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Background and Aims In patients with atrial fibrillation (AF), recurrent AF and sinus rhythm during follow-up are determined by interactions between cardiovascular disease processes and rhythm control therapy. Predictors of attaining sinus rhythm at follow-up are not well known. Methods To quantify the interaction between cardiovascular disease processes and rhythm outcomes, 14 biomarkers reflecting AF-related cardiovascular disease processes in 1586 patients in the EAST-AFNET 4 biomolecule study (71 years old, 45% women) were quantified at baseline. Mixed logistic regression models including clinical features were constructed for each biomarker. Biomarkers were interrogated for interaction with early rhythm control. Outcome was sinus rhythm at 12 months. Results were validated at 24 months and in external datasets. Results Higher baseline concentrations of three biomarkers were independently associated with a lower chance of sinus rhythm at 12 months: angiopoietin 2 (ANGPT2) (odds ratio [OR].76 [95% confidence interval.65–.89], P <.001), bone morphogenetic protein 10 (BMP10) (OR.83 [.71–.97], P =.017), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (OR.73 [.60–.88], P <.001). Analysis of rhythm at 24 months confirmed the results. Early rhythm control interacted with the predictive potential of NT-proBNP (P interaction =.033). The predictive effect of NT-proBNP was reduced in patients randomized to early rhythm control (usual care: OR.64 [.51–.80], P <.001; early rhythm control: OR.90 [.69–1.18], P =.453). External validation confirmed that low concentrations of ANGPT2, BMP10, and NT-proBNP predict sinus rhythm during follow-up. Conclusions Low concentrations of ANGPT2, BMP10, and NT-proBNP identify patients with AF who are likely to attain sinus rhythm during follow-up. The predictive ability of NT-proBNP is attenuated in patients receiving rhythm control. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) and heart failure frequently coexist. Prediction of left ventricular ejection fraction (LVEF) recovery after catheter ablation (CA) for AF remains difficult. The purpose of this study was to evaluate the value of biomarkers, alone and in combination with the Antwerp score, to predict LVEF recovery after CA for AF. Patients undergoing CA for AF with depressed LVEF (<50%) were included. Plasma levels of 13 biomarkers were measured immediately before CA. Patients were categorized into "responders" and "nonresponders" in a similar fashion to the Antwerp score performance derivation and validation cohorts. The predictive power of the biomarkers alone and combined in outcome prediction was evaluated. A total of 208 patients with depressed LVEF were included (median age 63 years; 39–19% female; median indexed left atrial volume 42 (33–52) mL/m2; median LVEF 43 (38–46)%). At a median follow-up time of 30 (20–34) months, 161 (77%) were responders and 47 (23%) were nonresponders. Of 13 biomarkers, –4—angiopoietin 2 (ANG2), growth differentiation factor 15 (GDF15), fibroblast growth factor 23, and myosin binding protein C3—were significantly different between responders and nonresponders (P ≤.001) and their combination could predict the end point with an area under the curve of 0.72 (95% confidence interval [CI] 0.64–0.81) overall, 0.69 (95% CI 0.59–0.78) in heart failure with mildly reduced ejection fraction, and 0.88 (95% CI 0.77–0.98) in heart failure with reduced ejection fraction. Only ANG2 and GDF15 remained significantly associated with LVEF recovery after adjustment for age, sex, and Antwerp score and significantly improved the accuracy of the Antwerp score predictions (P <.001). The area under the curve of the Antwerp score in the outcome prediction improved from 0.75 (95% CI 0.67–0.83) to 0.78 (95% CI 0.70–0.86). A biomarker panel (ANG2 and GDF15) significantly improved the accuracy of the Antwerp score. [Display omitted] [ABSTRACT FROM AUTHOR]

In 2018 there was a large yellow fever outbreak in São Paulo, Brazil, with a high fatality rate. Yellow fever virus can cause, among other symptoms, hemorrhage and disseminated intravascular coagulation, indicating a role for endothelial cells in disease pathogenesis. Here, we conducted a case-control study and measured markers related to endothelial damage in plasma and its association with mortality. We found that angiopoietin 2 is strongly associated with a fatal outcome and could serve as a predictive marker for mortality. This could be used to monitor severe cases and provide care to improve disease outcome. [ABSTRACT FROM AUTHOR]

Introduction: To assess changes in choriocapillaris (CC) vascular density surrounding macular neovascularization (MNV) in treatment-naïve age-related macular degeneration (AMD) after faricimab application using optical coherence tomography angiography (OCTA). Methods: Twenty-five eyes of 25 treatment-naïve individuals who underwent intravitreal faricimab injections for neovascular AMD (nAMD) with type 1 MNV were included. Spectral-domain optical coherence tomography (SD-OCT) images and en-face swept-source OCTA images were analyzed, and the percentage of CC flow deficit (FD%), FD average area (FDa) and FD number (FDn) in five progressive 20.0-μm-wide concentric rings (R1, R2, R3, R4 and R5) surrounding the dark halo around the MNV were calculated. Image acquisition was carried out prior to the first faricimab injection (T0) and 1 month after the injection (T1). Results: The topographical sub-analysis revealed noteworthy changes in all rings at T1 compared to T0. There was a notable progressive reduction in FD% at T1 compared to T0 values across all rings, indicating a gradual CC reperfusion following anti-VEGF treatment. Additionally, the average size of FD decreased after the loading phase. Although not reaching statistical significance, there was a progressive reduction in the FDa across all rings. Conclusion: Our study highlights a CC FD reduction following the administration of three consecutive faricimab injections. This effect was detected in all rings surrounding the dark halo. These observations suggest a partial CC reperfusion surrounding the MNV, potentially serving as an indicator for disease regression. [ABSTRACT FROM AUTHOR]

Abstract Introduction To assess changes in choriocapillaris (CC) vascular density surrounding macular neovascularization (MNV) in treatment-naïve age-related macular degeneration (AMD) after faricimab application using optical coherence tomography angiography (OCTA). Methods Twenty-five eyes of 25 treatment-naïve individuals who underwent intravitreal faricimab injections for neovascular AMD (nAMD) with type 1 MNV were included. Spectral-domain optical coherence tomography (SD-OCT) images and en-face swept-source OCTA images were analyzed, and the percentage of CC flow deficit (FD%), FD average area (FDa) and FD number (FDn) in five progressive 20.0-μm-wide concentric rings (R1, R2, R3, R4 and R5) surrounding the dark halo around the MNV were calculated. Image acquisition was carried out prior to the first faricimab injection (T0) and 1 month after the injection (T1). Results The topographical sub-analysis revealed noteworthy changes in all rings at T1 compared to T0. There was a notable progressive reduction in FD% at T1 compared to T0 values across all rings, indicating a gradual CC reperfusion following anti-VEGF treatment. Additionally, the average size of FD decreased after the loading phase. Although not reaching statistical significance, there was a progressive reduction in the FDa across all rings. Conclusion Our study highlights a CC FD reduction following the administration of three consecutive faricimab injections. This effect was detected in all rings surrounding the dark halo. These observations suggest a partial CC reperfusion surrounding the MNV, potentially serving as an indicator for disease regression.

To assess changes in choriocapillaris (CC) vascular density surrounding macular neovascularization (MNV) in age-related macular degeneration (AMD) when transitioning from various anti-VEGF treatments to faricimab, using optical coherence tomography angiography (OCTA). 25 eyes of 22 individuals who underwent intravitreal faricimab injections for neovascular AMD with type 1 MNV were included. OCTA images were obtained prior to (T0), after one (T1), and after three faricimab injections (T2); Noteworthy changes occurred in the first ring at T2 in comparison to T0. The percentage of CC flow deficit (FD%), FD average area (FDa), and FD number (FDn) in 5 rings (R1-R5) surrounding the dark halo around the MNV were calculated. A reduction in FD% at T2 compared to T0 (50.5 ± 10.2% at T0, 46.4 ± 10.6% at T2; p = 0.020) was seen, indicating CC reperfusion. Additionally, we observed a reduction in the average FDa (140.2 ± 172.1% at T0, 93.7 ± 101.8% at T2; p = 0.029). Our study highlights an FD% after three consecutive faricimab injections. The most pronounced effect was observed in the first ring, directly adjacent to the dark halo, suggesting a partial CC reperfusion surrounding the MNV, potentially indicating disease regression. [ABSTRACT FROM AUTHOR]

Abstract Management of vitreoretinal disorders (e.g., neovascular age-related macular degeneration [nAMD] and diabetic macular edema [DME]) have assumed the standard therapy of lifelong anti-VEGF injections with drugs like aflibercept, brolucizumab, ranibizumab and bevacizumab. However, the burden imposed on patients is a major deterrent for continual therapy and recovery. Faricimab, a bispecific antibody, blocking both VEGF-A and Ang-2 molecules, produces a comparable functional and anatomical results, with less injections, significantly reducing patient burden. Visual acuity, safety, adverse effects, and anatomical outcomes are discussed in the pivotal clinical trials (YOSEMITE/RHINE and TENAYA/LUCERNE), and early data from real-world studies (TRUCKEE, TAHOE, FARWIDE-DME, FARETINA and others). In YOSEMITE and RHINE, faricimab demonstrated non-inferior vision gains, better anatomical outcomes compared to aflibercept every 8 weeks. Faricimab in the personalized treatment interval (PTI), after week 96, achieved 12-week interval in 78.1% of the patients and 16-week interval in 62.3%. TENAYA and LUCERNE reported comparable best corrected visual acuity (BCVA) improvement and better anatomic outcomes during head-to-head phase, parallel to aflibercept, at its 8-week treatment schedule. Faricimab in the PTI regimen, after week 96 achieved 12-week interval in 77.8% of the patients and 16-week interval in 63.1%. Safety of faricimab has been comparable to aflibercept in these pivotal trials. Real-world data supports the data from the pivotal studies regarding the efficacy and safety profile of faricimab in heterogenous real world patient population. Moreover, in previously treated patients, it also demonstrated a faster fluid resolution, good safety profile. Considering faricimab has demonstrated anatomic and durability benefit in the treatment of nAMD and DME, additional data from ongoing extension clinical trials, AVONELLE-X and RHONE-X will help understand longer term outcomes for patients treated with faricimab as well as patients switching from aflibercept to faricimab after finishing the pivotal trials. Longer term data from the real-world studies will also continue to contribute to our understanding of long-term efficacy, safety and durability in the real world patient population.

