The transcription factor Foxm1 is essential for the quiescence and maintenance of hematopoietic stem cells.

Foxm1 is known as a typical proliferation-associated transcription factor. Here we found that Foxm1 was essential for maintenance of the quiescence and self-renewal capacity of hematopoietic stem cells (HSCs) in vivo in mice. Reducing expression of FOXM1 also decreased the quiescence of human CD34(+) HSCs and progenitor cells, and its downregulation was associated with a subset of myelodysplastic syndrome (MDS). Mechanistically, Foxm1 directly bound to the promoter region of the gene encoding the receptor Nurr1 (Nr4a2; called 'Nurr1' here), inducing transcription, while forced expression of Nurr1 reversed the loss of quiescence observed in Foxm1-deficient cells in vivo. Thus, our studies reveal a previously unrecognized role for Foxm1 as a critical regulator of the quiescence and self-renewal of HSCs mediated at least in part by control of Nurr1 expression.

The transcription factor DREAM represses the deubiquitinase A20 and mediates inflammation.

Here we found that the transcription repressor DREAM bound to the promoter of the gene encoding A20 to repress expression of this deubiquitinase that suppresses inflammatory NF-κB signaling. DREAM-deficient mice displayed persistent and unchecked A20 expression in response to endotoxin. DREAM functioned by transcriptionally repressing A20 through binding to downstream regulatory elements (DREs). In contrast, binding of the transcription factor USF1 to the DRE-associated E-box domain in the gene encoding A20 activated its expression in response to inflammatory stimuli. Our studies define the critical opposing functions of DREAM and USF1 in inhibiting and inducing A20 expression, respectively, and thereby the strength of NF-κB signaling. Targeting of DREAM to induce USF1-mediated A20 expression is therefore a potential anti-inflammatory strategy for the treatment of diseases associated with unconstrained NF-κB activity, such as acute lung injury.

CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation.

BACKGROUND: Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown. METHODS: In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events. RESULTS: Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation. Mechanistically, CD151 restrains endothelial release of proinflammatory molecules for less leukocyte infiltration. At the subcellular level, CD151 determines the integrity of multivesicular bodies/lysosomes and confines the production of exosomes that carry cytokines such as ANGPT2 (angiopoietin-2) and proteases such as cathepsin-D. At the molecular level, CD151 docks VCP (valosin-containing protein)/p97, which controls protein quality via mediating deubiquitination for proteolytic degradation, onto endolysosomes to facilitate VCP/p97 function. At the endolysosome membrane, CD151 links VCP/p97 to (1) IFITM3 (interferon-induced transmembrane protein 3), which regulates multivesicular body functions, to restrain IFITM3-mediated exosomal sorting, and (2) V-ATPase, which dictates endolysosome pH, to support functional assembly of V-ATPase. CONCLUSIONS: Distinct from its canonical function in strengthening cell adhesion at cell surface, CD151 maintains endolysosome function by sustaining VCP/p97-mediated protein unfolding and turnover. By supporting protein quality control and protein degradation, CD151 prevents proteins from (1) buildup in endolysosomes and (2) discharge through exosomes, to limit vascular inflammation. Also, our study conceptualizes that balance between degradation and discharge of proteins in endothelial cells determines vascular information. Thus, the IFITM3/V-ATPase-tetraspanin-VCP/p97 complexes on endolysosome, as a protein quality control and inflammation-inhibitory machinery, could be beneficial for therapeutic intervention against vascular inflammation.

Deep Electron Redistributions Induced by Dual Junctions Facilitating Electroreduction of Dilute Nitrate to Ammonia.

