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https://www.readbyqxmd.com/read/28422724/utilizing-combinatorial-engineering-to-develop-tie2-targeting-antagonistic-angiopoetin-2-ligands-as-candidates-for-anti-angiogenesis-therapy
#1
Tomer Shlamkovich, Lidan Aharon, William A Barton, Niv Papo
In many human cancers, the receptor tyrosine kinase (RTK) Tie2 plays important roles in mediating proliferation, survival, migration and angiogenesis. Thus, molecules that could potently inhibit activation of the Tie2 receptor would have a significant impact on cancer therapy. Nevertheless, attempts to develop Tie2-targeted inhibitors have met with little success, and there is currently no FDA-approved therapeutic selectively targeting Tie2. We used a combinatorial protein engineering approach to develop a new generation of angiopoietin (Ang) 2-derived Tie2 antagonists as potential cancer therapeutics and as tools to study angiogenesis...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28396439/structural-basis-of-tie2-activation-and-tie2-tie1-heterodimerization
#2
Veli-Matti Leppänen, Pipsa Saharinen, Kari Alitalo
The endothelial cell (EC)-specific receptor tyrosine kinases Tie1 and Tie2 are necessary for the remodeling and maturation of blood and lymphatic vessels. Angiopoietin-1 (Ang1) growth factor is a Tie2 agonist, whereas Ang2 functions as a context-dependent agonist/antagonist. The orphan receptor Tie1 modulates Tie2 activation, which is induced by association of angiopoietins with Tie2 in cis and across EC-EC junctions in trans Except for the binding of the C-terminal angiopoietin domains to the Tie2 ligand-binding domain, the mechanisms for Tie2 activation are poorly understood...
April 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28396397/dimerization-of-tie2-mediated-by-its-membrane-proximal-fniii-domains
#3
Jason O Moore, Mark A Lemmon, Kathryn M Ferguson
Tie1 and Tie2, members of the tyrosine kinase family with immunoglobulin and EGF homology domains, are receptor tyrosine kinases found primarily in endothelial cells with key roles in development and maintenance of the vasculature and in angiogenesis. They are attractive targets for therapeutic intervention in tumor angiogenesis, inflammation, and sepsis. Tie2 is regulated directly by the multimeric angiopoietin (Ang) ligands, with Ang1 being its primary activator. Structural studies have shown how Angs bind to the Tie2 ligand-binding region, but do not explain Tie2 activation and suggest a passive role for the Tie2 extracellular region (ECR) in ligand-induced receptor dimerization...
April 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28387902/angiogenesis-characteristics-of-infantile-hemangioma-and-feasibility-observation-of-transplantation-model-of-human-hemangioma-on-mice
#4
Y Fu, Z-G Yang, L-Y Zhao
OBJECTIVE: To study pathogenic features of pediatric hemangiomas, we successfully established a model in mice, by transplanting human hemangioma tissues. MATERIALS AND METHODS: The hemangioma from the leg of a two-month-old infant was dissected and sliced into several pieces. During a careful surgical procedure, the hemangioma tissues were individually transplanted into skin incisions in anesthetized mice. The volume of the transplanted tumors was measured and the changes in shape recorded at 1 day, and at 1, 2, 3, 4, 5 and 6 months after the transplantation...
March 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28372817/angiopoietin-2-in-placentation-and-tumor-biology-the-yin-and-yang-of-vascular-biology
#5
Qiong Wang, Gendie E Lash
There are several parallels between placental and tumor biology. Both require rapid acquisition of a blood supply to supply oxygen and nutrients, the placenta through neoangiogenesis and tumors by co-opting the existing vasculature. In addition, successful pregnancy also requires remodeling of the maternal uterine spiral arteries. Angiopoietins (Angs) are a family of angiogenic growth factors, the best studied being Ang-1 and Ang-2, which signal through the membrane tyrosine kinase receptor Tie2, and in simple terms have opposite effects with Ang-1 acting to stabilize newly formed blood vessels and Ang-2 having a destabilizing effect...
March 30, 2017: Placenta
https://www.readbyqxmd.com/read/28369068/all-trans-retinoic-acid-suppresses-the-angiopoietin-tie2-pathway-and-inhibits-angiogenesis-and-metastasis-in-esophageal-squamous-cell-carcinoma
#6
Na Li, Yanjuan Lu, Daoming Li, Xiangyu Zheng, Jingyao Lian, Shanshan Li, Huijuan Cui, Linda Zhang, Luqian Sang, Ying Wang, Jane J Yu, Taiying Lu
Esophageal squamous cell carcinoma (ESCC) is the second common cancer in Henan province and is well-known for aggressiveness and dismal prognosis. Adjuvant therapies, chemotherapy, radiotherapy and endoscopic treatment have not improved survival rates in patients with late stage esophageal carcinoma. All-trans retinoic acid (ATRA) is the active ingredient of Vitamin A and affects a wide spectrum of biological processes including development, growth, neural function, immune function, reproduction, and vision...
