A5005666850- Angiogenesis and VEGF in Cancer
- Zebrafish Biomedical Research Applications
- Hippo pathway signaling and YAP/TAZ
- RNA Research and Splicing
- Cellular Mechanics and Interactions
- Protein Kinase Regulation and GTPase Signaling
- Cell Adhesion Molecules Research
- Axon Guidance and Neuronal Signaling
- Congenital heart defects research
- Ubiquitin and proteasome pathways
- Platelet Disorders and Treatments
- Vitamin K Research Studies
- Cellular transport and secretion
- Inflammatory mediators and NSAID effects
- Developmental Biology and Gene Regulation
- RNA modifications and cancer
- Blood groups and transfusion
- Cancer-related molecular mechanisms research
- Histone Deacetylase Inhibitors Research
- Vascular Anomalies and Treatments
- Complement system in diseases
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Caveolin-1 and cellular processes
- Retinal Diseases and Treatments
- RNA Interference and Gene Delivery
University of Manchester
2016-2025
Manchester Academic Health Science Centre
2020
University of California, San Francisco
2009-2012
University of Leeds
2004-2010
Making Split Decisions Development of the vertebrate vasculature has been thought to involve just two mechanisms blood vessel formation. Herbert et al. (p. 294 ; see Perspective by Benedito and Adams ) identified a third mechanism in zebrafish which distinct, unconnected vessels can be derived from single precursor vessel. Several vascular endothelial growth factors signaling pathways, including ephrin notch signaling, coordinated sorting segregation mixture arterial venous-fated cells into...
Abstract Vascular endothelial growth factor A (VEGF‐A)‐induced signaling through VEGF receptor 2 (VEGFR2) regulates both physiological and pathological angiogenesis in mammals. However, the temporal spatial mechanism underlying VEGFR2‐mediated intracellular is not clear. Here, we define a pathway for VEGFR2 trafficking proteolysis that VEGF‐A‐stimulated cell migration. Ligand‐stimulated activation ubiquitination preceded cytoplasmic domain removal associated with endosomes. soluble fragment...
Angiogenesis, the fundamental process by which new blood vessels form from existing ones, depends on precise spatial and temporal gene expression within specific compartments of endothelium. However, molecular links between proangiogenic signals downstream remain unclear. During sprouting angiogenesis, specification endothelial cells into tip that lead vessel sprouts is coordinated vascular growth factor A (VEGFA) Delta-like ligand 4 (Dll4)/Notch signaling requires high levels Notch DLL4....
How do cells make efficient collective decisions during tissue morphogenesis? Humans and other organisms use feedback between movement sensing known as ‘sensorimotor coordination’ or ‘active perception’ to inform behaviour, but active perception has not before been investigated at a cellular level within organs. Here we provide the first proof of concept in silico / vivo study demonstrating that filopodia (actin-rich, dynamic, finger-like cell membrane protrusions) play an unexpected role...
The regulated generation of prostaglandins from endothelial cells is critical to vascular function. Here we identify a novel mechanism for the regulation cell prostaglandin generation. Cytosolic phospholipase A2-α (cPLA2α) cleaves phospholipids in Ca2+-dependent manner yield free arachidonic acid and lysophospholipid. Arachidonic then converted into by action cyclooxygenase enzymes downstream synthases. By previously undefined mechanisms, nonconfluent generate greater levels than confluent...
Polarised targeting of diverse mRNAs to cellular protrusions is a hallmark cell migration. Although widespread phenomenon, definitive functions for endogenous targeted and their relevance modulation in vivo tissue dynamics remain elusive. Here, using single-molecule analysis, gene editing zebrafish live-cell imaging, we report that mRNA polarisation acts as molecular compass orients motile polarity spatially directs movement. Clustering protrusion-derived RNAseq datasets defined core 192-nt...
Tissue branching morphogenesis requires the hierarchical organization of sprouting cells into leading "tip" and trailing "stalk" [1, 2]. During new blood vessel (angiogenesis), endothelial tip (TCs) lead vessels, extend filopodia, migrate in response to gradients secreted ligand, vascular growth factor (Vegf) [3]. In contrast, adjacent stalk (SCs) trail TCs, generate trunk critically maintain connectivity with parental vessels. Here, we establish that h2.0-like homeobox-1 (Hlx1) determines...
