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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 -
Romanian Journal of Ophthalmology 2021Neovascular glaucoma (NVG) is a type of secondary glaucoma, refractory to treatment, often incurable, with very poor visual prognosis. It is characterized by the... (Review)
Review
Neovascular glaucoma (NVG) is a type of secondary glaucoma, refractory to treatment, often incurable, with very poor visual prognosis. It is characterized by the appearance of new vessels over the iris and iridocorneal angle and frequently associates the presence of a fibrovascular membrane which limits the aqueous humor outflow from the anterior chamber. The most common causes of NVG are: central retinal vein occlusion, proliferative diabetic retinopathy, and ocular ischemic syndrome. Once the gonioscopy developed as a part of clinical examination, it became possible to visualize the new vessels of the anterior segment of the eye in early stages and to understand the mechanisms of increased intraocular pressure (IOP), including narrowing and closing of the iridocorneal angle. Also, the modern imaging techniques, such as optical coherence tomography angiography and fluorescein angiography became indispensable for the clinician. Thus, an early diagnosis, followed by starting an appropriate therapy: panretinal photocoagulation or administration of anti-VEGF drugs, with or without hypotensive ocular therapy, allows the preservation of visual functions for patient's better quality of life. However, one or more surgeries will often be required, especially in the advanced stages of the disease, which do not respond to drug therapy. Managing the NVG we should aim to: 1) reduce ocular ischemia and treat its underlying cause, 2) reduce elevated IOP, once installed and 3) control the inflammatory process. Anyway, the best treatment is prevention, so we must be very attentive at patients with risk factors for developing the NVG. NVG = neovascular glaucoma, ICA = iridocorneal angle, IOP = intraocular pressure, TM = trabecular meshwork, AH = aqueous humor, AC = anterior chamber, PRP = panretinal photocoagulation, VEGF = vascular endothelial growing factor, Anti-VEGF = anti- vascular endothelial growing factor, PAS = peripheral anterior synechiae, CRVO = central retinal vein occlusion, PDR = proliferative diabetic retinopathy, DR = diabetic retinopathy, OIS = ocular ischemic syndrome, CRAO = central retinal artery occlusion, ROP = retinopathy of prematurity, FEVR = familial exudative vitreoretinopathy, PVR = proliferative vitreoretinopathy, MMPs = matrix metalloproteinases, VEGFR = vascular endothelial growing factor receptor, PDGF = platelet-derived growth factor, PIGF = placental growth factor, NRP = neuropilins, HIF = hypoxia-inducible factor, SDF1 = stromal cell-derived factor 1, DDL4 = delta like ligand 4, NICD = Notch intracellular domain, TIMMPs = tissue inhibitors of matrix metalloproteinases, ANGPT = angiopoietin, Tie 2 = tyrosine-protein kinase receptor for angiopoietins, IGF-1 = insulin-like growth factor 1, RPE = retinal pigment epithelium, IL = interleukin, TNF = tumor necrosis factor, bFGF = basic fibroblast growth factor, TGF = transforming growth factor, HGF = hepatocyte growth factor, TNFR 2 = tumor necrosis factor receptor 2, OIR = oxygen induced retinopathy, NVI = neovascularization of the iris, NVA = neovascularization of the iridocorneal angle, FA = fluorescein angiography, RAPD = relative afferent pupillary defect, CNP = capillary non-perfusion, NVE = neovascularization elsewhere in the retina, NVD = neovascularization of the optic disc, FFA = fundus fluorescein angiography, OCTA = optical coherence tomography angiography, B-scan US = B-scan ocular ultrasound, AS-OCT = anterior segment optical coherence tomography, ARC = anterior retinal cryotherapy, FDA = food and drug administration, United States of America, BVZ = bevacizumab, RBZ = ranibizumab, AFB = aflibercept, AMD/ ARMD = age related macular degeneration, DME = diabetic macular edema, GDDs = glaucoma drainage devices, MMC = mitomycin C, 5-FU = 5-fluorouracil, AGV = Ahmed glaucoma valve, AADI = Aurolab aqueous drainage implant, MIGS = minimally invasive glaucoma surgery, BCVA = best corrected visual acuity, TVT = Tube versus Trabeculectomy study, MPC = micro-pulse cyclophotocoagulation.
Topics: Angiogenesis Inhibitors; Diabetic Retinopathy; Female; Glaucoma, Neovascular; Humans; Macular Edema; Placenta Growth Factor; Quality of Life
PubMed: 35087972
DOI: 10.22336/rjo.2021.66 -
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 -
Proceedings of the National Academy of... Mar 2021Loss-of-function mutations in Angiopoietin-like 3 () are associated with lowered blood lipid levels, making an attractive therapeutic target for the treatment of human...
