scholarly journals Thymidine phosphorylase, 2-deoxy-D-ribose and angiogenesis

1998 ◽  
Vol 334 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Nicholas S. BROWN ◽  
Roy BICKNELL
Keyword(s):  
Endothelial Cell ◽  
Cell Surface ◽  
Thymidine Phosphorylase ◽  
Endothelial Cell Migration ◽  
Cell Surface Receptor ◽  
Migratory Activity ◽  
Surface Receptors ◽  
Endothelial Cell Surface ◽  
Mechanistic Pathway

Angiogenesis is the term used to describe the formation of new blood vessels from the existing vasculature. In order to attract new vessels, a tissue must release an endothelial-cell chemoattractant. 2-Deoxy-d-ribose is produced in vivo by the catalytic action of thymidine phosphorylase (TP) on thymidine and has recently been identified as an endothelial-cell chemoattractant and angiogenesis-inducing factor. TP, previously known only for its role in nucleotide salvage, is now known to be angiogenic. TP expression is elevated in many solid tumours and in chronically inflamed tissues, both known areas of active angiogenesis. There is evidence that TP is also involved in physiological angiogenesis such as endometrial angiogenesis during the menstrual cycle. The majority of known endothelial-cell chemoattractants are polypeptides that bind to endothelial-cell-surface receptors. In contrast, 2-deoxy-d-ribose appears to lack a cell-surface receptor. Glucose is another sugar that acts as an endothelial-cell chemoattractant. The migratory activity of glucose is blocked by ouabain. It is possible that 2-deoxy-d-ribose and glucose stimulate endothelial-cell migration via a similar mechanistic pathway.

scholarly journals Surface charge distribution on the endothelial cell of liver sinusoids.

1984 ◽  
Vol 99 (2) ◽  
pp. 639-647 ◽  
Author(s):  
L Ghitescu ◽  
A Fixman
Keyword(s):  
Endothelial Cell ◽  
Cell Surface ◽  
Liver Sinusoid ◽  
Electron Microscopic ◽  
Coated Pits ◽  
Endothelial Cell Surface ◽  
Liver Sinusoids ◽  
Surface Charge Distribution ◽  
Cationic Residues

The topography of the charged residues on the endothelial cell surface of liver sinusoid capillaries was investigated by using electron microscopic tracers of different size and charge. The tracers used were native ferritin (pl 4.2-4.7) and its cationized (pl 8.4) and anionized (pl 3.7) derivatives, BSA coupled to colloidal gold (pl of the complex 5.1), hemeundecapeptide (pl 4.85), and alcian blue (pl greater than 10). The tracers were either injected in vivo or perfused in situ through the portal vein of the mouse liver. In some experiments, two tracers of opposite charge were sequentially perfused with extensive washing in between. The liver was processed for electron microscopy and the binding pattern of the injected markers was recorded. The electrostatic nature of the tracer binding was assessed by perfusion with high ionic strength solutions, by aldehyde quenching of the plasma membrane basic residues, and by substituting the cell surface acidic moieties with positively charged groups. Results indicate that the endothelial cells of the liver sinusoids expose on their surface both cationic and anionic residues. The density distribution of these charged groups on the cell surface is different. While the negative charge is randomly and patchily scattered all over the membrane, the cationic residues seem to be accumulated in coated pits. The charged groups co-exist in the same coated pit and bind the opposite charged macromolecule. It appears that the fixed positive and negative charges of the coated pit glycocalyx are mainly segregated in space. The layer of basic residues is located at 20-30-nm distance of the membrane, while most of the negative charges lie close to the external leaflet of the plasmalemma.

scholarly journals Leukocyte adhesion is governed by endolysosomal two pore channel 2 (TPC2)

2021 ◽  
Author(s):  
Jonas Goretzko ◽  
Nicole Heitzig ◽  
Katharina Thomas ◽  
Einar Kleinhans Krogsaeter ◽  
Johannes Nass ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Surface ◽  
Leukocyte Adhesion ◽  
Leukocyte Recruitment ◽  
Pore Channel ◽  
Initial Contact ◽  
Surface Receptors ◽  
Endothelial Cell Surface ◽  
Late Endosomes ◽  
Endothelial Functions

In response to pro-inflammatory challenges including pathogenic attack and tissue damage, the endothelial cell surface is rearranged to present leukocyte-engaging cell surface receptors. The initial contact needed for leukocyte tethering and rolling is mediated via adhesion demand-driven exocytosis of Weibel-Palade bodies (WPB) that contain the leukocyte receptor P-selectin together with the stabilizing co-factor CD63. We found that diminished expression of the endolysosomal non-selective cation channel TPC2 or inhibition of TPC2-mediated Ca2+-release via trans-Ned 19 led to reduced endolysosomal Ca2+ efflux, and blocked transfer of CD63 from late endosomes/lysosomes (LEL) to WPB, and a concomitant loss of P-selectin on the endothelial cell surface. Accordingly, P-selectin-mediated leukocyte recruitment to trans-Ned 19-treated HUVEC under flow was significantly reduced without disturbing VWF exocytosis. Our findings establish the endolysosome-related TPC2 Ca2+ channel as a key element in the maintenance of proper endothelial functions and a potential pharmacological target in the control of inflammatory leukocyte recruitment.