Angiogenesis is driven by the coordinated collective branching of specialized leading "tip" and trailing "stalk" endothelial cells (ECs). While Notch-regulated negative feedback suppresses excessive tip selection, roles for positive in EC identity decisions remain unexplored. Here, integrating computational modeling with vivo experimentation, we reveal that critically modulates magnitude, timing, robustness angiogenic responses. In silico predicts positive-feedback-mediated amplification...
AbstractSecretory granules called Weibel-Palade bodies (WPBs) containing Von Willebrand factor (VWF) are characteristic of the mammalian endothelium. We hypothesized that vascular-specific antigens such as VWF linked to endothelial identity and proliferation in vitro. To test this idea, cellular accumulation WPBs was monitored a function cell proliferation, confluence passage number human umbilical vein cells (HUVECs). found increased percentage reduced significantly, whilst protein still...
Arachidonic acid and its metabolites are implicated in regulating endothelial cell proliferation. Cytosolic phospholipase A2-alpha (cPLA2alpha) is responsible for receptor-mediated arachidonic evolution. We tested the hypothesis that cPLA2alpha activity linked to The specific inhibitor, pyrrolidine-1, inhibited umbilical vein (HUVEC) proliferation a dose-dependent manner. Exogenous addition reversed this inhibitory effect. Inhibition of sPLA2 did not affect HUVEC levels differ between...
Release of endothelial cells from contact-inhibition and cell cycle re-entry is required for the induction new blood vessel formation by angiogenesis. Using a combination chemical inhibition, loss function, gain function approaches, we demonstrate that re-entry, S phase progression, subsequent angiogenic tubule are dependent upon activity cytosolic phospholipase A(2)-alpha (cPLA(2)alpha). Inhibition cPLA(2)alpha small interfering RNA (siRNA)-mediated knockdown endogenous reduced...
Arachidonic acid and its metabolites have been previously implicated in the regulation of endothelial cell proliferation. may be liberated from cellular phospholipids by action group VIA calcium-independent phospholipase A2 (iPLA2-VIA). Consequently, we tested hypothesis that iPLA2-VIA activity is linked to Inhibition iPLA2 bromoenol lactone (BEL) was sufficient entirely block growth. BEL dose-dependently inhibited DNA synthesis a manner reversed upon exogenous addition arachidonic acid....
Cytosolic phospholipase A 2 ‐α (cPLA ‐α) is a calcium‐activated enzyme that plays an important role in agonist‐induced arachidonic acid release. In endothelial cells, free can be converted subsequently into prostacyclin, potent vasodilator and inhibitor of platelet activation, through the action cyclooxygenase (COX) enzymes. Here we study relocation cPLA human EA.hy.926 cells following stimulation with calcium‐mobilizing agonist, A23187. Relocation was seen to highly cell specific, occurred...
The mechanisms regulating the signaling pathways involved in angiogenesis are not fully known. Ristori et al. show that Lunatic Fringe (LFng) mediates crosstalk between Bone Morphogenic Protein 9 (Bmp9) and Notch signaling, thereby endothelial cell behavior temporal dynamics of their identity during sprouting angiogenesis.Bmp9 upregulates expression LFng cells.LFng regulates tip/stalk selection rearrangement.LFng indicated to play a role hereditary hemorrhagic telangiectasia.Bmp9 mediate...
ABSTRACT Polarised targeting of diverse mRNAs to motile cellular protrusions is a hallmark cell migration 1–3 . Although widespread phenomenon, definitive functions for endogenous targeted and their relevance modulation in-vivo tissue dynamics remain elusive. Here, using single-molecule analysis, gene-edited zebrafish live-cell imaging, we report that mRNA polarisation acts as molecular compass orients polarity spatially directs movement. Clustering protrusion-derived RNAseq datasets defined...
Abstract How do cells make efficient collective decisions during tissue morphogenesis? Humans and other organisms utilize feedback between movement sensing known as ‘sensorimotor coordination’ or ‘active perception’ to inform behaviour, but active perception has not before been investigated at a cellular level within organs. Here we provide the first proof of concept in silico/in vivo study demonstrating that filopodia (actin-rich, dynamic, finger like cell-membrane protrusions) play an...
The association of cytosolic phospholipase A(2)-alpha (cPLA(2)alpha) with intracellular membranes is central to the generation free arachidonic acid and thromboxane A(2) in activated platelets. Despite this, site nature this membrane has not been fully characterised upon platelet activation. High resolution imaging showed that cPLA(2)alpha was distributed a partly structured manner throughout resting platelet. Upon glass activation or thrombin stimulation, relocated peripheral region...