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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 -
Science (New York, N.Y.) Apr 2021Multivalent display of receptor-engaging antibodies or ligands can enhance their activity. Instead of achieving multivalency by attachment to preexisting scaffolds, here...
Multivalent display of receptor-engaging antibodies or ligands can enhance their activity. Instead of achieving multivalency by attachment to preexisting scaffolds, here we unite form and function by the computational design of nanocages in which one structural component is an antibody or Fc-ligand fusion and the second is a designed antibody-binding homo-oligomer that drives nanocage assembly. Structures of eight nanocages determined by electron microscopy spanning dihedral, tetrahedral, octahedral, and icosahedral architectures with 2, 6, 12, and 30 antibodies per nanocage, respectively, closely match the corresponding computational models. Antibody nanocages targeting cell surface receptors enhance signaling compared with free antibodies or Fc-fusions in death receptor 5 (DR5)-mediated apoptosis, angiopoietin-1 receptor (Tie2)-mediated angiogenesis, CD40 activation, and T cell proliferation. Nanocage assembly also increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus neutralization by α-SARS-CoV-2 monoclonal antibodies and Fc-angiotensin-converting enzyme 2 (ACE2) fusion proteins.
Topics: Angiopoietins; Antibodies; Antibodies, Monoclonal; Antibodies, Neutralizing; Antibodies, Viral; B-Lymphocytes; CD40 Antigens; Cell Line, Tumor; Cell Proliferation; Computer Simulation; Genes, Synthetic; Humans; Immunoglobulin Fc Fragments; Lymphocyte Activation; Models, Molecular; Nanostructures; Protein Binding; Protein Engineering; Receptor, TIE-2; Receptors, TNF-Related Apoptosis-Inducing Ligand; SARS-CoV-2; Signal Transduction; T-Lymphocytes
PubMed: 33795432
DOI: 10.1126/science.abd9994 -
Life Sciences Dec 2019The angiopoietin signal transduction system is a complex of vascular-specific kinase pathways that plays a crucial role in angiogenesis and maintenance of vascular... (Review)
Review
The angiopoietin signal transduction system is a complex of vascular-specific kinase pathways that plays a crucial role in angiogenesis and maintenance of vascular homeostasis. Angiopoietin1 (Ang1) and 2 (Ang2), the ligand proteins of the pathway, belong to a family of glycoproteins that signal primarily through the transmembrane Tyrosine-kinase-2 receptor. Despite a considerable sequence homology, Ang1 and Ang2 manifest antagonistic effects in pathophysiological conditions. While Ang1 promotes the activation of survival pathways and the stabilization of the normal mature vessels, Ang2 can either favor vessel destabilization and leakage or promote abnormal EC proliferation in a context-dependent manner. Altered Ang1/Ang2 balance has been reported in various pathological conditions in association with inflammation and deregulated angiogenesis. In particular, increased Ang2 levels have been documented in human cancer and cardiovascular disease (CVD), including ischemic myocardial injury, heart failure and other cardiovascular complications secondary to diabetes, chronic renal damage and hypertension. Despite the obvious phenotypic differences, CVD and cancer share some common Ang2-dependent etiopathological mechanisms such as inflammation, epithelial (or endothelial) to mesenchymal transition, and adverse vascular network remodeling. Interestingly, both cancer and CVD are negatively affected by thyroid hormone dyshomeostasis. This review provides an overview of the complex Ang2-dependent signaling involved in CVD and cancer, as well as a survey of the related clinical literature. Moreover, on the basis of recent molecular acquisitions in an experimental model of post ischemic cardiac disease, the putative novel role of the thyroid hormone in the regulation of Ang1/Ang2 balance is also briefly discussed.
Topics: Angiogenesis Inducing Agents; Angiopoietin-2; Cardiovascular Diseases; Endothelium, Vascular; Humans; Inflammation; Membrane Glycoproteins; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Signal Transduction; Vascular Remodeling
PubMed: 31756341
DOI: 10.1016/j.lfs.2019.117080 -
Current Opinion in Lipidology Feb 2022Over the last two decades, evolving discoveries around angiopoietin-like (ANGPTL) proteins, particularly ANGPTL3, ANGPTL4, and ANGPTL8, have generated significant... (Review)
Review
PURPOSE OF REVIEW
Over the last two decades, evolving discoveries around angiopoietin-like (ANGPTL) proteins, particularly ANGPTL3, ANGPTL4, and ANGPTL8, have generated significant interest in understanding their roles in fatty acid (FA) metabolism. Until recently, exactly how this protein family regulates lipoprotein lipase (LPL) in a tissue-specific manner to control FA partitioning has remained elusive. This review summarizes the latest insights into mechanisms by which ANGPTL3/4/8 proteins regulate postprandial FA partitioning.
