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European Journal of Clinical... Sep 2021Cardiorenal syndrome in diabetes is characterised by alterations of the cardiovascular system paralleled by kidney disease with progressive renal function decline. In... (Review)
Review
BACKGROUND
Cardiorenal syndrome in diabetes is characterised by alterations of the cardiovascular system paralleled by kidney disease with progressive renal function decline. In diabetes, chronic metabolic and haemodynamic perturbations drive endothelial dysfunction, inflammation, oxidative stress and progressive tissue fibrosis which, in turn, lead to heart and renal anatomo-functional damage. In physiology, vascular growth factors have been implicated in vascular homeostasis; their imbalance, in disease setting such as diabetes, leads to vascular dysfunction and cardiorenal damage.
AIMS
To define the role of vascular growth factors and angiopoietins in cardiorenal syndrome.
MATERIAL AND METHODS
We will focus on the two most studied vascular growth factors, vascular endothelial growth factor (VEGF) and angiopoietins (Angpt). The balance and crosstalk between these growth factors are important in organ development and in the maintenance of a healthy vasculature, heart and kidney. The observed alterations in expression/function of these vascular growth factors, as seen in diabetes, are a protective response against external perturbations.
RESULTS
The chronic insults driving diabetes-mediated cardiorenal damage results in a paradoxical situation, whereby the vascular growth factors imbalance becomes a mechanism of disease. Studies have explored the possibility of modulating the expression/action of vascular growth factors to improve disease outcome. Experimental work has been conducted in animals and has been gradually translated in humans.
DISCUSSION
Difficulties have been encountered especially when considering the magnitude, timing and duration of interventions targeting a selective vascular growth factor. Targeting VEGF in cardiovascular disease has been challenging, while modulation of the Angpt system seems more promising.
CONCLUSION
Future studies will establish the translatability of therapies targeting vascular growth factors for heart and kidney disease in patients with diabetes.
Topics: Angiopoietins; Cardio-Renal Syndrome; Diabetes Complications; Diabetes Mellitus; Diabetic Cardiomyopathies; Diabetic Nephropathies; Endothelium, Vascular; Humans; Vascular Endothelial Growth Factor A
PubMed: 33942293
DOI: 10.1111/eci.13579 -
Cellular Signalling Aug 2023The molecular mechanisms whereby angiopoietin-like 4 (ANGPTL4), a pluripotent protein implicated in cancer development, contributes to head and neck squamous cell...
OBJECTIVES
The molecular mechanisms whereby angiopoietin-like 4 (ANGPTL4), a pluripotent protein implicated in cancer development, contributes to head and neck squamous cell carcinoma (HNSCC) growth and dissemination are unclear.
MATERIALS AND METHODS
We investigated ANGPTL4 expression in human normal oral keratinocytes (NOKs), dysplastic oral keratinocytes (DOKs), oral leukoplakia cells (LEUK1), and HNSCC cell lines, as well as in tissue biopsies from patients with oral dysplasia, and primary and metastatic HNSCC. We further examined the contribution of ANGPTL4 cancer progression in an HNSCC orthotopic floor-of mouth tumor model and the signaling pathways linking ANGPTL4 to cancer cell migration.
RESULTS
ANGPTL4 expression was upregulated in premalignant DOKs and HNSCC cell lines compared to NOKs and was increased in tissue biopsies from patients with oral dysplasia, as well as in primary and metastatic HNSCC. We also observed that downregulation of ANGPTL4 expression inhibited primary and metastatic cancer growth in an HNSCC orthotopic tumor model. Interestingly, ANGPTL4 binding to the neuropilin1 (NRP1) receptor led to phosphorylation of the focal adhesion protein, paxillin (PXN), and tumor cell migration; this was dependent on the tyrosine kinase ABL1. Treatment with the ABL1 inhibitor, dasatinib and small interfering RNA silencing of NRP1 or ABL1 expression blocked PXN phosphorylation and tumor cell migration.
CONCLUSION
Our findings suggest an early, sustained, and angiogenesis-independent autocrine role for ANGPTL4 in HNSCC progression and expose ANGPTL4/NRP1/ABL1/PXN as an early molecular marker and vulnerable target for the prevention of HNSCC growth and metastasis.
Topics: Humans; Angiopoietins; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Head and Neck Neoplasms; Neuropilin-1; Paxillin; Squamous Cell Carcinoma of Head and Neck
PubMed: 37169211
DOI: 10.1016/j.cellsig.2023.110697 -
Nature Communications Oct 2021Primary congenital glaucoma (PCG) is a severe disease characterized by developmental defects in the trabecular meshwork (TM) and Schlemm's canal (SC), comprising the...
