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PubMed2004

Plasminogen activator inhibitor type-1 mutants regulate angiogenesis of human umbilical and lung vascular endothelial cells.

Plasminogen activator inhibitor type-1 (PAI-1) is considered one of the key regulators of tumor invasion, metastasis, as well as cancer-related angiogenesis. The literature suggests that PAI-1 plays a dual role in these processes because it inhibits plasmin-originated proteolysis and binds to vitronectin or integrins. Stimulation or inhibition of angiogenesis largely depends on which of these elements PAI-1 interacts. Wild PAI-1 converts quickly into its latent, inactive form and loses its anti-proteolytic activity, but still binds to vitronectin and integrins. Thus we constructed PAI-1s with extended half-life to prolong their anti-proteolytic activity. We have analyzed the effects of sprout formation inhibition by PAI-1s on two functionally different endothelial cell (EC) systems, human umbilical vein endothelial cells (HUVEC), expressing moderate amounts of urokinase (uPA), and human lung microvascular endothelial cells (HLMVEC), expressing high amounts of this enzyme. We have used wild-type PAI-1 (wPAI-1) (t(1/2) = 1.6 h) and PAI-1 cysteine mutants (CysPAI-1) characterized by their prolonged half-life time (hDbetaT) (t(1/2) = 63.6 h and t(1/2) = 7,000 h). We have observed a significant inhibitory dose-dependent effect exerted by the CysPAI-1s on sprout formation by HUVEC and HLMVEC cells. The inhibition rate was considerably stronger in lung capillary cell cultures and significantly more pronounced for CysPAI-1 mutants with longer anti-uPA activity (betaT). wPAI-1 with a short anti-proteolytic half-life has induced sprout formation in HUVEC, but not in HLMVEC cultures. This difference in behavior was most likely related to the presence of excessive amounts of uPA in HLMVEC cells and the known mechanism of clearing PAI-1/uPA/uPAR complexes from the cell surface. A less efficient system of HUVEC cells might give wPAI-1 the chance to interact with non-proteolytic pathways of angiogenesis stimulation. We conclude that while the anti-proteolytic properties of PAI-1 constructs are preserved, these proteins inhibit angiogenesis and inhibitory activity dominates over any stimulatory effects of PAI-1.

Cells, Cultured↗
PubMed1990

A murine very late activation antigen-like extracellular matrix receptor involved in CD2- and lymphocyte function-associated antigen-1-independent killer-target cell interaction.

CD2 and lymphocyte function-associated antigen (LFA)-1 are well known as T cell adhesion molecules involved in killer-target cell interactions. However, our recent study revealed that molecule(s) other than CD2 and LFA-1 might be involved in the lymphokine-activated killer (LAK) cell cytotoxicity against certain target cells. In order to characterize such unknown molecules, we established a mAb (RMV-7) which could inhibit CD2/LFA-1-independent LAK cell cytotoxicity and binding to target cells at the effector site. The Ag identified by RMV-7 appeared on splenic T cells late after mitogenic stimulation and was a noncovalently linked heterodimer composed of a 140-kDa alpha-chain and a 95-kDa beta-chain. RMV-7 blocked LAK cell binding to fibronectin (FN), fibrinogen, and vitronectin but not that to laminin or type IV collagen, indicating that the RMV-7-defined molecule is a unique extracellular matrix receptor for FN, fibrinogen, and vitronectin. One of its ligand, FN, was found on the surface of several target cells, and LAK cell cytotoxicity against them was blocked by anti-FN antibody at the target site. Similarly, cytotoxicity of a H-2d-specific CTL clone was inhibited by RMV-7 and anti-FN antibody as well. These results indicate that a unique very late activation Ag-like extracellular matrix receptor on murine CTL and LAK cells contributes to target cell binding and cytotoxicity.

Animals↗
PubMed1991

Selective recognition of adhesive sites in surface-bound fibrinogen by glycoprotein IIb-IIIa on nonactivated platelets.

