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PubMed1997

Constitutive and regulated expression of vitronectin.

Tissue homeostasis depends on spatially and temporally controlled expression of multifunctional adhesive glycoproteins and their cellular counter receptors, and on a tight regulation of proteolytic enzyme systems. The adhesive glycoprotein vitronectin (Vn) not only regulates adhesive events, but also controls a number of these proteolytic enzyme cascades, including the complement, coagulation, and fibrinolytic systems. However, understanding of the biological functions of this molecule is complicated due to it's conformationally lability and its tendency to self-associate. While plasma Vn is monomeric and lacks exposure of conformationally sensitive epitopes, platelet and tissue-associated Vn are believed to be conformationally altered and multimeric. The latter forms express a functional repertoire distinct from plasma Vn. While little Vn immunoreactivity is detectable in most normal tissues, increased depositions of Vn have been observed in areas of tissue injury and necrosis. Tissue Vn was believed to be plasma-derived, but recent studies indicate that extrahepatic cells have the biosynthetic potential to produce Vn and that its synthesis can be regulated under inflammatory conditions. Here, the constitutive and regulated expression of Vn, its locations in tissues and interaction with other matrix molecules are reviewed and their implications for the functions of this molecule are discussed.

Animals↗
PubMed1998

Vitronectin concentrates proteolytic activity on the cell surface and extracellular matrix by trapping soluble urokinase receptor-urokinase complexes.

Urokinase-type-plasminogen activator (uPA) and its receptor are localized in the vessel wall where they are involved in cellular activation and remodelling processes. Besides the cell surface glycolipid (GPI)-anchored urokinase receptor (uPAR), which binds uPA with high affinity, recent evidence points to the existence of soluble uPAR (suPAR), as well. In the present study, the origin, binding mechanism, and cellular effects of suPAR were examined. Under basal conditions human vascular smooth muscle cells (HVSMC), human umbilical vein endothelial cells (HUVEC), and monocytic cells released 0.1 to 2 ng/mL suPAR, which was increased twofold to fivefold after phorbol ester (PMA) stimulation, as measured by a function-dependent enzyme-linked immunosorbent assay (ELISA). suPAR alone did not bind to HVSMC or HUVEC, but reduced cellular uPA binding by 50% to 70%. However, after removal of GPI-uPAR with phosphatidylinositol-specific phospholipase C, suPAR dose-dependently increased uPA binding by fourfold to fivefold. This increase in binding was completely inhibited by vitronectin (VN) and by a monoclonal antibody against VN, but not by other matrix proteins or antibodies. Thus, VN-mediated uPA binding to cells was regulated by the ratio of soluble to surface-associated uPAR. In a uPAR-deficient cell line (LM-TK-), suPAR increased uPA binding up to 10-fold, whereas the truncated receptor lacking the amino-terminal uPA-binding domain was ineffective. The formation of a ternary uPA/suPAR/VN-complex on the cell surface and the free extracellular matrix could be inhibited by a monoclonal antibody against VN, as well as by plasminogen activator inhibitor-1 (PAI-1). Moreover, VN-mediated binding of the uPA/suPAR-complex led to a fivefold increase in plasminogen activator activity. Through this novel pathway, VN concentrates the uPA/suPAR-complex to cell surfaces and extracellular matrix sites, leading to the accumulation of plasminogen activator activity required for cell migration and tissue remodelling processes.

Cells, Cultured↗
PubMed2002

Engaged urokinase receptors enhance tumor breast cell migration and invasion by upregulating alpha(v)beta5 vitronectin receptor cell surface expression.

