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International Journal of Molecular... Nov 2021Angiogenesis, the growth of new blood vessels from preexisting vessels, is associated with inflammation in various pathological conditions. Well-known angiogenetic... (Review)
Review
Angiogenesis, the growth of new blood vessels from preexisting vessels, is associated with inflammation in various pathological conditions. Well-known angiogenetic factors include vascular endothelial growth factor (VEGF), angiopoietins, platelet-derived growth factor, transforming growth factor-β, and basic fibroblast growth factor. Yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) have recently been added to an important angiogenic factor. Accumulating evidence indicates associations between angiogenesis and chronic inflammatory skin diseases. Angiogenesis is deeply involved in the pathogenesis of psoriasis. VEGF, angiopoietins, tumor necrosis factor-a, interleukin-8, and interleukin-17 are unregulated in psoriasis and induce angiogenesis. Angiogenesis may be involved in the pathogenesis of atopic dermatitis, and in particular, mast cells are a major source of VEGF expression. Angiogenesis is an essential process in rosacea, which is induced by LL-37 from a signal cascade by microorganisms, VEGF, and MMP-3 from mast cells. In addition, angiogenesis by increased VEGF has been reported in chronic urticaria and hidradenitis suppurativa. The finding that VEGF is expressed in inflammatory skin lesions indicates that inhibition of angiogenesis is a useful strategy for treatment of chronic, inflammatory skin disorders.
Topics: Angiopoietins; Animals; Chronic Disease; Dermatitis; Dermatitis, Atopic; Humans; Neovascularization, Pathologic; Psoriasis; Rosacea; Vascular Endothelial Growth Factor A
PubMed: 34769465
DOI: 10.3390/ijms222112035 -
The Journal of Experimental Medicine Aug 2021The wound healing process that occurs after spinal cord injury is critical for maintaining tissue homeostasis and limiting tissue damage, but eventually results in a...
The wound healing process that occurs after spinal cord injury is critical for maintaining tissue homeostasis and limiting tissue damage, but eventually results in a scar-like environment that is not conducive to regeneration and repair. A better understanding of this dichotomy is critical to developing effective therapeutics that target the appropriate pathobiology, but a major challenge has been the large cellular heterogeneity that results in immensely complex cellular interactions. In this study, we used single-cell RNA sequencing to assess virtually all cell types that comprise the mouse spinal cord injury site. In addition to discovering novel subpopulations, we used expression values of receptor-ligand pairs to identify signaling pathways that are predicted to regulate specific cellular interactions during angiogenesis, gliosis, and fibrosis. Our dataset is a valuable resource that provides novel mechanistic insight into the pathobiology of not only spinal cord injury but also other traumatic disorders of the CNS.
Topics: Angiopoietins; Animals; Astrocytes; Cell Communication; Chemotaxis; Female; Fibroblasts; Fibrosis; Gliosis; Inflammation; Interleukin-6; Ligands; Macrophages; Mice, Inbred C57BL; Myeloid Cells; Neuroglia; Oncostatin M; Receptors, Oncostatin M; Signal Transduction; Single-Cell Analysis; Spinal Cord Injuries; Time Factors; Transcriptome; Vascular Endothelial Growth Factor A; Mice
PubMed: 34132743
DOI: 10.1084/jem.20210040 -
Eye (London, England) May 2021The angopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Ang/Tie) pathway is an emerging key regulator in vascular development... (Review)
Review
The angopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Ang/Tie) pathway is an emerging key regulator in vascular development and maintenance. Its relevance to clinicians and basic scientists as a potential therapeutic target in retinal and choroidal vascular diseases is highlighted by recent preclinical and clinical evidence. The Ang/Tie pathway plays an important role in the regulation of vascular stability, in angiogenesis under physiological and pathological conditions, as well as in inflammation. Under physiological conditions, angiopoietin-1 (Ang-1) binds to and phosphorylates the Tie2 receptor, leading to downstream signalling that promotes cell survival and vascular stability. Angiopoietin-2 (Ang-2) is upregulated under pathological conditions and acts as a context-dependent agonist/antagonist of the Ang-1/Tie2 axis, causing vascular destabilisation and sensitising blood vessels to the effects of vascular endothelial growth factor-A (VEGF-A). Ang-2 and VEGF-A synergistically drive vascular leakage, neovascularisation and inflammation, key components of retinal vascular diseases. Preclinical evidence suggests that modulating the Ang/Tie pathway restores vascular stabilisation and reduces inflammation. This review discusses how targeting the Ang/Tie pathway or applying Ang-2/VEGF-A combination therapy may be a valuable therapeutic strategy for restoring vascular stability and reducing inflammation in the treatment of retinal and choroidal vascular diseases.
