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Xin Wang, Wei Yuan, Xueqian Wang, Jialing Qi, Yinyin Qin, Yunwei Shi, Jie Zhang, Jie Gong, Zhangji Dong, Xiaoyu Liu, Chen Sun, Renjie Chai, Ferdinand Le Noble, Dong Liu
MAM and EGF containing gene (MAEG), also called Epidermal Growth Factor-like domain multiple 6 (EGFL6), belongs to the epidermal growth factor repeat superfamily. The role of Maeg in zebrafish angiogenesis remains unclear. It was demonstrated that maeg was dynamically expressed in zebrafish developing somite during a time window encompassing many key steps in embryonic angiogenesis. Maeg loss-of-function embryos showed reduced endothelial cell number and filopodia extensions of intersegmental vessels (ISVs)...
October 21, 2016: Oncotarget
Claire Peghaire, Marie Lise Bats, Raj Sewduth, Sylvie Jeanningros, Beatrice Jaspard, Thierry Couffinhal, Cécile Duplàa, Pascale Dufourcq
OBJECTIVE: Vessel formation requires precise orchestration of a series of morphometric and molecular events controlled by a multitude of angiogenic factors and morphogens. Wnt/frizzled signaling is required for proper vascular formation. In this study, we investigated the role of the Fzd7 (frizzled-7) receptor in retinal vascular development and its relationship with the Wnt/β-catenin canonical pathway and Notch signaling. APPROACH AND RESULTS: Using transgenic mice, we demonstrated that Fzd7 is required for postnatal vascular formation...
October 6, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
A Drouillard, F Puleo, J B Bachet, S Ouazzani, A Calomme, P Demetter, G Verset, J L Van Laethem, R Maréchal
BACKGROUND: There is an increasing interest for Notch signalling pathway and particularly Delta-like ligand 4 (DLL4) as potential therapeutic target to improve outcome for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Using immunohistochemistry (IHC) and tissue microarray (TMA), we assessed the expression patterns of DLL4, Notch1 and Notch3 in 151 patients from two independent cohorts of resected PDAC. We investigated the prognostic and the predictive significance of these proteins...
October 18, 2016: British Journal of Cancer
Zhong-Bao Ruan, Xing-Li Fu, Wei Li, Jun Ye, Ru-Zhu Wang, Li Zhu
BACKGROUND: Notch and NF-κB signaling pathways both play important roles in the regulation of atherosclerosis (AS). However, the mechanisms of notch and NF-κB signaling pathways on AS are still unclear. In this study, we aimed to investigate the effects of notch1,2,3 genes silicing by siRNA on notch and NF-κB signaling pathways of macrophages in patients with atherosclerosis (AS), so as to seek the treatment of AS from genetic perspective. METHODS: Peripheral blood mononuclears of 31 patients with AS were isolated by density gradient centrifugation and transformed by PMA to macrophages...
September 30, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Antonis Dagklis, Sofie Demeyer, Jolien De Bie, Enrico Radaelli, Daphnie Pauwels, Sandrine Degryse, Olga Gielen, Carmen Vicente, Roel Vandepoel, Ellen Geerdens, Anne Uyttebroeck, Nancy Boeckx, Charles E de Bock, Jan Cools
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive childhood leukemia that is caused by the accumulation of multiple genomic lesions resulting in transcriptional deregulation and increased cell proliferation and survival. Through analysis of gene expression data, we provide evidence that the hedgehog pathway is activated in 20% of T-ALL samples. Hedgehog pathway activation is associated with ectopic expression of the hedgehog ligands SHH or IHH, and with upregulation of the transcription factor GLI1...
September 30, 2016: Blood
Lindsey Dew, William R English, Chuh K Chong, Sheila MacNeil
One of the main challenges currently faced by tissue engineers is the loss of tissues post implantation due to delayed neovascularization. Several strategies are under investigation to create vascularized tissue but none have yet overcome this problem. In this study we produced a decellularized natural vascular scaffold from rat intestine to use as an in vitro platform for neovascularization studies for tissue engineered constructs. Decellularization resulted in almost complete (97%) removal of nuclei and DNA, while collagen, glycosaminoglycans and laminin content was preserved...
September 27, 2016: Tissue Engineering. Part A
Z B Ruan, X L Fu, W Li, J Ye, R Z Wang, Y G Yin, L Zhu
Objective: To investigate the effects of Notch1, 2, 3 genes silencing by siRNA on Notch signaling pathway (Delta-like 4(DLL4), Jagged 1(JAG1)) and nuclear factor-κB (NF-κB) signaling pathway (IκBα, P52) of macrophages derived from patients with coronary artery disease (CAD), thus to explore the potential genetic treatment perspectives for CAD. Methods: Peripheral blood mononuclear cells of CAD patients were isolated by density gradient centrifugation and transformed by phorbol-12-myristate-13-acetate (PMA) to macrophages...
