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Fluid therapy is a fundamental part of supportive therapy in critical care. However, it is also a suspected risk for endothelial glycocalyx degradation which is associated with poor clinical outcomes. This secondary analysis of RESPONSE randomized trial compares the effect of follow-up strategy (FU) on endothelial biomarkers to that of 500 ml crystalloid fluid bolus (FB) in oliguric, hemodynamically optimized intensive care unit (ICU) patients. 130 adult subjects were enrolled in two Finnish ICUs from January 2017 to November 2020. Blood and urine samples of 63 patients in FU group and 67 patients in FB group were collected before and after the intervention and analyzed using enzyme-linked immunosorbent assays. Single fluid bolus, given after median of 3887 ml (interquartile range 2842; 5359 ml) resuscitation fluids in the preceding 24 h, increased plasma hyaluronan concentration compared to the follow-up strategy (difference in medians 29.2 ng/ml with 95% CI [14.5ng/ml; 55.5ng/ml], P < 0.001). No treatment effect was detected in the plasma levels of syndecan-1, , angiopoietin-2, angiopoietin receptors Tie2 and Tie1, or in soluble thrombomodulin in the adjusted median regression analysis. The increase in hyaluronan was independent of its simultaneous renal clearance but correlated moderately with the increase in endothelium-specific Tie1. The follow-up strategy did not show consistent endothelium-sparing effect but protected against hyaluronan increase. The mechanisms and consequences of hyaluronan fluctuations need further clarification. Trial registration: clinicaltrials.gov, NCT02860572. Registered 1 August 2016, https://www.clinicaltrials.gov/study/NCT02860572?term=NCT02860572&rank=1 [ABSTRACT FROM AUTHOR]

Angiopoietin-like proteins are a group of seven proteins whose structure is different from that of angiopoietins in linkage to Tie2 or Tie1 receptors. Angiopoietin-like protein 4 (ANGPTL4), which is also known as peroxisome proliferator-activated receptor-γ (peroxisome proliferator-activated receptors-γ) angiopoietin-related or fasting-induced adipose factor, exists in two isoforms: Hyposialylated ANGPTL4 with a high-isoelectric point (high-pI), and normal sialylated ANGPTL4 with a neutral isoelectric point (neutral-pI). The present review discusses the role of ANGPTL4 in podocypopathies. Neutral-pI ANGPTL4 may also reduce proteinuria by binding β5 integrin and is secreted in various glomerulonephritis, while high-pI ANGPTL4 is upregulated in minimal change disease (MCD), modifying slight diaphragm power and increasing protein loss. In experimental animal models, high-pI ANGPTL4 is present in higher concentrations in MCD relapses than in disease remission. The administration of N-acetylmannosamine converts high-pI ANGPTL4 to neutral-pI ANGPTL4 and intraperitoneal epigallocatechin-3-gallate reduces the glomerular expression of ANGPTL4, with a reduction in albuminuria. Glomerular ANGPTL4 upregulation appears earlier in animal models, suggesting that the dysregulation of glomerular ANGPTL4 may result in foot process damage. Serum ANGPTL4 and proteinuria are likely reduced following glucocorticoid therapy. A high pI ANGPTL4/neutral pI ANGPTL4 ratios or their ratio compared to soluble urokinase-type plasminogen activator receptor could identify a marker for the differential diagnosis between early focal segmental glomerulosclerosis and MCD, in younger patients or in those who are not eligible for a kidney biopsy. [ABSTRACT FROM AUTHOR]

Background: Angiopoietin‐like 4 is a molecular hallmark that correlates with the growth and metastasis of head and neck squamous cell carcinoma, one of the most prevalent cancers worldwide. However, the molecular mechanisms by which angiopoietin‐like 4 promotes head and neck squamous cell carcinoma tumorigenesis are unclear. Methods: Using well‐characterized cell lines of head and neck squamous cell carcinoma development, including human normal oral keratinocytes, dysplastic oral keratinocytes, oral leukoplakia‐derived oral keratinocytes, and head and neck squamous cell carcinoma cell lines, HN13, HN6, HN4, HN12, and CAL27, we investigated the signaling pathways upstream and downstream of angiopoietin‐like 4‐induced head and neck squamous cell carcinoma tumorigenesis. Results: We found that both epidermal growth factor receptor ligands, epithelial growth factor, and amphiregulin led to angiopoietin‐like 4 upregulation in normal oral keratinocytes and dysplastic oral keratinocytes and cooperated with the activation of hypoxia‐inducible factor‐1 in this effect. Interestingly, amphiregulin and angiopoietin‐like 4 were increased in dysplastic oral keratinocytes and head and neck squamous cell carcinoma cell lines, and amphiregulin‐induced activation of cell proliferation was dependent on angiopoietin‐like 4. Although both p38 mitogen‐activated protein kinases (p38 MAPK) and protein kinase B (AKT) were activated by angiopoietin‐like 4, only pharmacological inhibition of p38 MAPK was sufficient to prevent head and neck squamous cell carcinoma cell proliferation and migration. We further observed that angiopoietin‐like 4 promoted the secretion of interleukin 11 (IL‐11), interleukin 12 (IL‐12), interleukin‐1 alpha (IL‐1α), vascular endothelial growth factor, platelet‐derived growth factor (PDGF), and tumour necrosis factor alpha (TNF‐α), cytokines and chemokines previously implicated in head and neck squamous cell carcinoma pathogenesis. Conclusion: Our results demonstrate that angiopoietin‐like 4 is a downstream effector of amphiregulin and promotes head and neck squamous cell carcinoma development both through direct activation of p38 kinase as well as paracrine mechanisms. [ABSTRACT FROM AUTHOR]

Abstract Fluid therapy is a fundamental part of supportive therapy in critical care. However, it is also a suspected risk for endothelial glycocalyx degradation which is associated with poor clinical outcomes. This secondary analysis of RESPONSE randomized trial compares the effect of follow-up strategy (FU) on endothelial biomarkers to that of 500 ml crystalloid fluid bolus (FB) in oliguric, hemodynamically optimized intensive care unit (ICU) patients. 130 adult subjects were enrolled in two Finnish ICUs from January 2017 to November 2020. Blood and urine samples of 63 patients in FU group and 67 patients in FB group were collected before and after the intervention and analyzed using enzyme-linked immunosorbent assays. Single fluid bolus, given after median of 3887 ml (interquartile range 2842; 5359 ml) resuscitation fluids in the preceding 24 h, increased plasma hyaluronan concentration compared to the follow-up strategy (difference in medians 29.2 ng/ml with 95% CI [14.5ng/ml; 55.5ng/ml], P

As an important component of transcellular pathway, Caveolae enables the transcellular transport of substances without disrupting cellular homeostasis. In kidney, albumin crosses glomerular filtration barrier (GFB) via Caveolae. Transcellular transport of albumin plays a crucial role in the pathology of proteinuria. Thus the importance of Caveolae cannot be overstated. However, the acting mechanism of Caveolae affecting transcellular albumin transport in kidney and their signaling pathways have remained largely elusive. This review summarized the latest studies on the regulation of Caveolae affecting transcellular albumin transport. Thus elucidating the relevant mechanisms of action and understanding the pathways of influence may provide potential therapeutic targets in the prevention and alleviation of proteinuria