scholarly journals Heterogeneity in VEGF Receptor-2 mobility and organization on the endothelial cell surface leads to diverse activation models by VEGF

2019 ◽  
Author(s):  
Bruno da Rocha-Azevedo ◽  
Sungsoo Lee ◽  
Aparajita Dasgupta ◽  
Anthony R. Vega ◽  
Luciana R. de Oliveira ◽  
...  
Keyword(s):  
Cell Surface ◽  
Single Molecule ◽  
Receptor Activation ◽  
Cell Surface Receptor ◽  
Vegf Receptor ◽  
Surface Receptors ◽  
Endothelial Cell Surface ◽  
Heterogeneous Nature ◽  
Surface Receptor ◽  
Complex Relationships

SummaryThe nanoscale organization of cell surface receptors plays an important role in signaling. We determined this organization and its relation to receptor activation for VEGF Receptor-2 (VEGFR-2), a critical receptor tyrosine kinase in endothelial cells (ECs), by combining live-cell single-molecule imaging of endogenous VEGFR-2 with rigorous computational analysis. We found that surface VEGFR-2 can be mobile or immobile/confined, and monomeric or non-monomeric, with a complex interplay between the two. The mobility and interaction heterogeneity of VEGFR-2 in the basal state led to heterogeneity in the sequence of steps leading to VEGFR-2 activation by VEGF. Specifically, we found that VEGF can bind to both monomeric and non-monomeric VEGFR-2, and, when binding to monomeric VEGFR-2, promotes dimer formation but only for immobile/confined receptors. Overall, our study highlights the dynamic and heterogeneous nature of cell surface receptor organization and its complex relationships with receptor activation and signaling.

scholarly journals The Arabidopsis receptor kinase STRUBBELIG undergoes clathrin-dependent endocytosis

2019 ◽  
Vol 70 (15) ◽  
pp. 3881-3894 ◽  
Author(s):  
Jin Gao ◽  
Ajeet Chaudhary ◽  
Prasad Vaddepalli ◽  
Marie-Kristin Nagel ◽  
Erika Isono ◽  
...  
Keyword(s):  
Cell Surface ◽  
Fluorescent Protein ◽  
Growth Patterns ◽  
Cell Surface Receptor ◽  
Receptor Kinase ◽  
Surface Receptors ◽  
Surface Receptor ◽  
Green Fluorescent ◽  
Golgi Network

AbstractSignaling mediated by cell surface receptor kinases is central to the coordination of growth patterns during organogenesis. Receptor kinase signaling is in part controlled through endocytosis and subcellular distribution of the respective receptor kinase. For the majority of plant cell surface receptors, the underlying trafficking mechanisms are not characterized. In Arabidopsis, tissue morphogenesis requires the atypical receptor kinase STRUBBELIG (SUB). Here, we studied the endocytic mechanism of SUB. Our data revealed that a functional SUB–enhanced green fluorescent protein (EGFP) fusion is ubiquitinated in vivo. We further showed that plasma membrane-bound SUB:EGFP becomes internalized in a clathrin-dependent fashion. We also found that SUB:EGFP associates with the trans-Golgi network and accumulates in multivesicular bodies and the vacuole. Co-immunoprecipitation experiments revealed that SUB:EGFP and clathrin are present within the same protein complex. Our genetic analysis showed that SUB and CLATHRIN HEAVY CHAIN (CHC) 2 regulate root hair patterning. By contrast, genetic reduction of CHC activity ameliorates the floral defects of sub mutants. Taken together, the data indicate that SUB undergoes clathrin-mediated endocytosis, that this process does not rely on stimulation of SUB signaling by an exogenous agent, and that SUB genetically interacts with clathrin-dependent pathways in a tissue-specific manner.

scholarly journals Tissue morphogenesis mediated by the Arabidopsis receptor kinase STRUBBELIG involves a clathrin-dependent process

2018 ◽  
Author(s):  
Jin Gao ◽  
Ajeet Chaudhary ◽  
Prasad Vaddepalli ◽  
Marie-Kristin Nagel ◽  
Erika Isono ◽  
...  
Keyword(s):  
Cell Surface ◽  
Growth Patterns ◽  
Negative Regulator ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
Receptor Kinase ◽  
Tissue Morphogenesis ◽  
Surface Receptors ◽  
Dependent Process