The electronic states of metal catalysts can be redistributed by the rectifying contact between metal and semiconductor e.g., N-doped carbon (NC), while the interfacial regulation degree is very limited. Herein, a deep electronic state regulation is achieved by constructing a novel double-heterojunctional Co/Co3O4@NC catalyst containing Co/Co3O4 and Co3O4/NC heterojunctions. When used for dilute electrochemical NO3 - reduction reaction (NO3RR), the as-prepared Co/Co3O4@NC exhibits an outstanding Faradaic efficiency for NH3 formation (FENH3) of 97.9%, -0.4 V versus RHE and significant NH3 yield of 303.5 mmol h-1 gcat -1 at -0.6 V at extremely low nitrate concentrations (100 ppm NO3 --N). Experimental and theoretical results reveal that the dual junctions of Co/Co3O4 and Co3O4/NC drive a unidirectional electron transfer from Co to NC (Co→Co3O4→NC), resulting in electron-deficient Co atoms. The electron-deficient Co promotes NO3 - adsorption, the rate-determining step (RDS) for NO3RR, facilitating the dilute NO3RR to NH3. The design strategy provides a novel reference for unidirectional multistage regulation of metal electronic states boosting electrochemical dilute NO3RR, which opens up an avenue for deep electronic state regulation of electrocatalyst breaking the limitation of the electronic regulation degree by rectifying contact.

Ratiometric Fluorescence Probes for In Situ Imaging of Membrane Tension in Live Cells.

Membrane tension is an important physical parameter of describing cellular homeostasis, and it is widely used in the study of cellular processes involving membrane deformation and reorganization, such as cell migration, cell spreading, and cell division. Despite the importance of membrane tension, direct measurement remains difficult. In this work, we developed a ratiometric fluorescent probe sensitive to membrane tension by adjusting the carbon chain structure based on polarity-sensitive fluorophores. The probe is sensitive to changes in membrane tension after cells were subjected to physical or chemical stimuli, such as osmotic shock, lipid peroxidation, and mechanical stress. When the polarity of the plasma membrane increases (the green/red ratio decreases) and the membrane tension increases, the relative magnitude of the membrane tension can be quantitatively calculated by fluorescence ratio imaging. Thus, the probe proved to be an efficient and sensitive membrane tension probe.

Highly effective and selective FeBr3-promoted deuterium bromination/cyclization of 1,n-enynes.

A highly effective and selective FeBr3-promoted deuterium bromination/cyclization of 1,n-enynes is reported. On the one hand, the Lewis acid FeBr3 as a catalyst promotes cyclization of 1,n-enynes to afford deuterium heterocyclic frameworks with high efficiency. On the other hand, FeBr3 serves as the bromine source (with D2O as the deuterium source) to promote the formation of the desired deuterated pyrrole derivatives containing alkenyl bromide groups. This protocol provides an effective pathway to afford deuterated alkenyl brominative compounds as (Z)-isomers with high yields and selectivity, offering a new method for introducing 2H into organic compounds.

Impact of LDLR polymorphisms on lipid levels and atorvastatin's efficacy in a northern Chinese adult Han cohort with dyslipidemia.

BACKGROUND: Dyslipidemia, a significant risk factor for atherosclerotic cardiovascular disease (ASCVD), is influenced by genetic variations, particularly those in the low-density lipoprotein receptor (LDLR) gene. This study aimed to elucidate the effects of LDLR polymorphisms on baseline serum lipid levels and the therapeutic efficacy of atorvastatin in an adult Han population in northern China with dyslipidemia. METHODS: In this study, 255 Han Chinese adults receiving atorvastatin therapy were examined and followed up. The 3' untranslated region (UTR) of the LDLR gene was sequenced to identify polymorphisms. The associations between gene polymorphisms and serum lipid levels, as well as changes in lipid levels after intervention, were evaluated using the Wilcoxon rank sum test, with a P < 0.05 indicating statistical significance. Assessment of linkage disequilibrium patterns and haplotype structures was conducted utilizing Haploview. RESULTS: Eleven distinct polymorphisms at LDLR 3' UTR were identified. Seven polymorphisms (rs1433099, rs14158, rs2738466, rs5742911, rs17249057, rs55971831, and rs568219285) were correlated with the baseline serum lipid levels (P < 0.05). In particular, four polymorphisms (rs14158, rs2738466, rs5742911, and rs17249057) were in strong linkage disequilibrium (r2 = 1), and patients with the AGGC haplotype had higher TC and LDL-C levels at baseline. Three polymorphisms (rs1433099, rs2738467, and rs7254521) were correlated with the therapeutic efficacy of atorvastatin (P < 0.05). Furthermore, carriers of the rs2738467 T allele demonstrated a significantly greater reduction in low-density lipoprotein cholesterol (LDL-C) levels post-atorvastatin treatment (P = 0.03), indicating a potentially crucial genetic influence on therapeutic outcomes. Two polymorphisms (rs751672818 and rs566918949) were neither correlated with the baseline serum lipid levels nor atorvastatin's efficacy. CONCLUSIONS: This research outlined the complex genetic architecture surrounding LDLR 3' UTR polymorphisms and their role in lipid metabolism and the response to atorvastatin treatment in adult Han Chinese patients with dyslipidemia, highlighting the importance of genetic profiling in enhancing tailored therapeutic strategies. Furthermore, this investigation advocates for the integration of genetic testing into the management of dyslipidemia, paving the way for customized therapeutic approaches that could significantly improve patient care. TRIAL REGISTRATION: This multicenter study was approved by the Ethics Committee of Xiangya Hospital Central South University (ethics number K22144). It was a general ethic. In addition, this study was approved by The First Hospital of Hebei Medical University (ethics number 20220418).