Loss-of-function mutations in Angiopoietin-like 3 () are associated with lowered blood lipid levels, making an attractive therapeutic target for the treatment of human lipoprotein metabolism disorders. In this study, we developed a lipid nanoparticle delivery platform carrying Cas9 messenger RNA (mRNA) and guide RNA for CRISPR-Cas9-based genome editing of in vivo. This system mediated specific and efficient gene knockdown in the liver of wild-type C57BL/6 mice, resulting in profound reductions in serum ANGPTL3 protein, low density lipoprotein cholesterol, and triglyceride levels. Our delivery platform is significantly more efficient than the FDA-approved MC-3 LNP, the current gold standard. No evidence of off-target mutagenesis was detected at any of the nine top-predicted sites, and no evidence of toxicity was detected in the liver. Importantly, the therapeutic effect of genome editing was stable for at least 100 d after a single dose administration. This study highlights the potential of LNP-mediated delivery as a specific, effective, and safe platform for Cas9-based therapeutics.
Topics: Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Animals; CRISPR-Associated Protein 9; Drug Carriers; Female; Gene Editing; Lipids; Liver; Mice; Mice, Inbred BALB C; Nanoparticles; Organ Specificity; RNA, Guide, CRISPR-Cas Systems; RNA, Messenger
PubMed: 33649229
DOI: 10.1073/pnas.2020401118 -
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 -
Ophthalmology Jun 2024To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend (T&E)-based regimen with up to every-16-week dosing in the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) phase 3 trials of diabetic macular edema (DME).
DESIGN
Randomized, double-masked, noninferiority phase 3 trials.
PARTICIPANTS
Adults with visual acuity loss (best-corrected visual acuity [BCVA] of 25-73 letters) due to center-involving DME.
METHODS
Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg every 8 weeks. The T&E up to every-16-week dosing regimen was based on central subfield thickness (CST) and BCVA change.
MAIN OUTCOME MEASURES
Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100.
RESULTS
In YOSEMITE and RHINE (n = 940 and 951, respectively), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92, 96, and 100 average) with faricimab every 8 weeks (YOSEMITE and RHINE, +10.7 letters and +10.9 letters, respectively) or T&E (+10.7 letters and +10.1 letters, respectively) were comparable with aflibercept every 8 weeks (+11.4 letters and +9.4 letters, respectively). The median number of study drug injections was lower with faricimab T&E (YOSEMITE and RHINE, 10 and 11 injections, respectively) versus faricimab every 8 weeks (15 injections) and aflibercept every 8 weeks (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was improved further during year 2, with > 60% of patients receiving every-16-week dosing and approximately 80% receiving every-12-week or longer dosing at week 96. Almost 80% of patients who achieved every-16-week dosing at week 52 maintained every-16-week dosing without an interval reduction through week 96. Mean CST reductions were greater (YOSEMITE/RHINE weeks 92/96/100 average: faricimab every 8 weeks -216.0/-202.6 µm, faricimab T&E -204.5/-197.1 µm, aflibercept every 8 weeks -196.3/-185.6 µm), and more patients achieved absence of DME (CST < 325 μm; YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 87%-92%/88%-93%, faricimab T&E 78%-86%/85%-88%, aflibercept every 8 weeks 77%-81%/80%-84%) and absence of intraretinal fluid (YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 59%-63%/56%-62%, faricimab T&E 43%-48%/45%-52%, aflibercept every 8 weeks 33%-38%/39%-45%) with faricimab every 8 weeks or T&E versus aflibercept every 8 weeks through year 2. Overall, faricimab was well tolerated, with a safety profile comparable with that of aflibercept.
CONCLUSIONS
Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to every 16 weeks were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2 and VEGF-A inhibition to promote vascular stability and to provide durable efficacy for patients with DME.
FINANCIAL DISCLOSURE(S)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Topics: Humans; Macular Edema; Diabetic Retinopathy; Visual Acuity; Intravitreal Injections; Double-Blind Method; Male; Female; Middle Aged; Angiogenesis Inhibitors; Vascular Endothelial Growth Factor A; Aged; Tomography, Optical Coherence; Treatment Outcome; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Angiopoietin-2; Follow-Up Studies; Antibodies, Monoclonal, Humanized
PubMed: 38158159
DOI: 10.1016/j.ophtha.2023.12.026