Primary congenital glaucoma (PCG) is a severe disease characterized by developmental defects in the trabecular meshwork (TM) and Schlemm's canal (SC), comprising the conventional aqueous humor outflow pathway of the eye. Recently, heterozygous loss of function variants in TEK and ANGPT1 or compound variants in TEK/SVEP1 were identified in children with PCG. Moreover, common variants in ANGPT1and SVEP1 have been identified as risk alleles for primary open angle glaucoma (POAG) in GWAS studies. Here, we show tissue-specific deletion of Angpt1 or Svep1 from the TM causes PCG in mice with severe defects in the adjacent SC. Single-cell transcriptomic analysis of normal and glaucomatous Angpt1 deficient eyes allowed us to identify distinct TM and SC cell populations and discover additional TM-SC signaling pathways. Furthermore, confirming the importance of angiopoietin signaling in SC, delivery of a recombinant ANGPT1-mimetic promotes developmental SC expansion in healthy and Angpt1 deficient eyes, blunts intraocular pressure (IOP) elevation and RGC loss in a mouse model of PCG and lowers IOP in healthy adult mice. Our data highlight the central role of ANGPT1-TEK signaling and TM-SC crosstalk in IOP homeostasis and provide new candidates for SC-targeted glaucoma therapy.
Topics: Angiopoietin-1; Animals; Anterior Chamber; Aqueous Humor; Calcium-Binding Proteins; Cell Adhesion Molecules; Cell Communication; Disease Models, Animal; Endothelial Cells; Gene Expression Profiling; Glaucoma, Open-Angle; Intraocular Pressure; Mice; Mice, Knockout; Neural Crest; Proteins; Recombinant Proteins; Signal Transduction; Single-Cell Analysis; Trabecular Meshwork
PubMed: 34663817
DOI: 10.1038/s41467-021-26346-0 -
Methods in Molecular Biology (Clifton,... 2023Cancer cells require higher oxygen levels and nutrition than normal cells. Cancer cells induce angiogenesis (the development of new blood vessels) from preexisting...
Cancer cells require higher oxygen levels and nutrition than normal cells. Cancer cells induce angiogenesis (the development of new blood vessels) from preexisting vessels. This biological process depends on the special, chemical, and physical properties of the microenvironment surrounding tumor tissues. The complexity of these properties hinders an understanding of their mechanisms. Various mathematical models have been developed to describe quantitative relationships related to angiogenesis. We developed a three-dimensional mathematical model that incorporates angiogenesis and tumor growth. We examined angiopoietin, which regulates the spouting and branching events in angiogenesis. The simulation successfully reproduced the transient decrease in new vessels during vascular network formation. This chapter describes the protocol used to perform the simulations.
Topics: Angiopoietins; Computer Simulation; Humans; Models, Biological; Neoplasms; Neovascularization, Pathologic; Oxygen; Tumor Microenvironment
PubMed: 36227549
DOI: 10.1007/978-1-0716-2617-7_14 -
Cells Dec 2020Angiopoietin (Ang) and its receptor, TIE signaling, contribute to the development and maturation of embryonic vasculature as well as vascular remodeling and permeability... (Review)
Review
Angiopoietin (Ang) and its receptor, TIE signaling, contribute to the development and maturation of embryonic vasculature as well as vascular remodeling and permeability in adult tissues. Targeting both this signaling pathway and the major pathway with vascular endothelial growth factor (VEGF) is expected to permit clinical applications, especially in antiangiogenic therapies against tumors. Several drugs targeting the Ang-TIE signaling pathway in cancer patients are under clinical development. Similar to how cancer increases with age, unsuitable angiogenesis or endothelial dysfunction is often seen in other ageing-associated diseases (AADs) such as atherosclerosis, Alzheimer's disease, type 2 diabetes, chronic kidney disease and cardiovascular diseases. Thus, the Ang-TIE pathway is a possible molecular target for AAD therapy. In this review, we focus on the potential role of the Ang-TIE signaling pathway in AADs, especially non-cancer-related AADs. We also suggest translational insights and future clinical applications of this pathway in those AADs.