RECENT FINDINGS
Accumulating evidence suggests that ANGPTL8 is an insulin-responsive protein that regulates ANGPTL3 and ANGPTL4 by forming complexes with them to increase or decrease markedly their respective LPL-inhibitory activities. After feeding, when insulin levels are high, ANGPTL3/8 secreted by hepatocytes acts in an endocrine manner to inhibit LPL in skeletal muscle, whereas ANGPTL4/8 secreted by adipocytes acts locally to preserve adipose tissue LPL activity, thus shifting FA toward the fat for storage. Insulin also decreases hepatic secretion of the endogenous ANGPTL3/8 inhibitor, apolipoprotein A5 (ApoA5), to accentuate ANGPTL3/8-mediated LPL inhibition in skeletal muscle.
SUMMARY
The ANGPTL3/4/8 protein family and ApoA5 play critical roles in directing FA toward adipose tissue postprandially. Selective targeting of these proteins holds significant promise for the treatment of dyslipidemias, metabolic syndrome, and their related comorbidities.
Topics: Angiopoietin-Like Protein 3; Angiopoietin-Like Protein 8; Angiopoietin-like Proteins; Angiopoietins; Fatty Acids; Humans; Insulins; Lipid Metabolism; Lipoprotein Lipase; Peptide Hormones; Postprandial Period
PubMed: 34789669
DOI: 10.1097/MOL.0000000000000798 -
Journal of Cosmetic Dermatology Oct 2022Early detection of psoriasis is still an open discussion. Psoriatic lesions are characterized by red/scaly plaques affecting different body-sites.
BACKGROUND
Early detection of psoriasis is still an open discussion. Psoriatic lesions are characterized by red/scaly plaques affecting different body-sites.
OBJECTIVES
To evaluate the levels of programmed cell death protein-1(PD-1) and Angiopoietins-2(Ang-2) in serum, lesional, and perilesional of psoriatic patients and correlate them with controls and disease severity.
SUBJECTS AND METHODS
Serum samples were obtained from 40 participants subdivided equally into psoriatic and healthy controls, 4 mm punch_biopsy equally from lesional and perilesional skin of individuals. PD-1/ANG-2 ELISA kits were used for determining the serum and tissue levels among groups.
RESULTS
Serum and tissue levels of PD-1 and Ang-2 were overexpressed in psoriatic patients compared with controls. There was a statistical difference between patients and controls in level of PD-1(serum and tissue) with p-value 0.006 and 0.0001, respectively. There was a statistical difference between both groups for ANG-2(serum and tissue) with p-value 0.03 and 0.0001, respectively. There were positive correlations between PASI score and PD-1 in tissue (r = 0.467, p = 0.038). Also, positive correlation between the level of PD-1 in serum and tissue (r = 0.369, p = 0.019), the serum levels of PD-1 and ANG-2 (r = 0.78, p > 0.0001), PD-1 and Ang-2 in tissue (r = 0.583,p = 0.0001) were detected.
CONCLUSION
PD-1 and ANG-2 can be highly recommended to determine the severity of psoriasis.
Topics: Humans; Apoptosis Regulatory Proteins; Biomarkers; Case-Control Studies; Programmed Cell Death 1 Receptor; Psoriasis; Severity of Illness Index; Skin; Angiopoietin-2
PubMed: 35506216
DOI: 10.1111/jocd.15039 -
Expert Opinion on Investigational Drugs Oct 2019: The Tie-2/Angiopoietin pathway is a therapeutic target for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME).... (Review)
Review
: The Tie-2/Angiopoietin pathway is a therapeutic target for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Activation of Tie-2 receptor via Ang-1 maintains vascular stability to limit exudation. Ang-2, a competitive antagonist to Ang-1, and VE-PTP, an endothelial-specific phosphatase, interfere with the Tie-2-Ang-1 axis, resulting in vascular leakage. : Faricimab, a bispecific antibody that inhibits VEGF-A and Ang-2, is in phase 3 trials for nAMD and DME. Nesvacumab is an Ang-2 inhibitor; when coformulated with aflibercept, it failed to show benefit over aflibercept monotherapy in achieving visual gains in phase 2 studies of nAMD and DME. ARP-1536 is an intravitreally administered VE-PTP inhibitor undergoing preclinical studies. AKB-9778 is a subcutaneously administered VE-PTP inhibitor that, when combined with monthly ranibizumab, reduced DME more effectively than ranibizumab monotherapy in a phase 2 study. AKB-9778 monotherapy did not reduce diabetic retinopathy severity score compared to placebo. AXT107, currently in the preclinical phase, promotes conversion of Ang-2 into a Tie-2 agonist and blocks signaling through VEGFR2 and other receptor tyrosine-kinases. : Tie-2/Angiopoietin pathway modulators show promise to reduce treatment burden and improve visual outcomes in nAMD and DME, with potential to treat cases refractory to current treatment modalities.