We demonstrate that unstimulated platelets attach to immobilized fibrinogen in a selective process mediated by the membrane glycoprotein (GP) complex IIb-IIIa (alpha IIb beta 3). The initial attachment, independent of platelet activation, is followed by spreading and irreversible adhesion even in the presence of activation inhibitors. Using fibrinogen fragments derived from plasmin digestion, we found that unstimulated platelets do not attach to immobilized fragment E, which contains an Arg-Gly-Asp sequence at A alpha 95-97, and adhere to fragments X and D, both containing the gamma 400-411 dodecapeptide adhesion sequence, less efficiently than to intact fibrinogen. Thus, the carboxyl terminus of the A alpha chain, missing in the "early" fragment X used in these studies, appears to be involved in the interaction of fibrinogen with unstimulated platelets. In contrast, activated platelets adhere to immobilized fibrinogen and fragments X, D, and E in a time-dependent and equivalent manner. Although activated platelets adhere to immobilized vitronectin, fibronectin, and von Willebrand factor through GP IIb-IIIa, unstimulated platelets fail to adhere to vitronectin and have only a limited capacity to adhere to fibronectin and von Willebrand factor. These results demonstrate that GP IIb-IIIa on unstimulated platelets displays a recognition specificity for attachment to immobilized adhesive proteins that is distinct from that seen following platelet activation. Thus, unstimulated platelets selectively interact with fibrinogen, and the initial attachment is followed by spreading and irreversible adhesion in the absence of exogenous agonists. This process may be regulated by plasmin cleavage of the fibrinogen A alpha chain and may play an important role during normal hemostasis and during the pathological development of thrombotic vascular occlusions.

Adenosine Diphosphate↗
PubMed1990

cDNA sequence of the human integrin beta 5 subunit.

A novel integrin receptor involved in cell adhesion to the matrix protein vitronectin has recently been described from a human lung epithelial-derived cell line (Cheresh, D. A., Smith, J. W., Cooper, H. M., and Quaranta, V. (1989) Cell 57, 59-69). This receptor has an alpha subunit that appears identical to the alpha v of the vitronectin receptor alpha v beta 3 expressed in melanoma and endothelial cells, but is complexed with a distinct beta subunit, beta 5. cDNA clones coding for beta 5 have been isolated and used to determine the mRNA and amino acid sequence of this new subunit. A 3.3-kilobase mRNA was found to code for a mature protein of 775 amino acid residues with a hydrophobic leader sequence of 24 amino acids. A 56% identity was found between the beta 5 and beta 3 protein sequences, making them the most closely related of the integrin beta subunits. Polymerase chain reaction abundance analysis revealed that alpha v and beta 5 mRNAs were found in seven very different cell lines, compared with beta 3 mRNA which was found in only three of the them, indicating that this new integrin receptor may be widely distributed.

Amino Acid Sequence↗
PubMed1990

Cation-dependent changes in the binding specificity of the platelet receptor GPIIb/IIIa.

The presence of manganese (Mn2+) significantly increases the binding of the platelet surface receptor GPIIb/IIIa to two synthetic peptides Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) and Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val (L10) that contain the recognition sequences RGD and KQAGDV, respectively. This results in an increase in the amount of GPIIb/IIIa adsorbed by GRGDSPK- and L10-Sepharose by 12-20-fold. Additionally, Mn2+ eliminates contaminating platelet vitronectin receptor, alpha v beta 3, which copurifies with GPIIb/IIIa on the peptide affinity columns in the absence of Mn2+. In contrast to this increased peptide binding of GPIIb/IIIa, Mn2+ reduces the binding of GPIIb/IIIa to its macromolecular RGD-containing ligands fibrinogen, fibronectin, and vitronectin. These results could mean that Mn2+ changes the structure of the binding site on GPIIb/IIIa such that it is now better suited to accommodate conformations available to the RGD sequence within short, linear synthetic peptides but not available to the RGD sequences within the natural ligands. To support this hypothesis we tested a conformationally restricted cyclic peptide, cyclic 2,10-GPenGHRGDLRCA, which in competition assays, preferentially inhibits the binding of GPIIb/IIIa to fibrinogen but does not inhibit well the binding of other RGD-dependent integrins, alpha v beta 3 and alpha 5 beta 1 to their respective ligands. In such assays, the presence of Mn2+ dramatically changed the binding specificity of GPIIb/IIIa by shifting the preference of the receptor away from the selective peptide, cyclic 2,10-GPen-GHRGDLRCA toward the nonselective GRGDSP peptide. This shift parallels the Mn2(+)-dependent change of the binding of GPIIb/IIIa to its natural protein ligands.