We have previously shown that urokinase receptor physically and functionally interacts with alpha(v)beta5 vitronectin receptor, leading to tumor breast cell migration and invasion. Here, the link between these 2 receptors was further investigated by analyzing the expression levels of urokinase receptor and alpha(v)beta5 integrin in 35 human breast carcinomas and 5 benign breast lesions. The occurrence of a positive correlation between urokinase receptor and alpha(v)beta5 protein levels in benign and malignant tumor specimens prompted us to investigate whether engaged urokinase receptors might modulate alpha(v)beta5 expression. Here, we report the receptor-dependent ability of catalytically inactive urokinase to upregulate the alpha(v) and beta5 chains in MDA-MB-231 and MCF-7 breast carcinoma cell lines in a time- and concentration-dependent manner. This effect is dependent on protein kinase C activity and requires new protein synthesis. Accordingly, the availability of assembled alpha(v)beta5 receptors on the cell surface increases upon urokinase treatment, as shown by immunoprecipitation and immunocytochemical analyses. Exposure to urokinase leads to enhanced tumor cell migration and invasion, which is prevented by the "phosphorylation-like" urokinase receptor antagonist His-uPA(138E/303E), the DNA-binding drug mithramycin, the protein kinase C inhibitor calphostin C and anti-alpha(v)beta5 antibodies. Finally, urokinase enables benign breast MCF-10A cells to cross Matrigel in a alpha(v)beta5- and urokinase receptor-dependent manner, indicating that urokinase controls a regulatory circuitry crucial to breast tumor progression.

Adult↗
PubMed2003

Quilty lesions are associated with increased expression of vitronectin receptor (alphavbeta3) and subsequent development of coronary vasculopathy.

BACKGROUND: Quilty lesions are common after heart transplantation; however, their relationship to vasculopathy has not been described. We tested the hypothesis that Quilty lesions are associated with increased expression of vitronectin receptor (alphavbeta3) and the subsequent development of coronary vasculopathy. METHODS: A total of 140 heart transplant recipients underwent coronary intravascular ultrasound at baseline and at 1 year after transplantation, and we measured the change in coronary maximal intimal thickness. Endomyocardial biopsy specimens taken within 8 weeks after transplantation showed Quilty lesions in 54 of 140 (39%) patients (Quilty group). We compared these results with the remaining 86 of 140 patients (61%) who had no evidence of Quilty lesions during the same period (control group). We evaluated 10 endomyocardial biopsy specimens from each group for alphavbeta3, using immunohistochemistry staining and immunoblotting. RESULTS: Quilty lesions stained positive for alphavbeta3, and Western blot analysis showed a 1.3-fold (p = 0.004) increase in expression of alphavbeta3. Compared with control, the Quilty group tended to have a greater incidence of post-transplant ischemic injury complicated by fibrosis (54% vs 38%, p = 0.08) and a greater reported incidence of "previous biopsy site" during the first 4 weeks after transplantation (48% vs 32%, p = 0.06). At 1 year, the Quilty group had a significant increase in the change in coronary maximal intimal thickness seen with intravascular ultrasound (0.54 +/- 0.34 vs 0.42 +/- 0.28 mm, p = 0.038). CONCLUSIONS: This is the first report to describe the association of Quilty lesions with coronary vasculopathy and its association with increased alphavbeta3 expression.

Adult↗
PubMedDate not supplied

Anaerobic 90Y- and 177Lu-labeling of a DOTA-conjugated nonpeptide vitronectin receptor antagonist.

This study describes the discovery and development of an anaerobic formulation for the routine preparation of (90)Y and (177)Lu complexes ((90)Y-TA138 and (177)Lu-TA138) of a DOTA-conjugated nonpeptide vitronectin receptor antagonist (TA138: 3-sulfon-N-[[4,7,10-tris(carboxymethyl)1,4,7,10-tetraazacyclododec-1-yl]acetyl]-l-alanyl-N-[2-[4-[[[(1S)-1-carboxy-2[[[1,4-dihydro-7-[(1H-imidazol-2-ylamino]meth-yl]-1-methyl-4-oxo-3-quinolinyl]carbonyl]amino]ethyl]amino]-sulfonyl]-3,5-dimethylphenoxy]-1-oxobutyl]amino]ethyl]-3-sulfo-l-alaninamide). Since (90)Y-TA138 and (177)Lu-TA138 are very sensitive to radiolytic degradation, exclusion of oxygen is necessary during the radiolabeling. Using the anaerobic formulation, (90)Y-TA138 and (177)Lu-TA138 can be prepared in high yield and high specific activity. The anaerobic formulation described in this study is particularly useful for (90)Y- and (177)Lu-labeling of DOTA-conjugated small biomolecules, which are sensitive to the radiolytic degradation during radiolabeling.

Biotin↗
PubMed1999

Human endothelial cell attachment to and growth on polypyrrole-heparin is vitronectin dependent.