2017: PloS One
https://www.readbyqxmd.com/read/28334876/pdgfrb-gain-of-function-mutations-in-sporadic-infantile-myofibromatosis
#7
Florence A Arts, Raf Sciot, Bénédicte Brichard, Marleen Renard, Audrey de Rocca Serra, Guillaume Dachy, Laura A Noël, Amélie I Velghe, Christine Galant, Maria Debiec-Rychter, An Van Damme, Miikka Vikkula, Raphaël Helaers, Nisha Limaye, Hélène A Poirel, Jean-Baptiste Demoulin
Infantile myofibromatosis is one of the most prevalent soft tissue tumors of infancy and childhood. Multifocal nodules with visceral lesions are associated with a poor prognosis. A few familial cases have been linked to mutations in various genes including PDGFRB. In this study, we sequenced PDGFRB, which encodes a receptor tyrosine kinase, in 16 cases of myofibromatosis or solitary myofibroma. Mutations in the coding sequence of PDGFRB were identified in 6 out of 8 patients with the sporadic multicentric form of the disease and in 1 out of 8 patients with isolated myofibroma...
March 3, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28328948/vascular-endothelial-overexpression-of-human-cyp2j2-tie2-cyp2j2-tr-modulates-cardiac-oxylipin-profiles-and-enhances-coronary-reactive-hyperemia-in-mice
#8
Ahmad Hanif, Matthew L Edin, Darryl C Zeldin, Christophe Morisseau, John R Falck, Mohammed A Nayeem
Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by cytochrome (CYP) P450 epoxygenases, and to ω-terminal hydroxyeicosatetraenoic acids (HETEs) by ω-hydroxylases. EETs and HETEs often have opposite biologic effects; EETs are vasodilatory and protect against ischemia/reperfusion injury, while ω-terminal HETEs are vasoconstrictive and cause vascular dysfunction. Other oxylipins, such as epoxyoctadecaenoic acids (EpOMEs), hydroxyoctadecadienoic acids (HODEs), and prostanoids also have varied vascular effects...
2017: PloS One
https://www.readbyqxmd.com/read/28320530/single-cell-rna-sequence-analysis-of-mouse-glomerular-mesangial-cells-uncovers-mesangial-cell-essential-genes
#9
Yuqiu Lu, Yuting Ye, Qianqian Yang, Shaolin Shi
Mesangial cells are essential for the structure and function of glomeruli, but the mechanisms underlying these roles are not well understood. Here, we performed a single-cell RNA-sequence (RNA-seq) analysis of mouse mesangial cells using the Fluidigm C1 platform. We found that gene expression in individual mesangial cells was tremendously heterogeneous, with mean correlation coefficients of 0.20, and most mesangial genes were actually expressed in only a portion of mesangial cells and are therefore presumably dispensable...
March 17, 2017: Kidney International
https://www.readbyqxmd.com/read/28298457/distinct-regulatory-effects-of-myeloid-cell-and-endothelial-cell-nox2-on-blood-pressure
#10
Can Martin Sag, Moritz Schnelle, Juqian Zhang, Colin E Murdoch, Sabine Kossmann, Andrea Protti, Celio X C Santos, Greta J Sawyer, Xiaohong Zhang, Heloise Mongue-Din, Daniel A Richards, Alison C Brewer, Oleksandra Prysyazhna, Lars S Maier, Philip Wenzel, Philip J Eaton, Ajay M Shah
Background -Hypertension due to increased renin angiotensin system (RAS) activation is associated with elevated reactive oxygen species (ROS) production. Previous studies implicate NADPH oxidase (Nox) proteins as important ROS sources during RAS activation, with different Nox isoforms being potentially involved. Among these, Nox2 is expressed in multiple cell types including endothelial cells, fibroblasts, immune cells and microglia. Blood pressure (BP) is regulated at central nervous system, renal and vascular levels but the cell-specific role of Nox2 in BP regulation is unknown...