Amino Acid Sequence↗
PubMed1989

An integrin receptor on normal and thrombasthenic platelets that binds thrombospondin.

The members of the integrin family of membrane glycoprotein heterodimer complexes function as cell surface receptors for adhesive proteins. We report here on the identification of two integrins on the surface of human platelets that bind to thrombospondin. When platelet membrane proteins are radiolabeled with 125I-lactoperoxidase, solubilized in n-octylglucoside, (Boehringer Mannheim Biochemicals, Indianapolis, IN), and applied to a column of thrombospondin-Sepharose, both complexes are bound to the column and specifically eluted with the peptide GRGDSP. One of these integrins, glycoprotein (GP) IIb-IIIa, appears to bind relatively weakly. The second integrin shares the same beta subunit (beta 3 or GPIIIa), but has a distinct alpha subunit that comigrates with the alpha subunit (alpha v) of the vitronectin receptor (VnR) on endothelial cells and reacts with a monoclonal antibody, LM142, which was raised against an integrin from M21 melanoma cells. The alpha v beta 3 integrin is present on a variety of cell types and appears to act as a receptor for thrombospondin on endothelial and smooth muscle cells. On endothelial and M21 melanoma cells this receptor is also involved in adhesion to fibrinogen, vitronectin, and von Willebrand factor (vWF). The alpha v beta 3 integrin is present at approximately equal levels on normal and thrombasthenic platelets, whereas levels of GPIIb-IIIa are greatly reduced on thrombasthenic platelets. The alpha v beta 3 integrin on thrombasthenic platelets also binds to thrombospondin-Sepharose and can be eluted with the peptide GRGDSP. These data indicate that the alpha v beta 3 integrin on platelets, endothelial cells, and smooth muscle cells functions as an Arg-Gly-Asp (RGD)-dependent receptor for thrombospondin.

Blood Platelet Disorders↗
PubMed1989

Human vascular endothelial cells express a membrane protein complex immunochemically indistinguishable from the platelet VLA-2 (glycoprotein Ia-IIa) complex.

Endothelial cells express surface molecules that are involved in cell-matrix interaction, including the vitronectin receptor and the fibronectin receptor, both members of a family of cell adhesion receptors (integrins). Here we provide evidence that endothelial cells express a membrane molecule, indistinguishable from the platelet VLA-2 complex, which is a collagen receptor and a member of the integrin family. To identify this endothelial molecule, we have used a monoclonal antibody, CLB-10G11, which recognizes the VLA-2 complex from platelets. The molecule recognized by CLB-10G11 from endothelial cells was characterized as follows. (1) The monoclonal antibody precipitated two proteins from surface-labeled endothelial cells that corresponded to the platelet VLA-2 subunits (glycoprotein Ia and IIa) as judged by one-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and two-dimensional nonreduced/reduced SDS-PAGE. (2) Preclearing of endothelial cells with monoclonal antibody A-1A5, an antibody that is directed against the common VLA beta subunit, removed all the CLB-10G11-binding material. (3) Crossed immunoelectrophoresis revealed that CLB-10G11 recognizes a single precipitation arc from either platelets or endothelial cells. Analysis of these two cell types in one gel again revealed one precipitation arc. The antigen of either cell type, recognized by CLB-10G11 could be precipitated by either polyclonal antiplatelet or polyclonal antiendothelial cell antiserum. Hence, it appears that endothelial cells express at least three different surface molecules (the vitronectin receptor, the fibronectin receptor and a collagen receptor), which may play an important role in controlling the anchorage of endothelial cells to the extracellular matrix.

Animals↗
PubMed1987

Relationship of a Mr 140 fibronectin receptor and other adhesion-related glycoproteins to tumor cell-cell interaction.

