Novel Proangiogenic Effect of Factor XIII Associated With Suppression of Thrombospondin 1 Expression

Dardik, Rima; Solomon, Arieh S.; Loscalzo, Joseph; Eskaraev, Regina; Bialik, Ann; Goldberg, Iris; Schiby, Ginette; Inbal, Aida

doi:10.1161/01.atv.0000081636.25235.c6

Cited by 86 publications

(103 citation statements)

References 27 publications

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“…It is known that HMVECs and rat MVECs synthesize TSP1 (Fischer et al, 2001;Dardik et al, 2003), whereas mouse MVECs synthesize little if any TSP2 (Armstrong et al, 2002). It is possible that endogenous synthesis of TSP1 confers some resistance to the effects of added exogenous protein, although one would expect a comparable resistance to TSP2 if, as we believe, the intracellular pathways leading to inhibition of cell cycle progression are the same for the two proteins.…”

Section: The Inhibition Of Ec Proliferation Is Mediated By Vldlrmentioning

confidence: 77%

Thrombospondins Use the VLDL Receptor and a Nonapoptotic Pathway to Inhibit Cell Division in Microvascular Endothelial Cells

Oganesian¹,

Armstrong

Migliorini

et al. 2008

MBoC

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TSPs 1 and 2 function as endogenous inhibitors of angiogenesis. Although thrombospondins (TSPs) have been shown to induce apoptosis in HMVECs, we reasoned that a homeostatic mechanism would also be needed to inhibit EC growth without causing cell death, e.g., in the maintenance of a normal vascular endothelium. HMVECs, cultured in low serum, responded to VEGF with an increase in [ 3 H]thymidine incorporation that was inhibited by TSPs and was accompanied by decreases in the phosphorylation of Akt and MAPK, without an increase in apoptosis. RAP, an inhibitor of the low-density lipoprotein (LDL) family of endocytic receptors, and blocking antibodies to VLDLR were as effective as TSPs in the inhibition of thymidine uptake in response to VEGF, and the effects of these agents were not additive. Supportive evidence for the role of the VLDLR in mediating this inhibition was provided by the demonstration of a high-affinity interaction between TSPs and the VLDLR. We propose that TSP1 and TSP2, together with the VLDLR, initiate a nonapoptotic pathway for maintenance of the normal adult vascular endothelium in a quiescent state, similar to that invoked for the regulation of mitogenesis by PDGF, but involving signaling via the VLDLR rather than LRP1. INTRODUCTIONAlthough thrombospondins (TSPs) 1 and 2 perform multiple functions during mammalian development and in response to injury (Murphy-Ullrich and Poczatek, 2000;Bornstein, 2001;Kyriakides and Bornstein, 2003;Adams and Lawler, 2004), these proteins are best known for their ability to inhibit angiogenesis (Adams, 2001;Lawler, 2002;Armstrong and Bornstein, 2003). Of particular interest is the capability of TSPs to inhibit tumor growth and metastatic spread (Lawler and Detmar, 2004) and consequently the potential of these proteins to serve as a basis for the development of therapeutic antiangiogenic agents (Zhang and Lawler, 2007).In view of these properties, it is to be expected that substantial efforts have been made to understand the mechanisms by which the growth of blood vessels can be inhibited by TSPs. The antiangiogenic activity of TSPs was first recognized by Bouck and coworkers, who identified the product of a tumor suppressor gene in hamster cells as a 140-kDa fragment of TSP1 (Rastinejad et al., 1989;Good et al., 1990). Subsequently, an analysis of the phenotype of the TSP2-null mouse and studies of wound healing and the foreign body reaction in these mice confirmed that TSP2 also possessed potent antiangiogenic properties (Kyriakides et al., 1998a;Kyriakides and Bornstein, 2003).The mechanisms by which TSPs inhibit angiogenesis are complex and comprise both indirect and direct effects on endothelial cells (ECs; Zhang and Lawler, 2007). Indirect effects include direct binding and clearance of a number of growth factors, including vascular endothelial growth factor (VEGF)-A (Greenaway et al., 2007), as well as inhibition of mobilization of growth factors from matrix stores, and clearance of TSP/metalloproteinase complexes from the pericellular environment by the ...

