scholarly journals An engineered tetra-valent antibody fully activates the Tie2 receptor with comparable potency to its natural ligand angiopoietin-1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yukari Koya ◽  
Hiromi Nara ◽  
Shigenori Yagi ◽  
Chihoko Ueno ◽  
Masazumi Kamohara
Keyword(s):  
Vascular Permeability ◽  
Vascular Diseases ◽  
Limb Ischemia ◽  
Mustard Oil ◽  
Tie2 Receptor ◽  
Natural Ligand ◽  
Promising Therapeutic Target ◽  
Epidermal Growth ◽  
Angiopoietin 1

AbstractActivation of the tyrosine kinase with Ig and epidermal growth factor homology domain 2 (Tie2) receptor by angiopoietin-1 (Ang1) is critical for vascular stabilization: it promotes survival signal transduction via auto-phosphorylation and reduces vascular permeability by strengthening tight junctions between endothelial cells. Thus, Tie2/Ang1 signaling is a promising therapeutic target for vascular diseases. However, in vivo use of existing Tie2 signaling modulators, such as recombinant Ang1, is restricted by limitations in manufacturability and stability. Here, we present a novel engineered tetra-valent agonistic antibody, ASP4021, which can specifically and fully activate the Tie2 receptor in an equivalent manner to Ang1. ASP4021 induced Tie2 self-phosphorylation and inhibited apoptosis in a human primary endothelial cell line. Additionally, single administration of ASP4021 significantly suppressed mustard-oil-induced vascular permeability in rats. ASP4021 may thus be a potential therapeutic candidate for diseases associated with vascular weakness such as diabetic retinopathy, diabetic macular edema and critical limb ischemia.

scholarly journals The engineered tetra-valent antibody, ASP4021, fully activates the Tie2 receptor with comparable potency to its natural ligand, angiopoietin-1

2021 ◽  
Author(s):  
Yukari Koya ◽  
Hiromi Nara ◽  
Shigenori Yagi ◽  
Chihoko Ueno ◽  
Masazumi Kamohara
Keyword(s):  
Vascular Permeability ◽  
Vascular Diseases ◽  
Limb Ischemia ◽  
Mustard Oil ◽  
Tie2 Receptor ◽  
Natural Ligand ◽  
Promising Therapeutic Target ◽  
Epidermal Growth ◽  
Angiopoietin 1

Abstract Activation of the tyrosine kinase with Ig and epidermal growth factor homology domain 2 (Tie2) receptor by angiopoietin-1 (Ang1) is critical for vascular stabilization: it promotes survival signal transduction via auto-phosphorylation and reduces vascular permeability by strengthening tight junctions between endothelial cells. Thus, Tie2/Ang1 signaling is a promising therapeutic target for vascular diseases. However, in vivo use of existing Tie2 signaling modulators, such as recombinant Ang1, is restricted by limitations in manufacturability and stability. Here, we present a novel engineered tetra-valent agonistic antibody, ASP4021, which can specifically and fully activate the Tie2 receptor in an equivalent manner to Ang1. ASP4021 induced Tie2 self-phosphorylation and inhibited apoptosis in a human primary endothelial cell line. Additionally, single administration of ASP4021 significantly suppressed mustard-oil-induced vascular permeability in rats. ASP4021 may thus be a potential therapeutic candidate for diseases associated with vascular weakness such as diabetic retinopathy, diabetic macular edema and critical limb ischemia.

scholarly journals Targeting VE-PTP phosphatase protects the kidney from diabetic injury

2019 ◽  
Vol 216 (4) ◽  
pp. 936-949 ◽  
Author(s):  
Isabel A. Carota ◽  
Yael Kenig-Kozlovsky ◽  
Tuncer Onay ◽  
Rizaldy Scott ◽  
Benjamin R. Thomson ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Tyrosine Phosphatase ◽  
Hypoxia Inducible Factor ◽  
Cell Loss ◽  
Tie2 Receptor ◽  
Nuclear Exclusion ◽  
Promising Therapeutic Target ◽  
End Stage ◽  
And Function

Diabetic nephropathy is a leading cause of end-stage kidney failure. Reduced angiopoietin-TIE2 receptor tyrosine kinase signaling in the vasculature leads to increased vascular permeability, inflammation, and endothelial cell loss and is associated with the development of diabetic complications. Here, we identified a mechanism to explain how TIE2 signaling is attenuated in diabetic animals. Expression of vascular endothelial protein tyrosine phosphatase VE-PTP (also known as PTPRB), which dephosphorylates TIE2, is robustly up-regulated in the renal microvasculature of diabetic rodents, thereby reducing TIE2 activity. Increased VE-PTP expression was dependent on hypoxia-inducible factor transcriptional activity in vivo. Genetic deletion of VE-PTP restored TIE2 activity independent of ligand availability and protected kidney structure and function in a mouse model of severe diabetic nephropathy. Mechanistically, inhibition of VE-PTP activated endothelial nitric oxide synthase and led to nuclear exclusion of the FOXO1 transcription factor, reducing expression of pro-inflammatory and pro-fibrotic gene targets. In sum, we identify inhibition of VE-PTP as a promising therapeutic target to protect the kidney from diabetic injury.

