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https://www.readbyqxmd.com/read/28089339/discovery-of-a-murine-model-of-clinical-pah-mission-impossible
#1
REVIEW
Zhiyu Dai, You-Yang Zhao
Pulmonary arterial hypertension (PAH) is a lung vascular disease characterized with a progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling resulting in right heart failure and premature death. In this brief review, we document the recent advances in identifying genetically modified murine models of PH, with a focus on the recent discovery of the mouse model of Tie2 Cre-mediated deletion of prolyl hydroxylase 2, which exhibits progressive obliterative vascular remodeling, severe PAH, and right heart failure, thus recapitulating many of the features of clinical PAH...
December 15, 2016: Trends in Cardiovascular Medicine
https://www.readbyqxmd.com/read/28079371/a-binding-pose-flip-explained-via-enthalpic-and-entropic-contributions
#2
Michael Schauperl, Paul Czodrowski, Julian E Fuchs, Roland G Huber, Birgit J Waldner, Maren Podewitz, Christian Kramer, Klaus R Liedl
The anomalous binding modes of five highly similar fragments of TIE2 inhibitors, showing three distinct binding poses are investigated. We report a quantitative rationalization for the changes in binding pose based on molecular dynamics simulations. We investigated five fragments in complex with the transforming growth factor β receptor type 1 kinase domain. Analyses of these simulations using Grid Inhomogeneous Solvation Theory (GIST), pKA calculations, and a tool to investigate enthalpic differences upon binding unraveled the various thermodynamic contributions to the different binding modes...
January 12, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28073001/normalization-of-tumor-vessels-by-tie2-activation-and-ang2-inhibition-enhances-drug-delivery-and-produces-a-favorable-tumor-microenvironment
#3
Jin-Sung Park, Il-Kug Kim, Sangyeul Han, Intae Park, Chan Kim, Jeomil Bae, Seung Ja Oh, Seungjoo Lee, Jeong Hoon Kim, Dong-Cheol Woo, Yulong He, Hellmut G Augustin, Injune Kim, Doheon Lee, Gou Young Koh
No abstract text is available yet for this article.
January 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28063039/xenotransplantation-model-of-psoriasis
#4
Jeremy Di Domizio, Curdin Conrad, Michel Gilliet
Psoriasis is a chronic autoimmune skin disease affecting approximately 2 % of the population with a major psychosocial and socioeconomic impact. A causal therapy leading to permanent cure is not available, and current treatments only lead to limited amelioration, and therefore new therapeutic targets need to be identified. Recent works demonstrated a predominant role of TH17 cells in the pathogenesis of psoriasis; yet the underlying molecular mechanisms driving the development of the disease are still largely elusive...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28062977/angiopoietin-pathway-gene-expression-associated-with-poor-breast-cancer-survival
#5
Rajesh Ramanathan, Amy L Olex, Mikhail Dozmorov, Harry D Bear, Leopoldo Jose Fernandez, Kazuaki Takabe
PURPOSE: Angiogenesis is one of the hallmarks of cancer and is essential for cancer progression and metastasis. However, clinical trials with vascular endothelial growth factor (VEGF) pathway inhibitors have failed to show overall survival benefit in breast cancer. Targeted therapy against the angiopoietin pathway, a downstream angiogenesis cascade, could be effective in breast cancer. This study investigates the association of angiopoietin pathway gene expression with breast cancer survival using a "big data" approach employing RNA sequencing data from The Cancer Genome Atlas (TCGA)...
January 6, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28060852/contribution-of-vascular-cells-to-neointimal-formation
#6
Falei Yuan, Dong Wang, Kang Xu, Jixian Wang, Zhijun Zhang, Li Yang, Guo-Yuan Yang, Song Li
The de-differentiation and proliferation of smooth muscle cells (SMCs) are widely accepted as the major contributor to vascular remodeling. However, recent studies indicate that vascular stem cells (VSCs) also play an important role, but their relative contribution remains to be elucidated. In this study, we used genetic lineage tracing approach to further investigate the contribution of SMCs and VSCs to neointimal thickening in response to endothelium denudation injury or artery ligation. In vitro and in vivo analysis of MYH11-cre/Rosa-loxP-RFP mouse artery showed that SMCs proliferated at a much slower rate than non-SMCs...