September 24, 2016: Zhonghua Xin Xue Guan Bing za Zhi
Laura Asnaghi, Arushi Tripathy, Qian Yang, Harpreet Kaur, Allison Hanaford, Wayne Yu, Charles G Eberhart
Retinoblastoma is the most common intraocular malignancy of childhood. Notch plays a key role in retinal cells from which retinoblastomas arise, and we therefore studied the role of Notch signaling in promoting retinoblastoma proliferation. Moderate or strong nuclear expression of Hes1 was found in 10 of 11 human retinoblastoma samples analyzed immunohistochemically, supporting a role for Notch in retinoblastoma growth. Notch pathway components were present in WERI Rb1 and Y79 retinoblastoma lines, with Jag2 and DLL4 more highly expressed than other ligands, and Notch1 and Notch2 more abundant than Notch3...
September 20, 2016: Oncotarget
David Reichman, Limor Man, Laura Park, Raphael Lis, Jeannine Gerhardt, Zev Rosenwaks, Daylon James
During development, endothelial cells (EC) display tissue-specific attributes that are unique to each vascular bed, as well as generic signaling mechanisms that are broadly applied to create a patent circulatory system. We have previously utilized human embryonic stem cells (hESC) to generate tissue-specific EC sub-types (Rafii et al., 2013) and identify pathways that govern growth and trans-differentiation potential of hESC-derived ECs (James et al., 2010). Here, we elucidate a novel Notch-dependent mechanism that induces endothelial to mesenchymal transition (EndMT) in confluent monolayer cultures of hESC-derived ECs...
September 13, 2016: Stem Cell Research
Lijun Meng, Shaoyan Hu, Jian Wang, Shan He, Yi Zhang
Dendritic cells (DCs) are critical regulators of adaptive immune responses. DCs can elicit primary T cell responses at low DC:T cell ratios through their expression of high levels of antigen-presenting molecules and costimulatory molecules. DCs are important for induction of functionally diverse T cell subsets such as CD4(+) T helper (Th)1 and Th17 cells and effector CD8(+) T cells able to reside in epithelial tissues. Recent studies begin illuminating the underlying mechanism by which DCs regulate specialized T cell subsets...
September 14, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Ledi Liu, Hiroe Wada, Natsuki Matsubara, Katsuto Hozumi, Motoyuki Itoh
Notch is a critical signaling pathway that controls cell fate and tissue homeostasis, but the functional characterization of Notch ligand domains that activate Notch receptors remains incomplete. Here, we established a method for immobilizing Notch ligand proteins onto beads to measure time-dependent Notch activity after the addition of Notch ligand-coated beads. A comparison between activities by the Notch ligand found on the cell surface to that of the ligand immobilized on beads showed that immobilized Notch ligand protein produces comparable signal activity during the first ten hours...
September 17, 2016: Journal of Cellular Biochemistry
Justyna Niderla-Bielińska, Bogdan Ciszek, Ewa Jankowska-Steifer, Aleksandra Flaht-Zabost, Grzegorz Gula, Dorota M Radomska-Leśniewska, Anna Ratajska
Angiogenesis contributes to the generation of the vascular bed but also affects the progression of many diseases, such as tumor growth. Many details of the molecular pathways controlling angiogenesis are still undefined due to the lack of appropriate models. We propose the proepicardial explant as a suitable model for studying certain aspects of angiogenesis. The proepicardium (PE) is a transient embryonic structure that contains a population of undifferentiated endothelial cells (ECs) forming a vascular net continuous with the sinus venosus...
September 15, 2016: Journal of Vascular Research
M Shin, T Beane, A Quillien, I Male, L J Zhu, N D Lawson
Vascular endothelial growth factor a (Vegfa) is essential for blood vessel formation and can induce activation of numerous signaling effectors in endothelial cells. However, it is unclear how and where these function in developmental contexts during vascular morphogenesis. To address this issue, we have visualized activation of presumptive Vegfa effectors at single cell resolution in zebrafish blood vessels. From these studies, we find that phosphorylation of the serine/threonine kinase ERK (pERK) preferentially occurs in endothelial cells undergoing angiogenesis, but not in committed arterial endothelial cells...