scholarly journals Effect of mini-tyrosyl-tRNA synthetase on ischemic angiogenesis, leukocyte recruitment, and vascular permeability

2008 ◽  
Vol 295 (4) ◽  
pp. R1138-R1146 ◽  
Author(s):  
Gang Cheng ◽  
Hua Zhang ◽  
Xianglei Yang ◽  
Eleni Tzima ◽  
Karla L. Ewalt ◽  
...  
Keyword(s):  
Vascular Permeability ◽  
Low Dose ◽  
Trna Synthetase ◽  
Mustard Oil ◽  
Blue Dye ◽  
High Dose ◽  
Mouse Ear ◽  
High Concentrations

Mini-tyrosyl-tRNA synthetase (mini-TyrRS), the N-terminal domain of tyrosyl-tRNA synthetase, is a recently identified protein released by endothelial cells that exhibits angiogenic and leukocyte chemoattractant, ELR-motif (Glu-Leu-Arg)-dependent activities in vitro. We sought to determine whether exogenous mini-TyrRS exerts these and other cytokine-like actions in physiological and pathological settings in vivo. High-dose mini-TyrRS (600 μg·kg−1·day−1) augmented while low-dose mini-TyrRS (3 μg·kg−1·day−1), unexpectedly, inhibited angiogenesis in the ischemic mouse ear. Enhanced angiogenesis was associated with increased CD45- and CD4-positive leukocyte accumulation. Mini-TyrRS also had biphasic actions on both basal and mustard oil-evoked and VEGF-evoked leakage of Evan's blue dye-albumin in nonischemic ear and in endothelial cell monolayers, that is, low-dose inhibited and high-dose augmented leakage. Mutation of the ELR motif of mini-TyrRS abolished the above activities. Mini-TyrRS was reduced (immunoblot) in extracts of ischemic calf muscle and in thoracic aorta explants exposed to hypoxia or VEGF. Inhibition of VEGF with a soluble Flt1 “trap” protein abolished this hypoxic-induced reduction in mini-TyrRS in aorta explants. These data show that mini-TyrRS has dose-dependent biphasic effects on ischemic angiogenesis and vascular permeability in vivo, that is, antiangiogenic and antipermeability activities at low concentration and proangiogenic, propermeability activities at high concentrations.

Abstract 1681: Haploinsufficiency of MEF2A Increases Risk of Atherosclerosis In Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Qing K Wang ◽  
Krishna M Bhagavatula ◽  
Eric J Topol ◽  
Jonathan D Smith
Keyword(s):  
Vascular Permeability ◽  
Knockout Mice ◽  
Genetic Model ◽  
Plasma Cholesterol ◽  
Atherosclerotic Lesion ◽  
Mustard Oil ◽  
Blue Dye ◽  
Aortic Lesion ◽  
Glucose Levels

MEF2A is a member of the myocyte enhancer factor-2 (MEF2) family of transcription factors. We showed that MEF2A was expressed in coronary arteries and mutations or rare variants of MEF2F were associated with risk of coronary artery disease (CAD) in humans. Both positive and negative replication studies were later reported. To further investigate the role of MEF2A in CAD and MI, we have characterized heterozygous MEF2A knockout mice and show here that haploinsufficiency of MEF2A in mice promotes atherosclerosis. Heterozygous MEF2A knockout mice were crossed to apoE-deficient mice, a widely used genetic model for atherosclerosis. The degree of atherogenesis was determined by the aortic root quantitative atherosclerosis assay. In vivo vascular permeability assay was performed using Evans blue dye upon stimulation with mustard oil in ears. Serum total cholesterol, HDL cholesterol, and triglyceride levels were measured with the Stanbio enzymatic kits. No significant differences were detected for total plasma cholesterol, HDL-C, VLDL-Cl and TG levels between MEF2A + ApoE −/− mice and their MEF2A +/+ ApoE −/− littermate controls (P = 0.14 – 0.44). The glucose levels before and after fasting were also similar between the two lines of mice (fasting, 106.25 ± 20.7 vs. 104.8 ± 21.9, P = 0.87; non-fasting, 175.3 ± 82 vs. 179.9 ± 119, P = 0.092). Total aortic lesion area was twofold greater in MEF2A + ApoE −/− mice than in MEF2A +/+ ApoE −/− littermate controls fed on western diet (83408 μm 2 vs. 46621 μm 2 in males, n = 11 vs. 15, P = 0.0003; 137822 μm 2 vs. 61568 μm 2 in females, n = 12 vs. 9, P = 0.00003). Permeability of the vasculature in response to a proinflammatory stimulus was 3.2 fold higher in MEF2A + ApoE −/− mice than in MEF2A + / + ApoE −/− littermate controls (P = 0.000012). MEF2A haploinsufficiency promotes atherosclerotic lesion formation in mice, which may be due to increased vascular permeability. Lipid or glucose levels do not contribute to the formation of atherosclerotic lesions in these mice.