2017: PloS One
https://www.readbyqxmd.com/read/28056085/vascular-endothelial-over-expression-of-human-soluble-epoxide-hydrolase-tie2-seh-tr-attenuates-coronary-reactive-hyperemia-in-mice-role-of-oxylipins-and-%C3%AF-hydroxylases
#7
Ahmad Hanif, Matthew L Edin, Darryl C Zeldin, Christophe Morisseau, John R Falck, Mohammed A Nayeem
Cytochromes P450 metabolize arachidonic acid (AA) into two vasoactive oxylipins with opposing biologic effects: epoxyeicosatrienoic acids (EETs) and omega-(ω)-terminal hydroxyeicosatetraenoic acids (HETEs). EETs have numerous beneficial physiological effects, including vasodilation and protection against ischemia/reperfusion injury, whereas ω-terminal HETEs induce vasoconstriction and vascular dysfunction. We evaluated the effect of these oxylipins on post-ischemic vasodilation known as coronary reactive hyperemia (CRH)...
2017: PloS One
https://www.readbyqxmd.com/read/28005151/activated-protein-c-binds-directly-to-tie2-possible-beneficial-effects-on-endothelial-barrier-function
#8
Nikita Minhas, Meilang Xue, Christopher J Jackson
Activated protein C (APC) is a natural anticoagulant with strong anti-inflammatory, anti-apoptotic, and barrier stabilizing properties. These cytoprotective properties of APC are thought to be exerted through its pathway involving the binding of APC to endothelial protein C receptor and cleavage of protease-activated receptors. In this study, we found that APC enhanced endothelial barrier integrity via a novel pathway, by binding directly to and activating Tie2, a transmembrane endothelial tyrosine kinase receptor...
December 22, 2016: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28005008/angiopoietin-receptor-tie2-is-required-for-vein-specification-and-maintenance-via-regulating-coup-tfii
#9
Man Chu, Taotao Li, Bin Shen, Xudong Cao, Haoyu Zhong, Luqing Zhang, Fei Zhou, Wenjuan Ma, Haijuan Jiang, Pancheng Xie, Zhengzheng Liu, Ningzheng Dong, Ying Xu, Yun Zhao, Guoqiang Xu, Peirong Lu, Jincai Luo, Qingyu Wu, Kari Alitalo, Gou Young Koh, Ralf H Adams, Yulong He
Mechanisms underlying the vein development remain largely unknown. Tie2 signaling mediates endothelial cell (EC) survival and vascular maturation and its activating mutations are linked to venous malformations. Here we show that vein formation are disrupted in mouse skin and mesentery when Tie2 signals are diminished by targeted deletion of Tek either ubiquitously or specifically in embryonic ECs. Postnatal Tie2 attenuation resulted in the degeneration of newly formed veins followed by the formation of haemangioma-like vascular tufts in retina and venous tortuosity...
December 22, 2016: ELife
https://www.readbyqxmd.com/read/28000664/endothelial-specific-inhibition-of-nf-%C3%AE%C2%BAb-enhances-functional-haematopoiesis
#10
Michael G Poulos, Pradeep Ramalingam, Michael C Gutkin, Maria Kleppe, Michael Ginsberg, Michael J P Crowley, Olivier Elemento, Ross L Levine, Shahin Rafii, Jan Kitajewski, Matthew B Greenblatt, Jae-Hyuck Shim, Jason M Butler
Haematopoietic stem cells (HSCs) reside in distinct niches within the bone marrow (BM) microenvironment, comprised of endothelial cells (ECs) and tightly associated perivascular constituents that regulate haematopoiesis through the expression of paracrine factors. Here we report that the canonical NF-κB pathway in the BM vascular niche is a critical signalling axis that regulates HSC function at steady state and following myelosuppressive insult, in which inhibition of EC NF-κB promotes improved HSC function and pan-haematopoietic recovery...
December 21, 2016: Nature Communications
https://www.readbyqxmd.com/read/27998825/hematopoietic-arginase-1-deficiency-results-in-decreased-leukocytosis-and-increased-foam-cell-formation-but-does-not-affect-atherosclerosis
#11
Baoyan Ren, Erik Van Kampen, Theo J C Van Berkel, Sheena M Cruickshank, Miranda Van Eck
BACKGROUND AND AIMS: Arginase1 (Arg1), an M2 macrophage marker, plays a critical role in a number of immunological functions in macrophages, which are the main cell type facilitating atherosclerotic lesion development. Arg1 uses the substrate l-arginine to create l-ornithine, a precursor molecule required for collagen formation and vascular smooth muscle cell differentiation. By reducing l-arginine availability, Arg1 limits the production of nitric oxide (NO), a pro-atherogenic factor in macrophages...