Aims Different disease processes can combine to cause atrial fibrillation (AF). Their contribution to recurrent AF after ablation in patients is not known. Cardiovascular processes associated with recurrent AF after AF ablation were determined by quantifying biomolecules related to inflammation, metabolism, proliferation, fibrosis, shear stress, atrial pressure, and others in the AXAFA biomolecule study. Methods and results Twelve circulating cardiovascular biomolecules (ANGPT2, BMP10, CA125, hsCRP, ESM1, FABP3, FGF23, GDF15, IGFBP7, IL6, NT-proBNP, and hsTnT) were quantified in plasma samples obtained prior to a first AF ablation using high-throughput, high-precision assays. Cox regression was used to identify biomolecules associated with recurrent AF during the first 3 months after AF ablation. In 433 patients (64 years [58, 70]; 33% women), baseline concentrations of ANGPT2, BMP10, hsCRP, FGF23, FABP3, GDF15, and NT-proBNP were elevated in patients with recurrent AF (120/433; 28%). After adjustment for 11 clinical features and randomized treatment, elevated NT-proBNP [hazard ratio (HR) 1.58, 95% confidence interval (1.29, 1.94)], ANGPT2 [HR 1.37, (1.12, 1.67)], and BMP10 [HR 1.24 (1.02, 1.51)] remained associated with recurrent AF. Concentrations of ANGPT2, BMP10, and NT-proBNP decreased in patients who remained arrhythmia free, but not in patients with recurrent AF, highlighting their connection to AF. The other eight biomarkers showed unchanged concentrations. Conclusion Elevated concentrations of ANGPT2, BMP10, and NT-proBNP are associated with recurrent AF after a first AF ablation, suggesting that processes linked to disturbed cardiomyocyte metabolism, altered atrial shear stress, and increased load contribute to AF after AF ablation in patients. [ABSTRACT FROM AUTHOR]

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Abstract Background 5α-Hydroxycostic acid is a eudemane sesquiterpene that is isolated from the natural plant, Laggera alata. It exerts anti-inflammatory and anti-angiogenic effects on human breast cancer cells, but its role and underlying mechanism in choroidal neovascularization (CNV) are still unclear. We conducted a study to verify that 5α-Hydroxycostic acid can inhibit the formation and leakage of CNV, and describe the possible dual pathway by which it exerts its inhibitory effects in this process. Methods An in vitro model of choroidal neovascularization was established using VEGF164, while a rat model of choroidal neovascularization was established using a 532 nm laser. In both models, the effects of 5α-Hydroxycostic acid in vivo and in vitro were evaluated to determine its inhibitory effect on abnormal cell proliferation, migration and tubule formation, as well as its effect on pathological changes in choroidal tissues and the area of neovascularization leakage in rats. The levels of components in the VEGF/VEGFR and Ang2/Tie2 signaling pathways were measured in tissues and cells. Results In vitro experiments have shown that 5α-Hydroxycostic acid can inhibit abnormal cell proliferation, migration and angiogenesis. Additionally, 5α-Hydroxycostic acid enhances cell adhesion by inhibiting the phosphorylation pathways of VEGFR2 and Tie2. In vivo experiments demonstrated that 5α-Hydroxycostic acid has a positive therapeutic effect on choroidal neovascularization in rats. It can effectively reduce vascular leakage, consistent with the results of the cell experiments. Conclusion 5α-Hydroxycostic acid can inhibit choroidal neovascularization by interfering with the VEGF- and Ang2/Tie2-related pathways, and it may be a good candidate drug for treating CNV.

Background Individuals infected with HIV have an increased risk of developing cardiovascular disease; yet, the underlying mechanisms remain unknown. Recent evidence has implicated the Tie-2 tyrosine kinase receptor system and its associated ligands ANG1 (angiopoietin 1) and ANG2 (angiopoietin 2) in maintaining vascular homeostasis. In the general population, lower ANG1 levels and higher ANG2 levels are strongly correlated with the development of cardiovascular disease. In this study, we aim to investigate the associations of HIV infection with angiopoietin levels and endothelial dysfunction. Methods and Results In this cross-sectional study, we compared measures of ANG1, ANG2, and endothelial dysfunction using flow-mediated vasodilation of the brachial artery in 39 untreated subjects infected with HIV, 47 treated subjects infected with HIV, and 46 uninfected subjects from the SCOPE (Observational Study of the Consequences of the Protease Inhibitor Era) cohort. Compared with uninfected controls, treated individuals infected with HIV had 53.1% lower mean ANG1 levels (P

Background: 5α-Hydroxycostic acid is a eudemane sesquiterpene that is isolated from the natural plant, Laggera alata. It exerts anti-inflammatory and anti-angiogenic effects on human breast cancer cells, but its role and underlying mechanism in choroidal neovascularization (CNV) are still unclear. We conducted a study to verify that 5α-Hydroxycostic acid can inhibit the formation and leakage of CNV, and describe the possible dual pathway by which it exerts its inhibitory effects in this process. Methods: An in vitro model of choroidal neovascularization was established using VEGF164, while a rat model of choroidal neovascularization was established using a 532 nm laser. In both models, the effects of 5α-Hydroxycostic acid in vivo and in vitro were evaluated to determine its inhibitory effect on abnormal cell proliferation, migration and tubule formation, as well as its effect on pathological changes in choroidal tissues and the area of neovascularization leakage in rats. The levels of components in the VEGF/VEGFR and Ang2/Tie2 signaling pathways were measured in tissues and cells. Results: In vitro experiments have shown that 5α-Hydroxycostic acid can inhibit abnormal cell proliferation, migration and angiogenesis. Additionally, 5α-Hydroxycostic acid enhances cell adhesion by inhibiting the phosphorylation pathways of VEGFR2 and Tie2. In vivo experiments demonstrated that 5α-Hydroxycostic acid has a positive therapeutic effect on choroidal neovascularization in rats. It can effectively reduce vascular leakage, consistent with the results of the cell experiments. Conclusion: 5α-Hydroxycostic acid can inhibit choroidal neovascularization by interfering with the VEGF- and Ang2/Tie2-related pathways, and it may be a good candidate drug for treating CNV. [ABSTRACT FROM AUTHOR]

To assess changes in choriocapillaris (CC) vascular density surrounding macular neovascularization (MNV) in age-related macular degeneration (AMD) when transitioning from various anti-VEGF treatments to faricimab, using optical coherence tomography angiography (OCTA). 25 eyes of 22 individuals who underwent intravitreal faricimab injections for neovascular AMD with type 1 MNV were included. OCTA images were obtained prior to (T0), after one (T1), and after three faricimab injections (T2); Noteworthy changes occurred in the first ring at T2 in comparison to T0. The percentage of CC flow deficit (FD%), FD average area (FDa), and FD number (FDn) in 5 rings (R1-R5) surrounding the dark halo around the MNV were calculated. A reduction in FD% at T2 compared to T0 (50.5 ± 10.2% at T0, 46.4 ± 10.6% at T2; p = 0.020) was seen, indicating CC reperfusion. Additionally, we observed a reduction in the average FDa (140.2 ± 172.1% at T0, 93.7 ± 101.8% at T2; p = 0.029). Our study highlights an FD% after three consecutive faricimab injections. The most pronounced effect was observed in the first ring, directly adjacent to the dark halo, suggesting a partial CC reperfusion surrounding the MNV, potentially indicating disease regression.