Topics: Aging; Angiopoietins; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Receptors, TIE; Renal Insufficiency, Chronic; Signal Transduction; Vascular Endothelial Growth Factor A
PubMed: 33302426
DOI: 10.3390/cells9122636 -
Current Opinion in Lipidology Dec 2023The aim of this study was to discuss the potential mechanisms and implications of the opposing liver safety results from recent angiopoietin-like 3 (ANGPTL3) inhibition... (Review)
Review
PURPOSE OF REVIEW
The aim of this study was to discuss the potential mechanisms and implications of the opposing liver safety results from recent angiopoietin-like 3 (ANGPTL3) inhibition studies.
RECENT FINDINGS
The clinical development of vupanorsen, a N-acetylgalactosamine (GalNAc) antisense targeting hepatic ANGPTL3, was recently discontinued due to a significant signal of liver transaminase increase. Vupanorsen elicited a dose-dependent increase in hepatic fat fraction up to 75%, whereas the small interfering RNA (siRNA) ARO-ANG3, has reported preliminary evidence of a dose-dependent decrease in hepatic fat fraction up to 30%.
SUMMARY
ANGPTL3 inhibition is an attractive therapeutic target to reduce all apoB-containing lipoproteins. The discrepancy in liver signal results between the antisense and siRNA approach may be explained by the level of target inhibition. An alternative explanation may relate to off-target effects of vupanorsen, which have a molecule- and/or platform-specific origin. For intrahepatic strategies, highly potent ANGPTL3 inhibition will for now require special attention for liver safety.
Topics: Humans; Angiopoietin-like Proteins; Angiopoietin-Like Protein 3; Liver; RNA, Small Interfering; Angiopoietins
PubMed: 37820081
DOI: 10.1097/MOL.0000000000000898 -
International Journal of Molecular... Jun 2022Angiogenesis is involved in physiological and pathological processes in the body. Tumor angiogenesis is a key factor associated with tumor growth, progression, and... (Review)
Review
Angiogenesis is involved in physiological and pathological processes in the body. Tumor angiogenesis is a key factor associated with tumor growth, progression, and metastasis. Therefore, there is great interest in developing antiangiogenic strategies. Hypoxia is the basic initiating factor of tumor angiogenesis, which leads to the increase of vascular endothelial growth factor (VEGF), angiopoietin (Ang), hypoxia-inducible factor (HIF-1), etc. in hypoxic cells. The pathways of VEGF and Ang are considered to be critical steps in tumor angiogenesis. A number of antiangiogenic drugs targeting VEGF/VEGFR (VEGF receptor) or ANG/Tie2, or both, are currently being used for cancer treatment, or are still in various stages of clinical development or preclinical evaluation. This article aims to review the mechanisms of angiogenesis and tumor angiogenesis and to focus on new drugs and strategies for the treatment of antiangiogenesis. However, antitumor angiogenic drugs alone may not be sufficient to eradicate tumors. The molecular chaperone heat shock protein 90 (HSP90) is considered a promising molecular target. The VEGFR system and its downstream signaling molecules depend on the function of HSP90. This article also briefly introduces the role of HSP90 in angiogenesis and some HSP90 inhibitors.
Topics: Angiogenesis Inhibitors; Angiopoietins; Antineoplastic Agents; HSP90 Heat-Shock Proteins; Humans; Hypoxia; Neoplasms; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 35805939
DOI: 10.3390/ijms23136934 -
Arteriosclerosis, Thrombosis, and... Aug 2023Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by arteriovenous malformations and blood vessel enlargements. However, there are no...
BACKGROUND
Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by arteriovenous malformations and blood vessel enlargements. However, there are no effective drug therapies to combat arteriovenous malformation formation in patients with HHT. Here, we aimed to address whether elevated levels of ANG2 (angiopoietin-2) in the endothelium is a conserved feature in mouse models of the 3 major forms of HHT that could be neutralized to treat brain arteriovenous malformations and associated vascular defects. In addition, we sought to identify the angiogenic molecular signature linked to HHT.
METHODS
Cerebrovascular defects, including arteriovenous malformations and increased vessel calibers, were characterized in mouse models of the 3 common forms of HHT using transcriptomic and dye injection labeling methods.
RESULTS
Comparative RNA sequencing analyses of isolated brain endothelial cells revealed a common, but unique proangiogenic transcriptional program associated with HHT. This included a consistent upregulation in cerebrovascular expression of ANG2 and downregulation of its receptor Tyr kinase with Ig and EGF homology domains (TIE2/TEK) in HHT mice compared with controls. Furthermore, in vitro experiments revealed TEK signaling activity was hampered in an HHT setting. Pharmacological blockade of ANG2 improved brain vascular pathologies in all HHT models, albeit to varying degrees. Transcriptomic profiling further indicated that ANG2 inhibition normalized the brain vasculature by impacting a subset of genes involved in angiogenesis and cell migration processes.