November 16, 2016: Atherosclerosis
https://www.readbyqxmd.com/read/27981571/haematopoietic-prolyl-hydroxylase-1-deficiency-promotes-m2-macrophage-polarization-and-is-both-necessary-and-sufficient-to-protect-against-experimental-colitis
#12
Sophie Van Welden, Martine De Vos, Ben Wielockx, Simon J Tavernier, Melissa Dullaers, Sara Neyt, Benedicte Descamps, Lindsey Devisscher, Sarah Devriese, Lien Van den Bossche, Tom Holvoet, Ann Baeyens, Carmen Correale, Silvia D'Alessio, Christian Vanhove, Filip De Vos, Bruno Verhasselt, Georg Breier, Bart N Lambrecht, Sophie Janssens, Peter Carmeliet, Silvio Danese, Dirk Elewaut, Debby Laukens, Pieter Hindryckx
Prolyl hydroxylase domain-containing proteins (PHD) regulate the adaptation of cells to hypoxia. Pan-hydroxylase inhibition is protective in experimental colitis in which PHD1 plays a prominent role. However, it is currently unknown how PHD1 targeting regulates this protection and which cell type(s) are involved. Here we demonstrated that Phd1 deletion in endothelial and haematopoietic cells (Phd1(f/)(f) Tie2:cre) protected mice from dextran sulphate sodium (DSS)-induced colitis with reduced epithelial erosions, immune cell infiltration and colonic microvascular dysfunction, whereas the response of Phd2(f/+) Tie2:cre and Phd3(f/)(f) Tie2:cre mice to DSS was similar to their littermate controls...
December 16, 2016: Journal of Pathology
https://www.readbyqxmd.com/read/27960151/il-35-inhibits-angiogenesis-through-vegf-ang2-tie2-pathway-in-rheumatoid-arthritis
#13
Shenyi Jiang, Yuxuan Li, Tiantian Lin, Lin Yuan, Yunxia Li, Suqin Wu, Liping Xia, Hui Shen, Jing Lu
BACKGROUND/AIMS: The pro-angiogenic factors vascular endothelial growth factor (VEGF) and angiopoietins (Angs) play a prominent role in synovial angiogenesis, an early and critical event in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)-35 is an anti-inflammatory cytokine that attenuates collagen-induced arthritis, however, the mechanisms involved are not fully understood. METHODS: The effects of IL-35 on endothelial cell migration, adhesion, and tube formation were examined using human umbilical vein endothelial cells (HUVEC) in vitro...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27960088/normalization-of-tumor-vessels-by-tie2-activation-and-ang2-inhibition-enhances-drug-delivery-and-produces-a-favorable-tumor-microenvironment
#14
Jin-Sung Park, Il-Kug Kim, Sangyeul Han, Intae Park, Chan Kim, Jeomil Bae, Seung Ja Oh, Seungjoo Lee, Jeong Hoon Kim, Dong-Cheol Woo, Yulong He, Hellmut G Augustin, Injune Kim, Doheon Lee, Gou Young Koh
A destabilized tumor vasculature leads to limited drug delivery, hypoxia, detrimental tumor microenvironment, and even metastasis. We performed a side-by-side comparison of ABTAA (Ang2-Binding and Tie2-Activating Antibody) and ABA (Ang2-Blocking Antibody) in mice with orthotopically implanted glioma, with subcutaneously implanted Lewis lung carcinoma, and with spontaneous mammary cancer. We found that Tie2 activation induced tumor vascular normalization, leading to enhanced blood perfusion and chemotherapeutic drug delivery, markedly lessened lactate acidosis, and reduced tumor growth and metastasis...
December 12, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27942589/interleukin-6-regulates-psoriasiform-inflammation-associated-thrombosis
#15
Yunmei Wang, Jackelyn B Golden, Yi Fritz, Xiufen Zhang, Doina Diaconu, Maya I Camhi, Huiyun Gao, Sean M Dawes, Xianying Xing, Santhi K Ganesh, Johann E Gudjonsson, Daniel I Simon, Thomas S McCormick, Nicole L Ward
Psoriasis patients are at increased risk of heart attack and stroke and have elevated MRP8/14 levels that predict heart attack. The KC-Tie2 psoriasiform mouse model exhibits elevated MRP8/14 and is prothrombotic. Mrp14(-/-) mice, in contrast, are protected from thrombosis, but, surprisingly, KC-Tie2xMrp14(-/-) mice remain prothrombotic. Treating KC-Tie2xMrp14(-/-) mice with anti-IL-23p19 antibodies reversed the skin inflammation, improved thrombosis, and decreased IL-6. In comparison, IL-6 deletion from KC-Tie2 animals improved thrombosis despite sustained skin inflammation, suggesting that thrombosis improvements following IL-23 inhibition occur secondary to IL-6 decreases...
