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Kaci A Bohn, Chris E Adkins, Mohamed I Nounou, Paul R Lockman
For metastases in the central nervous system, angiogenesis enhances metastatic potential and promotes progression. Primary factors which drive vessel growth are vascular endothelial growth factor (VEGF) and angiopoietin-2. Preclinical models show inhibition of either factor reduces metastases spread and inhibits growth. This work sets out to answer two questions in a preclinical mouse model. First, whether the combined inhibition of VEGF and angiopoietin-2, reduces passive permeability and limits drug uptake into brain metastases; and second, whether this inhibition reduces metastases burden in brain...
2017: Frontiers in Pharmacology
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...
May 16, 2017: Oncotarget
Amy Chui, Tilini Gunatillake, Shaun P Brennecke, Vera Ignjatovic, Paul T Monagle, John M Whitelock, Dagmar E van Zanten, Jasper Eijsink, Yao Wang, James Deane, Anthony J Borg, Janet Stevenson, Jan Jaap Erwich, Joanne M Said, Padma Murthi
OBJECTIVE: Biglycan (BGN) has reduced expression in placentae from pregnancies complicated by fetal growth restriction (FGR). We used first trimester placental samples from pregnancies with later small for gestational age (SGA) infants as a surrogate for FGR. The functional consequences of reduced BGN and the downstream targets of BGN were determined. Furthermore, the expression of targets was validated in primary placental endothelial cells isolated from FGR or control pregnancies. APPROACH AND RESULTS: BGN expression was determined using real-time polymerase chain reaction in placental tissues collected during chorionic villous sampling performed at 10 to 12 weeks' gestation from pregnancies that had known clinical outcomes, including SGA...
June 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
Jae-Ho Jeong, KwangSoo Kim, Daejin Lim, Kun-Hee Kim, Hyung-Seok Kim, Sungsu Lee, Joo-Hye Song, Byoung-Gon Moon, Hyon E Choy, Sang Chul Park
Inflammaging is defined as low-grade, chronic, systemic inflammation in aging, in the absence of overt infection. Age-associated deterioration of gastrointestinal function could be ascribed to the inflammaging, although evidence is yet to emerge. Here we show that microvessels in aging mouse intestine were progressively deprived of supportive structures, microvessel-associated pericytes and adherens junction protein vascular endothelial (VE)-cadherin, and became leaky. This alteration was ascribed to up-regulation of angiopoetin-2 in microvascular endothelial cells...
January 3, 2017: Scientific Reports
Ivanka Dacheva, Christoph Ullmer, Karolina Ceglowska, Everson Nogoceke, Guido Hartmann, Stephan Müller, Robert Rejdak, Katarzyna Nowomiejska, Michael Reich, Matthias Nobl, Tamer Tandogan, Florian T A Kretz, Gerd U Auffarth, Michael J Koss
PURPOSE: To analyze the levels of lysophosphatidic acids (LPAs) and autotaxin (ATX) in undiluted vitreous of untreated patients with retinal vein occlusion (RVO). METHODS: Sixty-four vitreous samples (40 RVO, 24 controls with idiopathic floaters) were analyzed in this retrospective case series using LC/MS for LPAs 16:0, 18:0, 18:1, 20:4, and ELISA kits or Luminex technology for ATX, angiopoetin-1 (ANG-1), interleukin-6 (IL-6), interleukin-7 (IL-7), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), pigment epithelium-derived factor (PEDF), and vascular endothelial growth factor (VEGF)...
December 2016: Retina
A K Filiz, E Ozdemir, H Gunes, H Gunes, M B Yılmaz
Objective: Hypertension is a common but incompletely understood disease. Emerging evidence supports a novel view of hypertension as a disease of inadequate or aberrant responses to angiogenic factors. In the present study we aimed to investigate the serum levels of vascular endothelial growth factor (VEGF), an angiogenic factor and soluble angiopoetin receptor Tie-2 (sTie-2) in patient with essential hypertension. Methods: In the present study 90 individuals (mean age 48 ± 7 years, 56 males and 34 females) have been divided in to three groups as 30 patients with hypertension, 30 healthy individuals (with a family history of hypertension) and 30 healthy individuals (no family history of hypertension)...
December 18, 2015: West Indian Medical Journal
Payal Shah, Navina Lueschen, Amin Ardestani, Jose Oberholzer, Johan Olerud, Per-Ola Carlsson, Kathrin Maedler
AIMS: Changes in the islet vasculature have been implicated in the regulation of β-cell survival and function during the progression to type 2 diabetes (T2D). Failure of the β-cell to compensate for the increased insulin demand in obesity eventually leads to diabetes; as a result of the complex interplay of genetic and environmental factors (e.g. ongoing inflammation within the islets) and impaired vascular function. The Angiopoietin/Tie (Ang/Tie) angiogenic system maintains vasculature and is closely related to organ inflammation and angiogenesis...