Primary melanocytes attach poorly to collagen type IV and laminin, in contrast to their firm attachment to collagen type I/III and fibronectin [Gilchrest et al., In vitro (Rockville), 21: 114-120, 1985]. We have now found that metastatic B16 melanoma cells attach well to collagen type IV, laminin, vitronectin, and fibronectin but show a selective defect in attachment and cell aggregation on native collagen type I. Both flattened and aggregated melanoma cells revealed the presence of a Mr 120,000 surface-iodinated species with affinity for a matrix containing the hexapeptide (glycylarginylglycylaspartylserylproline) which includes the fibronectin cell attachment sequence, but only flattened cells showed significant exposure of a Mr 140,000 iodinated component with affinity for a large cell attachment-promoting fibronectin polypeptide. Decrease of the Mr 140,000 fibronectin-binding external protein in the collagen-cultured melanoma cells was also associated with an inability to respond to the cell attachment activity of fibronectin, laminin, or vitronectin added to the collagen gels. Metabolic labeling with [3H]glucosamine and electrophoretic analysis showed that lack of attachment and cell aggregation was associated with an increase in high molecular weight wheat germ agglutinin-binding glycoconjugates and an increase in Mr 55,000 concanavalin A-binding glycoprotein species. Our data suggest that: (a) melanoma cell attachment requires the expression of the Mr 140,000 fibronectin receptor which appears to be down regulated in cells exposed to poorly adhesive substrates; (b) expression of the Mr 120,000 iodinated species with affinity for the fibronectin attachment sequence (arginylglycylaspartic acid) may be necessary but not sufficient for firm cell-substratum interactions; (c) increased tumor cell-cell interaction may involve a decreased attachment to substrate and the expression of different glycoproteins which may modulate cell-cell association.

Amino Acid Sequence↗
PubMed1994

Low-affinity material does not contribute to the antithrombotic activity of Orgaran (Org 10172) in human plasma.

Orgaran is a LMW heparinoid composed of heparan sulphate (83% w/w) of which 4-5% has high affinity for antithrombin, dermatan sulphate (12% w/w) and chondroitin sulphate (5% w/w). To examine the contribution of the low-affinity fraction to Orgaran's antithrombotic activity we have quantitated the binding of plasma proteins to Orgaran and its component fractions in whole, hirudin-anticoagulated human plasma. Antithrombin, largely bound to the high-affinity fraction, and histidine-rich glycoprotein, interacting with low-affinity components, were the dominant proteins bound to Orgaran. Vitronectin, fibrinogen, fibronectin, heparin cofactor II, and apolipoprotein B were also detected in small amounts. The ratio of bound antithrombin, histidine-rich glycoprotein and vitronectin to GAG was negatively correlated with the Orgaran concentration in plasma, implying that the efficacy of Orgaran may not be linearly related to dose. Binding of antithrombin to the high-affinity fraction was not decreased by other plasma proteins or affected by addition of low-affinity material. Moreover, the antithrombin and anti-factor Xa activities of the high-affinity material were unaltered by low-affinity GAGs. On the basis of our results we conclude that the low-affinity material does not contribute to the antithrombotic activity of Orgaran by binding non-anticoagulant plasma proteins and releasing the high-affinity chains to interact with antithrombin and its target proteinases.

Anticoagulants↗
PubMed1995

Bone marrow-derived murine mast cells migrate, but do not degranulate, in response to chemokines.

We have determined that several chemokines induce mast cell migration in vitro. This directed migration is dependent on the presence of particular extracellular matrix proteins and the activation status of the cells. Mast cell haptotactic responses were observed in response to various chemokines on vitronectin-, laminin-, and fibronectin-coated filters. Unstimulated mast cells were chemoattracted only by monocyte chemotactic protein-1 and RANTES on vitronectin-coated and, to a lesser extent, laminin-coated filters, whereas IgE-activated mast cells migrated in response to monocyte chemotactic protein-1, regulated on activation normal T expressed and secreted, platelet factor-4, and macrophage inflammatory protein-1 alpha on all three matrix proteins. No significant migration was observed on collagen type IV-coated or uncoated filters. Mast cell migration in response to chemokines on extracellular matrices and its enhancement by IgE-dependent activation provide a mechanism by which cells may be drawn to sites of inflammation. Chemokine-induced mast cell recruitment may be particularly relevant in host defense responses to parasitic infections, allergic reactions, Jones-Mote reactions, and in wound healing.

Animals↗
PubMed1995

Murine CD4+ T cells undergo TCR-activated adhesion to extracellular matrix proteins but not to nonantigenic MHC class II proteins.