Ambient Pressure Drying of Freeze-Cast Ceramics from Aqueous Suspension.

Freeze-casting has been wildly exploited to construct porous ceramics but usually requires costly and demanding freeze-drying (high vacuum, size limit, and supercooled chamber), which can be avoided by the ambient pressure drying (APD) technique. However, applying APD to freeze-cast ceramic based on an aqueous suspension is still challenging due to inert surface chemistry. Herein, a modified APD strategy is developed to improve the drying process of freeze-cast ceramics by exploiting the simultaneous ice etching, ionic cross-linking, and solvent exchange under mild conditions (-10-0 °C, ambient pressure). This versatile strategy is applicable to various ceramic species, metal ions, and freezing techniques. The incorporated metal ions not only enhance liquid-phase sintering, producing ceramics with higher density and mechanical properties than freeze-cast counterparts, but also render customizable coloration and antibacterial property. The cost-/time-efficient APD is promising for mass production and even successive production of large-size freeze-cast ceramics that exceed the size of commercial freeze-dryers.

Seeding alpine grasses in low altitude region increases global warming potential during early seedling growth.

Introduction of alpine grasses to low altitude regions has long been a crucial strategy for enriching germplasm diversity, cultivating and acclimating high-quality species, enhancing ecosystem resilience and adaptability, as well as facilitating ecosystem restoration. However, there is an urgent need to investigate the impacts of planting Gramineae seeds on greenhouse gas (GHG) emissions, particularly during the critical stage of early plant growth. In this study, four species of grass seeds (Stipa breviflora, Poa pratensis, Achnatherum splendens, Elymus nutans) were collected from 19 high-altitude regions surrounding the Qinghai-Tibet Plateau and sown at low-altitude. Measurements of GHG emissions at early seedling growth in the mesocosm experiment using static chamber method showed a strong increase in the cumulative emissions of CO2 (5.71%-9.19%) and N2O (11.36%-13.64%) (p < 0.05), as well as an elevated CH4 uptake (2.75%-5.50%) in sites where the four grass species were introduced, compared to bare soil. Consequently, there was a substantial rise in global warming potential (13.87%-16.33%) (p < 0.05) at grass-introduced sites. Redundancy analysis showed that seed traits, plant biomass, and seedling emergence percentage were the main driving biotic factors of three GHGs fluxes. Our study unveils the potential risk of escalating GHG emissions induced by introducing high altitude grasses to low altitude bare soil, elucidating the mechanism through linking seed traits with seedling establishment and environmental feedback. Furthermore, this offers a new perspective for assessing the impact of grass introduction on ecological environment of introduced site.

Multifunctional Cellulose Nanocrystals Electrolyte Additive Enable Ultrahigh-Rate and Dendrite-Free Zn Anodes for Rechargeable Aqueous Zinc Batteries.

The design of aqueous zinc (Zn) chemistry energy storage with high rate-capability and long serving life is a great challenge due to its inhospitable coordination environment and dismal interfacial chemistry. To bridge this big gap, herein, we build a highly reversible aqueous Zn battery by taking advantages of the biomass-derived cellulose nanocrystals (CNCs) electrolyte additive with unique physical and chemical characteristics simultaneously. The CNCs additive not only serves as fast ion carriers for enhancing Zn2+ transport kinetics but regulates the coordination environment and interface chemistry to form dynamic and self-repairing protective interphase, resulting in building ultra-stable Zn anodes under extreme conditions. As a result, the engineered electrolyte system achieves a superior average coulombic efficiency of 97.27 % under 140 mA cm-2, and steady charge-discharge for 982 h under 50 mA cm-2, 50 mAh cm-2, which proposes a universal pathway to challenge aqueous Zn chemistry in green, sustainable, and large-scale applications.