December 8, 2016: JCI Insight
https://www.readbyqxmd.com/read/27941161/angiopoietin-tie-signalling-in-the-cardiovascular-and-lymphatic-systems
#16
REVIEW
Lauri Eklund, Jaakko Kangas, Pipsa Saharinen
Endothelial cells that form the inner layer of blood and lymphatic vessels are important regulators of vascular functions and centrally involved in the pathogenesis of vascular diseases. In addition to the vascular endothelial growth factor (VEGF) receptor pathway, the angiopoietin (Ang)-Tie system is a second endothelial cell specific ligand-receptor signalling system necessary for embryonic cardiovascular and lymphatic development. The Ang-Tie system also regulates postnatal angiogenesis, vessel remodelling, vascular permeability and inflammation to maintain vascular homoeostasis in adult physiology...
January 1, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/27927766/phase-1-dose-finding-study-of-rebastinib-dcc-2036-in-patients-with-relapsed-chronic-myeloid-leukemia-and-acute-myeloid-leukemia
#17
Jorge Cortes, Moshe Talpaz, Hedy P Smith, David S Snyder, Jean Khoury, Kapil N Bhalla, Javier Pinilla-Ibarz, Richard Larson, David Mitchell, Scott C Wise, Thomas J Rutkoski, Bryan D Smith, Daniel L Flynn, Hagop M Kantarjian, Oliver Rosen, Richard A Van Etten
Available tyrosine kinase inhibitors for chronic myeloid leukemia bind in an ATP-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first in human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. Primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose (MTD) and recommended Phase 2 dose...
December 7, 2016: Haematologica
https://www.readbyqxmd.com/read/27923976/early-restriction-of-placental-growth-results-in-placental-structural-and-gene-expression-changes-in-late-gestation-independent-of-fetal-hypoxemia
#18
Song Zhang, Paige Barker, Kimberley J Botting, Claire T Roberts, Christine M McMillan, Isabella Caroline McMillen, Janna L Morrison
Placental restriction and insufficiency are associated with altered patterns of placental growth, morphology, substrate transport capacity, growth factor expression, and glucocorticoid exposure. We have used a pregnant sheep model in which the intrauterine environment has been perturbed by uterine carunclectomy (Cx). This procedure results in early restriction of placental growth and either the development of chronic fetal hypoxemia (PaO2≤17 mmHg) in late gestation or in compensatory placental growth and the maintenance of fetal normoxemia (PaO2>17 mmHg)...
December 2016: Physiological Reports
https://www.readbyqxmd.com/read/27920123/selective-enhancement-of-insulin-sensitivity-in-the-endothelium-in-vivo-reveals-a-novel-proatherosclerotic-signalling-loop
#19
Hema Viswambharan, Nadira Y Yuldasheva, Anshuman Sengupta, Helen Imrie, Matthew C Gage, Natalie J Haywood, Andrew M Walker, Anna Skromna, Natalia Makova, Stacey L Galloway, Pooja Shah, Piruthivi Sukumar, Karen E Porter, Peter J Grant, Ajay M Shah, Celio X Santos, Jing Li, David J Beech, Stephen Wheatcroft, Richard M Cubbon, Mark T Kearney
RATIONALE: In the endothelium, insulin stimulates endothelial nitric oxide synthase (eNOS) to generate the anti-atherosclerotic signalling radical NO. Insulin resistant type 2 diabetes is associated with reduced NO availability and accelerated atherosclerosis. The effect of enhancing endothelial insulin sensitivity on NO availability is unclear. OBJECTIVE: To answer this question we generated a mouse with endothelial cell (EC)-specific over-expression of the human insulin receptor (hIRECO) using the Tie2 promoter-enhancer...
December 5, 2016: Circulation Research
https://www.readbyqxmd.com/read/27917461/intussusceptive-angiogenesis-and-expression-of-tie-receptors-during-porcine-metanephric-kidney-development
#20
Anastasia Logothetidou, Tim Vandecasteele, Els Van Mulken, Kimberley Vandevelde, Pieter Cornillie
Intussusceptive angiogenesis (IA) is required for normal embryonic vascular development. The Tie family of receptors and their ligands, the angiopoietins, play an important role in the growth or regression of blood vessels which are important not only during development but also throughout an organism's life. The presence of IA was investigated in glomerular capillaries of the fetal porcine metanephros using Mercox II resin casts. The first signs of IA were observed in stage III glomeruli. Stage IV and V glomeruli showed numerous signs of aligned pillar formation and their successive merging to delineate the vascular entities...
December 5, 2016: Histology and Histopathology
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