Engagement of the TCR modulates the avidity of several receptors that play key roles in lymphocyte adhesion and/or signal transduction, including CD8, CD11a/CD18 (LFA-1), CD2, and several beta 1-integrins. Here, we investigated whether CD4+ T cells similarly undergo TCR-regulated adhesion to isolated MHC class II proteins through CD4. Strong adhesion of a number of CD4+ T cell clones to immobilized antigenic peptide/class II complexes was readily detectable. Adhesion to antigenic class II proteins was CD4 dependent and inhibited by pretreatment of T cells with the protein tyrosine kinase inhibitor herbimycin A, suggesting that adhesion requires TCR- and/or CD4-derived signal transduction. Treatment of T cells with anti-TCR Ab strongly increased subsequent adhesion to the extracellular matrix proteins, fibronectin and vitronectin, but, significantly, not to immobilized nonantigenic class II proteins. Suboptimal densities of antigenic peptide/class II complexes also activated adhesion of T cells to coimmobilized fibronectin or vitronectin, and this resulted in production of IFN-gamma to levels exceeding those stimulated by optimal densities of antigenic class II complexes alone. However, no augmentation of adhesion or cytokine secretion occurred when self or third party class II proteins were coimmobilized with antigenic class II complexes. The present results, therefore, suggest fundamental differences in the mechanism by which the TCR regulates coreceptor adhesion in CD4+ and CD8+ T cells.

Animals↗
PubMed1995

Echistatin, a disintegrin, inhibits sperm-oolemmal adhesion but not oocyte penetration.

OBJECTIVE: To study the effects of echistatin, a disintegrin known to block the binding of fibronectin (FN) and vitronectin to their respective integrin receptors, alpha 5 beta 1 and alpha v beta 3, on the adhesion of human spermatozoa to the oolemma of zona-free hamster eggs and their subsequent penetration. DESIGN: Motile capacitated human spermatozoa and zona-free hamster eggs were coincubated in the presence of echistatin or in its absence and observed at short serial intervals. Whole mounts of these eggs, washed out of sperm suspension and stained with acridine orange, were scored for numbers of oolemmal adherent and penetrating sperm. SETTING: University Hospital laboratories. PATIENTS: Known fertile semen donors. MAIN OUTCOME MEASURES: Numbers of spermatozoa adherent to the oolemma and those penetrating the oocyte. RESULTS: Sperm adherence to the oolemma was reduced significantly at micromolar concentrations of echistatin, in a concentration-dependent manner. In contrast, echistatin did not inhibit the penetration of oocytes by sperm that had become adherent to the oolemma despite the presence of echistatin. CONCLUSION: We propose that two processes occur in the binding of sperm to the oolemma, one that is echistatin sensitive and possibly involving the integrin receptors that recognize FN and vitronectin, and a second process, resistant to echistatin, that leads to gamete membrane fusion.

Animals↗
PubMed1993

1 alpha,25-dihydroxyvitamin D3 up-regulates expression of the osteoclast integrin alpha v beta 3.

Osteoclast precursors selectively attach to bone and differentiate into multinucleated cells that function to remodel and resorb it. We have shown previously that attachment of osteoclasts to bone and subsequent resorption are mediated by the integrin alpha v beta 3. 1 alpha,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) enhances osteoclast precursor differentiation in vivo by mechanisms that are still not clearly understood but entail enhanced attachment of cells to bone. This observation raises the possibility that at least one component of vitamin D-induced osteoclast precursor differentiation involves modulation of integrin expression. To test if the steroid modulates the osteoclast integrin alpha v beta 3 (the vitronectin receptor), we examined the effects of 1,25-(OH)2D3 on transcription of the alpha v gene as well as surface expression and function of alpha v beta 3, in chicken osteoclast precursors. Treatment of the cells with 1,25-(OH)2D3 led to a progressive dose-dependent increase in steady state alpha v mRNA levels with enhanced expression evident within 24 h. The effect was receptor-mediated as indicated by the effects of other vitamin D analogs. The increase in alpha v mRNA levels did not reflect decreased message degradation but, as demonstrated by nuclear run-on experiments, was due to accelerated rates of transcription. Most importantly, induction of alpha v mRNA by 1,25-(OH)2D3 was mirrored by higher levels of expression of alpha v beta 3 on the cell surface, as well enhanced attachment to its substrate, vitronectin.

Animals↗
PubMed1994

An immunohistochemical study of extracellular matrix components and integrins in human glomerular diseases.