Introduction: Renal injury is among the leading causes of morbidity and mortality; however, there are no reliable indicators for determining the likelihood of developing chronic kidney disease (CKD), CKD progression, or AKI events. Vascular growth factors called angiopoietins have a role in endothelial function, vascular remodeling, tissue stabilization, and inflammation and have been implicated as prognostic and predictive markers in AKI. Methods: Although the exact mechanism of the relationship between kidney injury and angiopoietins is unknown, this review demonstrates that AKI patients have higher angiopoietin-2 levels and that higher angiopoietin-1 to angiopoietin-2 ratio may potentially be linked with a reduced risk of the CKD progression. Results: This review therefore emphasizes the importance of angiopoietin-2 and proposes that it could be an important predictor of AKI in clinical settings. Conclusion: There is a need for further large-scale randomized clinical trials in order to have a better understanding of the significance of angiopoietin-2 and for the determination of its potential clinical implications. [ABSTRACT FROM AUTHOR]

Complications from diabetic retinopathy such as diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) constitute leading causes of preventable vision loss in working-age patients. Since vascular endothelial growth factor (VEGF) plays a major role in the pathogenesis of these complications, VEGF inhibitors have been the cornerstone of their treatment. Anti-VEGF monotherapy is an effective but burdensome treatment for DME. However, due to the intensive and burdensome treatment, most patients in routine clinical practice are undertreated, and therefore, their outcomes are compromised. Even in adequately treated patients, persistent DME is reported anywhere from 30% to 60% depending on the drug used. PDR is currently treated by anti-VEGF, panretinal photocoagulation (PRP) or a combination of both. Similarly, a number of eyes, despite these treatments, continue to progress to tractional retinal detachment and vitreous hemorrhage. Clearly there are other molecular pathways other than VEGF involved in the pathogenesis of DME and PDR. One of these pathways is the angiopoietin–Tie signaling pathway. Angiopoietin 1 (Ang1) plays a major role in maintaining vascular quiescence and stability. It acts as a molecular brake against vascular destabilization and inflammation that is usually promoted by angiopoietin 2 (Ang2). Several pathological conditions including chronic hyperglycemia lead to Ang2 upregulation. Recent regulatory approval of the bi-specific antibody, faricimab, may improve long term outcomes in DME. It targets both the Ang/Tie and VEGF pathways. The YOSEMITE and RHINE were multicenter, double-masked, randomized non-inferiority phase 3 clinical trials that compared faricimab to aflibercept in eyes with center-involved DME. At 12 months of follow-up, faricimab demonstrated non-inferior vision gains, improved anatomic outcomes and a potential for extended dosing when compared to aflibercept. The 2-year results of the YOSEMITE and RHINE trials demonstrated that the anatomic and functional results obtained at the 1 year follow-up were maintained. Short term outcomes of previously treated and treatment-naive eyes with DME that were treated with faricimab during routine clinical practice suggest a beneficial effect of faricimab over other agents. Targeting of Ang2 has been reported by several other means including VE-PTP inhibitors, integrin binding peptide and surrobodies. [ABSTRACT FROM AUTHOR]

Sepsis and concomitant multiorgan dysfunction are a group of common clinical syndromes, and their prevalence are increasing year by year due to the increase of the aging population. It reveals that 20 million cases of sepsis occur globally every year, with a mortality rate of 26%. Early diagnosis of sepsis facilitates the adoption of timely and targeted therapeutic strategies, which is a key element in reducing mortality. Endothelial cells (EC) are the early targets of exogenous pathogens and endogenous injury signals, and numerous studies suggest that structural changes and functional activation of EC play an important role in the development of sepsis. As an endothelial-exclusive signaling pathway, the angiopoietin (Ang)/tyrosine kinase receptor (Tie) signaling pathway plays an important role in the abnormal activation and injury of EC, and plays a central role in the regulation of dysfunctional changes in the disease process. The Ang/Tie signaling pathway mainly includes two tyrosine kinase receptors (Tie1, Tie2) located in EC and four secreted glycoprotein ligands (Ang-1, Ang-2, Ang-3, Ang-4). Ang-1 sustainably activates the Tie2 receptor, maintaining function between cells, and between cell and matrix, supporting the normal physiological functions of vascular EC. Ang-2 is an Ang-1 antagonist, competitively blocking the binding of Ang-1 to the Tie2 receptor. In a sepsis environment, the ratio of Ang-1/Ang-2 decreases （Ang-1 decreases, while Ang-2 increases). Ang-2 competitively blocks the binding of Ang-1 to Tie2 receptors, resulting in severe abnormal activation of EC. Ang-2 mediates the release of heparinase (HPSE), resulting in glycocalyx damage and an increase of vascular permeability. Ang-2 increase may promote inflammatory response. Ang/Tie signaling system dysfunction results in coagulation dysfunction, and Ang-2 elevation is a sentinel event in disseminated intravascular coagulation. In terms of disease monitoring, the sensitivity of Ang-2>5.61 ng/mL for diagnosing sepsis is 74.36%. Continuing rise of Ang-2 indicates that patients are in difficulty with restoring endothelial function and normal function in organs. Early dynamic mornitoring of Ang-2 can be used to predict sepsis related lung injury and acute kidney injury. The increase in Ang-2/Ang-1 ratio and Ang-2/soluble Tie ratio are independently correlated with the 90 d- mortality rate of sepsis patients（area under ROC curve is 0.787 and 0.704, respectively）. Decrease of Ang-2 and / or Tie-2 in levels indicates good efficay of plasma exchange in sepsis patients. Targeting the Ang/Tie signaling pathway have achieved certain success in animal experiments, but currently clinical trials have not yielded valuable results. Further in-depth research is needed on the Ang/Tie signaling pathway related to sepsis.

Hypoxia-inducible factor-1α (HIF-1α) is a major transcriptional factor, which plays an important role in cellular reprogramming processes under hypoxic conditions, which facilitate solid tumors' progression. HIF-1α is directly involved in the regulation of the angiogenesis, metabolic reprogramming, and extracellular matrix remodeling of the tumor microenvironment. Therefore, an in-depth study on the role of HIF-1α in solid tumor malignancies is required to develop novel anti-cancer therapeutics. HIF-1α also plays a critical role in regulating growth factors, such as the vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor, in a network manner. Additionally, it plays a significant role in tumor progression and chemotherapy resistance by regulating a variety of angiogenic factors, including angiopoietin 1 and angiopoietin 2, matrix metalloproteinase, and erythropoietin, along with energy pathways. Therefore, this review attempts to provide comprehensive insight into the role of HIF-1α in the energy and angiogenesis pathways of solid tumors. [ABSTRACT FROM AUTHOR]