Clinical and functional study of two de novo variations of CDKL5 gene.

The cyclin-dependent kinase like 5 (CDKL5) gene variation is X-linked dominant and is associated with type 2 developmental and epileptic encephalopathy (DEE). Although numerous cases of CDKL5 have been reported, there is limited discussion regarding functional verification. We described two children with DEE caused by de novo variations of CDKL5 gene, analyzed their clinical manifestations, and performed genetic testing on their gene variation sites. The two cases presented with tonic seizures followed by epileptic spasms, indicative of refractory epilepsy. Physical examination revealed abnormal facial features, including wide eye distance, low nose base, and high nose bridge. Both cases exhibited developmental disabilities. Cranial magnetic resonance imaging (MRI) showed widening of the bilateral frontotemporal extracerebral space. Genetic testing identified variations at the gene sites c.463 + 4A > G (splicing) and c.1854_1861delCAAAGTGA (p.D618Efs*18). Minigene experiments further confirmed that the intronic variation c.463 + 4A > G (splicing) disrupted splicing, leading to protein truncation. CDKL5 gene variation can lead to DEE, and intron variation site c.463 + 4A > G (splicing) can cause protein truncation, which is a pathogenic variation.

Synthesis and characterization of a macromolecular magnetic resonance imaging and delivery system with hyaluronic acid as a carrier.

Using hyaluronic acid (HA) as macromolecular drug carriers, a glutathione-responsive imaging drug delivery system HA-SS-a-Gd-DOTA was formed by conjugating gadolinium chelates and cytarabine. This system exhibited T1-reflexivity (21.9 mmol-1 L s-1, 0.5 T) that was higher than that of gadoterate meglumine. In an acidic environment, in vitro drug release reached 63.4% in 24 h. Low cytotoxicity indicated that this system has good biocompatibility. In vivo mouse imaging studies showed that tumor signaling was significantly enhanced. About 58% of the signal enhancement was obtained 50 min after injection of the drug. The degradation of the hyaluronic acid macromolecular chains in vivo makes it an ideal tumor imaging diagnostic agent because it did not cause damage to important organs of the mice.

Two-Dimensional Ultrathin Graphic Carbon Nitrides with Extended π-Conjugation as Extraordinary Efficient Hydrogen Evolution Photocatalyst.

Construction of 2D graphic carbon nitrides (g-CNx ) with wide visible light adsorption range and high charge separation efficiency concurrently is of great urgent demand and still very challenging for developing highly efficient photocatalysts for hydrogen evolution. To achieve this goal, a two-step pyrolytic strategy has been applied here to create ultrathin 2D g-CNx with extended the π-conjugation. It is experimentally proven that the extension of π-conjugation in g-CNx is not only beneficial to narrowing the bandgap, but also improving the charge separation efficiency of the g-CNx . As an integral result, extraordinary apparent quantum efficiencies (AQEs) of 57.3% and 7.0% at short (380 nm) and long (520 nm) wavelength, respectively, are achieved. The formation process of the extended π-conjugated structures in the ultrathin 2D g-CNx has been investigated using XRD, FT-IR, Raman, XPS, and EPR. Additionally, it has been illustrated that the two-step pyrolytic strategy is critical for creating ultrathin g-CNx nanosheets with extended π-conjugation by control experiments. This work shows a feasible and effective strategy to simultaneously expand the light adsorption range, enhance charge carrier mobility and depress electron-hole recombination of g-CNx for high-efficient photocatalytic hydrogen evolution.

A Scalable and Metal-Free Synthesis of Indazoles from 2-Aminophenones and In Situ Generated De-Boc-Protected O-Mesitylsulfonyl Hydroxylamine Derivatives.