The localization of extracellular matrix components and their cell surface receptors (integrins) was studied in 130 subjects in order to clarify their participation in the progression and aggravation of various types of nephritis. Included in the study were 2 normal subjects, 14 patients with minimal change disease, 2 patients with minimal change nephrotic syndrome, 65 patients with IgA nephropathy, 18 patients with mesangial proliferative glomerulonephritis, 15 patients with membranous glomerulonephritis, 5 patients with membranoproliferative glomerulonephritis and 9 patients with systemic lupus erythematosus (SLE). The distribution of fibronectin (FN), vitronectin (VN), laminin (LN), heparan sulfate proteoglycan (HSPG), type III, IV, V, VI collagen, fibronectin receptor (FNR) and vitronectin receptor (VNR) in the glomerulus was studied employing the indirect immunoperoxidase method. FN, LN, type IV, V and VI collagen, FNR and VNR were found to be distributed in the expanded mesangial region in IgA nephropathy, mesangial proliferative glomerulonephritis and membranoproliferative glomerulonephritis. Deposition of VN was observed in some of the patients. In membranous glomerulonephritis and membranoproliferative glomerulonephritis, the distribution of FN, LN, type IV collagen, FNR and VNR was increased in the thickened loop wall and VN deposition was also observed. Quantitative and functional changes in the extracellular matrix and integrins, therefore, appear to participate in the progression and aggravation of glomerulonephritis.

Adolescent↗
PubMed1994

Determinants of human astrocytoma migration.

A unique characteristic of astrocytic malignancies is their frequent dissemination through the brain. Cellular determinants of migration include adhesion to the substratum, restructuring of the actin cytoskeleton to generate motion, and (in the setting of invasion into tissue) secretion of enzymes for remodeling interstitial space to accommodate forward motion of the migrating cell. In order to better understand these features in the context of local brain invasion by astrocytoma cells, the adhesion and migratory properties of these cells have been investigated in an in vitro monolayer system. Adhesion of 8 different astrocytoma cell lines to different purified human extracellular matrix (ECM) proteins (collagen type IV, cellular fibronectin, laminin, and vitronectin) revealed that there is no "astrocytoma-specific" ECM protein that consistently leads to high cell binding. Similarly, migration of astrocytoma cells was found to be variable and dependent on different ECM proteins. Laminin was frequently the most permissive for adhesion and migration. Adhesion to collagen, fibronectin, and vitronectin was integrin dependent and could be blocked using anti-beta 1 integrin antibodies; in contrast, attachment to laminin could not be blocked using these antibodies. A comparison of adhesion with migration for each of the cell lines on each of the 4 ECM proteins revealed that poor adhesion was associated with minimal migration and that frequently, high adhesion was correlated with rapid migration. When tested for migration on autologous, cell-derived ECM, none of the cell lines were as migratory as they were on one of the purified ECM proteins, with the exception of SF767 cells. Furthermore, it was found that ECM from SF767 cells promoted the migration of other astrocytoma cells. The results from this study indicate that migration is a constitutive behavior of glioma cells which is dependent on, or modified by, the presence or absence of permissive ligands in the environment.

Astrocytoma↗
PubMed1994

Distribution of cell adhesion molecules in decidua of early human pregnancy. An immunohistochemical study.

