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Clinical and Experimental Medicine Aug 2021Mastocytosis is a disorder characterized by the abnormal proliferation and/or accumulation of mast cells in different organs. More than 90% of patients with systemic...
Mastocytosis is a disorder characterized by the abnormal proliferation and/or accumulation of mast cells in different organs. More than 90% of patients with systemic mastocytosis have a gain-of-function mutation in codon 816 of the KIT receptor on mast cells (MCs). The symptoms of mastocytosis patients are related to the MC-derived mediators that exert local and distant effects. MCs produce angiogenic and lymphangiogenic factors, including vascular endothelial growth factors (VEGFs) and angiopoietins (ANGPTs). Serum concentrations of VEGF-A, VEGF-C, VEGF-D, ANGPT1 and ANGPT2 were determined in 64 mastocytosis patients and 64 healthy controls. Intracellular concentrations and spontaneous release of these mediators were evaluated in the mast cell lines ROSA and ROSA and in human lung mast cells (HLMCs). VEGF-A, ANGPT1, ANGPT2 and VEGF-C concentrations were higher in mastocytosis patients compared to controls. The VEGF-A, ANGPT2 and VEGF-C concentrations were correlated with the symptom severity. ANGPT1 concentrations were increased in all patients compared to controls. ANGPT2 levels were correlated with severity of clinical variants and with tryptase levels. VEGF-A, ANGPT1 and VEGF-C did not differ between indolent and advanced mastocytosis. ROSA, ROSA and HLMCs contained and spontaneously released VEGFs and ANGPTs. Serum concentrations of VEGFs and ANGPTs are altered in mastocytosis patients.
Topics: Adult; Aged; Angiopoietins; Case-Control Studies; Cell Line; Female; Gain of Function Mutation; Humans; Male; Mastocytosis; Middle Aged; Patient Acuity; Proto-Oncogene Proteins c-kit; Retrospective Studies; Up-Regulation; Vascular Endothelial Growth Factors; Young Adult
PubMed: 33687603
DOI: 10.1007/s10238-021-00693-0 -
European Journal of Medical Research Aug 2022The migration, proliferation, and inflammatory factor secretion of vascular smooth muscle cells (VSMCs) are involved in the important pathological processes of several...
The migration, proliferation, and inflammatory factor secretion of vascular smooth muscle cells (VSMCs) are involved in the important pathological processes of several vascular occlusive diseases, including coronary atherosclerosis (CAS). Interleukin 1β(IL-1β), as a bioactive mediator of VSMC synthesis and secretion, can promote the pathological progress of CAS. In this study, we further explored the underlying molecular mechanisms by which IL-1β regulates VSMC migration, invasion. We pretreated A7r5 and HASMC with IL-1β for 24 h, and measured the expression of IL-1β, proliferating cell nuclear antigen (PCNA), cyclin D1, matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 2 (MMP9) in the cells by Western blotting. Cell migration and invasion ability were measured by Transwell and wound healing assays. Cell viability was measured by an MTT assay. We found that IL-1β upregulated the expression of proliferation-related proteins (PCNA and Cyclin D1) in A7r5 and HASMC, and induces the secretion of MMP2 and MMP9, promotes cell invasion and migration. In addition, in A7r5 and HASMCs treated with IL-1β, the expression of Angiopoietin-2 (Angpt-2) increased in a time-dependent manner, transfection with si-Angpt-2 suppressed cell migration and invasion, with downregulated MMP2 and MMP9 expression. Parallelly, we further found that the p38-MAPK pathway is activated in cells induced by IL-1β, p38-MAPK inhibitors can down-regulate the expression of Angpt-2. Collectively, these data demonstrated that IL-1β promotes A7r5 and HASMC migration and invasion via the p38-MAPK/Angpt-2 pathway.