March 15, 2017: Circulation
https://www.readbyqxmd.com/read/28288344/stereological-and-immunogold-studies-on-tie1-and-tie2-localization-in-glomeruli-indicate-angiopoietin-signaling-in-podocytes
#11
Anastasia Logothetidou, Ward De Spiegelaere, Wim Van den Broeck, Tim Vandecasteele, Liesbeth Couck, Paul Simoens, Pieter Cornillie
Angiopoietins and their TIE receptors are important regulators of vascular stability and remodeling. These molecules are involved not only in the normal development of kidney glomeruli, but also in disease, thus making them promising targets for therapies. Although TIE receptors are mainly found in endothelial cells, some reports observed TIE2 expression in glomerular podocytes as well. This suggests a role of angiopoietins in the regulation of podocytes. In the present study, we aimed to map the subcellular localization of TIE receptors in metanephric glomeruli of fetal pigs using high-resolution immunogold electron microscopy and the relative labeling index stereological approach...
March 2, 2017: Micron: the International Research and Review Journal for Microscopy
https://www.readbyqxmd.com/read/28276491/flunarizine-suppresses-endothelial-angiopoietin-2-in-a-calcium-dependent-fashion-in-sepsis
#12
Jennifer Retzlaff, Kristina Thamm, Chandra C Ghosh, Wolfgang Ziegler, Hermann Haller, Samir M Parikh, Sascha David
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection leading to systemic inflammation and endothelial barrier breakdown. The vascular-destabilizing factor Angiopoietin-2 (Angpt-2) has been implicated in these processes in humans. Here we screened in an unbiased approach FDA-approved compounds with respect to Angpt-2 suppression in endothelial cells (ECs) in vitro. We identified Flunarizine - a well-known anti-migraine calcium channel (CC) blocker - being able to diminish intracellular Angpt-2 protein in a time- and dose-dependent fashion thereby indirectly reducing the released protein...
March 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28248004/highly-efficient-differentiation-of-endothelial-cells-from-pluripotent-stem-cells-requires-the-mapk-and-the-pi3k-pathways
#13
Aja Harding, Elizabeth Cortez-Toledo, Nataly L Magner, Julie R Beegle, Dane P Coleal-Bergum, Dake Hao, Aijun Wang, Jan A Nolta, Ping Zhou
Pluripotent stem cells are a promising source of endothelial cells (ECs) for the treatment of vascular diseases. We have developed a robust protocol to differentiate human induced pluripotent stem cells (hiPSCs) and embryonic stem cells (hESCs) into ECs with high purities (94%-97% CD31(+) and 78%-83% VE-cadherin(+) ) in 8 days without cell sorting. Passaging of these cells yielded a nearly pure population of ECs (99% of CD31(+) and 96.8% VE-cadherin(+) ). These ECs also expressed other endothelial markers vWF, Tie2, NOS3, and exhibited functions of ECs such as uptake of Dil-acetylated low-density lipoprotein and formation of tubes in vitro or vessels in vivo on matrigel...
March 1, 2017: Stem Cells
https://www.readbyqxmd.com/read/28219791/bone-marrow-mesenchymal-stem-cells-conditioned-medium-enhances-vascular-remodeling-after-stroke-in-type-2-diabetic-rats
#14
Jie Xiang, Jinxia Hu, Tong Shen, Bin Liu, Fang Hua, Kun Zan, Jie Zu, Guiyun Cui, Xinchun Ye
Our previous studies have found that stem cells conditioned medium (CM) facilitated functional recovery after stroke in non-diabetics. However, whether bone marrow stromal cells conditioned medium (BMSCs-CM) treatment after stroke in type 2 diabetic (T2DM) rats improve functional outcomes remains unclear. T2DM rats were induced and subjected to stroke then treated with or without BMSCs-CM. Functional outcomes and blood-brain barrier (BBB) leakage were performed, the expression of Angiopoietin (Ang) 1 and tyrosine kinase (Tie) 2 were also assessed...
February 17, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28198371/method-for-dual-viral-vector-mediated-crispr-cas9-gene-disruption-in-primary-human-endothelial-cells
#15
Haixia Gong, Menglin Liu, Jeff Klomp, Bradley J Merrill, Jalees Rehman, Asrar B Malik
Human endothelial cells (ECs) are widely used to study mechanisms of angiogenesis, inflammation, and endothelial permeability. Targeted gene disruption induced by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-Associated Protein 9 (Cas9) nuclease gene editing is potentially an important tool for definitively establishing the functional roles of individual genes in ECs. We showed that co-delivery of adenovirus encoding EGFP-tagged Cas9 and lentivirus encoding a single guide RNA (sgRNA) in primary human lung microvascular ECs (HLMVECs) disrupted the expression of the Tie2 gene and protein...