Topics: Angiopoietins; Humans; Receptor, TIE-2; Signal Transduction; Vascular Diseases; Vascular Endothelial Growth Factor A
PubMed: 33564135
DOI: 10.1038/s41433-020-01377-x -
Hepatology (Baltimore, Md.) Sep 2023Acute-on-chronic liver failure (ACLF) is an acute liver and multisystem failure in patients with previously stable cirrhosis. A common cause of ACLF is sepsis secondary...
BACKGROUND AND AIMS
Acute-on-chronic liver failure (ACLF) is an acute liver and multisystem failure in patients with previously stable cirrhosis. A common cause of ACLF is sepsis secondary to bacterial infection. Sepsis-associated ACLF involves a loss of differentiated liver function in the absence of direct liver injury, and its mechanism is unknown. We aimed to study the mechanism of sepsis-associated ACLF using a novel mouse model.
APPROACH AND RESULTS
Sepsis-associated ACLF was induced by cecal ligation and puncture procedure (CLP) in mice treated with thioacetamide (TAA). The combination of TAA and CLP resulted in a significant decrease in liver synthetic function and high mortality. These changes were associated with reduced metabolic gene expression and increased CCAAT enhancer binding protein beta (C/EBPβ) transcriptional activity. We found that C/EBPβ binding to its target gene promoters was increased. In humans, C/EBPβ chromatin binding was similarly increased in the ACLF group compared with control cirrhosis. Hepatocyte-specific Cebpb knockout mice had reduced mortality and increased gene expression of hepatocyte differentiation markers in TAA/CLP mice, suggesting that C/EBPβ promotes liver failure in these mice. C/EBPβ activation was associated with endothelial dysfunction, characterized by reduced Angiopoietin-1/Angiopoietin-2 ratio and increased endothelial production of HGF. Angiopoietin-1 supplementation or Hgf knockdown reduced hepatocyte C/EBPβ accumulation, restored liver function, and reduced mortality, suggesting that endothelial dysfunction induced by sepsis drives ACLF through HGF-C/EBPβ pathway.
CONCLUSIONS
The transcription factor C/EBPβ is activated in both mouse and human ACLF and is a potential therapeutic target to prevent liver failure in patients with sepsis and cirrhosis.
Topics: Humans; Mice; Animals; Acute-On-Chronic Liver Failure; Angiopoietin-1; Angiopoietin-2; Sepsis; Liver Cirrhosis; Hepatocyte Growth Factor
PubMed: 36943063
DOI: 10.1097/HEP.0000000000000354 -
Expert Opinion on Investigational Drugs Mar 2021Intravitreal antivascular endothelial growth factor (VEGF) drugs represent the first-line treatment option for wet age-related macular degeneration (w-AMD) and diabetic... (Comparative Study)
Comparative Study Review
INTRODUCTION
Intravitreal antivascular endothelial growth factor (VEGF) drugs represent the first-line treatment option for wet age-related macular degeneration (w-AMD) and diabetic macular edema (DME); however, the frequent injection intervals have illuminated to the necessity for new molecules allowing a more prolonged treatment regimen. Faricimab is a promising bispecific drug targeting VEGF-A and the Ang-Tie/pathway. Phase II STAIRWAY and AVENUE Trials showed its clinical efficacy for the treatment of w-AMD, while the phase II BOULEVARD Trial revealed its superiority to monthly ranibizumab in the management of DME with a monthly treatment regimen. The agents are awaiting approval for the treatment of w-AMD and DME.