Topics: Angiopoietin-2; Cell Movement; Cell Proliferation; Cyclin D1; Humans; Interleukin-1beta; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Proliferating Cell Nuclear Antigen; p38 Mitogen-Activated Protein Kinases
PubMed: 35978364
DOI: 10.1186/s40001-022-00781-1 -
Medicina (Kaunas, Lithuania) Nov 2021Angiogenesis is a biological process that involves the formation of new blood vessels from the existing vasculature, and it plays a fundamental role in the development... (Review)
Review
Angiogenesis is a biological process that involves the formation of new blood vessels from the existing vasculature, and it plays a fundamental role in the development and progression of several types of cancer, including lung cancer. The angiopoietin/Tie2 ligand/receptor system orchestrates vascular integrity. In particular, Angiopoietin-1 activates the endothelial cell (EC)-specific receptor tyrosine kinase,Tie2,which is essential for preserving endothelial quiescence. On the other hand, Angiopoietin-2 acts as an inhibitor of the Angiopoietin-1/Tie2 signaling pathways, thus facilitating the destabilization of quiescent endothelium in cases of inflammation and cancer. Clinical studies have proven that high levels of Angiopoietin-2 indicate the development of non-small-cell lung carcinomas (NSCLC), while high levels of Angiopoietin-2 are strongly related to tumor angiogenesis, lymphangiogenesis, metastasis, and poor prognosis. Interestingly, the association of Angiopoietin-2 levels with the type of surgical approach makes Angiopoietin-2 a valuable factor in selecting the most suitable therapeutic strategy for lung cancer patients. The role of the Angiopoietin-1 and Angiopoietin-4 levels in NSCLC development requires further investigation. The present review focuses on the clinical impact of the Angiopoietin-1, Angiopoietin-2, and Angiopoietin-4 levels in patients diagnosed with NSCLC, emphasizing the interaction between them, and how they affect the development, progression, and metastasis of lung disease. Finally, it estimates the role of angiopoietins levels in the effective therapy of lung cancer patients.
Topics: Angiopoietins; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Neovascularization, Pathologic; Receptor, TIE-2
PubMed: 34833409
DOI: 10.3390/medicina57111191 -
Investigative Ophthalmology & Visual... Oct 2022Defects in the iridocorneal angle tissues, including the trabecular meshwork (TM) and Schlemm's canal (SC), impair aqueous humor flow and increase the intraocular...
PURPOSE
Defects in the iridocorneal angle tissues, including the trabecular meshwork (TM) and Schlemm's canal (SC), impair aqueous humor flow and increase the intraocular pressure (IOP), eventually resulting in glaucoma. Activation of endothelial tyrosine kinase receptor Tie2 by angiopoietin-1 (Angpt1) has been demonstrated to be essential for SC formation, but roles of the other two Tie2 ligands, Angpt2 and Angpt4, have been controversial or not yet characterized, respectively.
METHODS
Angpt4 expression was investigated using genetic cell fate mapping and reporter mice. Congenital deletion of Angpt2 and Angpt4 and tamoxifen-inducible deletion of Angpt1 in mice were used to study the effects of Angpt4 deletion alone and in combination with the other angiopoietins. SC morphology was examined with immunofluorescent staining. IOP measurements, electron microscopy, and histologic evaluation were used to study glaucomatous changes.
RESULTS
Angpt4 was postnatally expressed in the TM. While Angpt4 deletion alone did not affect SC and Angpt4 deletion did not aggravate Angpt1 deletion phenotype, absence of Angpt4 combined with Angpt2 deletion had detrimental effects on SC morphology in adult mice. Consequently, Angpt2-/-;Angpt4-/- mice displayed glaucomatous changes in the eye. Mice with Angpt2 deletion alone showed only moderate SC defects, but Angpt2 was necessary for proper limbal vasculature development. Mechanistically, analysis of Tie2 phosphorylation suggested that Angpt2 and Angpt4 cooperate as agonistic Tie2 ligands in maintaining SC integrity.
CONCLUSIONS
Our results indicated an additive effect of Angpt4 in SC maintenance and Tie2 activation and a spatiotemporally regulated interplay between the angiopoietins in the mouse iridocorneal angle.
Topics: Angiopoietin-1; Angiopoietin-2; Angiopoietins; Animals; Aqueous Humor; Glaucoma; Intraocular Pressure; Mice; Tamoxifen; Trabecular Meshwork
PubMed: 36190459
DOI: 10.1167/iovs.63.11.1 -
EBioMedicine Sep 2023Children with SARS-CoV-2 related Multisystem Inflammatory Syndrome in Children (MIS-C) often present with clinical features that resemble Kawasaki disease (KD). Disease...
Transient anti-cytokine autoantibodies superimpose the hyperinflammatory response in Kawasaki disease and multisystem inflammatory syndrome in children: a comparative cohort study on correlates of disease.