Background and Aims: Although the understanding of pre‐eclampsia (PE) has improved, there is still insufficient knowledge on the exact etiology and pathophysiological mechanisms. Dysregulation of angiogenic factors has emerged as a significant contributing factor. Among these factors, angiopoietins (Ang‐1 and Ang‐2) have gained considerable attention due to their crucial role in regulating vascular development and endothelial function. This study explored the maternal serum levels of angiopoietins and perinatal outcomes in PE. Methods: A case‐control study involving women with PE (cases) and normotensive pregnancies (controls) was conducted at the Maternity unit of the Korle‐Bu Teaching Hospital. Descriptive analysis was performed and the Mann–Whitney U test (two‐sided) was used to compare maternal serum levels of angiopoietins between the cases and controls. Results: We included 188 participants comprising 94 cases (women with PE) and 94 controls (normotensive pregnancies) with an average maternal age of 29.76 ± 5.56 and 28.43 ± 5.57 years, respectively. Maternal serum levels of Ang‐2 were significantly lower among the PE cases compared to the normotensive controls (1.25 [0.90, 2.15] vs. 2.14 [1.18, 5.73] ng/mL, p = 0.001) but no significant difference in Ang‐1 levels (92.61 [80.92, 114.92] vs. 99.26 [81.76, 113.12] ng/mL, p = 0.429) was observed between the groups. The Ang‐1/Ang‐2 ratio was significantly elevated among women with PE compared to normotensive controls (74.47 [37.69, 110.59] vs. 45.98 [16.11, 88.22] ng/mL, p = 0.014). Also, women who delivered vaginally had significantly high maternal serum levels of Ang‐1 compared to women who had cesarean section delivery (107.98 ± 27.79 vs. 89.02 ± 32.62 ng/mL). Conclusion: Maternal serum levels of Ang‐2 but not Ang‐1 were significantly depressed in women with PE compared to the pregnant normotensive controls. No significant associations were observed between Ang‐1, Ang‐2 levels, or the Ang‐1/Ang‐2 ratio and pregnancy outcomes such as preterm birth, birth weight, and severity of hypertension. [ABSTRACT FROM AUTHOR]

Neovascular age-related macular degeneration (nAMD) is a major cause of vision loss in older adults. Neovascularization is caused by angiogenic mechanisms of the angiopoietin and vascular endothelial growth factor (VEGF) pathways. Standard treatments for nAMD target the VEGF pathway, but the efficacy of single-target anti-VEGF agents is limited by angiopoietin. Some patients may respond inadequately. Faricimab is a bispecific antibody targeting VEGF-A and angiopoietin-2. Its efficacy and safety have been illustrated in the TENAYA, LUCERNE, and TRUCKEE studies. Compared with aflibercept 2 mg, faricimab 6 mg demonstrated rapid best-corrected visual acuity gains and central subfield thickness reductions. A larger proportion of patients did not develop subretinal fluid during the loading phase. Faricimab is well tolerated with a risk-benefit profile comparable to the standard anti-VEGF treatment. Guidelines from the National Institute for Health and Care Excellence and the European Society of Retina Specialists recommend early diagnostic imaging and examinations for timely treatment of nAMD. Faricimab is an efficacious, well-tolerated, and long-acting treatment option for nAMD, with the potential for long-term cost savings. [ABSTRACT FROM AUTHOR]

Though vascular endothelial growth factors (VEGF) and other proangiogenic factors, such as angiopoietins (Ang), may be involved in the development of neovascular age-related macular degeneration (nvAMD), only drugs that inhibit the VEGF family are available for the treatment. The newly approved anti-VEGF drug faricimab, which also inhibits Ang-2, is expected to be effective in patients with AMD refractory to conventional anti-VEGF drugs. Therefore, we prospectively investigated the efficacy of faricimab in the treatment of aflibercept-refractory nvAMD. Patients with nvAMD who had been treated with aflibercept in the last year and required bimonthly injections were recruited. 25 eyes showed persistent exudative changes immediately before the faricimab injection (baseline). In these 25 eyes, switching to faricimab did not change visual acuity or central retinal thickness 2 months after the injection; however, 56% of eyes showed reduction or complete absorption of fluid. Notably, 25% of the eyes that showed dry macula at month 2 had no fluid recurrence for up to 4 months. These results indicate that faricimab could benefit some patients with aflibercept-refractory nvAMD. [ABSTRACT FROM AUTHOR]

Abstract Background and Aims Although the understanding of pre‐eclampsia (PE) has improved, there is still insufficient knowledge on the exact etiology and pathophysiological mechanisms. Dysregulation of angiogenic factors has emerged as a significant contributing factor. Among these factors, angiopoietins (Ang‐1 and Ang‐2) have gained considerable attention due to their crucial role in regulating vascular development and endothelial function. This study explored the maternal serum levels of angiopoietins and perinatal outcomes in PE. Methods A case‐control study involving women with PE (cases) and normotensive pregnancies (controls) was conducted at the Maternity unit of the Korle‐Bu Teaching Hospital. Descriptive analysis was performed and the Mann–Whitney U test (two‐sided) was used to compare maternal serum levels of angiopoietins between the cases and controls. Results We included 188 participants comprising 94 cases (women with PE) and 94 controls (normotensive pregnancies) with an average maternal age of 29.76 ± 5.56 and 28.43 ± 5.57 years, respectively. Maternal serum levels of Ang‐2 were significantly lower among the PE cases compared to the normotensive controls (1.25 [0.90, 2.15] vs. 2.14 [1.18, 5.73] ng/mL, p = 0.001) but no significant difference in Ang‐1 levels (92.61 [80.92, 114.92] vs. 99.26 [81.76, 113.12] ng/mL, p = 0.429) was observed between the groups. The Ang‐1/Ang‐2 ratio was significantly elevated among women with PE compared to normotensive controls (74.47 [37.69, 110.59] vs. 45.98 [16.11, 88.22] ng/mL, p = 0.014). Also, women who delivered vaginally had significantly high maternal serum levels of Ang‐1 compared to women who had cesarean section delivery (107.98 ± 27.79 vs. 89.02 ± 32.62 ng/mL). Conclusion Maternal serum levels of Ang‐2 but not Ang‐1 were significantly depressed in women with PE compared to the pregnant normotensive controls. No significant associations were observed between Ang‐1, Ang‐2 levels, or the Ang‐1/Ang‐2 ratio and pregnancy outcomes such as preterm birth, birth weight, and severity of hypertension.

Complications from diabetic retinopathy such as diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) constitute leading causes of preventable vision loss in working-age patients. Since vascular endothelial growth factor (VEGF) plays a major role in the pathogenesis of these complications, VEGF inhibitors have been the cornerstone of their treatment. Anti-VEGF monotherapy is an effective but burdensome treatment for DME. However, due to the intensive and burdensome treatment, most patients in routine clinical practice are undertreated, and therefore, their outcomes are compromised. Even in adequately treated patients, persistent DME is reported anywhere from 30% to 60% depending on the drug used. PDR is currently treated by anti-VEGF, panretinal photocoagulation (PRP) or a combination of both. Similarly, a number of eyes, despite these treatments, continue to progress to tractional retinal detachment and vitreous hemorrhage. Clearly there are other molecular pathways other than VEGF involved in the pathogenesis of DME and PDR. One of these pathways is the angiopoietin–Tie signaling pathway. Angiopoietin 1 (Ang1) plays a major role in maintaining vascular quiescence and stability. It acts as a molecular brake against vascular destabilization and inflammation that is usually promoted by angiopoietin 2 (Ang2). Several pathological conditions including chronic hyperglycemia lead to Ang2 upregulation. Recent regulatory approval of the bi-specific antibody, faricimab, may improve long term outcomes in DME. It targets both the Ang/Tie and VEGF pathways. The YOSEMITE and RHINE were multicenter, double-masked, randomized non-inferiority phase 3 clinical trials that compared faricimab to aflibercept in eyes with center-involved DME. At 12 months of follow-up, faricimab demonstrated non-inferior vision gains, improved anatomic outcomes and a potential for extended dosing when compared to aflibercept. The 2-year results of the YOSEMITE and RHINE trials demonstrated that the anatomic and functional results obtained at the 1 year follow-up were maintained. Short term outcomes of previously treated and treatment-naive eyes with DME that were treated with faricimab during routine clinical practice suggest a beneficial effect of faricimab over other agents. Targeting of Ang2 has been reported by several other means including VE-PTP inhibitors, integrin binding peptide and surrobodies.