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Section: The Inhibition Of Ec Proliferation Is Mediated By Vldlrmentioning

confidence: 77%

Thrombospondins Use the VLDL Receptor and a Nonapoptotic Pathway to Inhibit Cell Division in Microvascular Endothelial Cells

Oganesian¹,

Armstrong

Migliorini

et al. 2008

MBoC

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“…Thymosin beta 4 has roles in promoting angiogenesis by supporting endothelial cell attachment, spreading and migration (158). Furthermore, FXIIIa downregulates thrombospondin-1, an inhibitor of angiogenesis (159). As predicted from these biological effects, factor XIIIa has been shown to have a direct proangiogenic effect in vitro (reviewed in reference 160) and in vivo (160)(161)(162).…”

Section: Transglutaminase Activity and Angiogenesismentioning

confidence: 99%

Roles of transglutaminases in cardiac and vascular diseases

Sane

Kontos²,

Greenberg³

2007

Front Biosci

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All transglutaminases share the common enzymatic activity of transamidation, or the cross-linking of glutamine and lysine residues to form N epsilon (gamma-glutamyl) lysyl isopeptide bonds. The plasma proenzyme factor XIII is responsible for stabilizing the fibrin clot against physical and fibrinolytic disruption. Another member of the transglutaminase family, tissue transglutaminase or TG2 is abundantly expressed in cardiomyocytes, vascular cells and macrophages. The transglutaminases have a variety of functions independent of their transamidating activity. For example, TG2 binds and hydrolyzes GTP, thereby fostering signal transduction by several G protein coupled receptors. Accumulating evidence points to novel roles for factor XIII and TG2 in cardiovascular biology including: (a) modulating platelet activity, (b) regulating glucose control, (c) contributing to the development of hypertension, (d) influencing the progression of atherosclerosis, (e) regulating vascular permeability and angiogenesis (f) and contributing to myocardial signaling, contractile activity and ischemia/reperfusion injury. In this review, we summarize the cardiovascular biology of two members of the family of transglutaminases, Factor XIII and TG2.

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“…37 In addition, the protective effect might reflect alternate activities of FXIII, such as the promotion of angiogenesis. 38 …”

Section: Factor XIIImentioning

confidence: 99%

Genetic Determinants of Arterial Thrombosis

Voetsch

Loscalzo

2004

ATVB

Self Cite

158

112

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Abstract-Arterial thrombosis is a complex disorder that involves multiple genetic and environmental factors interacting to produce the characteristic phenotype. In the past decades, investigators have focused on the molecular genetics of arterial vascular disorders and have identified numerous polymorphisms and mutations in genes related to the hemostatic system and to enzymes involved in the synthesis and bioavailability of nitric oxide (NO); however, the relation between most polymorphisms and the risk of coronary artery disease, ischemic stroke, and peripheral vascular disease remains highly controversial. In this review, we describe the most common genetic variations involved in the pathogenesis of arterial thrombosis, their functional implications, and their association with disease risk. Specifically, we consider polymorphisms in coagulation factors (fibrinogen, prothrombin, FV Leiden, FVII, and FXIII); fibrinolytic factors (tissue-type plasminogen activator, plasminogen activator inhibitor-1, and thrombin-activatable fibrinolysis inhibitor); platelet surface receptors; methylenetetrahydrofolate reductase; endothelial NO synthase; and the antioxidant enzymes paraoxonase and plasma glutathione peroxidase. Overall, there seems to be a modest contribution of individual genetic variants in the hemostatic and antioxidant systems to the risk of arterial thrombosis. Thus, future research ought to focus on identifying novel genetic determinants and on the interaction of these genetic risk factors with each other and the environment to understand better the pathobiology and susceptibility to arterial thrombotic disease.

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Novel Proangiogenic Effect of Factor XIII Associated With Suppression of Thrombospondin 1 Expression

Cited by 86 publications

References 27 publications

Thrombospondins Use the VLDL Receptor and a Nonapoptotic Pathway to Inhibit Cell Division in Microvascular Endothelial Cells

Thrombospondins Use the VLDL Receptor and a Nonapoptotic Pathway to Inhibit Cell Division in Microvascular Endothelial Cells

Roles of transglutaminases in cardiac and vascular diseases

Genetic Determinants of Arterial Thrombosis

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