CONCLUSIONS
Elevation of ANG2 in the brain vasculature is a shared trait among the mouse models of the common forms of HHT. Inhibition of ANG2 activity can significantly limit or prevent brain arteriovenous malformation formation and blood vessel enlargement in HHT mice. Thus, ANG2-targeted therapies may represent a compelling approach to treat arteriovenous malformations and vascular pathologies related to all forms of HHT.
Topics: Animals; Mice; Telangiectasia, Hereditary Hemorrhagic; Endothelial Cells; Angiopoietin-2; Arteriovenous Malformations; Phenotype
PubMed: 37288572
DOI: 10.1161/ATVBAHA.123.319385 -
Retina (Philadelphia, Pa.) Jan 2021To provide a concise overview for ophthalmologists and practicing retina specialists of available clinical evidence of manipulating the angiopoietin/tyrosine kinase with... (Review)
Review
PURPOSE
To provide a concise overview for ophthalmologists and practicing retina specialists of available clinical evidence of manipulating the angiopoietin/tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains (Tie) pathway and its potential as a therapeutic target in retinal vascular diseases.
METHODS
A literature search for articles on the angiopoietin/Tie pathway and molecules targeting this pathway that have reached Phase 2 or 3 trials was undertaken on PubMed, Association for Research in Vision and Ophthalmology meeting abstracts (2014-2019), and ClinicalTrials.gov databases. Additional information on identified pipeline drugs was obtained from publicly available information on company websites.
RESULTS
The PubMed and Association for Research in Vision and Ophthalmology meeting abstract search yielded 462 results, of which 251 publications not relevant to the scope of the review were excluded. Of the 141 trials related to the angiopoietin/Tie pathway on ClinicalTrials.gov, seven trials focusing on diseases covered in this review were selected. Vision/anatomic outcomes from key clinical trials on molecules targeting the angiopoietin/Tie pathway in patients with retinal vascular diseases are discussed.
CONCLUSION
Initial clinical evidence suggests a potential benefit of targeting the angiopoietin/Tie pathway and vascular endothelial growth factor-A over anti-vascular endothelial growth factor-A monotherapy alone, in part due to of the synergistic nature of the pathways.
Topics: Angiopoietins; Humans; Retinal Diseases; Retinal Vessels; Signal Transduction
PubMed: 33136975
DOI: 10.1097/IAE.0000000000003003 -
Human Molecular Genetics Jul 2023Rare missense and nonsense variants in the Angiopoietin-like 7 (ANGPTL7) gene confer protection from primary open-angle glaucoma (POAG), though the functional mechanism...
Rare missense and nonsense variants in the Angiopoietin-like 7 (ANGPTL7) gene confer protection from primary open-angle glaucoma (POAG), though the functional mechanism remains uncharacterized. Interestingly, a larger variant effect size strongly correlates with in silico predictions of increased protein instability (r = -0.98), suggesting that protective variants lower ANGPTL7 protein levels. Here, we show that missense and nonsense variants cause aggregation of mutant ANGPTL7 protein in the endoplasmic reticulum (ER) and decreased levels of secreted protein in human trabecular meshwork (TM) cells; a lower secreted:intracellular protein ratio strongly correlates with variant effects on intraocular pressure (r = 0.81). Importantly, accumulation of mutant protein in the ER does not increase expression of ER stress proteins in TM cells (P > 0.05 for all variants tested). Cyclic mechanical stress, a glaucoma-relevant physiologic stressor, also significantly lowers ANGPTL7 expression in primary cultures of human Schlemm's canal (SC) cells (-2.4-fold-change, P = 0.01). Collectively, these data suggest that the protective effects of ANGPTL7 variants in POAG stem from lower levels of secreted protein, which may modulate responses to physiologic and pathologic ocular cell stressors. Downregulation of ANGPTL7 expression may therefore serve as a viable preventative and therapeutic strategy for this common, blinding disease.
Topics: Humans; Glaucoma, Open-Angle; Glaucoma; Trabecular Meshwork; Intraocular Pressure; Angiopoietins; Angiopoietin-like Proteins; Angiopoietin-Like Protein 7
PubMed: 37220876
DOI: 10.1093/hmg/ddad083