Endothelial cell (EC) dysfunction is a hallmark of Systemic Lupus Erythematosus (SLE) and Tie2 is a receptor essential for vascular stability. Inflammatory processes promote inhibition of Tie2 homeostatic activation, driving vascular dysfunction. In this work we determined whether type I Interferons (IFN) induce Tie2 signalling-mediated endothelial dysfunction in patients with SLE. Serum levels of Angiopoietin (Ang)-1, Ang-2 and soluble (s)Tie1 in patients with SLE and healthy controls were measured by ELISA. Monocytes from patients with SLE and Human Umbilical Vein EC (HUVEC) were stimulated with IFN-α, IFN-β (1000 I.U.) or SLE serum (20%). mRNA and protein expression, phosphorylation and translocation were determined by quantitative PCR, ELISA, Western Blot, flow cytometry and confocal microscopy. Viability and angiogenic capacity were determined by calcein and tube formation assays. We found that sTie1 and Ang-2 serum levels were increased and Ang-1 decreased in patients with SLE and were associated with clinical characteristics. Type I IFN significantly decreased Ang-1 and increased Ang-2 in monocytes from patients with SLE. Type I IFN increased sTie1 and Ang-2 secretion and reduced Tie2 activation in HUVEC. Functionally, type I IFN significantly reduced EC viability and impaired angiogenesis in a Tie2 signalling-dependent manner. Finally, SLE serum increased Ang-2 and sTie1 secretion and significantly decreased tube formation. Importantly, Tie1 and IFNAR1 knockdown reversed these effects in tube formation. Overall, type I IFN play an important role in the stability of EC by inhibiting Tie2 signalling, suggesting that these processes may be implicated in the cardiovascular events observed in patients with SLE.

Objective: Peripheral sensory neuropathy (PSN) is a common complication of type 2 diabetes (T2DM) that can lead to frequent ulcerations, lower extremities, and reduced quality of life. Imbalance in the circulating levels of angiogenic growth factors, notably, angiopoietin (Ang)-1, Ang-2 and vascular endothelial growth factor (VEGF) may be among the underlying mechanisms of PSN in T2DM patients. We studied the association between PSN and angiogenic growth factors, Ang-1, Ang-2 and VEGF in T2DM patients in Ghana. Methods: In a case-control study design, PSN was evaluated in 160 patients with T2DM and 108 nondiabetic controls using vibration perception threshold (VPT) and diabetic neurological examination (DNE). The definition of PSN was abnormal VPT (≥25 mV) or the presence of neuropathic symptoms on examination (DNE score > 3). In addition, fasting venous blood samples were collected to measure circulating levels of Ang-1, Ang-2 and VEGF. Results: Compared to non-diabetic controls, patients with T2DM had a higher prevalence of PSN using abnormal VPT (20.6 % vs 2.8 %, p

Endotheliopathy plays a role in the development of acute kidney and lung injury in COVID-19, probably due to inflammation, endothelial permeability, vascular leakage and edema formation. This study examined alterations in the circulation of patients with mild and severe COVID-19 on in vitro endothelial permeability and its relation to the endothelial angiopoietin/Tie2 system, which is involved in the regulation of endothelial permeability. Plasma was obtained from COVID-19 patients admitted to the ward (n = 14) or ICU (n = 20) at admission and after 1 and 2 weeks and healthy controls (n = 5). Human kidney and lung endothelial cells were exposed to patient plasma and treated with recombinant angiopoietin-1. In vitro endothelial barrier function was assessed using electric cell-substrate impedance sensing. Circulating markers of the angiopoietin/Tie2 system, endothelial dysfunction and glycocalyx degradation were measured by ELISA. Plasma from COVID-19 patients reduced endothelial resistance compared to healthy controls, but COVID-19 plasma-induced drop in endothelial resistance did not differ between ward and ICU patients. Circulating angiopoietin-2, soluble Tie2 and soluble Tie1 levels increased over time in ICU patients, whereas levels remained stable in ward patients. The increase in angiopoietin-2 was able to predict 90-day mortality (AUC = 0.914, p < 0.001). Treatment with recombinant angiopoietin-1 did not restore COVID-19 plasma-induced hyperpermeability. In conclusion, these results suggest that indirect effects of the virus represented in the circulation of COVID-19 patients induced endothelial hyperpermeability irrespective of disease severity and changes in the endothelial angiopoietin/Tie2 system. Nonetheless, angiopoietin-2 might be of interest in the context of organ injury and patient outcome in COVID-19. [ABSTRACT FROM AUTHOR]

Secreted angiopoietin/angiopoietin-like (ANGPT/ANGPTL) proteins are involved in many biological processes. However, the role of these proteins in human breast cancers (BCs) remains largely unclear. Here, we conducted integrated omics analyses to evaluate the clinical impact of ANGPT/ANGPTL proteins and to elucidate their biological functions. In BCs, we identified rare mutations in ANGPT/ANGPTL genes, frequent gains of ANGPT1, ANGPT4, and ANGPTL1, and frequent losses of ANGPT2, ANGPTL5, and ANGPTL7, but observed that ANGPTL1, 2, and 4 were robustly downregulated in multiple datasets. The expression levels of ANGPTL1, 5, and 8 were positively correlated with overall survival (OS), while the expression levels of ANGPTL4 were negatively correlated with OS. Additionally, the expression levels of ANGPTL1 and 7 were positively correlated with distant metastasis-free survival (DMFS), while the expression levels of ANGPT2 and ANGPTL4 were negatively correlated with DMFS. The prognostic impacts of ANGPT/ANGPTL genes depended on the molecular subtypes and on clinical factors. We discovered that various ANGPT/ANGPTL genes were co-expressed with various genes involved in different pathways. Finally, with the exception of ANGPTL3, the remaining genes showed significant correlations with cancer-associated fibroblasts, endothelial cells, and microenvironment score, whereas only ANGPTL6 was significantly correlated with immune score. Our findings provide strong evidence for the distinct clinical impact and biological function of ANGPT/ANGPTL proteins, but the question of whether some of them could be potential therapeutic targets still needs further investigation in BCs.

Hypoxia-inducible factor-1α (HIF-1α) is a major transcriptional factor, which plays an important role in cellular reprogramming processes under hypoxic conditions, which facilitate solid tumors’ progression. HIF-1α is directly involved in the regulation of the angiogenesis, metabolic reprogramming, and extracellular matrix remodeling of the tumor microenvironment. Therefore, an in-depth study on the role of HIF-1α in solid tumor malignancies is required to develop novel anti-cancer therapeutics. HIF-1α also plays a critical role in regulating growth factors, such as the vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor, in a network manner. Additionally, it plays a significant role in tumor progression and chemotherapy resistance by regulating a variety of angiogenic factors, including angiopoietin 1 and angiopoietin 2, matrix metalloproteinase, and erythropoietin, along with energy pathways. Therefore, this review attempts to provide comprehensive insight into the role of HIF-1α in the energy and angiogenesis pathways of solid tumors.