Topics: Angiogenesis Inhibitors; Angiopoietin-1; Angiopoietin-2; Animals; Diabetic Retinopathy; Humans; Macular Degeneration; Macular Edema; Receptor, TIE-2; Signal Transduction
PubMed: 31513439
DOI: 10.1080/13543784.2019.1667333 -
Scientific Reports Oct 2023Early detection of atrial fibrillation (AF) enables initiation of anticoagulation and early rhythm control therapy to reduce stroke, cardiovascular death, and heart... (Observational Study)
Observational Study
Early detection of atrial fibrillation (AF) enables initiation of anticoagulation and early rhythm control therapy to reduce stroke, cardiovascular death, and heart failure. In a cross-sectional, observational study, we aimed to identify a combination of circulating biomolecules reflecting different biological processes to detect prevalent AF in patients with cardiovascular conditions presenting to hospital. Twelve biomarkers identified by reviewing literature and patents were quantified on a high-precision, high-throughput platform in 1485 consecutive patients with cardiovascular conditions (median age 69 years [Q1, Q3 60, 78]; 60% male). Patients had either known AF (45%) or AF ruled out by 7-day ECG-monitoring. Logistic regression with backward elimination and a neural network approach considering 7 key clinical characteristics and 12 biomarker concentrations were applied to a randomly sampled discovery cohort (n = 933) and validated in the remaining patients (n = 552). In addition to age, sex, and body mass index (BMI), BMP10, ANGPT2, and FGF23 identified patients with prevalent AF (AUC 0.743 [95% CI 0.712, 0.775]). These circulating biomolecules represent distinct pathways associated with atrial cardiomyopathy and AF. Neural networks identified the same variables as the regression-based approach. The validation using regression yielded an AUC of 0.719 (95% CI 0.677, 0.762), corroborated using deep neural networks (AUC 0.784 [95% CI 0.745, 0.822]). Age, sex, BMI and three circulating biomolecules (BMP10, ANGPT2, FGF23) are associated with prevalent AF in unselected patients presenting to hospital. Findings should be externally validated. Results suggest that age and different disease processes approximated by these three biomolecules contribute to AF in patients. Our findings have the potential to improve screening programs for AF after external validation.
Topics: Humans; Male; Aged; Female; Atrial Fibrillation; Angiopoietin-2; Cross-Sectional Studies; Biomarkers; Stroke; Risk Factors; Bone Morphogenetic Proteins
PubMed: 37798357
DOI: 10.1038/s41598-023-42331-7 -
Growth Factors (Chur, Switzerland) 2021"Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. growth factor concentration) is high or low...
BACKGROUND
"Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. growth factor concentration) is high or low relative to its distribution.
METHODS
Quantile-regression analysis was applied to family sets from the Framingham Heart Study to determine whether the heritability () of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), angiopoietin-2, and angiopoietin-2 (sTie-2) and VEGFR1 (sFlt-1) receptor concentrations were quantile-specific.
RESULTS
Quantile-specific (±SE) increased with increasing percentiles of the age- and sex-adjusted VEGF (<10), HGF (=0.0004), angiopoietin-2 (=0.0002), sTie-2 (=1.2 × 10), and sFlt-1 distributions (=0.04).
CONCLUSION
Heritabilities of VEGF, HGF, angiopoitein-2, sTie-2 and sFlt-1 concentrations are quantile dependent. This may explain reported interactions of genetic loci (rs10738760, rs9472159, rs833061, rs3025039, rs2280789, rs1570360, rs2010963) with metabolic syndrome, diet, recurrent miscarriage, hepatocellular carcinoma, erysipelas, diabetic retinopathy, and bevacizumab treatment in their effect on VEGF concentrations.
Topics: Angiopoietin-2; Phenotype; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1
PubMed: 35312415
DOI: 10.1080/08977194.2022.2049261 -
The American Journal of Cardiology Oct 2023
Topics: Humans; Angiopoietin-2; Fontan Procedure
PubMed: 37633796
DOI: 10.1016/j.amjcard.2023.07.125