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PubMed1982

Synovial fluid and plasma fibronectin levels in rheumatoid arthritis.

1. Plasma fibronectin levels were similar in 60 healthy subjects and 88 with the rheumatoid arthritis. 2. In 42 patients with rheumatoid arthritis synovial fluid fibronectin levels were significantly higher than plasma levels (P less than 0.001). Intermediate fibronectin levels were found in synovial fluid from six patients with psoriatic arthritis, eight patients with osteoarthritis and seven with seronegative arthritis. 3. Plasma and synovial fluid fibronectin levels were not related to indices of inflammatory activity such as the erythrocyte sedimentation rate, the Ritchie articular index or synovial fluid cell counts. Nor did fibronectin behave as an acute-phase protein. 4. Immunofluorescent studies showed that fibronectin was adsorbed on fibrinous debris in rheumatoid arthritic joints. 5. These findings suggest that there is local production of fibronectin by the synovium and suggest that measurement of fibronectin levels in the synovial fluid may serve as an indicator of the tissue response to rheumatoid arthritis.

Adolescent↗

PubMed2002

Inhibition of cell proliferation and fibronectin biosynthesis by Na ascorbate.

BACKGROUND: The importance of ascorbate on the production of extracellular matrix proteins (as elastin and collagens) is now well documented, but no studies have been published concerning its effects on fibronectin biosynthesis. Fibronectin is important for cell attachment and for proliferation. MATERIALS AND METHODS: The effects of Na ascorbate were investigated on cell attachment, proliferation, viability and fibronectin biosynthesis by human skin fibroblasts in vitro. Proliferation was followed by the monitoring of [(3)H]-thymidine incorporation; viability by the MTT-test, cell adherence by counting adherent and nonadherent cells and fibronectin biosynthesis by immunoprecipitation of biosynthetically labelled fibronectin. RESULTS: In the presence of ascorbate, the fibroblasts showed a biphasic growth pattern. At 500 microM ascorbate, [(3)H]-thymidine incorporation was stimulated by 15% as compared to the controls. Higher concentrations gradually decreased proliferation up to 36% of the control value at 5 mM. These effects of ascorbate on DNA synthesis were followed to > 1.25 mM by a strong inhibition, cytotoxic effect and cell death. The non-adherent cell count increased to 10% of the total population at 2.5 mM and to 31% at 5.0 mM ascorbate.Increasing concentrations of ascorbate resulted in a dose-dependent decrease of fibronectin biosynthesis, both in the culture supernates and cell extracts. This inhibition mainly concerned cell membrane-associated fibronectin.Superoxide-dismutase or catalase could inhibit Na ascorbate-induced cytotoxicity and partially re-establish fibronectin biosynthesis. Desferrioxamine, ergothionein and vitamin E were inefficient. CONCLUSIONS: Our results indicate that ascorbate decreases fibronectin biosynthesis of cultured human skin fibroblasts, thereby producing cell detachment and decreased proliferation. This effect is mainly mediated by the reactive oxygen species and can be inhibited by superoxide-dismutase and catalase.

Antioxidants↗

PubMedDate not supplied

Homologous serum-stimulated fibronectin synthesis in human retinal pigmented epithelial cells.

PURPOSE: Fibronectin expression has been recorded in subretinal membranes from patients with proliferative vitreoretinopathy (PVR). Retinal pigmented epithelial (RPE) cells are a major cellular component of PVR membranes and synthesize fibronectin. We investigated the effects of human serum (as a model of vascular leakage in vivo) on the expression of fibronectin by cultured human RPE cells and compared the responses to those stimulated by fetal bovine serum (FBS). METHODS: Human RPE cells were incubated in M199 with 1, 10 and 40% human adult serum or FBS for 72 h. RESULTS: Retinal pigmented epithelial cells expressed maximum extracellular matrix fibronectin when exposed to 40% human serum using immunohistochemistry. Using ELISA to quantify fibronectin, 10 and 40% human serum significantly increased the total fibronectin (P < 0.01; n = 4), whereas FBS did not affect fibronectin expression. CONCLUSIONS: The results show that human serum contains substances stimulating fibronectin synthesis in human RPE cells.

Blood Physiological Phenomena↗

PubMed1999

Cellular fibronectin is induced in ultraviolet-exposed human skin and induces IL-10 production by monocytes/macrophages.