AREAS COVERED
This article presents an overview of w-AMD and diabetic retinopathy and examines the progress of Faricimab through clinical trials. It offers insights on where Faricimab may be placed in the future market of anti-VEGF treatments and discusses the role of Ang/Tie pathway as a potential additive weapon for the treatment of w-AMD, DME, and retinal vein occlusion (RVO).
EXPERT OPINION
The possibility of administering faricimab with more prolonged treatment intervals represents an important advantage to decrease the treatment burden and improve patient compliance. Further phase III trials should provide more evidence on clinical efficacy.
Topics: Angiogenesis Inhibitors; Angiopoietins; Animals; Diabetic Retinopathy; Humans; Macular Edema; Ranibizumab; Receptor, TIE-2; Retinal Diseases; Vascular Endothelial Growth Factor A; Wet Macular Degeneration
PubMed: 33471572
DOI: 10.1080/13543784.2021.1879791 -
International Journal of Biological... Nov 2022Angiogenesis forms new vessels from existing ones. Abnormal angiogenesis, which is what gives tumor microenvironments their distinctive features, is characterised by... (Review)
Review
Angiogenesis forms new vessels from existing ones. Abnormal angiogenesis, which is what gives tumor microenvironments their distinctive features, is characterised by convoluted, permeable blood vessels with a variety of shapes and high perfusion efficiency. Tumor angiogenesis controls cancer growth by allowing invasion and metastasis and is highly controlled by signalling networks. Therapeutic techniques targeting VEGF, PDGF, FGF Notch, Angiopoietin, and HGF signalling restrict the tumor's vascular supply. Numerous pathways regulate angiogenesis, and when one of those processes is blocked, the other pathways may step in to help. VEGF signalling inhibition alone has limits as an antiangiogenic therapy, and additional angiogenic pathways such as FGF, PDGF, Notch, angiopoietin, and HGF are important. For the treatment of advanced solid tumors, there are also new, emerging medicines that target multiple angiogenic pathways. Recent therapies block numerous signalling channels concurrently. This study focuses on 'alternative' methods to standard antiangiogenic medicines, such as cyclooxygenase-2 blocking, oligonucleotide binding complementary sites to noncoding RNAs to regulate mRNA target, matrix metalloproteinase inhibition and CRISPR/Cas9 based gene edition and dissecting alternative angiogenesis mechanism in tumor microenvironment.
Topics: Humans; Vascular Endothelial Growth Factor A; Angiopoietins; Neovascularization, Pathologic; Signal Transduction; Angiogenesis Inhibitors; Neoplasms; Tumor Microenvironment; Hepatocyte Growth Factor
PubMed: 36122781
DOI: 10.1016/j.ijbiomac.2022.09.129 -
Nature Medicine Dec 2022Osteoarthritis (OA) is a common, debilitating, chronic disease with no disease-modifying drug approved to date. We discovered LNA043-a derivative of angiopoietin-like 3... (Randomized Controlled Trial)
Randomized Controlled Trial
Osteoarthritis (OA) is a common, debilitating, chronic disease with no disease-modifying drug approved to date. We discovered LNA043-a derivative of angiopoietin-like 3 (ANGPTL3)-as a potent chondrogenesis inducer using a phenotypic screen with human mesenchymal stem cells. We show that LNA043 promotes chondrogenesis and cartilage matrix synthesis in vitro and regenerates hyaline articular cartilage in preclinical OA and cartilage injury models in vivo. LNA043 exerts at least part of these effects through binding to the fibronectin receptor, integrin αβ on mesenchymal stem cells and chondrocytes. In a first-in-human (phase 1), randomized, double-blinded, placebo-controlled, single ascending dose, single-center trial ( NCT02491281 ; sponsored by Novartis Pharmaceuticals), 28 patients with knee OA were injected intra-articularly with LNA043 or placebo (3:1 ratio) either 2 h, 7 d or 21 d before total knee replacement. LNA043 met its primary safety endpoint and showed short serum pharmacokinetics, cartilage penetration and a lack of immunogenicity (secondary endpoints). Post-hoc transcriptomics profiling of cartilage revealed that a single LNA043 injection reverses the OA transcriptome signature over at least 21 d, inducing the expression of hyaline cartilage matrix components and anabolic signaling pathways, while suppressing mediators of OA progression. LNA043 is a novel disease-modifying OA drug candidate that is currently in a phase 2b trial ( NCT04864392 ) in patients with knee OA.