2016: PloS One
Anil Gulati
Endothelium is a site of metabolic activity and has a major reservoir of multipotent stem cells. It plays a vital role in the vascular physiological, pathophysiological and reparative processes. Endothelial functions are significantly altered following hypovolemic shock due to ischemia of the endothelial cells and by reperfusion due to resuscitation with fluids. Activation of endothelial cells leads to release of vasoactive substances (nitric oxide, endothelin, platelet activating factor, prostacyclin, mitochondrial N-formyl peptide), mediators of inflammation (tumor necrosis factor α, interleukins, interferons) and thrombosis...
2016: Current Vascular Pharmacology
Fernanda Van Petten Vasconcelos Azevedo, Daiana Silva Lopes, Sarah Natalie Cirilo Gimenes, David Collares Achê, Lara Vecchi, Patrícia Terra Alves, Denise de Oliveira Guimarães, Renata Santos Rodrigues, Luiz Ricardo Goulart, Veridiana de Melo Rodrigues, Kelly Aparecida Geraldo Yoneyama
This work shows the antitumoral effects of BnSP-6, a Lys 49 PLA2 isolated from Bothrops pauloensis venom, on human breast cancer MDA-MB-231 cells. BnSP-6 caused a dose-dependent cytotoxicity and inhibited cell adhesion. Interestingly, cytotoxic activity of BnSP-6 was significantly lower against MCF10A, a non-tumorigenic breast cell line, suggesting that this PLA2 presented a possible preference for targets in cancer cells. Analysis of cell death on MDA-MB-231 cells showed that BnSP-6 stimulated the autophagy process, as evidenced by labeling of autophagic vacuoles...
January 2016: International Journal of Biological Macromolecules
Natalia Kalinina, Galina Klink, Eugeniy Glukhanyuk, Tatiana Lopatina, Anastassia Efimenko, Zhanna Akopyan, Vsevolod Tkachuk
Mesenchymal stromal cells including those from adipose tissue (MSCs) regulate angiogenesis in adult tissues. MicroRNAs (miRs), small noncoding RNAs that control gene expression by binding to target mRNAs, reducing their stability and/or inhibiting translation, appear to be important regulators of blood vessel growth. In this study, we examined the impact of angio-miRs on paracrine activities of MSCs. Using Illumina microarrays we found that miR-92a is one of the most abundant angio-miRs in human MSCs. We transfected MSC with pre-miR-92a or anti-miR-92a which led to the coordinated changes of known miR-92a target mRNA levels...
November 15, 2015: Experimental Cell Research
Oleh Andrukhov, Anja C Gemperli, Yan Tang, Nadia Howald, Michel Dard, Frank Falkensammer, Andreas Moritz, Xiaohui Rausch-Fan
OBJECTIVES: Enamel matrix derivative (EMD) is an effective biomaterial for periodontal tissue regeneration and might stimulate angiogenesis. In order to clarify mechanisms underlying its biological activity, we separated two EMD fractions with different molecular weight protein components and investigated their effects on human umbilical vein endothelial cells (HUVECs) in vitro. METHODS: Fraction Low-Molecular Weight (LMW) included proteins with a molecular weight (M...
July 2015: Dental Materials: Official Publication of the Academy of Dental Materials
Hsiu-Mei Chen, Chia-Hua Tsai, Wen-Chun Hung
Foretinib, a multiple kinase inhibitor undergoing clinical trials, could suppress the activity of hepatocyte growth factor (HGF) receptor c-MET and vascular endothelial growth factor receptor-2 (VEGFR-2). In addition, Foretinib may inhibit two critical lymphangiogenic signaling receptors VEGFR-3 and TIE-2. However, the effect of Foretinib on lymphatic endothelial cells (LECs) in vitro and lymphangiogenesis in vivo is still unknown. We found Foretinib decreased basal- and HGF-induced c-MET activity at low concentrations...
June 20, 2015: Oncotarget
O Coutelle, L M Schiffmann, M Liwschitz, M Brunold, V Goede, M Hallek, H Kashkar, U T Hacker
BACKGROUND: Effective vascular normalisation following vascular endothelial growth factor (VEGF) inhibition is associated with endothelial cell regression leaving empty basement membrane sleeves (BMS). These long-lived BMS permit the rapid regrowth of tumour vasculature upon treatment cessation and promote resistance to VEGF-targeting drugs. Previous attempts at removing BMS have failed. Angiopoietin-2 (Ang2) is a vascular destabilizing factor that antagonises normalisation. We hypothesised that Ang2 inhibition could permit vascular normalisation at significantly reduced doses of VEGF inhibition, avoiding excessive vessel regression and the formation of empty BMS...
February 3, 2015: British Journal of Cancer
Susan S Cohen, Bethany R Powers, Alexandra Lerch-Gaggl, Ru-Jeng Teng, Girija Ganesh Konduri
BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is associated with increased risk of neuro-developmental impairments. Whether relative fetal hypoxia during evolution of PPHN renders the fetal brain vulnerable to perinatal brain injury remains unclear. We hypothesized that in utero ductal constriction, which induces PPHN also impairs cerebral angiogenesis. METHODS: Fetal lambs with PPHN induced by prenatal ligation of the ductus arteriosus were compared to gestation matched twin controls...