August 30, 2016: Development
S Wang, J Sun, D D Zhang, P K Wong
The formation of microvascular networks plays essential roles in regenerative medicine and tissue engineering. Nevertheless, the self-organization mechanisms underlying the dynamic morphogenic process are poorly understood due to a paucity of effective tools for mapping the spatiotemporal dynamics of single cell behaviors. By establishing a single cell nanobiosensor along with live cell imaging, we perform dynamic single cell analysis of the morphology, displacement, and gene expression during microvascular self-organization...
October 14, 2016: Nanoscale
Zhixing Yao, Zaki A Sherif
The Li-Fraumeni Syndrome (LFS), a genetically rare heterogeneous cancer syndrome, is characterized primarily by a germline p53 (TP53) gene mutation. We recently discovered a balanced reciprocal chromosomal translocation t(11;15)(q23;q15) in the non-cancerous skin fibroblasts of a bilateral breast cancer patient in LFS family. This prompted us to investigate the breakpoint region of the translocation, which uncovered a gene that encodes a Notch ligand, DLL4, (locus at 15q15.1), a key target in tumor vasculature...
August 16, 2016: Oncotarget
Yujiro Kida, Joseph A Zullo, Michael S Goligorsky
Peritubular capillary (PTC) rarefaction along with tissue fibrosis is a hallmark of chronic kidney disease (CKD). However, molecular mechanisms of PTC loss have been poorly understood. Previous studies have demonstrated that functional loss of endothelial sirtuin 1 (SIRT1) impairs angiogenesis during development and tissue damage. Here, we found that endothelial SIRT1 dysfunction causes activation of endothelial Notch1 signaling, which leads to PTC rarefaction and fibrosis following kidney injury. In mice lacking functional SIRT1 in the endothelium (Sirt1 mutant), kidney injury enhanced apoptosis and senescence of PTC endothelial cells with impaired endothelial proliferation and expanded myofibroblast population and collagen deposition...
September 23, 2016: Biochemical and Biophysical Research Communications
Teng Zhang, Yufeng Yao, Jingjing Wang, Yong Li, Ping He, Vinay Pasupuleti, Zhengkun Hu, Xinzhen Jia, Qixue Song, Xiaoli Tian, Changqin Hu, Qiuyun Chen, Qing Kenneth Wang
Aggf1 is the first gene identified for Klippel-Trenaunay syndrome (KTS), and encodes an angiogenic factor. However, the in vivo roles of Aggf1 are incompletely defined. Here we demonstrate that Aggf1 is essential for both physiological angiogenesis and pathological tumor angiogenesis in vivo Two lines of Aggf1 knockout (KO) mice showed particularly severe phenotype as no homozygous embryos were observed and heterozygous mice also showed embryonic lethality (haploinsufficient lethality) observed only for Vegfa and Dll4 Aggf1(+/-) KO caused defective angiogenesis in yolk sacs and embryos...
August 13, 2016: Human Molecular Genetics
Yanhong Wei, Junsong Gong, Zhenhua Xu, Elia J Duh
Revascularization of ischemic tissue is a highly desirable outcome in multiple diseases, including cardiovascular diseases and ischemic retinopathies. Oxidative stress and inflammation are both known to play a role in suppressing reparative angiogenesis in ischemic disease models including oxygen-induced retinopathy (OIR), but the regulatory molecules governing these pathophysiologic processes in retinal ischemia are largely unknown. Nrf2 is a major stress-response transcription factor that has been implicated in regulating ischemic angiogenesis in the retina and other tissue beds...
August 10, 2016: Free Radical Biology & Medicine
Kasmir Ramo, Koichi Sugamura, Siobhan Craige, John F Keaney, Roger J Davis
Arterial occlusive diseases are major causes of morbidity and mortality. Blood flow to the affected tissue must be restored quickly if viability and function are to be preserved. We report that disruption of the mixed-lineage protein kinase (MLK) - cJun NH2-terminal kinase (JNK) signaling pathway in endothelial cells causes severe blockade of blood flow and failure to recover in the murine femoral artery ligation model of hindlimb ischemia. We show that the MLK-JNK pathway is required for the formation of native collateral arteries that can restore circulation following arterial occlusion...
2016: ELife
Tessa D Nauta, Monique C A Duyndam, Ester M Weijers, Victor M W van Hinsbergh, Pieter Koolwijk
BACKGROUND: During short-term hypoxia, Hypoxia Inducible Factors (particular their subunits HIF-1α and HIF-2α) regulate the expression of many genes including the potent angiogenesis stimulator VEGF. However, in some pathological conditions chronic hypoxia occurs and is accompanied by reduced angiogenesis. OBJECTIVES: We investigated the effect of prolonged hypoxia on the proliferation and sprouting ability of human microvascular endothelial cells and the involvement of the HIFs and Dll4/Notch signaling...
2016: PloS One
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