BACKGROUND
Children with SARS-CoV-2 related Multisystem Inflammatory Syndrome in Children (MIS-C) often present with clinical features that resemble Kawasaki disease (KD). Disease severity in adult COVID-19 is associated to the presence of anti-cytokine autoantibodies (ACAAs) against type I interferons. Similarly, ACAAs may be implicated in KD and MIS-C. Therefore, we explored the immunological response, presence of ACAAs and disease correlates in both disorders.
METHODS
Eighteen inflammatory plasma protein levels and seven ACAAs were measured in KD (n = 216) and MIS-C (n = 56) longitudinally by Luminex and/or ELISA. Levels (up to 1 year post-onset) of these proteins were related to clinical data and compared with healthy paediatric controls.
FINDINGS
ACAAs were found in both patient groups. The presence of ACAAs lagged behind the inflammatory plasma proteins and peaked in the subacute phase. ACAAs were mostly directed against IFN-γ (>80%) and were partially neutralising at best. KD presented with a higher variety of ACAAs than MIS-C. Increased levels of anti-IL-17A (P = 0·02) and anti-IL-22 (P = 0·01) were inversely associated with ICU admission in MIS-C. Except for CXCL10 in MIS-C (P = 0·002), inflammatory plasma proteins were elevated in both KD and MIS-C. Endothelial angiopoietin-2 levels were associated with coronary artery aneurysms in KD (P = 0·02); and sCD25 (P = 0·009), angiopoietin-2 (P = 0·001), soluble IL-33-receptor (ST2, P = 0·01) and CXCL10 (P = 0·02) with ICU admission in MIS-C.
INTERPRETATION
Markers of endothelial activation (E-selectin, angiopoietin-2), and innate and adaptive immune responses (macrophages [CD163, G-CSF], neutrophils [lipocalin-2], and T cells [IFN-γ, CXCL10, IL-6, IL-17]), are upregulated in KD and MIS-C. ACAAs were detected in both diseases and, although only partly neutralising, their transient presence and increased levels in non-ICU patients may suggest a dampening role on inflammation.
FUNDING
The Kawasaki study is funded by the Dutch foundation Fonds Kind & Handicap and an anonymous donor. The sponsors had no role in the study design, analysis, or decision for publication.
Topics: Adult; Humans; Child; Cytokines; Mucocutaneous Lymph Node Syndrome; Angiopoietin-2; COVID-19; Cohort Studies; SARS-CoV-2; Autoantibodies
PubMed: 37524002
DOI: 10.1016/j.ebiom.2023.104736 -
Journal of the American Heart... Nov 2023Background ANGPTL3 (angiopoietin-like protein 3) is an acknowledged crucial regulator of lipid metabolism by virtue of its inhibitory effect on lipoprotein lipase and...
Background ANGPTL3 (angiopoietin-like protein 3) is an acknowledged crucial regulator of lipid metabolism by virtue of its inhibitory effect on lipoprotein lipase and endothelial lipase. It is currently unknown whether and to which lipoproteins ANGPTL3 is bound and whether the ability of ANGPTL3 to inhibit lipase activity is affected by binding to lipoproteins. Methods and Results Incubation of ultracentrifugation-isolated low-density lipoprotein (LDL) and high-density lipoprotein (HDL) fractions from healthy volunteers with recombinant ANGPTL3 revealed that ANGPTL3 associates with both HDL and LDL particles ex vivo. Plasma from healthy volunteers and a patient deficient in HDL was fractionated by fast protein liquid chromatography, and ANGPTL3 distribution among lipoprotein fractions was measured. In healthy volunteers, ≈75% of lipoprotein-associated ANGPTL3 resides in HDL fractions, whereas ANGPTL3 was largely bound to LDL in the patient deficient in HDL. ANGPTL3 activity was studied by measuring lipolysis and uptake of H-trioleate by brown adipocyte T37i cells. Unbound ANGPTL3 did not suppress lipase activity, but when given with HDL or LDL, ANGPTL3 suppressed lipase activity by 21.4±16.4% (=0.03) and 25.4±8.2% (=0.006), respectively. Finally, in a subset of the EPIC (European Prospective Investigation into Cancer) Norfolk study, plasma HDL cholesterol and amount of large HDL particles were both positively associated with plasma ANGPTL3 concentrations. Moreover, plasma ANGPTL3 concentrations showed a positive association with incident coronary artery disease (odds ratio, 1.25 [95% CI, 1.01-1.55], =0.04). Conclusions Although ANGPTL3 preferentially resides on HDL, its activity was highest once bound to LDL particles.