BACKGROUND: How to effectively repair and reconstruct critical bone defects has become a difficult problem in clinical medicine. Dental pulp stem cells have certain advantages as transgenic target cells to repair damaged tissues or organs. OBJECTIVE: To investigate the effect of hypoxia-inducible factor-1α on osteogenesis and angiogenesis of dental pulp stem cells in vitro. METHODS: The pulp tissues of healthy and intact bicuspid teeth extracted by orthodontic treatment in patients aged 12 to 18 years were isolated to culture dental pulp stem cells. The hypoxia-inducible factor-1α gene was transfected into dental pulp stem cells in the experimental group. The control group did not do any treatment. The expression of the hypoxia-inducible factor 1α gene was detected by qPCR and the expression of osteogenic and angiogenic factors was detected by western blot assay. RESULTS AND CONCLUSION: (1) Dental pulp stem cells were short spindle-shaped fibroblast-like cells, and the cells grew in colonies. (2) Hypoxia-inducible factor-1α gene was stably transfected into dental pulp stem cells. The expression of the hypoxia-inducible factor-1α gene increased gradually with the extension of time, reached a peak at 14 days, and significantly decreased at 21 days. (3) Compared with the control group, the expression level of angiogenesis-related factors in the experimental group was higher. The protein expression levels of vascular endothelial growth factor, stromal cell-derived factor 1, angiopoietin 2, and placental growth factor were significantly increased at 1 day after gene transfection and reached a peak at 4 days. After that, the expression of angiogenesis-associated protein in the experimental group decreased slightly, but was significantly higher than that in the control group. (4) Compared with the control group, the expression level of osteogenic-related factors in the experimental group was higher. The protein expression levels of human bone morphogenetic protein 2, osteocalcin, and Runt-related transcription factor 2 were significantly increased at 1 day after gene transfection, with the highest protein expression at 4 days. (5) It is concluded that hypoxia-inducible factor-1α can promote the osteogenesis and the expression of angiogenic factors in dental pulp stem cells. [ABSTRACT FROM AUTHOR]

Abstract Macrotrabecular‐massive hepatocellular carcinoma (MTM‐HCC) is a subtype of HCC with a very poor prognosis and exhibits biological behaviors and clinical presentations that distinguish it from conventional HCC. Vessels encapsulating tumor clusters (VETC) is a unique pattern of vascular growth that is more common in patients with MTM‐HCC. This unique interaction between the angiogenic system and tumor cells is of general interest. Early diagnosis and appropriate treatment of HCC with MTM and VETC patterns help prevent early recurrence and improve prognosis. This review summarizes the existing findings for HCC with MTM and VETC patterns.

OBJECTIVES: Given the complex interrelatedness of fluid overload (FO), creatinine, acute kidney injury (AKI), and clinical outcomes, the association of AKI with poor outcomes in critically ill children may be underestimated due to definitions used. We aimed to disentangle these temporal relationships in a large cohort of children with acute respiratory distress syndrome (ARDS). DESIGN: Retrospective cohort study. SETTING: Quaternary care PICU. PATIENTS: Seven hundred twenty intubated children with ARDS between 2011 and 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Daily fluid balance, urine output (UOP), and creatinine for days 1–7 of ARDS were retrospectively abstracted. A subset of patients had angiopoietin 2 (ANGPT2) quantified on days 1, 3, and 7. Patients were classified as AKI by Kidney Disease Improving Global Outcomes (KDIGO) stage 2/3 then grouped by timing of AKI onset (early if days 1–3 of ARDS, late if days 4–7 of ARDS, persistent if both) for comparison of PICU mortality and ventilator-free days (VFDs). A final category of "Cryptic AKI" was used to identify subjects who met KDIGO stage 2/3 criteria only when creatinine was adjusted for FO. Outcomes were compared between those who had Cryptic AKI identified by FO-adjusted creatinine versus those who had no AKI. Conventionally defined AKI occurred in 26% of patients (early 10%, late 3%, persistent 13%). AKI was associated with higher mortality and fewer VFDs, with no differences according to timing of onset. The Cryptic AKI group (6% of those labeled no AKI) had higher mortality and fewer VFDs than patients who did not meet AKI with FO-adjusted creatinine. FO, FO-adjusted creatinine, and ANGPT2 increased 1 day prior to meeting AKI criteria in the late AKI group. CONCLUSIONS: AKI was associated with higher mortality and fewer VFDs in pediatric ARDS, irrespective of timing. FO-adjusted creatinine captures a group of patients with Cryptic AKI with outcomes approaching those who meet AKI by traditional criteria. Increases in FO, FO-adjusted creatinine, and ANGPT2 occur prior to meeting conventional AKI criteria. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) frequently affects patients with liver cirrhosis, diagnosed by changes in serum creatinine and urine output. This study aimed to evaluate the diagnostic and prognostic utility of serum cystatin C (Cys C) and angiopoietin 2 (Ang 2) in patients with liver cirrhosis complicated by AKI. Methods: A total of 81 cirrhotic patients with AKI were included. AKI was diagnosed according to Kidney Disease Improving Global Outcomes criteria. All patients were assessed clinically and biochemically. Baseline serum Cys C and Ang 2 were assessed, and patients were prospectively followed‐up to assess patients' and renal survival. Results: Cys C significantly predicted AKI (p < 0.001). Ang 2 (≤179.7 pg/ml) was an independent predictor of mortality in multivariate analysis. Marked ascites and partial pressure of carbon dioxide ≤ 29 were significant predictors of nonrenal recovery. Conclusion: Cys C showed validity AKI diagnosis in cirrhotic patients while Ang 2 was an independent predictor of mortality. [ABSTRACT FROM AUTHOR]

IntroductionKaposiform lymphangiomatosis (KLA) is a rare and complex lymphatic anomaly with a poor prognosis. There is no standard treatment, and drug therapies are the most common therapeutic method. However, some patients' symptoms become gradually aggravated despite medical treatment. Splenectomy may be an alternative option when pharmacological therapies are ineffective.Materials and MethodsWe reviewed and evaluated the cases of 3 patients with KLA who ultimately underwent splenectomy. Results: The lesions were diffusely distributed and involved the lungs and spleens of the 3 patients. Laboratory examinations revealed that all three patients had thrombocytopenia and reduced fibrinogen levels. All patients underwent symptomatic splenectomy after the medication failed. Surprisingly, their symptoms greatly improved. Histopathological investigation of the splenic lesions of the three patients confirmed the diagnosis of KLA. Immunohistochemical staining showed positivity for CD31, CD34, podoplanin, Prox-1 and angiopoietin 2 (Ang-2).DiscussionThis study aimed to review the features of KLA patients treated by splenectomy and explore the underlying link between splenectomy and prognosis. The reason for the improvement after splenectomy may be related to increased Ang-2 levels and platelet activation in patients with KLA. Future research should seek to develop more targeted drugs based on molecular findings, which may give new hope for the treatment of KLA.

Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed disease of uncertain etiology. Altered endothelial homeostasis, defective angiogenesis and inflammation are implicated. Angiopoietin 2 (Ang2) impairs acute thrombus resolution and is associated with vasculopathy in idiopathic pulmonary arterial hypertension. We assessed circulating proteins associated with these processes in serum from patients with CTEPH (n = 71) before and after pulmonary endarterectomy (PEA), chronic thromboembolic pulmonary disease without pulmonary hypertension (CTEPD, n = 9) and healthy controls (n = 20) using Luminex multiplex arrays. Comparisons between groups were made using multivariable rank regression models. Ang2 and high-sensitivity C-reactive protein (hsCRP) were measured in a larger validation dataset (CTEPH = 277, CTEPD = 26). Cox proportional hazards models were used to identify markers predictive of survival. In CTEPH patients, Ang2, interleukin (IL) 8, tumor necrosis factor α, and hsCRP were elevated compared to controls, while vascular endothelial growth factor (VEGF) c was lower (p < 0.05). Ang2 fell post-PEA (p < 0.05) and was associated with both pre- and post-PEA pulmonary hemodynamic variables and functional assessments (p < 0.05). In the validation dataset, Ang2 was significantly higher in CTEPH compared to CTEPD. Pre-operative hsCRP was an independent predictor of mortality. We hypothesize that CTEPH patients have significant distal micro-vasculopathy and consequently high circulating Ang2. Patients with CTEPD without pulmonary hypertension have no discernible distal micro-vasculopathy and therefore have low circulating Ang2. This suggests Ang2 may be critical to CTEPH disease pathogenesis (impaired thrombus organization and disease severity). [ABSTRACT FROM AUTHOR]

Increased angiogenesis, especially the pathological type, has been documented in Alzheimer's disease (AD) brains, and it is considered to be activated due to a vascular dysfunction-mediated hypoxic condition. To understand the role of the amyloid β (Aβ) peptide in angiogenesis, we analyzed its effects on the brains of young APP transgenic AD model mice. Immunostaining results revealed that Aβ was mainly localized intracellularly, with very few immunopositive vessels, and there was no extracellular deposition at this age. Solanum tuberosum lectin staining demonstrated that compared to their wild-type littermates, the vessel number was only increased in the cortex of J20 mice. CD105 staining also showed an increased number of new vessels in the cortex, some of which were partially positive for collagen4. Real-time PCR results demonstrated that placental growth factor (PlGF) and angiopoietin 2 (AngII) mRNA were increased in both the cortex and hippocampus of J20 mice compared to their wild-type littermates. However, vascular endothelial growth factor (VEGF) mRNA did not change. Immunofluorescence staining confirmed the increased expression of PlGF and AngII in the cortex of the J20 mice. Neuronal cells were positive for PlGF and AngII. Treatment of a neural stem cell line (NMW7) with synthetic Aβ1–42 directly increased the expression of PlGF and AngII, at mRNA levels, and AngII at protein levels. Thus, these pilot data indicate that pathological angiogenesis exists in AD brains due to the direct effects of early Aβ accumulation, suggesting that the Aβ peptide regulates angiogenesis through PlGF and AngII expression. [ABSTRACT FROM AUTHOR]