BACKGROUND: The aim of the study was to investigate human decidua for cell adhesion molecules involved in interactions between the various different maternal and fetal cell populations, homing of the unusual intradecidual population of CD56+ lymphocytes, and organization of the decidual extracellular matrix. EXPERIMENTAL DESIGN: First trimester human decidua from normal pregnancies was investigated immunohistochemically with antibodies against integrin subunits (alpha 1-6, alpha L, alpha M, alpha X, alpha IIb, alpha V, beta 1, beta 3, and beta 4), platelet-endothelial cell adhesion molecule, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and L-selectin. RESULTS: Endometrial glands stained for alpha 1, alpha 2, alpha 3, alpha 5, alpha 6, alpha V, beta 1, beta 3, and beta 4, and stromal cells for alpha 1, alpha 3, alpha 5, alpha 6, alpha V, beta 1, beta 3, ICAM-1, and VCAM-1. Endothelium stained for alpha 1, alpha 2, alpha 3, alpha 4, alpha 5, alpha 6, alpha V, alpha IIb, beta 1, beta 3, and beta 4; platelet-endothelial cell adhesion molecule and ICAM-1 also were found on the endothelium of a large number of blood vessels of all types, and VCAM-1 on the endothelium of a moderate number of arterioles and venules, and a few capillaries. Weak staining for E-selectin was seen in a moderate number of arterioles and venules. Large numbers of lymphocytes stained for alpha 4, alpha L, alpha M, alpha X, beta 1, and moderate or small numbers for alpha 1, alpha 3, alpha 5, alpha v, beta 3, platelet-endothelial cell adhesion molecule, ICAM-1, and L-selectin. CONCLUSIONS: Decidual stromal cells, like endometrial glands and endothelium, express integrins that bind basement membrane components. These integrins represent the basis for the formation of the pericellular basement membrane of these cells. They also bind certain glycoproteins that support outgrowth and attachment of the trophoblast in vitro. Vitronectin-binding integrins on endometrial glands, stromal cells, and endothelium may be involved in adhesion of the trophoblast through vitronectin on its surface. From our findings and published data it seems that adhesion of alpha 1 beta 2 (leukocyte function-associated antigen-1) on lymphocytes to ICAM-1 on the endothelium plays the most important role in the migration of CD56+ lymphocytes from the peripheral blood into the decidua. The expression of several beta 1 (VLA) integrins on lymphocytes suggests that these cells are activated, and, like the expression of ICAM-1 and VCAM-1 on stromal cells, probably contributes to their retention in the decidual stroma.

Cell Adhesion Molecules↗
PubMed1994

Potential role of apolipoprotein-E in fibrillogenesis.

Immunohistochemical and biochemical studies have demonstrated several different proteins in amyloid deposits that are not intrinsic components of the fibril itself but may play a role in their deposition and fibril formation. We compared the distribution of several amyloid-associated proteins, ie, amyloid P component, apolipoprotein-E, apolipoprotein-J, and vitronectin, in the deposits of several different amyloids, in particular light chain amyloid, with those in the deposits of nonamyloid monoclonal immunoglobulin, which may be considered a form of preamyloid disease. Although 100% of amyloid specimens (7 amyloid A, 15 immunoglobulin light chain, and 1 transthyretin) had amyloid P component and 100% had apolipoprotein-E (2 amyloid A, 10 immunoglobulin light chain, and 1 transthyretin) co-localized with the primary amyloid protein, none of the monoclonal nonamyloid cases (14 light chain deposition disease and 6 light and heavy chain deposition disease) had amyloid P component and only 1 of 11 had apolipoprotein-E. On the other hand, staining for apolipoprotein-J and vitronectin was positive in 100% of cases of amyloid and nonamyloid monoclonal deposits. The association between the presence of apolipoprotein-E and amyloid P component in the fibrillar form of monoclonal light chain deposits and their absence in the nonfibrillar form of deposits suggest a role for these proteins in the process of fibrillogenesis. This lends support for the previously proposed concept that apolipoprotein-E functions as a pathological chaperone by altering the conformation of amyloidogenic proteins.

Amyloidosis↗
PubMed1993

Interaction of immobilised unfractionated and LMW heparins with proteins in whole human plasma.

The profile of proteins bound to immobilised heparins in hirudin-anticoagulated human plasma was analysed. In molar terms, antithrombin III was the most abundant protein bound to therapeutic doses of unfractionated heparin (M(r) = 12,000), whereas heparin cofactor II constituted < 1% of the protein bound. Histidine-rich glycoprotein was the only plasma protein likely to influence anticoagulant activity by direct competition with antithrombin III, though significant quantities of complement Factor H, fibrinogen, fibronectin, vitronectin and apolipoprotein B were also detected. Only traces of von Willebrand factor, complement factor I, inter-alpha-trypsin inhibitor, alpha 2-macroglobulin, serum amyloid P and transferrin were identified, and neither thrombospondin nor platelet factor 4 were measurable. Binding of both antithrombin III and histidine-rich glycoprotein varied with the ratio of heparin to plasma. Clexane (M(r) = 4,500) also bound antithrombin III, but both histidine-rich glycoprotein and vitronectin were quantitatively significant neutralising proteins. Neutralising proteins dominated the binding profile for Oligo H (M(r) = 2,200).

Blood Proteins↗