The ability to comprehensively monitor physiological and detect pathophysiologic processes early during pregnancy can reduce maternal and fetal morbidity and mortality. Contrast-enhanced ultrasound (CEUS) is a non-invasive imaging technology that utilizes the acoustic detection of microbubbles to examine vascular spaces. Furthermore, microbubbles conjugated to specific compounds can focus studies on precise physiological pathways. We hypothesized that CEUS with phosphatidylserine microbubbles (MB-PS) could be employed to monitor placental inflammation. We tested this hypothesis in rhesus macaques (Macaca mulatta), a translational and relevant animal model of human placental health. As placental inflammation impacts many at-risk pregnancies, we performed CEUS with MB-PS in pregnant macaques fed a high-fat diet (e.g., a western-style diet, WSD) in the presence or absence of testosterone (T) to mimic the increased risk of polycystic ovary syndrome and subfertility. We have previously demonstrated a placental inflammation phenotype in this model, and, thus, we related the MB-PS CEUS signal intensity to placental inflammation markers: selectin p and angiopoietins. Testosterone exposure increased the MB-PS signal in the placental microcirculation on the maternal side compared to control animals. We found that T increased placental weight and decreased angiopoietin 2 (ANGPT2) immunoreactivity. Furthermore, a significant inverse correlation was found between MB-PS signal and ANGPT2. This indicated that CEUS with MB-PS can be used to monitor placental parameters. We propose that CEUS with MB-PS could aid in the identification of pregnancies at risk of placental vascular compromise. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) represents a worldwide health matter with a major care burden, high prevalence, and poor prognosis. Its pathogenesis mainly varies depending on the underlying etiological factors, although it develops from liver cirrhosis in the majority of cases. This review summarizes the role of the most interesting soluble factors as biomarkers for early diagnosis and as recommended targets for treatment in accordance with the new challenges in precision medicine. In the premalignant environment, inflammatory cells release a wide range of cytokines, chemokines, growth factors, prostaglandins, and proangiogenic factors, making the liver environment more suitable for hepatocyte tumor progression that starts from acquired genetic mutations. A complex interaction of pro-inflammatory (IL-6, TNF-α) and anti-inflammatory cytokines (TGF-α and -β), pro-angiogenic molecules (including the Angiopoietins, HGF, PECAM-1, HIF-1α, VEGF), different transcription factors (NF-kB, STAT-3), and their signaling pathways are involved in the development of HCC. Since cytokines are expressed and released during the different stages of HCC progression, their measurement, by different available methods, can provide in-depth information on the identification and management of HCC. [ABSTRACT FROM AUTHOR]

The M2 isoform of pyruvate kinase (PKM2) is highly expressed in most cancer cells, and has been studied extensively as a driver of oncogenic metabolism. In contrast, the role of PKM2 in nontransformed cells is little studied, and nearly nothing is known of its role, if any, in quiescent cells. We show here that endothelial cells express PKM2 almost exclusively over PKM1. In proliferating endothelial cells, PKM2 is required to suppress p53 and maintain cell cycle progression. In sharp contrast, PKM2 has a strikingly different role in quiescent endothelial cells, where inhibition of PKM2 leads to degeneration of tight junctions and barrier function. Mechanistically, PKM2 regulates barrier function independently of its canonical activity as a pyruvate kinase. Instead, PKM2 suppresses NF-kB and its downstream target, the vascular permeability factor angiopoietin 2. As a consequence, loss of endothelial cell PKM2 in vivo predisposes mice to VEGF-induced vascular leak, and to severe bacteremia and death in response to sepsis. Together, these data demonstrate new roles of PKM2 in quiescent cells, and highlight the need for caution in developing cancer therapies that target PKM2.

• Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for about 50% of all HF patients. • Angiopoietin 1 (ANGPT1) was decreased in HF with reduced ejection fraction (HFrEF). • ANGPT2 levels were increased in both HFpEF and HFrEF compared to controls. • VEGF-D was increased in both HFpEF and HFrEF compared to controls. • Secretory phospholipase A 2 was increased in HFrEF but not in HFpEF compared to controls. Heart failure (HF) is a growing public health burden, with high prevalence and mortality rates. A proportion of patients with HF have a normal ventricular ejection fraction (EF), referred to as HF with preserved EF (HFpEF), as opposed to patients with HF with reduced ejection fraction (HFrEF). HFpEF currently accounts for about 50% of all HF patients, and its prevalence is rising. Angiopoietins (ANGPTs), vascular endothelial growth factors (VEGFs) and secretory phospholipases A 2 (sPLA 2 s) are proinflammatory mediators and key regulators of endothelial cells. Methods: The aim of this study was to analyze the plasma concentrations of angiogenic (ANGPT1, ANGPT2, VEGF-A) and lymphangiogenic (VEGF-C, VEGF-D) factors and the plasma activity of sPLA 2 in patients with HFpEF and HFrEF compared to healthy controls. The concentration of ANGPT1 was reduced in HFrEF compared to HFpEF patients and healthy controls. ANGPT2 levels were increased in both HFrEF and HFpEF subjects compared to controls. The ANGPT2/ANGPT1 ratio was increased in HFrEF patients compared to controls. The concentrations of both VEGF-A and VEGF-C did not differ among the three groups examined. VEGF-D was increased in both HFrEF and HFpEF patients compared to controls. Plasma activity of sPLA 2 was increased in HFrEF but not in HFpEF patients compared to controls. Our results indicate that three different classes of proinflammatory regulators of vascular permeability and smoldering inflammation are selectively altered in HFrEF or HFpEF patients. Studies involving larger cohorts of these patients will be necessary to demonstrate the clinical implications of our findings. [ABSTRACT FROM AUTHOR]

Angiopoietin-2 (Ang-2) has been implicated in the development of several types of cancer, including lung malignancy. In the present study, we examined the impact of Ang-2 serum concentration on the development, dissemination, and 5-year overall survival of NSCLC and SCLC. A total of 99 patients with lung cancer were tested. The OS of NSCLC and SCLC patients was estimated using Kaplan–Meier curves and compared through log-rank test. The median serum level of Ang-2 at baseline in both NSCLC and SCLC patients was significantly higher than that of controls (p < 0.0001). The Ang-2 serum concentration was not related to metastasis, neither in NSCLC nor in SCLC cases. The OS was found to be significantly shorter for stage IIIβ NSCLC patients with a high baseline Ang-2 serum concentration (p = 0.012), while Cox regression analysis showed that Ang-2 is a significant independent factor for poor prognosis for stage IIIβ NSCLC (hazard ratio = 2.97, 95% CI: 1.05–8.40, p = 0.04). The concentration of Ang-2 has no impact on the prognosis of SCLC. Ang-2 could be considered as a significant molecular marker that enables the prediction of NSCLC and SCLC development, and is involved in the poor prognosis of stage IIIβ NSCLC. [ABSTRACT FROM AUTHOR]