A one-pot metal-free protocol to access indazoles from easily available 2-aminophenones and hydroxylamine derivatives has been achieved. The reaction is operationally simple, mild, and insensitive to air and moisture. A broad range of indazoles were prepared in good to excellent yield (up to 97% yield), and the reaction displayed a broad functional group tolerance. The reaction was performed at gram scale, and its synthetic application was exhibited through the rapid and efficient preparation of bioactive molecule YC-3 and FDA-approved drug axitinib.

The effects of different endometrial preparation regimens on pregnancy outcomes in frozen-thawed embryo transfer cycles: a prospective randomized controlled study.

OBJECTIVE: An increasing number of research have emerged to compare the pregnancy outcomes between the natural cycle and the hormone replacement therapy (HRT) cycle in preparing the endometrium for frozen-thawed embryo transfer (FET), but the results are controversial. This prospective randomized controlled study was hence designed to obtain more solid evidence. MATERIALS AND METHODS: In this study, patients with regular menstrual cycle length (21-35 days) who underwent FET between January 2010 to December 2017 were recruited for this study. Upon further filtering with the selection criteria of patients being, a total of 405 patients were recruited and randomized. Finally, analysis was performed on 384 patients: 178 belonged to the natural cycle group whereas the remaining 206 were in the HRT group. The primary outcome was live birth rate, while the secondary outcomes were implantation rate, clinical pregnancy rate, early miscarriage rate, late miscarriage rate, multiple birth rate and low birth weight rate. RESULTS: The live birth rate (37.6% vs 30.1%, p = 0.119) of natural cycle group were higher than those of the hormone replacement therapy group, although the difference was not significant. The secondary outcomes were not found to differ significantly between the two groups. Nonetheless, the endometrium was found to be thicker in the natural cycle group (10.75 mm) than the HRT group (9.00 mm) (p < 0.001). CONCLUSION: No significant differences were observed between the pregnancy outcomes of the natural cycle group and the HRT group which comprised of patients with regular menstrual cycle length.

Efficacy of agomelatine with cognitive behavioral therapy for delayed sleep-wake phase disorder in young adults: A randomized controlled study.

BACKGROUND: Delayed sleep-wake phase disorder (DSWPD) is common and easily misdiagnosed in young people, and to date, there is no evidence-based treatment. PURPOSE: A nonblinded randomized controlled study evaluated the effect of agomelatine therapy (AT) and cognitive behavior therapy (CBT) on DSWPD in young adults. METHODS: Sixty adolescents and young adults (range = 19-24 years, mean = 22 years, 52% female) diagnosed with DSWPD were randomized to receive 4 weeks of agomelatine therapy with or without cognitive behavior therapy. Sleep diaries, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Insomnia Severity Index (ISI), and World Health Organization wellbeing questionnaire (WHO-5) were measured pre-treatment and post-treatment. RESULTS: Agomelatine therapy for 4 weeks shifted the sleep-wake rhythm (p < .001) forward in both groups at the week 4 assessment. There were no significant differences in sleep onset (p = .099) and sleep offset (p = .959) between the CBT group and the no treatment (NT) group at the follow-up visits. However, significant differences were found in sleep duration (p = .002), sleep quality (p=0.005), sleep difficulties (p < .001), daytime sleepiness (p = .001), and wellbeing (p = .007) between groups. CONCLUSIONS: The improvements were received largely through the sleep-promoting effects of agomelatine therapy, and combining with cognitive behavior therapy on maintenance of altered sleep rhythms might be feasible.

Egln1Tie2Cre Mice Exhibit Similar Therapeutic Responses to Sildenafil, Ambrisentan, and Treprostinil as Pulmonary Arterial Hypertension (PAH) Patients, Supporting Egln1Tie2Cre Mice as a Useful PAH Model.