AbstractHighlightThe Arabidopsis receptor kinase STRUBBELIG is internalized by clathrin-mediated endocytosis and affects clathrin-dependent processes in a tissue-dependent manner.AbstractSignaling mediated by cell surface receptor kinases is central to the coordination of growth patterns during organogenesis. Receptor kinase signaling is in part controlled through endocytosis and subcellular distribution of the respective receptor kinase. For the majority of plant cell surface receptors the underlying trafficking mechanisms are not characterized. In Arabidopsis, tissue morphogenesis relies on the atypical receptor kinase STRUBBELIG (SUB). Here, we approach the endocytic mechanism of SUB. Our data reveal that a functional SUB:EGFP fusion is ubiquitinated in vivo. We further show that plasma membrane-bound SUB:EGFP becomes internalized in a clathrin-dependent fashion. We also find that SUB:EGFP associates with the trans-Golgi network and accumulates in multivesicular bodies and the vacuole. Coimmunoprecipitation experiments reveal that SUB:EGFP and clathrin are present within the same protein complex. Our genetic analysis shows that SUB and CLATHRIN HEAVY CHAIN 2 promote root hair patterning. By contrast, SUB behaves as a negative regulator of a clathrin-dependent process during floral development. Taken together, the data indicate that SUB undergoes clathrin-mediated endocytosis, that this process does not dependent on stimulation of SUB signaling by an exogenous agent, and that SUB genetically interacts with clathrin-dependent pathways in a tissue-specific manner.

Binding of heparin to plasma proteins and endothelial surfaces is inhibited by covalent linkage to antithrombin

2004 ◽  
Vol 91 (05) ◽  
pp. 1009-1018 ◽  
Author(s):  
Nethnapha Paredes ◽  
Bruce Thong ◽  
Paul Chindemi ◽  
Bosco Paes ◽  
Leslie Berry ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Surface ◽  
Half Life ◽  
Plasma Proteins ◽  
Anticoagulant Activity ◽  
Surface Proteins ◽  
Coagulation Cascade ◽  
Covalent Linkage ◽  
Endothelial Cell Surface

SummaryUnfractionated heparin (UFH) and low molecular weight heparin (LMWH) are used for prophylaxis and treatment of thrombosis. However, UFH has a short plasma half-life and variable anticoagulant response in vivo due to plasma or vessel wall protein binding and LMWH has a decreased ability to inactivate thrombin, the pivotal enzyme in the coagulation cascade. Covalent linkage of antithrombin to heparin gave a complex (ATH) with superior anticoagulant activity compared to UFH and LMWH, and longer intravenous half-life compared to UFH. We found that plasma proteins bound more to UFH than ATH, and least to LMWH. Also, UFH bound significantly more to endothelial cells than ATH, with 100% of UFH and 94% of ATH binding being on the cell surface and the remainder was endocytosed. Competition studies with UFH confirmed that ATH binding was likely through its heparin moiety. These findings suggest that differences in plasma protein and endothelial cell binding may be due to available heparin chain length. Although ATH is polydisperse, the covalently-linked antithrombin may shield a portion of the heparin chain from association with plasma or endothelial cell surface proteins. This model is consistent with ATH’s better bioavailability and more predictable dose response.

scholarly journals Activation Mechanism of Anticoagulant Protein C in Large Blood Vessels Involving the Endothelial Cell Protein C Receptor

1998 ◽  
Vol 187 (7) ◽  
pp. 1029-1035 ◽  
Author(s):  
Kenji Fukudome ◽  
Xiaofen Ye ◽  
Naoko Tsuneyoshi ◽  
Osamu Tokunaga ◽  
Keishin Sugawara ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Surface ◽  
Blood Coagulation ◽  
Protein C ◽  
Cell Surface Receptor ◽  
Activation Mechanism ◽  
Cell Protein ◽  
Endothelial Cell Surface ◽  
Surface Receptor ◽  
Large Vessels

Protein C is an important regulatory mechanism of blood coagulation. Protein C functions as an anticoagulant when converted to the active serine protease form on the endothelial cell surface. Thrombomodulin (TM), an endothelial cell surface receptor specific for thrombin, has been identified as an essential component for protein C activation. Although protein C can be activated directly by the thrombin–TM complex, the conversion is known as a relatively low-affinity reaction. Therefore, protein C activation has been believed to occur only in microcirculation. On the other hand, we have identified and cloned a novel endothelial cell surface receptor (EPCR) that is capable of high-affinity binding of protein C and activated protein C. In this study, we demonstrate the constitutive, endothelial cell–specific expression of EPCR in vivo. Abundant expression was particularly detected in the aorta and large arteries. In vitro cultured, arterial endothelial cells were also found to express abundant EPCR and were capable of promoting significant levels of protein C activation. EPCR was found to greatly accelerate protein C activation by examining functional activity in transfected cell lines expressing EPCR and/or TM. EPCR decreased the dissociation constant and increased the maximum velocity for protein C activation mediated by the thrombin–TM complex. By these mechanisms, EPCR appears to enable significant levels of protein C activation in large vessels. These results suggest that the protein C anticoagulation pathway is important for the regulation of blood coagulation not only in microvessels but also in large vessels.

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