scholarly journals Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data

Eye ◽  
2021 ◽  
Author(s):  
Antonia M. Joussen ◽  
Federico Ricci ◽  
Liliana P. Paris ◽  
Claudia Korn ◽  
Carlos Quezada-Ruiz ◽  
...  
Keyword(s):  
Growth Factor ◽  
Therapeutic Strategy ◽  
Vascular Diseases ◽  
Vascular Endothelial ◽  
Tie2 Receptor ◽  
Pathological Conditions ◽  
Vascular Stability ◽  
Angiopoietin 2 ◽  
Endothelial Growth Factor ◽  
Angiopoietin 1

AbstractThe 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.

scholarly journals Lack of adrenomedullin in mouse endothelial cells results in defective angiogenesis, enhanced vascular permeability, less metastasis, and more brain damage

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Laura Ochoa-Callejero ◽  
Andrea Pozo-Rodrigálvarez ◽  
Ricardo Martínez-Murillo ◽  
Alfredo Martínez
Keyword(s):  
Endothelial Cells ◽  
Vascular Permeability ◽  
Vascular Diseases ◽  
Conditional Knockout ◽  
Brain Response ◽  
Vascular Stability ◽  
Permanent Occlusion ◽  
Important Regulator ◽  
Syngeneic Model

Abstract Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. AM plays critical roles in blood vessels, including regulation of vascular stability and permeability. To elucidate the autocrine/paracrine function of AM in endothelial cells (EC) in vivo, a conditional knockout of AM in EC (AMEC-KO) was used. The amount of vascularization of the matrigel implants was lower in AMEC-KO mice indicating a defective angiogenesis. Moreover, ablation of AM in EC revealed increased vascular permeability in comparison with wild type (WT) littermates. In addition, AMEC-KO lungs exhibited significantly less tumor growth than littermate WT mice using a syngeneic model of metastasis. Furthermore, following middle cerebral artery permanent occlusion, there was a significant infarct size decrease in animals lacking endothelial AM when compared to their WT counterparts. AM is an important regulator of EC function, angiogenesis, tumorigenesis, and brain response to ischemia. Studies of AM should bring novel approaches to the treatment of vascular diseases.

Toxicity and efficacy evaluation of multiple targeted polymalic acid conjugates for triple-negative breast cancer treatment

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Triple Negative ◽  
Growth Factor Receptor ◽  
Engineered Nanoparticles ◽  
Efficacy Evaluation ◽  
Dual Action ◽  
Epidermal Growth ◽  
Laminin 411 ◽  
Immunologic Analysis

Engineered nanoparticles are widely used for delivery of drugs but frequently lack proof of safetyfor cancer patient's treatment. All-in-one covalent nanodrugs of the third generation have beensynthesized based on a poly(β-L-malic acid) (PMLA) platform, targeting human triple-negativebreast cancer (TNBC). They significantly inhibited tumor growth in nude mice by blockingsynthesis of epidermal growth factor receptor, and α4 and β1 chains of laminin-411, the tumorvascular wall protein and angiogenesis marker. PMLA and nanodrug biocompatibility and toxicityat low and high dosages were evaluated in vitro and in vivo. The dual-action nanodrug and singleactionprecursor nanoconjugates were assessed under in vitro conditions and in vivo with multipletreatment regimens (6 and 12 treatments). The monitoring of TNBC treatment in vivo withdifferent drugs included blood hematologic and immunologic analysis after multiple intravenousadministrations. The present study demonstrates that the dual-action nanoconju-gate is highlyeffective in preclinical TNBC treatment without side effects, supported by hematologic andimmunologic assays data. PMLA-based nanodrugs of the Polycefin™ family passed multipletoxicity and efficacy tests in vitro and in vivo on preclinical level and may prove to be optimizedand efficacious for the treatment of cancer patients in the future.

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