Tumour growth and metastasis are specific to advanced stages of epithelial ovarian cancer (EOC). Tumour angiogenesis is an essential part of these processes. It is responsible for providing tumours with nutrients, metabolites, and cytokines and facilitates tumour and immune cell relocation. Destabilised vasculature, a distinctive feature of tumours, is also responsible for compromising drug delivery into the bulk. Angiogenesis is a complex process that largely depends on how the tumour microenvironment (TME) is composed and how a specific organ is formed. There are contrary reports on whether Tie-2-expressing monocytes/macrophages (TEMs) reported as the proangiogenic population of monocytes have any impact on tumour development. The aim of this paper is to summarise knowledge about ovarian-cancer-specific angiogenesis and the unique role of Tie-2-expressing monocytes/macrophages in this process. The significance of this cell subpopulation for the pathophysiology of EOC remains to be investigated. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy is a devastating and frequent complication of poorly controlled diabetes, whose pathogenesis is still only partially understood. Advances in basic research over the last two decades have led to the discovery of angiopoietins, proteins that strongly influence the growth and integrity of blood vessels in many vascular beds, with particular importance in the retina. Angiopoietin 1 (Ang1), produced mostly by pericytes and platelets, and angiopoietin 2 (Ang2), produced mainly by endothelial cells, bind to the same receptor (Tie2), but exert opposing effects on target cells. Ang1 maintains the stability of the mature vasculature, while Ang2 promotes vessel wall destabilization and disruption of the connections between endothelial cells and pericytes. Human retinal endothelial cells exposed to Ang2 show reduced membrane expression of the adhesion molecule VE-cadherin, and patients with proliferative diabetic retinopathy or diabetic macular edema have markedly increased vitreal concentrations of Ang2. Faricimab, a bi-specific antibody simultaneously directed against Ang2 and VEGF, has shown promising results in clinical trials among patients with diabetic retinopathy, and other agents targeting the angiopoietin system are currently in development. [ABSTRACT FROM AUTHOR]

Background: Various types of vitreoretinal surgery are used for the treatment of severe diabetic retinopathy (DR), with vitreous hemorrhage being a common postoperative complication. Impaired angiopoietin system function in type 2 diabetes mellitus (T2DM) patients with DR plays a role in retinal vascular damage and may determine the development of vitreous hemorrhage, e.g., after vitrectomy. Purpose: To identify the effects of angiopoietins on and their prognostic value in the development of vitreous hemorrhage after advanced vitreoretinal surgery in T2DM patients with DR. Material and Methods: The study included 118 T2DM patients (118 eyes) with DR. These included patients with mild nonproliferative DR (NPDR; Group 1; n = 28), moderate or severe NPDR (Group 2; n = 49), and proliferative DR (PDR; Group 3; n = 41). They underwent a 25-G closed subtotal vitrectomy (CSTV) with panretinal laser photocoagulation. Either a mixture of perfluoropropane (18% C3F8) and air was used to perform tamponade of the vitreous cavity or balance salt solution (BSS plus) was left in the vitreous cavity. Vitreous samples were obtained during vitrectomy, and Ang1 and Ang2 concentrations and their ratio for these samples were measured by enzyme-linked immunosorbent assay. Models were developed using the EZR version 1.54 software (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing; Vienna, Austria). Results: Vitreous hemorrhage developed in 33.1% of patients with T2DM by three months after vitrectomy for DR, and was directly associated with increased levels of Ang1 and Ang2 in the vitreous (p < 0.005). After adjustment for DR severity stage, the risk of postoperative vitreous hemorrhage in patients with mild NPDR was associated with an increased level of Ang2 in the vitreous (OR, 1.95; 95% CI, 1.06-3.59 per 100 pg/ml), with an optimal cut-off point of 1246 pg/ml (р = 0.003). The risk of postoperative vitreous hemorrhage in patients with severe NPDR and PDR was associated with the level of Ang2 as well as the Ang2/ Ang1 ratio in the vitreous. The study identified cut-off vitreous levels of Ang2 of (a) 2806 pg/mL for moderate or severe NPDR (AUC=0.84; 95% CI, 0.71-0.93; p < 0.001) and (b) 4610 pg/mL for PDR (AUC=0.71; 95% CI, 0.55-0.84; p = 0.013). Conclusion: The results obtained demonstrated that Ang2 accumulation in the vitreous resulted in an increased risk of postoperative vitreous hemorrhage, and was of high prognostic significance.

The Xenopus laevis embryo has been subjected to almost saturating screens for molecules specifically expressed in dorsal Spemann organizer tissue. In this study, we performed high-throughput RNA sequencing of ectodermal explants, called animal caps, which normally give rise to epidermis. We analyzed dissociated animal cap cells that, through sustained activation of MAPK, differentiate into neural tissue. We also microinjected mRNAs for Cerberus, Chordin, FGF8, BMP4, Wnt8, and Xnr2, which induce neural or other germ layer differentiations. The searchable database provided here represents a valuable resource for the early vertebrate cell differentiation. These analyses resulted in the identification of a gene present in frog and fish, which we call Bighead. Surprisingly, at gastrula, it was expressed in the Spemann organizer and endoderm, rather than in ectoderm as we expected. Despite the plethora of genes already mined from Spemann organizer tissue, Bighead encodes a secreted protein that proved to be a potent inhibitor of Wnt signaling in a number of embryological and cultured cell signaling assays. Overexpression of Bighead resulted in large head structures very similar to those of the well-known Wnt antagonists Dkk1 and Frzb-1. Knockdown of Bighead with specific antisense morpholinos resulted in embryos with reduced head structures, due to increased Wnt signaling. Bighead protein bound specifically to the Wnt coreceptor lipoprotein receptor-related protein 6 (Lrp6), leading to its removal from the cell surface. Bighead joins two other Wnt antagonists, Dkk1 and Angptl4, which function as Lrp6 endocytosis regulators. These results suggest that endocytosis plays a crucial role in Wnt signaling.

Human basophils, first identified over 140 years ago, account for just 0.5-1% of circulating leukocytes. While this scarcity long hampered basophil studies, innovations during the past 30 years, beginning with their isolation and more recently in the development of mouse models, have markedly advanced our understanding of these cells. Although dissimilarities between human and mouse basophils persist, the overall findings highlight the growing importance of these cells in health and disease. Indeed, studies continue to support basophils as key participants in IgE-mediated reactions, where they infiltrate inflammatory lesions, release pro-inflammatory mediators (histamine, leukotriene C4: LTC4) and regulatory cytokines (IL-4, IL-13) central to the pathogenesis of allergic diseases. Studies now report basophils infiltrating various human cancers where they play diverse roles, either promoting or hampering tumorigenesis. Likewise, this activity bears remarkable similarity to the mounting evidence that basophils facilitate wound healing. In fact, both activities appear linked to the capacity of basophils to secrete IL-4/IL-13, with these cytokines polarizing macrophages toward the M2 phenotype. Basophils also secrete several angiogenic factors (vascular endothelial growth factor: VEGF-A, amphiregulin) consistent with these activities. In this review, we feature these newfound properties with the goal of unraveling the increasing importance of basophils in these diverse pathobiological processes.