Background: Several biomarkers could be intercalated with traditional measures to improve ARDS diagnostics. Methods: There were 211 ICU patients enrolled in this retrospective, nested case-control study. Participants were divided into an ARDS (n = 79) and non-ARDS (n = 132) groups, according to the Berlin criteria. Patient characteristics, vital signs, and laboratory tests were collected within three hours of admission. CC16, Ang-2, sRAGE, HMGB1, and SPD were measured within three hours and again at 24 hours, after admission to ICU. Receiver Operating Characteristic curves and multivariate logistic regression analyses were applied for predictive purposes. Results: C-reactive protein (CRP), NT-proBNP, and pH values were intercalated with five established ARDS indicators, and the PaO2/FiO2 ratio. Only four potential indicators were analyzed, with CRP having high diagnostic value. Areas under curve (AUC) were as follows: CC16 (AUC: 0.752; 95% CI 0.680 - 0.824), Ang-2 (AUC: 0.695; 95% CI 0.620 - 0.770), HMGB1 (AUC: 0.668; 95% CI 0.592 - 0.744), sRAGE (AUC: 0.665; 95% CI 0.588 - 0.743), CRP (AUC: 0.701; 95% CI 0.627 - 0.776). No single indicator improved upon the PaO2/FiO2 ratio which had an AUC: 0.844 (95% CI 0.789 - 0.898). However, when the binary logistic model was transformed and the model was constructed, the AUC increased from 0.647 (95% CI 0.568 - 0.726) to 0.911 (95% CI 0.864 - 0.946). Among the combinations tested, PaO2/FiO2 + CRP + Ang-2 + CC16 + HMGB1 resulted in the highest AUC of 0.910 (95% CI 0.863 - 0.945), although there are other factors which must be considered. Conclusions: A combination of biomarkers could enhance ARDS diagnostics, which has obvious ramifications for patient care and prognosis. It may be possible to develop a predictive ARDS nomogram; however, of the combinations tested here, we tentatively recommend PaO2/FiO2 + CRP + Ang-2 + CC16 + HMGB1. This is because of the cost implications in contrast with benefit involved in utilizing the more elaborate model. Further health economics research is required to consider the opportunity cost for emergency care policy. [ABSTRACT FROM AUTHOR]

Introduction: There are few circulating biomarkers for valvular heart disease. Angiopoietin (Ang) 1, Ang2, and vascular endothelial growth factor are important inflammation-associated cytokines. The aim of this study was to investigate the clinical significance and association of Ang1, Ang2, and vascular endothelial growth factor in valvular heart disease. Methods: This is a retrospective study; a total of 62 individuals (valvular heart disease patients [n=42] and healthy controls [n=20]) were included. Plasma levels of Ang1, Ang2, and vascular endothelial growth factor were detected by enzyme-linked immunosorbent assays. We retrospectively collected the baseline characteristics and short-term outcomes; logistic regression was performed to identify predictor for short-term mortality. Results: Ang2 was significantly decreased in the valvular heart disease group compared with the healthy control group (P=0.023), while no significant difference was observed in the Ang1 and vascular endothelial growth factor levels. The Ang2 level of New York Heart Association (NYHA) I/II patients -- but not NYHA III/IV patients -- was significantly decreased compared with that of healthy control individuals (NYHA I/II: P=0.017; NYHA III/IV: P=0.485). Univariable logistic regression analysis indicated that Ang2 was a significant independent predictor for short-term mortality (odds ratio 18.75, P=0.033, 95% confidence interval 8.08-102.33). Ang1 was negatively correlated with Ang2 (P=0.032, Pearson's correlation coefficient = -0.317) and was positively correlated with vascular endothelial growth factor (P=0.019, Pearson's correlation coefficient = 0.359). Conclusion: Ang2 might serve as a therapeutic and prognostic target for valvular heart disease. [ABSTRACT FROM AUTHOR]

Abstract Cardiac remodeling is the initial process in heart failure development. The aim of this study is to evaluate the association between endothelium‐related biomarkers and cardiac remodeling in hemodialysis (HD) patients and how the presence of high blood pressure and diabetes mellitus modulates these associations. This was a cross‐sectional study with adult HD and normal left ventricular (LV) ejection fraction—LVEF—patients. The authors correlated several endothelium‐related biomarkers with echocardiographic indices—LV mass index (LVMi), LVEF, global longitudinal strain, mitral E/e’, and aortic root diameter. Seventy‐one patients were included, with 37 women (52.1%) and mean age of 54.3 ± 16.8 years. Angiopoietin‐2 (AGPT2) was inversely correlated with global longitudinal strain (r = ‐.374, p = .001) and directly with E/e’ (r = .265, p = .025). After adjustment, only AGPT2 was significantly associated with global longitudinal strain. blood pressure and diabetes mellitus were independent moderators for the AGPT2 and global longitudinal strain association. The conditional association was significant only when the mean pre‐HD blood pressure was above 97.5 mmHg or in diabetes mellitus patients. Finally, there was an interaction between diabetes mellitus and blood pressure when moderating the conditional effect of AGPT2 on global longitudinal strain. While in non‐diabetic patients, the association between AGPT2 with global longitudinal strain was significant only with pre‐HD blood pressure levels as high as 110 mmHg, in diabetic patients, this association was significant with pre‐HD blood pressure as low as 90 mmHg. Higher levels of AGPT2 were associated with worse cardiac function as determined by lower global longitudinal strain values. This association was moderated by blood pressure and diabetes mellitus, suggesting that the effects of AGPT2 on cardiac remodeling is dependent of such circumstances.

Abstract Invasive nonfunctioning (NF) pituitary neuroendocrine tumors (PitNETs) are non‐resectable neoplasms associated with frequent relapses and significant comorbidities. As the current therapies of NF‐PitNETs often fail, new therapeutic targets are needed. The observation that circulating angiopoietin‐2 (ANGPT2) is elevated in patients with NF‐PitNET and correlates with tumor aggressiveness prompted us to investigate the ANGPT2/TIE2 axis in NF‐PitNETs in the GH3 PitNET cell line, primary human NF‐PitNET cells, xenografts in zebrafish and mice, and in MENX rats, the only autochthonous NF‐PitNET model. We show that PitNET cells express a functional TIE2 receptor and secrete bioactive ANGPT2, which promotes, besides angiogenesis, tumor cell growth in an autocrine and paracrine fashion. ANGPT2 stimulation of TIE2 in tumor cells activates downstream cell proliferation signals, as previously demonstrated in endothelial cells (ECs). Tie2 gene deletion blunts PitNETs growth in xenograft models, and pharmacological inhibition of Angpt2/Tie2 signaling antagonizes PitNETs in primary cell cultures, tumor xenografts in mice, and in MENX rats. Thus, the ANGPT2/TIE2 axis provides an exploitable therapeutic target in NF‐PitNETs and possibly in other tumors expressing ANGPT2/TIE2. The ability of tumor cells to coopt angiogenic signals classically viewed as EC‐specific expands our view on the microenvironmental cues that are essential for tumor progression.

OBJECTIVE: To investigate the curative effect of Ang-2 combined with novel carbon nanotubes (CNTs) scaffold critical-size bone defect in rabbits. MATERIALS AND METHODS: CNTs with good properties were first prepared by freeze-drying method. The mechanical properties and surface hydrophilicity of scaffolds were improved by adjusting the addition ratio of polylactic acid (LPA) and chitin fibers (CHI). After purification and functionalization of CNTs, CNTs/PLA/ CHI three-dimensional porous scaffolds were prepared for animal experiments. Subsequently, the CNTs/PLA/CHI scaffolds were implanted into the rabbit critical-sized radius defect model to evaluate the osteogenic properties in vivo. Adult male New Zealand white rabbits were randomly allocated into three groups. Group A was the control group, and both groups B and C underwent radial bone defect surgery and implanted CNTs/PLA/CHI scaffolds. Animals in group C received a daily local injection of 1 mL of 400 ng/mL Ang-2 dissolved in physiological saline in the bone defect area for up to 14 days after surgery, while group B received the same amount of physiological saline. RESULTS: Scanning electron microscope results showed that the porosity of the CNTs/PLA/ CHI three-dimensional porous scaffolds was as high as 80%. The surface contact angle was 35° to 55°, and the hydrophilicity was suitable for cell adhesion and growth. The CNTs/PLA/CHI three-dimensional porous scaffolds had excellent biological properties. The general observation and X-ray imaging after 12 weeks together indicated that the CNTs/PLA/CHI scaffolds could accelerate bone repair with the combination of endogenous angiogenic factor Ang2. The results of western blotting and histology revealed that the expression of mitophagy proteins LC3, Beclin-1, PINK1 and Parkin was elevated in the new bone, and the expression of pyroptosis proteins Nod-like receptor protein NLRP3, caspase-1 and Gasdermin D (GSDMD) was decreased. CONCLUSIONS: Ang-2 associated with CNTs/ PLA/CHI scaffolds accelerated bone regeneration through autophagy-pyroptosis pathway. [ABSTRACT FROM AUTHOR]

Angiogenic factors play an important role in protecting, repairing, and reconstructing vessels after ischemic stroke. In the brains of transient focal cerebral ischemic mice, we observed a reduction in infarct volume after the administration of Angiopoietin 2 (Angpt2), but whether this process is promoted by Angpt2-induced angiogenesis has not been fully elaborated. Therefore, this study explored the angiogenic activities, in reference to CD34 which is a marker of activated ECs and blood vessels, of cultured ECs in vitro and in ischemic damaged cerebral area in mice following Angpt2 administration. Our results demonstrate that Angpt2 administration (100 ng/mL) is neuroprotective by significantly increasing the CD34 expression in in vitro-cultured ECs, reducing the infarct volume and mitigating neuronal loss, as well as enhancing CD34+ vascular length and area. In conclusion, these results indicate that Angpt2 promotes repair and attenuates ischemic injury, and that the mechanism of this is closely associated with angiogenesis in the brain after stroke. [ABSTRACT FROM AUTHOR]