Topics: Humans; Osteoarthritis, Knee; Chondrocytes; Cartilage, Articular; Signal Transduction; Angiopoietins; Angiopoietin-Like Protein 3
PubMed: 36456835
DOI: 10.1038/s41591-022-02059-9 -
Theranostics 2021Emerging evidence indicates that the growth of blood vessels and osteogenesis is tightly coordinated during bone development. However, the molecular regulators of...
Emerging evidence indicates that the growth of blood vessels and osteogenesis is tightly coordinated during bone development. However, the molecular regulators of intercellular communication in the bone microenvironment are not well studied. Therefore, we aim to investigate whether BMMSC-Exo promotes osteogenesis and angiogenesis via transporting lnc-H19 in the CBS- heterozygous mouse model. Using RT2 lncRNA PCR array screening, we identify a bone-specific, long noncoding RNA-H19 (lncRNA-H19/lnc-H19) in exosomes derived from bone marrow mesenchymal stem cells (BMMSC-Exo) during osteogenesis. Using bioinformatics analysis, we further discovered the seed sequence of miR-106a that could bind to lnc-H19. A luciferase reporter assay was performed to demonstrate the direct binding of miR-106a to the target gene angiopoietin 1 (Angpt1). We employed an immunocompromised Nude mouse model, to evaluate the effects of BMMSC-Exo on angiogenesis . Using a micro-CT scan, we monitored microstructural changes of bone in the experimental mice. BMMSC-Exo possessed exosomal characteristics including exosome size, and typical markers including CD63, CD9, and TSD101. , BMMSC-Exo significantly promoted endothelial angiogenesis and osteogenesis. Mechanistic studies have shown that exosomal lnc-H19 acts as "sponges" to absorb miR-106 and regulate the expression of angiogenic factor, Angpt1 that activates lnc-H19/Tie2-NO signaling in mesenchymal and endothelial cells. Both of these effects on osteogenesis and angiogenesis are inhibited by antagonizing Tie2 signaling. Treatment of BMMSC-Exo also restored the bone formation and mechanical quality . These findings provide a novel insight into how the extracellular role of exosomal lnc-H19 affects osteogenesis and angiogenesis through competing endogenous RNA networks.
Topics: Angiopoietin-1; Animals; Bone and Bones; Cell Line, Tumor; Endothelial Cells; Exosomes; Genes, Tumor Suppressor; Mesenchymal Stem Cells; Mice; MicroRNAs; Neovascularization, Pathologic; Nitric Oxide; Osteogenesis; RNA, Long Noncoding; Receptor, TIE-2; Signal Transduction
PubMed: 34335960
DOI: 10.7150/thno.58410 -
Inflammation Research : Official... Jun 2023Angiopoietin-like 4 (ANGPTL4) belongs to the angiopoietin-like protein family and mediates the inhibition of lipoprotein lipase activity. Emerging evidence suggests that... (Review)
Review
BACKGROUND
Angiopoietin-like 4 (ANGPTL4) belongs to the angiopoietin-like protein family and mediates the inhibition of lipoprotein lipase activity. Emerging evidence suggests that ANGPTL4 has pleiotropic functions with anti- and pro-inflammatory properties.
METHODS
A thorough search on PubMed related to ANGPTL4 and inflammation was performed.
RESULTS
Genetic inactivation of ANGPTL4 can significantly reduce the risk of developing coronary artery disease and diabetes. However, antibodies against ANGPTL4 result in several undesirable effects in mice or monkeys, such as lymphadenopathy and ascites. Based on the research progress on ANGPTL4, we systematically discussed the dual role of ANGPTL4 in inflammation and inflammatory diseases (lung injury, pancreatitis, heart diseases, gastrointestinal diseases, skin diseases, metabolism, periodontitis, and osteolytic diseases). This may be attributed to several factors, including post-translational modification, cleavage and oligomerization, and subcellular localization.