Experimental in vivo data have recently shown complementary neuroprotective actions of rhEPO and growth hormone (rhGH) in a neonatal murine model of hypoxic brain injury. Here, we hypothesized that rhGH and rhEPO mediate stabilization of the blood–brain barrier (BBB) and regenerative vascular effects in hypoxic injury to the developing brain. Using an established model of neonatal hypoxia, neonatal mice (P7) were treated i.p. with rhGH (4000 µg/kg) or rhEPO (5000 IU/kg) 0/12/24 h after hypoxic exposure. After a regeneration period of 48 h or 7 d, cerebral mRNA expression of Vegf-A, its receptors and co-receptors, and selected tight junction proteins were determined using qRT-PCR and ELISA. Vessel structures were assessed by Pecam-1 and occludin (Ocln) IHC. While Vegf-A expression increased significantly with rhGH treatment (p < 0.01), expression of the Vegfr and TEK receptor tyrosine kinase (Tie-2) system remained unchanged. RhEPO increased Vegf-A (p < 0.05) and Angpt-2 (p < 0.05) expression. While hypoxia reduced the mean vessel area in the parietal cortex compared to controls (p < 0.05), rhGH and rhEPO prevented this reduction after 48 h of regeneration. Hypoxia significantly reduced the Ocln+ fraction of cortical vascular endothelial cells. Ocln signal intensity increased in the cortex in response to rhGH (p < 0.05) and in the cortex and hippocampus in response to rhEPO (p < 0.05). Our data indicate that rhGH and rhEPO have protective effects on hypoxia-induced BBB disruption and regenerative vascular effects during the post-hypoxic period in the developing brain. [ABSTRACT FROM AUTHOR]

To investigate the interventional effect of cultured mycelia of Cordyceps sinensis on a mouse model of CCl4 - induced liver fibrosis and its effect on the Toll -like receptor 4 ( TLR4 )/ nuclear transcription factor - κB (NF - κB) pathway and angiopoietin -like protein 4 ( ANGPTL4 ) . Methods A total of 60 specific pathogen - free male C57/ BL6J mice were randomly divided into normal group, model group, Fuzheng Huayu group, and low -, middle -, and high - dose Cordyceps sinensis groups, with 10 mice in each group. The mice in the model group and each medication group were intraperitoneally injected with 15 % CCl4 - olive oil for 6 weeks of modeling, and drug intervention was started on the first day of week 4 and lasted for 3 consecutive weeks. Blood biochemistry was used to measure the serum level or activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil); HE and SR staining was used to observe liver histopathology; alkaline hydrolysis was used to measure the content of hydroxyproline (HYP) in liver tissue; PCR was used to measure the mRNA expression of alpha-smooth muscle actin (α-SMA) and collagen type I (Col-I), immunohistochemistry was used to measure the protein expression of α -SMA, Col I, and ANGPTIA in liver tissue, and Western blot (WB) was used to measure the protein expression of α -SMA, ANGPTL4, TLR4, NF-κB/phosphorylated NF-κB (P-NF-κB), and CD163. A one-way-analysis of variance was used for comparison of continuous data between multiple groups, and the LSD-t test was used for further comparison between two groups. Results Compared with the normal group, the model group had significant increases in the serum levels of ALT, AST, way a and TBil (all P <0.01), and compared with the model group, the high-dose Cordyceps sinensis group had a significant improvement in the degree of liver fibrosis and significant reductions in the serum levels of ALT, AST, and TBil (all P <0.05). HE staining revealed that the high-dose Cordyceps sinensis group had a significant reduction in inflammatory cell infiltration in liver tissue, and SR staining showed that high-dose Cordyceps sinensis significantly alleviated collagen deposition in the liver tissue. Compared with the normal group, the model group had significant increases in HYP content and Sirius red - positive area ratio in liver tissue (both P <0.01), and compared with the model group, the high-dose Cordyceps sinensis group had significant reductions in HYP content and Sirius red - positive area ratio (both P<0.05). Compared with the normal group based on the results of immunohistochemistry, PCR, and WB, the model had significant group increases in the mRNA and protein expression levels of a -SMA and Col-I in liver tissue (all P <0.01), and compared with the model group, the high-dose Cordyceps sinensis group had significant reductions in the expression levels of a SMA and Col-I (P<0.05). Compared with the normal group, the model group had significant increases in the protein expression of ANGPTL4, TLR4, P-NF-κB/NF κB, and CD163 in liver tissue (all P <0.01), and compared with the model group, the high-dose Cordyceps sinensis group had significant re ductions in the protein expression of ANGPTL4, TLR4, P-NF-κB/NF-κB, and CD163 in liver tissue (all P <0.05). Conclusion Cordyceps sinensis mycelia have a marked therapeutic effect on CCI,-induced liver fibrosis in mice, possibly by regulating the TLR4/NF [ABSTRACT FROM AUTHOR]

Angiopoietin-like 4 (ANGPTL4) is a secreted signaling protein that is implicated in cardiovascular disease, metabolic disorder, and cancer. Outside of its role in lipid metabolism, ANGPTL4 signaling remains poorly understood. Here, we identify ANGPTL4 as a Wnt signaling antagonist that binds to syndecans and forms a ternary complex with the Wnt co-receptor Lipoprotein receptor-related protein 6 (LRP6). This protein complex is internalized via clathrin-mediated endocytosis and degraded in lysosomes, leading to attenuation of Wnt/β-catenin signaling. Angptl4 is expressed in the Spemann organizer of Xenopus embryos and acts as a Wnt antagonist to promote notochord formation and prevent muscle differentiation. This unexpected function of ANGPTL4 invites re-interpretation of its diverse physiological effects in light of Wnt signaling and may open therapeutic avenues for human disease.

Background: The ANGPT (angiopoietin)-TEK (tyrosine kinase, endothelial) vascular signaling pathway plays a key role in the formation of Schlemm canal, and loss-of-function mutations in the TEK or ANGPT1 gene are associated with primary congenital glaucoma in children. In genome-wide association studies, an association was identified between protection from primary open-angle glaucoma and the single-nucleotide polymorphism rs76020419 (G>T), located within a predicted miR-145 -binding site in the 3' untranslated region of ANGPT2 . To date, the functional impact of this variant in the anterior chamber of the eye remains largely unexplored., Methods: MT (mutant) mice harboring an orthologous rs76020419 minor allele (T) were generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9). Plasma and tissue samples, including eyes, were collected, and ANGPT2 expression was quantified using ELISA. Anterior segments from eyes were collected from WT (wild-type) and MT mice, and Schlemm canal area was quantified., Results: In the MT group, higher ANGPT2 concentrations were observed in the plasma, lungs, kidneys, and eyes ( P =0.0212, P <0.001, P =0.0815, and P =0.0215, respectively). Additionally, the Schlemm canal was larger in MT mice compared with WT mice ( P =0.0430)., Conclusions: The rs76020419 minor allele (T) is associated with increased levels of ANGPT2 and a larger Schlemm canal in mice. These findings suggest a potential protective mechanism in glaucoma.