February 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28188225/inflammation-induced-caveolin-1-and-bmprii-depletion-promotes-endothelial-dysfunction-and-tgf%C3%AE-driven-pulmonary-vascular-remodeling
#16
Suellen Darc Santos Oliveira, Maricela Castellon, Jiwang Chen, Marcelo G Bonini, Xiaowu Gu, Michael H Elliott, Roberto F Machado, Richard D Minshall
Endothelial cell (EC) activation and vascular injury are hallmark features of Acute Lung Injury and Acute Respiratory Distress Syndrome (ALI/ARDS). Caveolin-1 (Cav-1) is highly expressed in pulmonary microvascular ECs and plays a key role in maintaining vascular homeostasis. The aim of this study was to determine whether the lung inflammatory response to Escherichia coli lipopolysaccharide (LPS) promotes priming of ECs via Cav-1 depletion and whether this contributes to the onset of pulmonary vascular remodeling...
February 10, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28179430/polydom-is-an-extracellular-matrix-protein-involved-in-lymphatic-vessel-remodeling
#17
Nanami Morooka, Sugiko Futaki, Ryoko Sato-Nishiuchi, Masafumi Nishino, Yuta Totani, Chisei Shimono, Itsuko Nakano, Hiroyuki Nakajima, Naoki Mochizuki, Kiyotoshi Sekiguchi
Rationale: Lymphatic vasculature constitutes a second vascular system, essential for immune surveillance and tissue fluid homeostasis. Maturation of the hierarchical vascular structure, with a highly-branched network of capillaries and ducts, is crucial for its function. Environmental cues mediate the remodeling process, but the mechanism that underlies this process is largely unknown. Objective: Polydom (also called Svep1) is an extracellular matrix protein identified as a high-affinity ligand for integrin α9β1...
February 8, 2017: Circulation Research
https://www.readbyqxmd.com/read/28159737/stem-and-progenitor-cell-alterations-in-myelodysplastic-syndromes
#18
REVIEW
Aditi Shastri, Britta Will, Ulrich Steidl, Amit Verma
Recent studies have demonstrated that myelodysplastic syndromes (MDSs) arise from a small population of disease-initiating hematopoietic stem cells (HSCs) that persist and expand through conventional therapies and are major contributors to disease progression and relapse. MDS stem and progenitor cells are characterized by key founder and driver mutations and are enriched for cytogenetic alterations. Quantitative alterations in hematopoietic stem and progenitor cell (HSPC) numbers are also seen in a stage-specific manner in human MDS samples as well as in murine models of the disease...
March 23, 2017: Blood
https://www.readbyqxmd.com/read/28151770/organ-specific-differences-in-endothelial-permeability-regulating-molecular-responses-in-mouse-and-human-sepsis
#19
Adnan Aslan, Matijs van Meurs, Jill Moser, Eliane R Popa, Rianne M Jongman, Peter J Zwiers, Grietje Molema, Jan G Zijlstra
In patients with sepsis-induced MODS, diverging patterns of oedema formation and loss of function in organs such as lung and kidney suggest that endothelial permeability-regulating molecular responses are differentially regulated. This potential differential regulation has been insufficiently studied at the level of components of adherens and tight junctions. We hypothesized that such a regulation by endothelial cells in sepsis takes place in an organ-specific manner. We addressed our hypothesis by studying by quantitative RT-PCR the expression of a predefined subset of EC permeability-related molecules (occludin, claudin-5, PV-1, CD-31, endomucin, Angiopoietin-1, Angiopoietin-2, Tie2, VEGFA, VEGFR1, VEGFR2, and VE-cadherin) in kidney and lung after systemic LPS injection in mice, and in kidneys of patients who died of sepsis...
February 1, 2017: Shock
https://www.readbyqxmd.com/read/28122355/plumbagin-restrains-hepatocellular-carcinoma-angiogenesis-by-suppressing-the-migration-and-invasion-of-tumor-derived-vascular-endothelial-cells
#20
YanFei Wei, Qi Yang, Yuan Zhang, TieJian Zhao, XueMei Liu, Jing Zhong, Jing Ma, YongXin Chen, Chuan Zhao, JunXuan Li
Tumor occurrence and development are very complicated processes. In addition to the roles of exogenous carcinogenic factors, the body's internal factors also play important roles. These factors include the host response to the tumor and the tumor effect on the host. In particular, the proliferation, migration and activation of endothelial cells are involved in tumor angiogenesis. Angiogenesis is one of the hallmarks of cancer. In this study, we investigate whether plumbagin can abrogate angiogenesis-mediated tumor growth in hepatocellular carcinoma (HCC) and, if so, through which molecular mechanisms...
February 28, 2017: Oncotarget
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