To investigate the expression of serum vascular endothelial cadherin (VE CAD), angiopoietin-2 (Ang-2) and urinary renal injury molecule-1 (KIM-1) in patients with renal failure and their correlation with the severity of the disease. 76 patients with chronic renal failure treated in our hospital from February 2018 to February 2021 were selected as the research objects. They were divided into renal function compensation group (n=25), azotemia group (n=18), renal failure group (n=21) and uremia group (n=12) according to the severity of their condition. The expressions of ve-cad, Ang-2 and KIM-1 in the four groups were compared and analyzed Correlation between KIM-1 and the severity of chronic renal failure. All patients were followed up by telephone or reexamination. 76 patients with chronic renal failure were divided into two subgroups according to the prognosis, survival group (n=56) and death group (n=20). The clinical conditions and index levels of the two groups were compared, and the predictive value of ve-cad, Ang-2 and KIM-1 on the prognosis of chronic renal failure was analyzed by logistic regression analysis. The expression levels of ve-cad, Ang-2 and KIM-1 in uremia group were significantly higher than those in renal failure group, azotemia group and renal function compensation group (P<0.05); Spearman correlation analysis showed that VE CAD, Ang-2 and KIM-1 were positively correlated with the severity of chronic renal failure (P<0.05); There was no significant difference in gender, age, BMI, organ failure ≥ 2, oliguria and ve CAD between the survival group and the death group (P>0.05). There was significant difference in Apache Ⅱ score, CysC, Ang-2 and KIM-1 between the survival group and the death group (P<0.05); Logistic regression analysis showed that Apache Ⅱ score, CysC and KIM-1 were independent risk factors affecting the prognosis of chronic renal failure (P<0.05). Ve-cad, Ang-2 and KIM-1 are positively correlated with the severity of patients with chronic renal failure. It can be considered to evaluate the severity of patients with chronic renal failure by referring to the levels of the three. Among the three, only KIM-1 has a certain relationship with the prognosis of patients with renal failure. Therefore, it can be considered to add KIM-1 index to judge on the basis of Apache Ⅱ score and CysC prediction of prognosis, so as to improve the accuracy of prognosis prediction. [ABSTRACT FROM AUTHOR]

BACKGROUND: Severe cases of coronavirus disease 2019 (COVID-19) are characterized by progressive respiratory failure and the development of acute respiratory distress syndrome (ARDS), with high mortality rates for patients requiring mechanical ventilation. Levels of the vascular growth factor Angiopoietin 2 (Ang2) in plasma have been strongly correlated with increased ARDS risk in patients with pneumonia or sepsis. The intent of this study was to determine whether LY3127804, an anti-Ang2 monoclonal antibody, could reduce the need for mechanical ventilation among patients admitted to the hospital with pneumonia and presumed or confirmed COVID-19. METHODS: Patients admitted to hospital with confirmed pneumonia, presumed or confirmed COVID-19, and infiltrates on chest imaging and/or oxygen saturation of ≤ 95% on room air were stratified by age group (< 65 years and ≥ 65 years), sex, and site and randomly assigned 1:1 within each stratum to receive either LY3127804 (20 mg/kg) or placebo on Day 1 and possibly on Day 15. The primary end point for this study was number of days in which a patient did not require a ventilator over the 28-day study period. RESULTS: Interim analysis assessed study futility after 95 randomized patients had 28-day data available and showed no benefit of LY3127804 in reducing the number of ventilator days over placebo. The study was subsequently terminated. CONCLUSION: LY3127804 treatment did not decrease the need for ventilator usage in patients hospitalized with pneumonia and presumed or confirmed COVID-19. ClinicalTrials.gov identifier: NCT04342897 [ABSTRACT FROM AUTHOR]

Diabetes is a disease that leads to proliferative diabetic retinopathy (PDR), which is associated with an increase of new vessels formation due to an overexpression of angiogenic factors, such as angiopoietin 2 (ANGPT2). The aim of this work was to design a siRNA targeting ANGPT2 to decrease the retinal neovascularization associated with PDR. Adult male Wistar rats weighing 325–375 g were used. Diabetes was induced by a single dose of streptozotocin (STZ, 60 mg/kg i.p.). The siRNAs were designed, synthesised, and administered intravitreally at the beginning of diabetes induction (t0), and after 4 weeks of diabetes evolution (t4), subsequently evaluated the retinal neovascularization (junctions and lacunarity) and ANGPT2 expression in the retina by RT-PCR, after 4 weeks of the siRNAs administration. The results showed that the administration of STZ produced significant increases in blood glucose levels, retinal neovascularization (augmented junctions and lower lacunarity), and ANGPT2 expression, while the administration of the ANGPT2-siRNAs at different groups (t0 and t4) reduces the junctions and increases the lacunarity in diabetic rats. Therefore, we conclude that the administration of siRNAs targeting ANGPT2 could be an option to decrease the retinal neovascularization associated with PDR and halt the progression of blindness caused by diabetes. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is a common malignant tumor with a poor prognosis and is a major public health burden in Taiwan. Angiogenesis, the formation of new blood vessels, promotes tumor proliferation, maintenance, and metastasis. Angiopoietin 2 (Angpt2), a mitogen with a strong angiogenic effect, is highly specific to endothelial cells and a key player in angiogenesis. The inflammatory chemokine (C-C motif) ligand 4 (CCL4) is also important in the pathogenesis and progression of cancer. In this study, an analysis of records from The Cancer Genome Atlas (TCGA) database found higher CCL4 expression in oral cancer tissue than in normal healthy tissue. CCL4 treatment of oral cancer cells upregulated Angpt2 expression and stimulated mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase 1/2 (ERK), and signal transducer and activator of transcription 3 (STAT3) phosphorylation. Transfection of oral cancer cells with MEK, ERK, and STAT3 inhibitors and their small interfering RNAs inhibited CCL4-induced promotion of Angpt2 expression and angiogenesis. In a mouse model of OSCC, CCL4-treated cells promoted neovascularization in implanted Matrigel plugs, whereas inhibiting CCL4 expression suppressed Angpt2 expression and angiogenesis. CCL4 shows promise as a new molecular therapeutic target for inhibiting angiogenesis and metastasis in OSCC. [ABSTRACT FROM AUTHOR]

Invasive nonfunctioning (NF) pituitary neuroendocrine tumors (PitNETs) are non‐resectable neoplasms associated with frequent relapses and significant comorbidities. As the current therapies of NF‐PitNETs often fail, new therapeutic targets are needed. The observation that circulating angiopoietin‐2 (ANGPT2) is elevated in patients with NF‐PitNET and correlates with tumor aggressiveness prompted us to investigate the ANGPT2/TIE2 axis in NF‐PitNETs in the GH3 PitNET cell line, primary human NF‐PitNET cells, xenografts in zebrafish and mice, and in MENX rats, the only autochthonous NF‐PitNET model. We show that PitNET cells express a functional TIE2 receptor and secrete bioactive ANGPT2, which promotes, besides angiogenesis, tumor cell growth in an autocrine and paracrine fashion. ANGPT2 stimulation of TIE2 in tumor cells activates downstream cell proliferation signals, as previously demonstrated in endothelial cells (ECs). Tie2 gene deletion blunts PitNETs growth in xenograft models, and pharmacological inhibition of Angpt2/Tie2 signaling antagonizes PitNETs in primary cell cultures, tumor xenografts in mice, and in MENX rats. Thus, the ANGPT2/TIE2 axis provides an exploitable therapeutic target in NF‐PitNETs and possibly in other tumors expressing ANGPT2/TIE2. The ability of tumor cells to coopt angiogenic signals classically viewed as EC‐specific expands our view on the microenvironmental cues that are essential for tumor progression. Synopsis: There is currently no treatment for nonfunctioning pituitary neuroendocrine tumors (NF‐PitNETs), which are intracranial tumors associated with frequent relapse and severe comorbidities. This study establishes the ANGPT2/Tie2 signaling axis as a novel therapeutic target for NF‐PitNETs. Circulating ANGPT2 levels were elevated in NF‐PitNET patients and correlated with tumor proliferation rate, an indicator of tumor aggressiveness.Bioactive ANGPT2 was expressed and secreted by NF‐PitNET cells, and promoted angiogenesis and tumor cell growth in an autocrine and paracrine fashion.Functional TIE2 receptor was expressed by NF‐PitNET cells, and was directly activated by angiopoietins.PitNET cell growth was suppressed upon TIE2 knockout in mouse xenografts in vivo.ANGPT2/TIE2 pharmacological inhibition reduced the growth of NF‐PitNET primary tumor cells in vitro, as well as tumor xenografts and autochthonous NF‐PitNETs in MENX rats. [ABSTRACT FROM AUTHOR]