Aims: Remnant cholesterol and very low-density lipoprotein cholesterol (VLDL-C) are increasingly recognized risk factors for atherosclerotic disease with few therapeutic options. Angiopoietin-like 3 (ANGPTL3), a key protein in the metabolism of triglyceride-rich lipoproteins, is a promising target., Methods and Results: TRANSLATE-TIMI 70 was a double-blind, placebo-controlled randomized trial testing seven dose regimens of vupanorsen, an antisense oligonucleotide against ANGPTL3, in adults with non-HDL-C ≥ 100 mg/dL and triglycerides 150-500 mg/dL. The primary endpoint of this analysis was percentage change in remnant cholesterol (total cholesterol minus directly measured LDL-C minus HDL-C) and VLDL-C (directly measured) over 24 weeks. Two hundred eighty-six patients were enrolled, with a median age of 64 years and 44% female. Median baseline remnant cholesterol and VLDL-C were 42 and 31 mg/dL, respectively (reference: <30 mg/dL). Vupanorsen lowered remnant cholesterol by 42-59% at 24 weeks over placebo (P < 0.001), achieving a median level of 18 mg/dL at the highest dose. Over the same period, VLDL-C was reduced by 52-67% over placebo (P < 0.001), with a median achieved level of 2.5 mg/dL at the highest dose. The effect of vupanorsen on remnant cholesterol and VLDL-C reduction was dose-dependent and directly associated with the degree of ANGPTL3 inhibition: at 90% ANGPTL3 reduction, there was a 61% and 81% decrease in remnant cholesterol and VLDL-C, respectively., Conclusion: Inhibition of ANGPTL3 protein synthesis significantly lowered remnant cholesterol and VLDL-C in patients with hypertriglyceridaemia. The magnitude of reduction was associated with the degree of ANGPTL3 inhibition. These findings support ANGPTL3 inhibition as a promising target for lowering cholesterol on triglyceride-rich lipoproteins., Competing Interests: Conflict of interest: A.Z., S.D.W., J.-G.P., S.A.M., X.R., A.J., J.F.K., M.S.S., B.A.B., and N.A.M. are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Inc., Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis Pharmaceuticals, Inc., Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Saghmos Therapeutics, Inc., Siemens Healthcare Diagnostics, Inc., Softcell Medical Limited, The Medicines Company, Verve Therapeutics, Inc., and Zora Biosciences. S.D.W. reports grants from Amgen, Arena, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Janssen, Merck, and Sanofi; and consulting fees from Arena, AstraZeneca, Aegerion, Allergan, AngelMed, Boehringer Ingelheim, Boston Clinical Research Institute, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Icon Clinical, Janssen, Lexicon, Merck, Servier, St Jude Medical, and Xoma. His spouse, Dr Caroline Fox, is an employee of Merck. C.R.B., M.C., V.R., and S.G.T. are employees and shareholders of Pfizer. S.V. holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management Inc., and Sanofi. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. W.W. reports lecture fees from Pfizer, Astra Zeneca, and Boehringer Ingelheim. M.S.S. reports research grant support through Brigham and Women’s Hospital from: Abbott; Amgen; Anthos Therapeutics; AstraZeneca; Boehringer Ingelheim; Daiichi-Sankyo; Eisai; Intarcia; Ionis; Medicines Company; MedImmune; Merck; Novartis; Pfizer; Saghmos Therapeutics; and Verve Therapeutics. M.S.S. reports consulting for: Althera; Amgen; Anthos Therapeutics; AstraZeneca; Beren Therapeutics; Bristol-Myers Squibb; DalCor; Dr. Reddy’s Laboratories; Fibrogen; Intarcia; Merck; Moderna; Novo Nordisk; and Silence Therapeutics. B.A.B. reports grant support through the Brigham and Women’s Hospital: Pfizer, Ionis, AstraZeneca, and Abbott Vascular; and consulting/personal fees from Abiomed, CSI, Philips, Abbott Vascular, Servier, DaiichiSankyo, Janssen, and Quark. N.A.M. reports funds through a National Institutes of Health grant (K08HL153950) and is involved in clinical trials with Amgen, Pfizer, Ionis, Novartis, and AstraZeneca without personal fees, payments, or increase in salary. The other authors report no conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Ebtisam Al-Ofi,1 Aziza Alrafiah,2 Salman Maidi,2 Safa Almaghrabi,1 Nora Hakami2 1Department of Physiology, Faculty of Medicine, King AbdulAziz University, Jeddah, Saudi Arabia; 2Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King AbdulAziz University, Jeddah, Saudi ArabiaCorrespondence: Aziza AlrafiahDepartment of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King AbdulAziz University, PO Box 80200, Jeddah, 21589, Saudi ArabiaTel +966 126401000 Ext. 23495Fax +966 126401000 Ext. 21686Email aalrafiah@kau.edu.saBackground: Gestational diabetes mellitus (GDM) typically occurs during the third trimester of pregnancy. Maternal hyperglycemic may influence the expression of pro-and anti-angiogenic factors. Altered levels of angiogenic biomarkers in GDM pregnant women are associated with abnormal placentation. This study aimed to investigate the rates of expression of five angiogenic biomarkers called vascular endothelial growth factor-A (VEGF-A), angiopoietin-2, endoglin, endothelin-1, and granulocyte colony-stimulating factor (G-CSF) in GDM.Methods: The samples were obtained from normal (n=9) and GDM (n=10) pregnancies. Multiplex assay was used to assess the levels of angiogenic biomarkers including VEGF-A, endoglin, endothelin-1, angiopoietin-2, and G-CSF in serum samples. All data were statistically analyzed using an unpaired Student’s t-test. Correlations between measured parameters were made using Pearson correlations.Results: VEGF-A, endoglin, endothelin-1, and angiopoietin-2 levels in GDM were significantly higher (P value = 0.001, 0.042, 0.049, 0.001; respectively) compared to control. However, G-CSF level exhibited a non-significant increase (P=0.466) in GDM compared to healthy controls. There was a significant positive correlation between angiopoietin-2 with endoglin, endothelin-1, and VEGF-A. Moreover, there was a significant positive correlation between VEGF-A with endoglin and endothelin-1. Most interestingly, there was a significant positive correlation between G-CSF with endothelin-1.Conclusion: The angiogenic biomarkers were highly altered in pregnant women with GDM. The study provides a novel advance in the field of gestational diabetes, in terms of increase of angiogenic factors that can modify the vascularization of the placenta, the development of fetal vascular system and the insulin resistance itself.Keywords: gestational diabetes mellitus, vascular endothelial growth factor A, angiopoietins, endoglin, endothelin-1, granulocyte colony-stimulating factor, pre-eclampsia

Very preterm infants are exposed to prenatal inflammatory processes and early postnatal hemodynamic and respiratory complications, but limited data are available about the endothelial effect of these conditions. The present pilot study investigates the perinatal endothelial phenotype in very preterm infants (VPIs) and explores its predictive value on neonatal mortality and hemodynamic and respiratory complications. Angiopoietin 1 (Ang-1), Ang-2, E-selectin, vascular adhesion molecule 1 (VCAM-1), tissue factor (TF), and endothelin 1 (ET-1) concentrations were tested in first (T1), 3rd (T2), and 7–10th (T3) day of life in 20 VPIs using Luminex technology and compared with 14 healthy full-term infants (FTIs). Compared to FTIs, VPIs had lower Ang-1 at T1 and T2; higher Ang-2 at T1, T2, and T3; higher Ang-2/Ang-1 ratio at T1, T2, and T3; lower E-selectin at T1, T2, and T3; higher VCAM-1 at T1; higher TF at T2. No differences in concentrations were found in neonatal deaths. VPIs with hemodynamic or respiratory complications had higher Ang-2 at T3. Perinatal low Ang-1 and high Ang-2 associated with high VCAM-1 and TF in VPIs suggest a proinflammatory endothelial phenotype, resulting from the synergy of a pathological prenatal inheritance and a premature extrauterine transition. [ABSTRACT FROM AUTHOR]