November 2014: International Journal of Developmental Neuroscience
Elina Korpela, Darren Yohan, Lee Cl Chin, Anthony Kim, Xiaoyong Huang, Shachar Sade, Paul Van Slyke, Daniel J Dumont, Stanley K Liu
BACKGROUND: Most cancer patients are treated with radiotherapy, but the treatment can also damage the surrounding normal tissue. Acute skin damage from cancer radiotherapy diminishes patients' quality of life, yet effective biological interventions for this damage are lacking. Protecting microvascular endothelial cells from irradiation-induced perturbations is emerging as a targeted damage-reduction strategy. Since Angiopoetin-1 signaling through the Tie2 receptor on endothelial cells opposes microvascular perturbations in other disease contexts, we used a preclinical Angiopoietin-1 mimic called Vasculotide to investigate its effect on skin radiation toxicity using a preclinical model...
2014: BMC Cancer
Juergen Debus, Amir Abdollahi
Glioblastoma (GBM) is the most common malignant brain tumor. Radiotherapy post surgical resection remained the mainstay of the management of GBM for decades until the addition of temozolomide was shown to prolong the median overall survival (OS) by 2.5 months to 14.6 months in 2005. Infiltrative growth to surrounding normal brain tissue and cooption of vascular niches, peripheral microvasuclar hyperplasia, and central hypoxic regions with pseudopalisading necrosis are characteristics of GBM and are causally linked to their exceptional radio- and chemo-resistant phenotype...
2014: American Society of Clinical Oncology Educational Book
Rajesh N Gacche, Rohan J Meshram
Formation of new blood vessels (angiogenesis) has been demonstrated to be a basic prerequisite for sustainable growth and proliferation of tumor. Several growth factors, cytokines, small peptides and enzymes support tumor growth either independently or in synergy. Decoding the crucial mechanisms of angiogenesis in physiological and pathological state has remained a subject of intense interest during the past three decades. Currently, the most widely preferred approach for arresting tumor angiogenesis is the blockade of vascular endothelial growth factor (VEGF) pathway; however, the clinical usage of this modality is still limited by several factors such as adverse effects, toxicity, acquired drug resistance, and non-availability of valid biomarkers...
August 2014: Biochimica et Biophysica Acta
H M C Shantha Kumara, Elizabeth A Myers, Sonali A C Herath, Linda Njoh, Xiaohong Yan, Daniel Kirchoff, Nadav Dujovny, Richard L Whelan
BACKGROUND: Minimally invasive colorectal resection for cancer is associated with increased plasma levels of numerous proangiogenic proteins for 3 to 4 weeks postoperatively, and plasma from postoperative weeks 2 and 3 stimulates proangiogenic endothelial cell behavior in vitro. It is unknown if similar plasma changes occur after minimally invasive colorectal resection for benign pathology. OBJECTIVE: The aim of this study is to assess 1) plasma levels of angiopoetin-2, placental growth factor, and soluble vascular cell adhesion molecule-1 after minimally invasive colorectal resection for benign pathology and 2) postoperative plasma's effects on in vitro endothelial cell proliferation (branch point formation), migration, and invasion...
June 2014: Diseases of the Colon and Rectum
Anastasia Efimenko, Nina Dzhoyashvili, Natalia Kalinina, Tatiana Kochegura, Renat Akchurin, Vsevolod Tkachuk, Yelena Parfyonova
Tissue regeneration is impaired in aged individuals. Adipose-derived mesenchymal stromal cells (ADSCs), a promising source for cell therapy, were shown to secrete various angiogenic factors and improve vascularization of ischemic tissues. We analyzed how patient age affected the angiogenic properties of ADSCs. ADSCs were isolated from subcutaneous fat tissue of patients with coronary artery disease (CAD; n = 64, 43-77 years old) and without CAD (n = 31, 2-82 years old). ADSC phenotype characterized by flow cytometry was CD90(+)/CD73(+)/CD105(+)/CD45(-)/CD31(-) for all samples, and these cells were capable of adipogenic and osteogenic differentiation...
January 2014: Stem Cells Translational Medicine
Christopher A Moxon, Ngawina V Chisala, Samuel C Wassmer, Terrie E Taylor, Karl B Seydel, Malcolm E Molyneux, Brian Faragher, Neil Kennedy, Cheng-Hock Toh, Alister G Craig, Robert S Heyderman
Endothelial dysregulation is central to the pathogenesis of acute Plasmodium falciparum infection. It has been assumed that this dysregulation resolves rapidly after treatment, but this return to normality has been neither demonstrated nor quantified. We therefore measured a panel of plasma endothelial markers acutely and in convalescence in Malawian children with uncomplicated or cerebral malaria. Evidence of persistent endothelial activation and inflammation, indicated by increased plasma levels of soluble intracellular adhesion molecule 1, angiopoetin 2, and C-reactive protein, were observed at 1 month follow-up visits...
February 15, 2014: Journal of Infectious Diseases
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