Topics: Humans; Lipoproteins, HDL; Angiopoietin-like Proteins; Prospective Studies; Lipoproteins; Lipase; Angiopoietins; Triglycerides; Angiopoietin-Like Protein 3
PubMed: 37889183
DOI: 10.1161/JAHA.123.030476 -
Expert Opinion on Therapeutic Targets Jan 2020: Angiopoietin-like (ANGPTL) proteins belong to a family of eight secreted factors that are structurally related to proteins that modulate angiogenesi, commonly known as... (Review)
Review
: Angiopoietin-like (ANGPTL) proteins belong to a family of eight secreted factors that are structurally related to proteins that modulate angiogenesi, commonly known as angiopoietins. Specifically, ANGPTL3, ANGPTL4, and ANGPTL8 (the 'ANGPT L3-4-8 triad'), have surfaced as principal regulators of plasma lipid metabolism by functioning as potent inhibitors of lipoprotein lipase. The targeting of these proteins may open up future therapeutic avenues for metabolic and cardiovascular disease.: This article systematically summarizes the compelling literature describing the mechanistic roles of ANGPTL3, 4, and 8 in lipid metabolism, emphasizing their importance in determining the risk of cardiovascular disease. We shed light on population-based studies linking loss-of-function variations in ANGPTL3, 4, and 8 with decreased risk of metabolic conditions and cardiovascular disorders. We also discuss how the strategies aiming at targeting the ANGPT L3-4-8 triad could offer therapeutic benefit in the clinical scenario.: Monoclonal antibodies and antisense oligonucleotides that target ANGPTL3, 4, and 8 are potentially an efficient therapeutic strategy for hypertriglyceridemia and cardiovascular risk reduction, especially in patients with limited treatment options. These innovative therapeutical approaches are at an embryonic stage in development and hence further investigations are necessary for eventual use in humans.
Topics: Angiopoietin-like Proteins; Animals; Antibodies, Monoclonal; Cardiovascular Diseases; Humans; Hypertriglyceridemia; Lipid Metabolism; Molecular Targeted Therapy; Oligonucleotides, Antisense
PubMed: 31856617
DOI: 10.1080/14728222.2020.1707806 -
Cellular and Molecular Life Sciences :... Mar 2020Purinergic P2 receptors are critical regulators of several functions within the vascular system, including platelet aggregation, vascular inflammation, and vascular...
Purinergic P2 receptors are critical regulators of several functions within the vascular system, including platelet aggregation, vascular inflammation, and vascular tone. However, a role for ATP release and P2Y receptor signalling in angiogenesis remains poorly defined. Here, we demonstrate that blood vessel growth is controlled by P2Y receptors. Endothelial sprouting and vascular tube formation were significantly dependent on P2Y expression and inhibition of P2Y using a selective antagonist blocked microvascular network generation. Mechanistically, overexpression of P2Y in endothelial cells induced the expression of the proangiogenic molecules CXCR4, CD34, and angiopoietin-2, while expression of VEGFR-2 was decreased. Interestingly, elevated P2Y expression caused constitutive phosphorylation of ERK1/2 and VEGFR-2. However, stimulation of cells with the P2Y agonist UTP did not influence sprouting unless P2Y was constitutively expressed. Finally, inhibition of VEGFR-2 impaired spontaneous vascular network formation induced by P2Y overexpression. Our data suggest that P2Y receptors have an essential function in angiogenesis, and that P2Y receptors present a therapeutic target to regulate blood vessel growth.