Composite materials comprised of the electrically conducting polymer, polypyrrole, with a variety of biologically active molecules, e.g. proteins or polysaccharides, are emerging as a novel class of "smart" biomaterials. In the present work we have studied the utility of a heparin-polypyrrole composite as a substrate for human umbilical vein endothelial cell (HUVEC) growth. We found that the polymer composites were well suited to support cell attachment and growth; displaying low surface hydrophobicity (water contact angle of approximately 20 degrees ) and roughness, Rq of approximately 10-12 nm. Doubling times for HUVEC on heparin-polypyrrole were greater than observed for gelatin-coated tissue culture polystyrene (44 and 36 h, respectively), however, the cells did proliferate to cover the polymer in an even monolayer. The initial mechanism of attachment and subsequent proliferation of HUVEC on heparin-polypyrrole was critically dependent on the presence of the serum adhesion glycoprotein vitronectin. Polymers that were composed of polypyrrole and sodium nitrate were more hydrophobic than heparin-polypyrrole and they did not support HUVEC growth. Given the relative ease with which these polymer composites can be electrochemically synthesized, the diverse range of cellular "signal agents", e.g. growth factors, that can be incorporated within them, and the high degree of control that can be achieved in the release-surface exposure of these agents, we suggest that polypyrrole composites could serve a useful role as "smart" biomaterials in the near future.

Journal Article↗
PubMedDate not supplied

Binding of vitronectin and clusterin by coagulase-negative staphylococci interfering with complement function.

Coagulase-negative staphylococci (CoNS) are commonly associated with infections of prosthetic devices mediated by adsorbed host factors on biomaterial surfaces. Complement activation is known to occur and induce unspecific inflammation around the biomaterials. Human vitronectin (Vn) and clusterin (Clu), two potent inhibitors of complement, can be bound by CoNS. With a hypothesis whether binding of Vn or Clu influences complement activation, two measurements were determined. For Vn, complement activation was measured with a mouse anti-activated human C9 antibody. In the presence of Vn-binding strain, Staphylococcus hemolyticus SM13I, complement activation on a surface pre-coated with Vn occurred as it did in the absence of Vn pre-coating. For S. epidermidis 3380, which does not express binding of Vn, complement activation on a Vn-presented surface was significantly decreased. For Clu, erythrocytes lysis was measured to reflect the end product of complement activation (membrane attack complex). The complement-induced hemolysis increased when human serum was pre-incubated with Clu-binding strains, S. epidermidis J9P. The enhancement of hemolysis by J9P decreased when serum was supplemented by exogenous Clu. The data imply that interaction between CoNS and Vn or Clu interferes with one of their physiological functions, complement inhibition.

Journal Article↗
PubMed2003

Recruitment of nectin-3 to cell-cell junctions through trans-heterophilic interaction with CD155, a vitronectin and poliovirus receptor that localizes to alpha(v)beta3 integrin-containing membrane microdomains.

Nectins present a novel class of Ig superfamily adhesion molecules that, cooperatively with cadherins, establish and maintain cell-cell adherens junctions. CD155, the cognate receptor for poliovirus, undergoes cell-matrix contacts by binding to the extracellular matrix protein vitronectin. The significant homology of nectins with CD155 prompted us to investigate the possibility of their interaction. We determined that nectin-3 binds CD155 and its putative mouse homologue Tage4 in cell-based ligand binding assays. Coculture of nectin-3- and CD155-expressing HeLa cells led to CD155-dependent recruitment of nectin-3 to cell-cell contacts. In a heterologous coculture system with CD155 expressing mouse neuroblastoma cells, HeLa cell-expressed nectin-3 was recruited to contact sites with CD155 bearing neurites. CD155 and nectin-3 colocalized to epithelial cell-cell junctions in renal proximal tubules and in the amniotic membrane. Efficient interaction depended on CD155 dimerization, which appears to be aided by cell type-specific cofactors. We furthermore found CD155 to codistribute with alpha(v) integrin microdomains on the surface of transfected mouse fibroblasts and at amniotic epithelial cell junctions. Our findings demonstrate the possible trans-interaction between the bona fide cell-cell adherens type adhesion system (cadherin/nectin) and the cell-matrix adhesion system (integrin/CD155) by virtue of their nectin-3 and CD155 components, respectively.