To study the relationship between serum angiopoietin 2 (Ang-2), potential transforming growth factor binding protein 2 (LTBP2), chemokine ligand 14 (CXCL14) and prognosis in patients with idiopathic pulmonary fibrosis (IPF). A total of 100 patients with IPF admitted to the Department of Respiratory Medicine, East Hospital of the Second Hospital of Hebei Medical University from March 2019 to March 2020 were selected as the study subjects. According to the follow-up results, they were divided into 59 cases in the poor prognosis group and 41 cases in the good prognosis group. The levels of Ang-2, LTBP2 and CXCL14, lung function indexes, laboratory indexes and baseline data were compared between the two groups. Pearson correlation analysis was used to analyze the correlation between the levels of Ang-2, LTBP2 and CXCL14 and lung function. Multivariate logistic regression analysis was used to analyze the factors affecting the prognosis of patients with IPF. Receiver operating characteristic (ROC) curve was used to analyze the predictive value of Ang-2, LTBP2 and CXCL14 on the prognosis of patients with IPF. The levels of Ang-2, LTBP2 and CXCL14 in the poor prognosis group were higher than those in the good prognosis group (P＜0.05). The forced expiratory volume at 1 s (FVC1), the percentage of carbon monoxide dispersion in the predicted value (DLCO%) and arterial partial pressure of oxygen (PaO2) / oxygen volume fraction (FiO2) in the poor prognosis group were lower than those in the good prognosis group, while the proportion of smoking history and pulmonary hypertension was higher than those in the poor prognosis group (P<0.05). Pearson correlation analysis showed that Ang-2, LTBP2 and CXCL14 levels were negatively correlated with FVC1 and DLCO% in IPF patients (P<0.05). Multivariate Logistic regression analysis showed that FVC1, DLCO%, PaO2/FiO2, smoking history, pulmonary hypertension and serum Ang-2, LTBP2 and CXCL14 levels were the influencing factors for poor prognosis of IPF patients (P<0.05). ROC curve analysis showed that the area under curve of Ang-2, LTBP2 and CXCL14 in predicting the poor prognosis of patients with IPF was higher than that of the above three indexes. The levels of serum Ang-2, LTBP2 and CXCL14 in patients with IPF are closely related to the prognosis, which can be used as an auxiliary index for early monitoring the prognosis. [ABSTRACT FROM AUTHOR]

Cardiac remodeling is the initial process in heart failure development. The aim of this study is to evaluate the association between endothelium‐related biomarkers and cardiac remodeling in hemodialysis (HD) patients and how the presence of high blood pressure and diabetes mellitus modulates these associations. This was a cross‐sectional study with adult HD and normal left ventricular (LV) ejection fraction—LVEF—patients. The authors correlated several endothelium‐related biomarkers with echocardiographic indices—LV mass index (LVMi), LVEF, global longitudinal strain, mitral E/e', and aortic root diameter. Seventy‐one patients were included, with 37 women (52.1%) and mean age of 54.3 ± 16.8 years. Angiopoietin‐2 (AGPT2) was inversely correlated with global longitudinal strain (r = ‐.374, p =.001) and directly with E/e' (r =.265, p =.025). After adjustment, only AGPT2 was significantly associated with global longitudinal strain. blood pressure and diabetes mellitus were independent moderators for the AGPT2 and global longitudinal strain association. The conditional association was significant only when the mean pre‐HD blood pressure was above 97.5 mmHg or in diabetes mellitus patients. Finally, there was an interaction between diabetes mellitus and blood pressure when moderating the conditional effect of AGPT2 on global longitudinal strain. While in non‐diabetic patients, the association between AGPT2 with global longitudinal strain was significant only with pre‐HD blood pressure levels as high as 110 mmHg, in diabetic patients, this association was significant with pre‐HD blood pressure as low as 90 mmHg. Higher levels of AGPT2 were associated with worse cardiac function as determined by lower global longitudinal strain values. This association was moderated by blood pressure and diabetes mellitus, suggesting that the effects of AGPT2 on cardiac remodeling is dependent of such circumstances. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: There are few circulating biomarkers for valvular heart disease. Angiopoietin (Ang) 1, Ang2, and vascular endothelial growth factor are important inflammation-associated cytokines. The aim of this study was to investigate the clinical significance and association of Ang1, Ang2, and vascular endothelial growth factor in valvular heart disease. Methods: This is a retrospective study; a total of 62 individuals (valvular heart disease patients [n=42] and healthy controls [n=20]) were included. Plasma levels of Ang1, Ang2, and vascular endothelial growth factor were detected by enzyme-linked immunosorbent assays. We retrospectively collected the baseline characteristics and short-term outcomes; logistic regression was performed to identify predictor for short-term mortality. Results: Ang2 was significantly decreased in the valvular heart disease group compared with the healthy control group (P=0.023), while no significant difference was observed in the Ang1 and vascular endothelial growth factor levels. The Ang2 level of New York Heart Association (NYHA) I/II patients — but not NYHA III/IV patients — was significantly decreased compared with that of healthy control individuals (NYHA I/II: P=0.017; NYHA III/IV: P=0.485). Univariable logistic regression analysis indicated that Ang2 was a significant independent predictor for short-term mortality (odds ratio 18.75, P=0.033, 95% confidence interval 8.08-102.33). Ang1 was negatively correlated with Ang2 (P=0.032, Pearson’s correlation coefficient =-0.317) and was positively correlated with vascular endothelial growth factor (P=0.019, Pearson’s correlation coefficient = 0.359). Conclusion: Ang2 might serve as a therapeutic and prognostic target for valvular heart disease.

In 2018 there was a large yellow fever outbreak in São Paulo, Brazil, with a high fatality rate. Yellow fever virus can cause, among other symptoms, hemorrhage and disseminated intravascular coagulation, indicating a role for endothelial cells in disease pathogenesis. Here, we conducted a case-control study and measured markers related to endothelial damage in plasma and its association with mortality. We found that angiopoietin 2 is strongly associated with a fatal outcome and could serve as a predictive marker for mortality. This could be used to monitor severe cases and provide care to improve disease outcome., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

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To investigate VEGF and Ang-2 level changes in the systemic circulation after laser photocoagulation in premature infants with ROP. Methods: Eleven infants (4 girls and 7 boys) had serum levels determined for VEGF and Ang-2, collected 1 day prior to and 7 days after ROP laser therapy. Serum levels of VEGF and Ang-2 were quantified by enzyme-linked immunosorbent assay (ELISA). Results: Serum VEGF levels were significantly lower at 7 days after laser therapy compared to that at 1 day prior to laser therapy (p = 0.045). Serum Ang-2 levels increased significantly at 7 days after laser therapy compared with that at 1 day prior to laser therapy (p = 0.046). Conclusions: Serum VEGF levels in patients with ROP were suppressed and Ang-2 levels elevated significantly after laser therapy. The results suggest that changes in VEGF and Ang-2 serum levels may reflect regression and treatment of ROP. [ABSTRACT FROM AUTHOR]

Biomarker-assisted diagnosis of acute aortic dissection (AAD) is important for initiation of treatment and improved survival. However, identification of biomarkers for AAD in blood is a challenging task. The present study aims to find the potential AAD biomarkers using a transcriptomic strategy. Arrays based genome-wide gene expression profiling were performed using ascending aortic tissues which were collected from AAD patients and healthy donors. The differentially expressed genes were validated using quantitative reverse transcriptase PCR (qRT-PCR) and western blot. The plasma levels of a potential biomarker, angiopoietin 2 (ANGPT2) were determined in case-control cohort (77 AAD patients and 82 healthy controls) by enzyme linked immunosorbent assay. Receiver operating characteristic curve (ROC) was used to evaluate the diagnostic power of ANGPT2 for AAD. Transcriptome data demonstrated that a total of 18 genes were significantly up-regulated and 28 genes were significantly down-regulated among AAD tissues (foldchange>3.0, p < 0.01). By bioinformatic analysis, we identified ANGPT2 as a candidate biomarker for blood-based detection of AAD. The qRT-PCR and protein expression demonstrated that ANGPT2 increased 2.4- and 4.2 folds, respectively in aortic tissue of AAD patients. Immunohistochemical staining demonstrated that ANGPT2 was markedly increased in intima of the aortic wall in AAD. Furthermore, ANGPT2 was significantly elevated in AAD patients as compared with controls (median 1625 vs. 383 pg/ml, p < 1E-6). ROC curve analysis showed that ANGPT2 was highly predictive of a diagnosis of type A AAD (area under curve 0.93, p < 1E-6). Sensitivity and specificity were 81 and 90%, respectively at the cutoff value of 833 pg/ml. In conclusion, ANGPT2 could be a promising biomarker for diagnosis of AAD; however, more studies are still needed to verify its specificity in diagnosing of AAD.

Background Individuals infected with HIV have an increased risk of developing cardiovascular disease; yet, the underlying mechanisms remain unknown. Recent evidence has implicated the Tie‐2 tyrosine kinase receptor system and its associated ligands ANG1 (angiopoietin 1) and ANG2 (angiopoietin 2) in maintaining vascular homeostasis. In the general population, lower ANG1 levels and higher ANG2 levels are strongly correlated with the development of cardiovascular disease. In this study, we aim to investigate the associations of HIV infection with angiopoietin levels and endothelial dysfunction. Methods and Results In this cross‐sectional study, we compared measures of ANG1, ANG2, and endothelial dysfunction using flow‐mediated vasodilation of the brachial artery in 39 untreated subjects infected with HIV, 47 treated subjects infected with HIV, and 46 uninfected subjects from the SCOPE (Observational Study of the Consequences of the Protease Inhibitor Era) cohort. Compared with uninfected controls, treated individuals infected with HIV had 53.1% lower mean ANG1 levels (P

Angiogenic factors play an important role in protecting, repairing, and reconstructing vessels after ischemic stroke. In the brains of transient focal cerebral ischemic mice, we observed a reduction in infarct volume after the administration of Angiopoietin 2 (Angpt2), but whether this process is promoted by Angpt2-induced angiogenesis has not been fully elaborated. Therefore, this study explored the angiogenic activities, in reference to CD34 which is a marker of activated ECs and blood vessels, of cultured ECs in vitro and in ischemic damaged cerebral area in mice following Angpt2 administration. Our results demonstrate that Angpt2 administration (100 ng/mL) is neuroprotective by significantly increasing the CD34 expression in in vitro-cultured ECs, reducing the infarct volume and mitigating neuronal loss, as well as enhancing CD34+ vascular length and area. In conclusion, these results indicate that Angpt2 promotes repair and attenuates ischemic injury, and that the mechanism of this is closely associated with angiogenesis in the brain after stroke.