Topics: Angiopoietin-2; Antigens, CD34; Cells, Cultured; Endothelial Cells; Endothelium, Vascular; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neovascularization, Physiologic; Phosphorylation; Platelet Aggregation; Purinergic P2Y Receptor Antagonists; RNA Interference; RNA, Small Interfering; Receptors, CXCR4; Receptors, Purinergic P2Y2; Vascular Endothelial Growth Factor Receptor-2
PubMed: 31278420
DOI: 10.1007/s00018-019-03213-2 -
Journal of the American Heart... Nov 2021Background Individuals infected with HIV have an increased risk of developing cardiovascular disease; yet, the underlying mechanisms remain unknown. Recent evidence has... (Observational Study)
Observational Study
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 (<0.01) and similar ANG2 levels. On the other hand, untreated individuals infected with HIV had similar ANG1 levels, and 29.2% had higher ANG2 levels (<0.01) compared with uninfected controls. When compared with individuals with untreated HIV infection, those with treated HIV infection had 56% lower ANG1 levels (<0.01) and 22% lower ANG2 levels (<0.01).Both treated and untreated HIV infection were associated with significant impairment in hyperemic velocity, a key measure of microvascular dysfunction (median 61 versus 72 cm/s, <0.01), compared with uninfected controls (median 73 cm/s). This difference persisted after adjustment for ANG1 and ANG2 levels. Interestingly, when compared with untreated individuals infected with HIV, treated individuals infected with HIV had worse hyperemic velocity (-12.35 cm/s, =0.05). In contrast, HIV status, ANG1 levels, and ANG2 levels were not associated with macrovascular dysfunction as measured by flow-mediated dilatation and brachial artery diameter, 2 other measures of vascular homeostasis. Conclusions HIV infection affects the balance between levels of ANG1 and ANG2 and may disturb endothelial homeostasis through disruption of vascular homeostasis. Individuals with treated HIV had decreased ANG1 levels and similar ANG2 levels, whereas individuals with untreated HIV had similar ANG1 levels and increased ANG2 levels, suggesting that treatment status may alter the balance between ANG1 and ANG2. HIV also promotes endothelial dysfunction via impairment of microvascular dysfunction, independent of the Tie-2 receptor system; the finding of worse microvascular dysfunction in the setting of treated HIV infection may reflect the impact of viral persistence on the microvasculature or toxicities of specific antiretroviral regimens. Further research to clarify the mechanism of HIV-mediated endothelial dysfunction is necessary to advance treatment of cardiovascular complications of HIV infection.
Topics: Angiopoietin-1; Angiopoietin-2; Cardiovascular Diseases; Cross-Sectional Studies; HIV Infections; HIV-1; Humans; Receptor, TIE-2
PubMed: 34726064
DOI: 10.1161/JAHA.121.021397 -
International Journal of Molecular... Aug 2023The early identification of women with an increased risk of preeclampsia (PE) is desirable, but apart from soluble fms-like tyrosine kinase-1 (sFlt-1), few biomarkers... (Meta-Analysis)
Meta-Analysis Review
The early identification of women with an increased risk of preeclampsia (PE) is desirable, but apart from soluble fms-like tyrosine kinase-1 (sFlt-1), few biomarkers have previously been identified as relevant for predicting preeclampsia. Since kinases and phosphatases regulate critical biological processes and previous evidence suggests a potential role of these molecules in preeclampsia, we performed this systematic review and metanalysis. The objective was to determine if there are kinases and phosphatases whose serum levels are different between women with and without PE, being relevant biomarkers of PE. We followed the recommendations of Cochrane and the Preferred Reported Items for Systematic Reviews and Metanalysis (PRISMA) to perform this study. The MESH terms preeclampsia, kinases, phosphatases, angiopoietins, soluble tyrosine protein kinase receptor (sTIE2), and cellular-mesenchymal-epithelial transition factor (c-MET) were combined to find relevant articles in the PubMed, PROSPERO, and Cochrane databases. Then, a qualitative and quantitative analysis was performed in R Studio software. From 580 abstracts identified, 37 were included in the final analysis, which comprised 24,211 pregnant women (2879 with PE and 21,332 women without PE [HP]. The pooled analysis showed that serum creatine kinase (CK) (SMD: 2.43, CI 95% 0.25-4.62) was significantly higher in PE, whereas sTIE2 and anti-angiogenic factor soluble c-Met (sMet)were significantly lower in PE than in HP (SMD: -0.23, CI95% -0.37 to -0.09; and SMD:0.24, CI95% 0.01-0.47, respectively). Adenosine monophosphate-activated protein kinase (AMPK), angiopoietin-1 (ANG-1), angiopoietin-2 (ANG-2), the ratio angiopoietin-1/angiopoietin-2, acid phosphatase, and alkaline phosphatase were not different between women with PE and HP. In summary CK, sTIE2, and c-MET are relevant biomarkers of PE. It is desirable to incorporate them into current models for PE prediction to evaluate their utility as biomarkers.
Topics: Pregnancy; Female; Humans; Phosphoric Monoester Hydrolases; Angiopoietin-1; Angiopoietin-2; Pre-Eclampsia; Antibodies; Receptor, trkA
PubMed: 37629025
DOI: 10.3390/ijms241612842