Amnion↗
PubMed2004

Apparent absolute oral bioavailability in excess of 100% for a vitronectin receptor antagonist (SB-265123) in rat. I. Investigation of potential experimental and mechanistic explanations.

1. SB-265123 is a novel alphavbeta3 (the vitronectin receptor) antagonist. Previous rat studies with it revealed an apparent absolute oral bioavailability (Fapp) of greater than 100%. The present studies were conducted to investigate the potential causes for this observation. 2. Of 49 SB-265123 analogues evaluated in rat using an identical experimental design, Fapp > 100% was observed for 22 of them, suggesting that the observed Fapp >100% with SB-265123 was not anomalous. All 22 compounds had clearances < 15 ml min(-1) kg(-1). However, Fapp>100% were not recorded for all low-clearance analogues. 3. Using SB-265123 as a model to investigate potential artefacts, it was demonstrated that using a chiral assay did not decrease Fapp. Additionally, qualitative sample analysis demonstrated that no metabolites were present in the plasma that could interfere with the liquid chromatography coupled with tandem mass spectrometry detection assay. The high Fapp was also dose-order-, delivery system- and vehicle-independent, and was not affected by the feeding status of the animals. Furthermore, a linearity experiment and an absorption study indicated that oral administration of SB-265123 does not result in hepatic portal vein concentrations that exceed the pharmacokinetic linearity of SB-265123. 4. These observations suggest that the observed Fapp > 100% for SB-265123 is not due to an experimental artefact or an obvious pharmacokinetic non-linearity. The mechanism(s) for this phenomenon is explored further in the second part of the present paper.

Acetates↗
PubMed2006

Interaction of macrophages with apoptotic cells enhances HIV Type 1 replication through PGE2, PAF, and vitronectin receptor.

Phagocytosis of apoptotic cells by macrophages increases secretion of soluble mediators and generates an antiinflammatory environment. We previously reported that phagocytosis of apoptotic cells by HIV-1-infected macrophages enhances viral replication, with the participation of the cytokine transforming growth factor- beta1 and an integrin receptor. Now, we describe the role of prostaglandin E2 (PGE2), platelet-activating factor (PAF), and the integrin alphaVbeta3 (vitronectin receptor, VnR) in this phenomenon. Exacerbation of HIV-1 growth induced by phagocytosis of apoptotic cells was inhibited when HIV-1-infected macrophages were treated with a cyclooxygenase 2 inhibitor, or with a PAF receptor antagonist (BN 52021) immediately after macrophage interaction with apoptotic cells. Treatment of HIV-1-infected macrophages with BN 52021 decreased viral replication, whereas addition of PGE2 or PAF to these cells enhanced viral replication. Monoclonal antibodies (MAbs) to VnR reduced the macrophage uptake of apoptotic cells, prevented the enhancement of HIV-1 growth upon the engulfment of apoptotic cells, and potently augmented viral replication in HIV-1-infected macrophages in the absence of apoptotic cells. In conclusion, PGE2 and PAF, and ligation of VnR as well, contribute to amplify viral growth in HIV-1-infected macrophages upon uptake of apoptotic cells.

Apoptosis↗
PubMed1988

Modulation of heparin cofactor II function by S protein (vitronectin) and formation of a ternary S protein-thrombin-heparin cofactor II complex.

The complement inhibitor S protein, which is identical to the adhesive protein vitronectin, functions as heparin-neutralizing factor by protecting thrombin as well as factor Xa against fast inactivation by antithrombin III. The interference of S protein with glycosaminoglycan-catalyzed inhibition of thrombin by heparin cofactor II was investigated in these studies. S protein significantly counteracted the anticoagulant activity of heparin and pentosan polysulfate but not of dermatan sulfate. In the presence of 0.3 micrograms/ml heparin, 0.5 micrograms/ml pentosan polysulfate, or 2 micrograms/ml dermatan sulfate, S protein induced a concentration-dependent reduction of the inhibition rate of thrombin by heparin cofactor II. This resulted in a decrease of the apparent pseudo first-order rate constants by about 17-fold (heparin), or about 7-fold (pentosan polysulfate), whereas no neutralization of dermatan sulfate was demonstrable at a physiological ratio of S protein to heparin cofactor II. Exposure of the glycosaminoglycan-binding region of S protein by reduction and carboxymethylation of the protein increased the neutralizing activity of S protein towards heparin and pentosan polysulfate. The results of these functional experiments correlated well with the demonstration of direct binding of S protein to both polysaccharides but not to dermatan sulfate. While reduced/carboxymethylated S protein remained also ineffective in neutralizing other dermatan sulfate compounds with varying degree of sulfation, a synthetic highly basic tridecapeptide, representing a portion of the glycosaminoglycan-binding domain of S protein, counteracted their anticoagulant activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Antithrombins↗
PubMed1988