CD11b+ monocytic/macrophagic cells that infiltrate human skin after in vivo ultraviolet exposure potently produce interleukin-10. We hypothesized that binding of monocyte beta1 integrins to ultraviolet-induced extracellular matrix ligands, such as fibronectin, after entry of blood monocytes into the dermis, is involved in the modulation of immunoregulatory monocytic cytokines. Immunostaining of human skin and reverse transcriptase-polymerase chain reaction studies revealed that the embryonic isoform of cellular fibronectin, in which the extra domain A (EDA) segment is spliced in (EDA+ cellular fibronectin), and confers enhanced binding to beta1 integrins, is newly induced and is associated with infiltrating CD11b+ cells post in vivo ultraviolet exposure. We then tested the effect of fibronectin on resting purified peripheral monocytes in vitro. We found that monocyte interleukin-10, but not interleukin-12, was significantly induced in a concentration-dependent manner by in vitro binding to cellular fibronectin (n = 6), but not plasma fibronectin. Tumor necrosis factor-alpha was also induced in a concentration-dependent manner, but to a lesser extent. Monoclonal antibodies to beta1 integrins beta-subunit (CD29) also strongly induced tumor necrosis factor-alpha and interleukin-10 production, but not interleukin-12. Neutralization of tumor necrosis factor-alpha reduced by 54% the interleukin-10 production that was induced by monocytes binding to cellular fibronectin, indicating that interleukin-10 induction is at least in part dependent upon concomitant autocrine tumor necrosis factor-alpha release. In conclusion, ultraviolet skin injury results in increased production and deposition of EDA+ cellular fibronectin in the papillary dermis, which may be one of the key signals capable of inducing interleukin-10 but not interleukin-12 in monocytes that infiltrate micromilieu of human skin after ultraviolet exposure.

Adult↗

PubMed2000

Effect of lovastatin on small GTP binding proteins and on TGF-beta1 and fibronectin expression.

We have shown that lovastatin, an inhibitor of 3 hydroxy-3-methylglutary coenzyme A (HMG CoA) reductase, delays development and progression of diabetic nephropathy in streptozotocine-induced diabetic rats through suppression of glomerular transforming growth factor (TGF)-beta1 mRNA expression. We have also shown that lovastatin suppresses both control and high glucose (HG)-induced TGF-beta1 and fibronectin mRNA expression and protein synthesis by rat mesangial cell (RMC) and that this down-regulation by lovastatin is reversed by mevalonate. It was postulated that this down-regulation may be linked to signaling of small guanine triphosphate (GTP)-binding proteins and mediated by the limitation of isoprenoids such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) in RMC. To determine the isoprenoid and small GTP-binding proteins involved in TGF-beta1 and fibronectin expression. FPP or GGPP was added alone or in combination to RMC treated with lovastatin cultured under normal or high glucose condition. Suppression of TGF-beta1 and fibronectin expression by lovastatin was reversed effectively when GGPP was added alone. Partial reversal of lovastatin effect on fibronectin and TGF-beta1 expression was found when FPP was added alone. Adding both GGPP and FPP resulted in complete reversal of lovastatin effect on fibronectin but not TGF-beta1 suggesting that fibronectin and TGF-beta1 are regulated differently. Furthermore, luciferase activity of RMC cotransfected with fibronectin promoter reporter system and plasmid-expressing C3 exoenzyme (a specific inactivator of Rho family GTP binding proteins, pEFC3) was completely suppressed when compared with RMC cotransfected with empty vector, pEF. Because geranylgeranylation is usually involved in post-translational modification and membrane targeting of Rho family small GTP binding proteins, these data indicate that Rho family small GTP-binding proteins rather than Ras family small GTP binding proteins may play a key role in the TGF-beta1 and fibronectin expression in RMC.

Animals↗

PubMedDate not supplied

Evaluation of factor VIII-rich cryoprecipitate and the plasma fibronectin-rich, heparin-precipitable fraction prepared from single-donor plasma units.

A plasma fibronectin-rich component was prepared by heparin-induced 4 degrees C precipitation of fresh or stored (21 days at 4 degrees C), single-donor plasma. The recovery of plasma fibronectin was 45 percent at a concentration of 0.05 mg heparin per ml (7.5 units/ml) and 75 percent at 0.1 mg per ml (15 units/ml). The biologic activity of plasma fibronectin, as assessed by the spreading of Chinese hamster ovary cells or attachment of monocytes to gelatin-coated surfaces, was similar to that of plasma fibronectin concentrates made from fresh or stored plasma. Only 20 to 30 percent of the factor VIII activity in fresh plasma was recovered in cryoprecipitate produced after the heparin-induced precipitate containing fibronectin was removed. Cryoprecipitate prepared from the supernatant plasma that remains after heparin-induced cold precipitation in the presence of CaCl2 (5 mM) contained approximately 50 percent less factor VIII. The relatively low recovery of factor VIII in cryoprecipitate prepared from fibronectin-depleted plasma makes cryoprecipitation an unsuitable method of producing fibronectin-rich and factor VIII-rich components effectively from a single unit of fresh plasma. However, heparin-induced cold precipitation provides an efficient method for preparing plasma fibronectin concentrates from small plasma pools or single units of stored or fresh plasma.