CONCLUSION
Understanding the potential underlying mechanisms of ANGPTL4 in inflammation in different tissues and diseases will aid in drug discovery and treatment development.
Topics: Mice; Animals; Angiopoietin-Like Protein 4; Inflammation; Protein Processing, Post-Translational; Angiopoietins
PubMed: 37300585
DOI: 10.1007/s00011-023-01753-9 -
Journal of the American Society of... Jun 2023Ischemia-reperfusion AKI (IR-AKI) is common and causes significant morbidity. Effective treatments are lacking. However, preclinical studies suggest that inhibition of...
SIGNIFICANCE STATEMENT
Ischemia-reperfusion AKI (IR-AKI) is common and causes significant morbidity. Effective treatments are lacking. However, preclinical studies suggest that inhibition of angiopoietin-Tie2 vascular signaling promotes injury, whereas activation of Tie2 is protective. We show that kidney ischemia leads to increased levels of the endothelial-specific phosphatase vascular endothelial protein tyrosine phosphatase (VE-PTP; PTPRB), which inactivates Tie2. Activation of Tie2 through VE-PTP deletion, or delivery of a novel angiopoietin mimetic (Hepta-ANG1), abrogated IR-AKI in mice. Single-cell RNAseq analysis showed Tie2 activation promotes increased Entpd1 expression, downregulation of FOXO1 target genes in the kidney vasculature, and emergence of a new subpopulation of glomerular endothelial cells. Our data provide a molecular basis and identify a candidate therapeutic to improve endothelial integrity and kidney function after IR-AKI.
BACKGROUND
Ischemia-reperfusion AKI (IR-AKI) is estimated to affect 2%-7% of all hospitalized patients. The significant morbidity and mortality associated with AKI indicates urgent need for effective treatments. Previous studies have shown activation of the vascular angiopoietin-Tie2 tyrosine kinase signaling pathway abrogates ischemia-reperfusion injury (IRI). We extended previous studies to (1) determine the molecular mechanism(s) underlying kidney injury and protection related to decreased or increased activation of Tie2, respectively, and (2) to test the hypothesis that deletion of the Tie2 inhibitory phosphatase vascular endothelial protein tyrosine phosphatase (VE-PTP) or injection of a new angiopoietin mimetic protects the kidney from IRI by common molecular mechanism(s).
METHODS
Bilateral IR-AKI was performed in VE-PTP wild-type or knockout mice and in C57BL/6J mice treated with Hepta-ANG1 or vehicle. Histologic, immunostaining, and single-cell RNA sequencing analyses were performed.
RESULTS
The phosphatase VE-PTP, which negatively regulates the angiopoietin-Tie2 pathway, was upregulated in kidney endothelial cells after IRI, and genetic deletion of VE-PTP in mice protected the kidney from IR-AKI. Injection of Hepta-ANG1 potently activated Tie2 and protected the mouse kidney from IRI. Single-cell RNAseq analysis of kidneys from Hepta-ANG1-treated and vehicle-treated mice identified endothelial-specific gene signatures and emergence of a new glomerular endothelial subpopulation associated with improved kidney function. Overlap was found between endothelial-specific genes upregulated by Hepta-ANG1 treatment and those downregulated in HUVECs with constitutive FOXO1 activation, including Entpd1 / ENTPD1 that modulates purinergic receptor signaling.
CONCLUSIONS
Our data support a key role of the endothelium in the development of IR-AKI, introduce Hepta-ANG1 as a putative new therapeutic biologic, and report a model to explain how IRI reduces Tie2 signaling and how Tie2 activation protects the kidney.
PODCAST
This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_05_23_JSN_Ang_EP23_052323.mp3.
Topics: Mice; Animals; Endothelial Cells; Angiopoietins; Receptor-Like Protein Tyrosine Phosphatases, Class 3; Mice, Inbred C57BL; Endothelium; Kidney; Signal Transduction; Receptor, TIE-2; Angiopoietin-1; Mice, Knockout; Acute Kidney Injury; Ischemia
PubMed: 36787763
DOI: 10.1681/ASN.0000000000000098