite scaffolds composed of porous polyurethane (PU) block copolymer and nano-hydroxyapatite (n-HA) have demonstrated significant potential in bone defect repair. However, the co-effect of osteogenesis and angiogenesis during the process of large bone defect repair is still not yet fully understood. Recent research has found that erythropoietin (EPO) is essential for both osteogenesis and angiogenesis, offering a new research direction for bone regeneration strategies. In this study, a polydopamine (pDA)-modified, EPO-functionalized HA/PU scaffold was fabricated, and its physicochemical properties, release kinetics, and effects on bone repair were systematically investigated.In vitro, a co-culture system of human umbilical vein endothelial cells and rat bone marrow mesenchymal stem cells was used to evaluate the scaffold's effects on cell proliferation, osteogenic, angiogenic, and HIF-1α/ vascular endothelial growth factor (VEGF) pathway.In vivo, the modified composite scaffold was implanted onto the cranial bone defects of Sprague-Dawley rats to assess its efficacy in promoting bone repair and HIF-1α/VEGF pathway.In vitro, the EPO/pDA/HA/PU group showed more three-dimensional cell morphology with prominent pseudopodia, facilitating cell adhesion, and significantly increased mRNA expression of ALP, Runx2, CD31, CD34, HIF-1αand VEGF.In vivo, the EPO/pDA/HA/PU group exhibited the most significant bone regeneration, with micro- computed tomography analysis confirming a significantly higher the ratio of bone tissue volume to total tissue volume (BV/TV) compared to the blank and HA/PU control groups. These results indicated that the modified composite scaffold enabled sustained release of EPO, which upregulated the expression of HIF-1αand VEGF, thereby enhancing osteogenic and angiogenic capabilities bothin vitroandin vivo. Our research demonstrated that loading of EPO onto the HA/PU composite scaffold could effectively promote osteogenesis and angiogenesis. HIF-1α/VEGF signaling plays a crucial role in this process. This discovery provides novel insights and methods for using HIF-1α/VEGF as a regulatory target to advance the clinical translation of large bone defects repair.

Erythropoietin (EPO) has emerging tissue-protective roles, including anti-apoptotic, anti-inflammatory, and pro-angiogenic effects. In reconstructive surgery, where flap necrosis remains a significant challenge, EPO has been investigated as an agent to enhance flap survival. Currently, no pharmacological agent has consistently improved flap survival, underscoring the need for novel therapeutics. A systematic review was conducted in accordance with PRISMA guidelines. PubMed, Embase, and CENTRAL databases were searched from inception to September 2025. Eligible studies investigated the effect of EPO on surgical flap survival in animal or human models compared with placebo/no treatment, reporting percentage flap necrosis. Secondary outcomes included perfusion, histological and molecular parameters, and safety. Nine animal studies met the pre-defined inclusion criteria (mice, n = 139; rats, n = 196) using random-pattern dorsal, musculocutaneous, and TRAM flap models. All studies evaluated the effect of recombinant human EPO with a variety of different doses, routes, and time applications. Across all studies, EPO was associated with reduced flap necrosis versus controls, with the greatest benefit observed from short-course, low-dose peri-operative regimes. High-dose or prolonged schedules were less effective and occasionally detrimental. EPO improved perfusion (capillary density, arteriolar flow), enhanced microvascularity and tissue preservation, and upregulated vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (NOS) with reduced oxidative stress. No thrombotic events or treatment-related mortality were reported. EPO improves flap survival in experimental animal models. Short-term, low-dose preconditioning appears most effective, while higher doses raise safety concerns. Translation to clinical practice requires optimization of dosing strategies and rigorous clinical trials.

Regular physical activity improves vascular function and promotes angiogenesis and erythropoiesis, which are further augmented by hypoxia. Early evidence suggests that long-term exogenous ketosis (EK) can enhance vascular function and angiogenesis. However, the acute responses and underlying mechanisms remain unknown. Moreover, acute and prolonged EK may increase blood erythropoietin (EPO) concentrations in normoxia. Nonetheless, whether this effect is additive to hypoxia is unclear, as an EK-mediated attenuation of blood deoxygenation may counteract the [EPO] increase. In a randomized, placebo-controlled, crossover design, 13male and two female participants completed four experimental sessions. Each included a high-intensity interval training session, followed by recovery either in normoxia or normobaric hypoxia (3000m simulated altitude, : 14.5%), supplemented with placebo or the commercial ketone precursor Ketone-IQ®. Macro- and microvascular function were assessed throughout a vascular occlusion protocol, using femoral artery blood flow and muscle oxygenation, respectively, after 2.5 and 5.5h recovery. Additionally, serum EPO and endothelin-1 (ET-1) concentrations, and skeletal muscle expression of pro-angiogenic and vascular integrity markers were evaluated. In normoxia and hypoxia, EK increased post-occlusion blood velocity (+15%) and muscle reoxygenation rate (+9%). Furthermore, muscle expression of pro-angiogenic and vascular integrity markers (including vascular endothelial growth factor, peroxisome proliferator-activated receptor γ coactivator 1α, and angiopoietin-1) as well as serum [EPO] (+15%) increased with EK, while serum [ET-1] was reduced (-13%). EK appears as a promising strategy to enhance vascular function and integrity, angiogenic signalling, and circulating [EPO] in response to exercise and hypoxia, thereby facilitating beneficial adaptive responses. KEY POINTS: Exogenous ketosis (EK) enhances macro- and microvascular function during post-exercise recovery, in both normoxia and hypoxia, likely through reducing serum [ET-1]. Moreover, EK upregulates markers of exercise-induced angiogenesis and vascular integrity. Finally, an EK-related, post-exercise increase in serum [EPO] is additive to hypoxic exposure alone.