Pulmonary arterial hypertension (PAH) is a progressive and inevitably fatal disease characterized by the progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling, which lead to right-sided heart failure and premature death. Many of the genetically modified mouse models do not develop severe PH and occlusive vascular remodeling. Egln1Tie2Cre mice with Tie2Cre-mediated deletion of Egln1, which encodes hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2), is the only mouse model with severe PAH, progressive occlusive pulmonary vascular remodeling, and right-sided heart failure leading to 50-80% mortality from the age of 3-6 months, indicating that the Egln1Tie2Cre mice model is a long-sought-after murine PAH model. However, it is unknown if Egln1Tie2Cre mice respond to FDA-approved PAH drugs in a way similar to PAH patients. Here, we tested the therapeutic effects of the three vasodilators: sildenafil (targeting nitric oxide signaling), ambrisentan (endothelin receptor antagonist), and treprostinil (prostacyclin analog) on Egln1Tie2Cre mice. All of them attenuated right ventricular systolic pressure (RVSP) in Egln1Tie2Cre mice consistent with their role as vasodilators. However, these drugs have no beneficial effects on pulmonary arterial function. Cardiac output was also markedly improved in Egln1Tie2Cre mice by any of the drug treatments. They only partially improved RV function and reduced RV hypertrophy and pulmonary vascular remodeling as well as improving short-term survival in a drug-dependent manner. These data demonstrate that Egln1Tie2Cre mice exhibit similar responses to these drugs as PAH patients seen in clinical trials. Thus, our study provides further evidence that the Egln1Tie2Cre mouse model of severe PAH is an ideal model of PAH and is potentially useful for enabling identification of drug targets and preclinical testing of novel PAH drug candidates.

Selective nitridation-corrosion process to recover vanadium, titanium, chromium, and iron from vanadium slag.

Vanadium slag (V-slag) is an important secondary V source, but other valuable elements are discarded in the tailings in industry. Herein, a green nitridation-corrosion process is proposed for the comprehensive recovery of valuable elements (V, Ti, Cr, Fe) from V-slag without producing hazardous waste. Thermodynamic results indicate that ammonia gas (NH3) can selectively reduce Fe and nitride V, Cr, and Ti. The main phase composition of the nitrided V-slag included metallic Fe, nitrides, and diopside under optimal conditions, and their relative contents were 42.5, 26.2, and 31.3%, respectively, after roasting at 1000 °C for 6 h. The effects of the main parameters on corrosion test were investigated, and the highest weight-gain ratio attained was 19.6%. FeOOH crystallizes on the surface of the nitrided V-slag due to the oxidization of metallic Fe. The phase evolution during the entire process is spinel/olivine/diopside → Fe/nitrides/diopside → FeOOH/nitrides/diopside. Owing to finer particle sizes, most FeOOH is separated by wet sieving (<1400 mesh). The purity of the enriched nitrides attained was 43% after pickling to remove excess Fe. The total recovery rates of Fe, V, Ti, Cr were 87.76%, 95.92%, 92.92%, 92.11%, respectively. This paper provides a sustainable strategy for the comprehensive utilization of V-slag, and guides the cleaner treatment of other similar minerals.

Endothelial PHD2 deficiency induces nitrative stress via suppression of caveolin-1 in pulmonary hypertension.

BACKGROUND: Nitrative stress is a characteristic feature of the pathology of human pulmonary arterial hypertension. However, the role of nitrative stress in the pathogenesis of obliterative vascular remodelling and severe pulmonary arterial hypertension remains largely unclear. METHOD: Our recently identified novel mouse model (Egln1Tie2Cre, Egln1 encoding prolyl hydroxylase 2 (PHD2)) has obliterative vascular remodelling and right heart failure, making it an excellent model to use in this study to examine the role of nitrative stress in obliterative vascular remodelling. RESULTS: Nitrative stress was markedly elevated whereas endothelial caveolin-1 (Cav1) expression was suppressed in the lungs of Egln1Tie2Cre mice. Treatment with a superoxide dismutase mimetic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride or endothelial Nos3 knockdown using endothelial cell-targeted nanoparticle delivery of CRISPR-Cas9/guide RNA plasmid DNA inhibited obliterative pulmonary vascular remodelling and attenuated severe pulmonary hypertension in Egln1Tie2Cre mice. Genetic restoration of Cav1 expression in Egln1Tie2Cre mice normalised nitrative stress, reduced pulmonary hypertension and improved right heart function. CONCLUSION: These data suggest that suppression of Cav1 expression secondary to PHD2 deficiency augments nitrative stress through endothelial nitric oxide synthase activation, which contributes to obliterative vascular remodelling and severe pulmonary hypertension. Thus, a reactive oxygen/nitrogen species scavenger might have therapeutic potential for the inhibition of obliterative vascular remodelling and severe pulmonary arterial hypertension.