Diabetic Nephropathy (DN) is considered a serious capillary complication of diabetes mellitus (DM) which leads to end-stage renal disease. Endostatin (EST) is considered as collagen XVIII fragment formed during extracellular matrix remodeling (ECMR). EST acts as an anti-angiogenic factor. Angiopoietin-2 (Ang II) is a growth factor that increases in several conditions, such as hyperglycemia. The present study was to scrutinize the association of EST and Ang II serum levels with nephropathy in patients with type 2 diabetes mellitus (T2DM). A total of 30 healthy individuals (control) and 120 T2DM patients classified into 60 patients with microalbuminuria and 60 patients without microalbuminuria), aged 45-65 years were included. Fasting Plasma Glucose (FPG), HbA1C%, lipid profile, urinary albumin/creatinine ratio of 30-300 mg/g (UACR), serum urea and creatinine levels were assessed. Both EST and Ang II were measured using the ELISA technique. Ang II and EST levels were elevated in patients with T2DM groups compared with the healthy control group (P

Oral squamous cell carcinoma (OSCC) is a common malignant tumor with a poor prognosis and is a major public health burden in Taiwan. Angiogenesis, the formation of new blood vessels, promotes tumor proliferation, maintenance, and metastasis. Angiopoietin 2 (Angpt2), a mitogen with a strong angiogenic effect, is highly specific to endothelial cells and a key player in angiogenesis. The inflammatory chemokine (C-C motif) ligand 4 (CCL4) is also important in the pathogenesis and progression of cancer. In this study, an analysis of records from The Cancer Genome Atlas (TCGA) database found higher CCL4 expression in oral cancer tissue than in normal healthy tissue. CCL4 treatment of oral cancer cells upregulated Angpt2 expression and stimulated mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase 1/2 (ERK), and signal transducer and activator of transcription 3 (STAT3) phosphorylation. Transfection of oral cancer cells with MEK, ERK, and STAT3 inhibitors and their small interfering RNAs inhibited CCL4-induced promotion of Angpt2 expression and angiogenesis. In a mouse model of OSCC, CCL4-treated cells promoted neovascularization in implanted Matrigel plugs, whereas inhibiting CCL4 expression suppressed Angpt2 expression and angiogenesis. CCL4 shows promise as a new molecular therapeutic target for inhibiting angiogenesis and metastasis in OSCC.

Secretory phospholipase A 2 (PLA 2) hydrolyzes LDL phospholipids generating modified LDL particles (PLA 2 -LDL) with increased atherogenic properties. Exocytosis of Weibel–Palade bodies (WPB) releases angiopoietin 2 (Ang2) and externalizes P-selectin, which both play important roles in vascular inflammation. Here, we investigated the effects of PLA 2 -LDL on exocytosis of WPBs. Human coronary artery endothelial cells (HCAECs) were stimulated with PLA 2 - LDL, and its uptake and effect on Ang2 release, leukocyte adhesion, and intracellular calcium levels were measured. The effects of PLA 2 -LDL on Ang2 release and WPB exocytosis were measured in and ex vivo in mice. Exposure of HCAECs to PLA 2 -LDL triggered Ang2 secretion and promoted leukocyte-HCAEC interaction. Lysophosphatidylcholine was identified as a critical component of PLA 2 -LDL regulating the WPB exocytosis, which was mediated by cell-surface proteoglycans, phospholipase C, intracellular calcium, and cytoskeletal remodeling. PLA 2 -LDL also induced murine endothelial WPB exocytosis in blood vessels in and ex vivo, as evidenced by secretion of Ang2 in vivo, P-selectin translocation to plasma membrane in intact endothelial cells in thoracic artery and tracheal vessels, and reduced Ang2 staining in tracheal endothelial cells. Finally, in contrast to normal human coronary arteries, in which Ang2 was present only in the endothelial layer, at sites of advanced atherosclerotic lesions, Ang2 was detected also in the intima, media, and adventitia. Our studies reveal PLA 2 -LDL as a potent agonist of endothelial WPB exocytosis, resulting in increased secretion of Ang2 and translocation of P-selectin. The results provide mechanistic insight into PLA 2 -LDL-dependent promotion of vascular inflammation and atherosclerosis. • Phospholipase A 2 -modified LDL induces secretion of angiopoietin 2 and translocation of P-selectin from endothelial cells. • Lysophosphatidylcholine is responsible for the effect of phospholipase A 2 -modified LDL on endothelial cells. • Phospholipase A 2 -modified LDL mediates its effects via cell surface proteoglycans. [ABSTRACT FROM AUTHOR]

Objective To investigate the level changes of serum clara-cell protein 16(CC16)and angiopoietin 2 (Ang-2)in patients with severe pneumonia and their predictive value on prognosis. Methods A total of 132 patients with severe pneumonia were selected as the severe pneumonia group, and 100 healthy subjects were selected as the healthy control group. The levels of serum Ang-2 and CC16 between the two groups were compared. According to the prognosis of patients with severe pneumonia, they were divided into the survival group(n = 90)and death group(n = 42). Clinical data and serum levels of Ang-2 and CC16 in the survival group and the death group were compared. We analyzed the factors influencing the prognosis of patients with severe pneumonia. Receiver operating characteristic(ROC)curve was used to evaluate the prognostic value of serum Ang-2 and CC16 on prognosis of patients with severe pneumonia. Results Compared with the healthy control group, the level of serum Ang-2 increased and the level of serum CC16 decreased in the ob servation group(all P <0. 05). Compared with the survival group, the level of serum Ang-2 in the death group increased, while the levels of CC16, PaO2 and PaO2/FiO2 decreased(all P<0. 05). The level of serum Ang-2(OR=1. 698, 95%CI: 1. 233-3. 185, P<0. 01)was an independent risk factor for prognosis of patients with severe pneumonia. CC16 level(OR= 0. 739, 95%CI: 0. 332-0. 957, P<0. 01), PaO2 level(OR=0. 523, 95%CI: 0. 307-0. 814, P<0. 05)and PaO2/FiO2 level (OR=0. 496, 95%CI: 0. 496, P<0. 01), 0. 251-0. 794, P<0. 05)were protective factors for the prognosis of patients with severe pneumonia. The area under the ROC curve of serum Ang-2 combined with serum CC16 in predicting severe pneumonia was 0. 885, and the sensitivity, specificity and Youden coefficients were 79. 23%, 82. 71% and 0. 619, respectively, which were significantly higher than those of serum Ang-2 and serum CC16 alone(all P<0. 05). Conclusions The level of serum Ang-2 is increased, while the level of serum CC16 is decreased in patients with severe pneumonia, which are closely related to the poor prognosis of patients. Serum Ang-2 combined with CC16 detection is helpful to predict the prognosis of patients with severe pneumonia, and has certain clinical value in predicting the prognosis of patients with severe pneumonia. [ABSTRACT FROM AUTHOR]

Background: Psoriasis and lichen planus (LP) are common chronic inflammatory skin diseases. The exact pathogenesis of these diseases until now is not fully determined. Angiogenesis is tightly regulated by a balance between pro- and anti-angiogenic mediators. Objective: To assess the relation of Ang-2 serum level with angiogenesis and inflammation that occurs in psoriasis and lichen planus. Patients and Methods: Thirty adult patients were included in this study. They were divided into 2 groups, 15 patients each, of psoriasis and lichen planus (8 patients with combined cutaneous and oral LP and 7 patients with cutaneous LP only). In addition to fifteen healthy subjects taken as control. The activity of the diseases was estimated at the time of examination using specific activity index for each disease. The serum level of angiopoietin 2 had been estimated by ELISA. Results: It was found that these diseases had significantly higher serum levels of angiopoietin 2 than the control group. The serum levels of angiopoietin 2 were higher in psoriasis compared to lichen planus, but the difference between psoriasis and lichen planus was not statistically significant. There was significant positive correlation between serum levels of angiopoietin 2 and the clinical severity of psoriasis. On the other hand, there was no correlation between serum level of angiopoietin 2 and the clinical severity of lichen planus. Conclusion: An important evidence on the importance of angiopoietin 2 serum level in pathogenesis of lichen planus as well as psoriasis. It elevated in serum of psoriasis and lichen planus patients that reflects its role in angiogenesis and inflammation that are important events in the development of these diseases. [ABSTRACT FROM AUTHOR]