Uncoupling in the expression of platelet GP IIb/IIIa in human endothelial cells and K562 cells: absence of immunologic crossreactivity between platelet GP IIb and the vitronectin receptor alpha chain.

Platelet glycoproteins (GP) IIb and IIIa exist as noncovalently associated Ca++-dependent heterodimer complexes within the platelet membrane and express the major platelet alloantigens Leka (Baka) and PIA1 (Zwa), which are genetic markers of GP IIb and GP IIIa, respectively. Since heterodimers immunologically related to platelet GP IIb/IIIa have been identified in a number of nucleated cell types, we tested anti-Leka and anti-PIA1 antiserum, polyclonal anti-platelet GP IIb/IIIa IgG, as well as a panel of 28 monoclonal anti-GP IIb, GP IIIa, or complex dependent anti-GP IIb/IIIa antibodies on endothelial cells, peripheral blood mononuclear cells, and the erythroleukemic cells HEL and K562 in order to determine whether nucleated cell GP IIb/IIIa related proteins and platelet GP IIb/IIIa are immunologically related. Using immunofluorescence, immunoblotting, and immunoprecipitation experiments, evidence is presented that (1) the alloantigen Leka is not expressed in endothelial cells of an individual whose platelets are of the Leka/PIA1 phenotype, whereas the PIA1 alloantigen is readily detectable in these cells, (2) that in contrast to HEL cells, which express platelet GP IIb/IIIa and are of the Leka/PIA1 phenotype, platelet GP IIb is immunologically undetectable in 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-treated K562 cells despite the presence of platelet GP IIIa, and (3) that peripheral blood mononuclear cells do not express platelet GP IIb or GP IIIa on their cell surface.

Adult↗
PubMed1997

Increased phosphate content in complement component C3, fibrinogen, vitronectin, and other plasma proteins in systemic lupus erythematosus: covariation with platelet activation and possible association with thrombosis.

OBJECTIVE: To investigate whether extracellular phosphorylation of plasma proteins takes place in vivo in patients with systemic lupus erythematosus (SLE), to determine possible correlations between phosphate levels and clinical and/or laboratory parameters, and to identify individual phosphorylated plasma proteins. METHODS: Sera from SLE patients were analyzed for total amounts of protein-bound phosphate by a colorimetric technique, and for levels of beta-thromboglobulin by radioimmunoassay. In addition, the ability of these sera to activate platelets, resulting in the release of protein kinase, was tested using an assay in which platelet-rich plasma from healthy blood donors was incubated with sera or immune complexes from SLE patients. In this assay, [gamma-32P]ATP was added, and 32P-labeled C3 was quantified. Phosphate in individual proteins was detected by Western blot analysis. RESULTS: 32P-labeled, activated platelets were able to phosphorylate exogenously added proteins, without the addition of ATP or cations. Platelet-rich plasma from healthy blood donors became activated by sera or by polyethylene glycol-precipitated immune complexes from patients with SLE, which led to the extracellular phosphorylation of plasma proteins, exemplified in the C3 assay. The phosphate content in plasma proteins was increased in SLE patients with previous thrombosis. The degree of phosphorylation increased up to 3-fold in serial samples obtained from 2 SLE patients during periods of disease exacerbation. Substantial phosphate increases were seen in C3 and fibrinogen. The changes were linked to platelet activation because of the observed covariation with the levels of beta-thromboglobulin. CONCLUSION: In SLE patients, the phosphate content in plasma proteins (including C3 and fibrinogen) increases due to platelet activation.

Adolescent↗