Purpose: A majority of diabetes mellitus patients with disturbances of glucose metabolism present with vascular complications. This study aimed to explore regulatory mechanisms of miR145 and its potential target gene ANGPT2 on diabetic vasculopathy under hyperglycemia. Methods: Based on the fact that miR145 is detected in rat aortic endothelial cells (RAECs) under hyperglycemia, RAECs were transfected with miR145 mimics/inhibitor for further confirmation. RAEC proliferation was detected with CCK8 assays, and cell apoptosis and CD34+-cell population with annexinV–PI staining and anti-CD34FITC on flow cytometry, respectively. Then, qPCR and Western blot were applied to detect mRNA and protein expression of ANGPT2 and involved pathway factor NFκB p65. Subsequently, dual luciferase–reporter gene analysis was utilized to verify whether miR145 acted directly upon the 3ʹUTR of ANGPT2 mRNA. Results: The ANGPT2 gene was confirmed to be a direct target of miR145. miR145 mimics markedly downregulated the expression of ANGPT2 and NFκB p65, boosted the percentage of the CD34+ phenotype, and promoted proliferation and suppressed apoptosis of RAECs under hyperglycemia. Conclusion: miR145 might regulate the viability of RAECs via targeting ANGPT2 and involving NFκB signaling to exert a protective effect on diabetic vasculature. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin disease, and the mechanism remains unknown. The present study found that the level of miR‐205‐5p was downregulated in psoriatic skin tissues. miR‐205‐5p inhibited proliferation in HaCaT cells. miR‐205‐5p impaired proliferation, migration and tube formation in human umbilical vein endothelial cells. Angiopoietin (Ang)‐2, vascular endothelial growth factor (VEGFA) and bone morphogenetic protein and activin membrane‐bound inhibitor (BAMBI) were confirmed as the targets of miR‐205‐5p. Moreover, miR‐205‐5p suppressed the phosphorylation of p38 and extracellular regulated protein kinase, and inhibited expression level of β‐catenin. In vivo, miR‐205‐5p significantly alleviated imiquimod (IMQ)‐induced psoriasis in mice, and deactivated mitogen‐activated protein kinase (MAPK) and Wnt/β‐catenin pathways. In summary, we demonstrated that miR‐205‐5p alleviated IMQ‐induced psoriasis in mice by restraining epidermal hyperproliferation and excessive neovascularization. miR‐205‐5p may play its roles by targeting Ang‐2, VEGFA and BAMBI, and deactivating the Wnt/β‐catenin and MAPK signaling pathways. These findings may provide a potential therapeutic target for clinical treatment of psoriasis. [ABSTRACT FROM AUTHOR]

Aims: Different disease processes can combine to cause atrial fibrillation (AF). Their contribution to recurrent AF after ablation in patients is not known. Cardiovascular processes associated with recurrent AF after AF ablation were determined by quantifying biomolecules related to inflammation, metabolism, proliferation, fibrosis, shear stress, atrial pressure, and others in the AXAFA biomolecule study., Methods and Results: Twelve circulating cardiovascular biomolecules (ANGPT2, BMP10, CA125, hsCRP, ESM1, FABP3, FGF23, GDF15, IGFBP7, IL6, NT-proBNP, and hsTnT) were quantified in plasma samples obtained prior to a first AF ablation using high-throughput, high-precision assays. Cox regression was used to identify biomolecules associated with recurrent AF during the first 3 months after AF ablation. In 433 patients (64 years [58, 70]; 33% women), baseline concentrations of ANGPT2, BMP10, hsCRP, FGF23, FABP3, GDF15, and NT-proBNP were elevated in patients with recurrent AF (120/433; 28%). After adjustment for 11 clinical features and randomized treatment, elevated NT-proBNP [hazard ratio (HR) 1.58, 95% confidence interval (1.29, 1.94)], ANGPT2 [HR 1.37, (1.12, 1.67)], and BMP10 [HR 1.24 (1.02, 1.51)] remained associated with recurrent AF. Concentrations of ANGPT2, BMP10, and NT-proBNP decreased in patients who remained arrhythmia free, but not in patients with recurrent AF, highlighting their connection to AF. The other eight biomarkers showed unchanged concentrations., Conclusion: Elevated concentrations of ANGPT2, BMP10, and NT-proBNP are associated with recurrent AF after a first AF ablation, suggesting that processes linked to disturbed cardiomyocyte metabolism, altered atrial shear stress, and increased load contribute to AF after AF ablation in patients., Competing Interests: Conflict of interest: K.G.H. reports lecture fees/advisory board fees from Abbott, Alexion, Amarin, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Edwards Lifesciences, Medtronic, Pfizer, Premier Research, SUN Pharma, and W. L. Gore & Associates. R.B.S. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under the grant agreement no. 648131, from the European Union’s Horizon 2020 research and innovation programme under the grant agreement no. 847770 (AFFECT-EU), German Center for Cardiovascular Research (DZHK e.V.; 81Z1710103), German Ministry of Research and Education (BMBF 01ZX1408A), and ERACoSysMed3 (031L0239). R.B.S. has received lecture fees and advisory board fees from BMS/Pfizer outside this work. P.K. receives research support for basic, translational, and clinical research projects from the European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Cardiovascular Research, from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies in the past, but not in the last 3 years. P.K. is listed as inventor on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). U.S. received research grants from the Netherlands Heart Foundation (CVON2014-09, RACE V Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF) and the European Union (ITN Network Personalize AF: Personalized Therapies for Atrial Fibrillation: a translational network, grant number 860974; CATCH ME: Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly, grant number 633196; MAESTRIA: Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation, grant number 965286; REPAIR: Restoring cardiac mechanical function by polymeric artificial muscular tissue, grant number 952166). U.S. received consultancy fees or honoraria from Università della Svizzera Italiana (USI, Switzerland), Roche Diagnostics (Switzerland), EP Solutions Inc. (Switzerland), Johnson & Johnson Medical Limited (UK), and YourRhythmics BV. U.S. is co-founder and shareholder of YourRhythmics BV, a spin-off company of the University Maastricht. U.-H.W.-T. is an employee of Roche Diagnostics. T.Z. received funding from the German Science Foundation, German Center for Cardiovascular Research (DZHK e.V.; 81Z1710101, partner site project), The European Union euCanSHare project (grand agreement 825903), the ERA CVD project PREMED-CAD (FKZ01KL1807), and the ERA PerMed project (01KU1910B) outside this work. L.M. reports honoraries as consultant, lecturer, and advisory board from Boston Scientific, Abbott Medical, Johnson & Johnson, and Medtronic. He is a shareholder of Galgo Medical SL. J.P. is supported by R01AG074185 from the National Institutes of Aging, grants for clinical research from Abbott, American Heart Association, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, iRhythm, and Philips, and serves as a consultant to Abbott, AbbVie, Bayer, Biotronik, Boston Scientific, Bristol Myers Squibb, Element Science, Itamar Medical, LivaNova, Medtronic, Milestone, ElectroPhysiology Frontiers, ReCor, Sanofi, Philips, and Up-to-Date. The other authors have nothing to disclose. L.F. received institutional research support from EU Horizon 2020 CATCH ME (grant agreement number 633196), and MAESTRIA (grant agreement number 965286). L.F. has received funding from Accelerator Award by the British Heart Foundation AA/18/2/34218. L.F. is further part-funded by National Institute for Health and Care Research (NIHR) award 1002898 (APRAISE-AS) at University of Birmingham, AFFECT-EU grant agreement number 847770 and German Center for Cardiovascular Research (DZHK)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Microalbuminuria is a common clinical symptom that manifests in the early stages of diabetic kidney disease (DKD) and is also the main feature of glomerular endothelial cells (GECs) injury. There is increasing evidence that the transcytosis of albumin across GECs is closely related to the formation of albuminuria. Our previous studies have shown that angiopoietin 2 (ANGPT2) can inhibit albumin transcytosis across renal tubular epithelial cells by activating caveolin 1 (CAV1) phosphorylation during high glucose (HG) exposure. The role of ANGPT2 in albumin transcytosis across GECs remains unclear. Losartan significantly reduces albuminuria, but the mechanism has not been clarified., Methods: We established an in vitro albumin transcytosis model to investigate the change in albumin transcytosis across human renal glomerular endothelial cells (hrGECs) under normal glucose (NG), high glucose (HG) and losartan intervention. We knocked down ANGPT2 and CAV1 to evaluate their roles in albumin transcytosis across hrGECs and verified the relationship between them. In vivo, DKD mouse models were established and treated with different doses of losartan. Immunohistochemistry and Western blot were used to detect the expression of ANGPT2 and CAV1., Results: In vitro, the transcytosis of albumin across hrGECs was significantly increased under high glucose stimulation, and losartan inhibited this process. The expression of ANGPT2 and CAV1 were both increased in hrGECs under HG conditions and losartan intervention reduced the expression of them. Moreover, ANGPT2 downregulation reduced albumin transcytosis in hrGECs by regulating CAV1 expression. In vivo, the expression of ANGPT2 and CAV1 in the glomerulus was both increased significantly in DKD mice. Compared with DKD mice, losartan treatment reduced albuminuria and decreased the expression of ANGPT2 and CAV1 in a dose-dependent manner., Conclusions: ANGPT2 exacerbated albumin transcytosis across GECs by increasing CAV1 expression during HG exposure, thereby increasing albuminuria. Losartan reduces albumin transcytosis and albuminuria formation in DKD by inhibiting the upregulation of ANGPT2 under HG conditions. Our findings suggest that ANGPT2 and CAV1 may be novel therapeutic targets for diabetic albuminuria. In addition, we provide new evidence to elaborate on the mechanism of losartan in the development of DKD., (Copyright © 2022 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)