Blood Preservation↗

PubMed1990

Plasma levels of fibronectin and prostacyclin metabolite in peripartum preeclamptic women.

Plasma fibronectin and prostacyclin levels have been reported to vary in preeclamptic women when compared with pregnant control women. Elevation of fibronectin and deficiency of prostacyclin have been postulated to be due to endothelial cell disruption or dysfunction. Eighteen preeclamptic women and 19 normal pregnant controls were evaluated for plasma levels of fibronectin and the prostacyclin metabolite 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). 6-keto-PGF1 alpha and fibronectin plasma levels in patients were significantly different from control patients, with preeclamptic patients exceeding control subjects. Five patients had serial samples of 6-keto-PGF1 alpha prior to, during, and after intravenous magnesium sulfate therapy and no consistent effect was noted. No correlation existed between fibronectin and 6-keto-PGF1 alpha levels or between either compound and platelet count or liver function tests. Despite an overall elevation of fibronectin in preeclamptic patients, two patients with the hemolysis, elevated liver tests, and low platelet count syndrome showed low normal fibronectin levels coinciding with thrombocytopenia, hemolysis, and liver dysfunction. The magnitude of fibronectin elevation may therefore not predict the severity of preeclampsia. The significance of these findings is discussed.

Adolescent↗

PubMed1991

Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery.

BACKGROUND: Preterm delivery is the leading cause of neonatal mortality in the United States, but efforts to address the problem are hampered by the inability to predict accurately which pregnancies are at risk. We postulated that damage to the fetal membranes may release fetal fibronectin into the cervix and vagina, giving rise to a biochemical marker for preterm delivery. METHODS: We measured fetal-fibronectin concentrations in cervical and vaginal secretions, amniotic fluid, and maternal plasma with a sensitive immunoassay using the monoclonal antibody FDC-6. Immunohistochemical studies were used to determine the distribution of fetal fibronectin in the placenta and amniochorionic membranes and to ascertain its cell of origin. RESULTS: Women with uncomplicated pregnancies (n = 163) who delivered at term rarely had cervicovaginal fetal-fibronectin concentrations above 0.05 micrograms per milliliter between 21 and 37 weeks of gestation (11 of 267 cervical samples [4 percent] and 9 of 267 vaginal samples [3 percent]. High levels of fetal fibronectin were detected in amniotic fluid and in the cervical or vaginal secretions of 93.8 percent of the women with preterm rupture of membranes (n = 65). Cervical or vaginal fetal fibronectin was also present in 50.4 percent of the women with preterm uterine contractions and intact membranes (n = 117), and its presence identified the women who delivered before term (n = 60) with a sensitivity of 81.7 percent and a specificity of 82.5 percent. In the placenta and membranes, fetal fibronectin was found at points of contact with the uterine wall. CONCLUSIONS: The presence of cervicovaginal fetal fibronectin in the second and third trimesters of pregnancy identifies a subgroup of women who are at high risk for preterm delivery. This phenomenon may reflect the separation of the chorion from the decidual layer of the uterus, with the release of intact or degraded chorionic components of the extracellular matrix into the cervical and vaginal secretions.

Amniotic Fluid↗

PubMed2003

Fetal fibronectin: the impact of a rapid test on the treatment of women with preterm labor symptoms.

OBJECTIVE: The purpose of this study was to determine whether knowledge of the results of a rapid fetal fibronectin test affects treatment decisions during the evaluation and treatment of possible preterm labor. Previous observational studies have suggested that a negative test might help to avoid unnecessary intervention. STUDY DESIGN: This was a randomized study of women who were between 24 weeks and 34 weeks 6 days of gestation with symptoms of preterm labor and who were seen in three community hospitals. A rapid fetal fibronectin test was performed on all subjects. Patients were assigned randomly to a group whose results were known to physician or to a group whose results were not known. Treatment decisions were at the discretion of the physician. RESULTS: One hundred eight samples were collected between September 2000 and December 2001. There were 10 positive fetal fibronectin tests. The overall prevalence of delivery within 2 weeks for the study population was 2.8%. For women who had negative fetal fibronectin test results, the hospital stay was not significantly shorter when the result was known (6.8 hours) than when it was not known (8.1 hours, P =.35). However, when the physician knew the fetal fibronectin status of women with a negative test result who were observed for >6 hours, the hospital stay was shortened 40%, to 22.7 hours from 37.8 hours (P =.04). CONCLUSION: Fetal fibronectin testing may be able to supplement clinical judgment in the evaluation of the condition of patients with symptoms of preterm labor. The greatest benefit of fetal fibronectin testing might be for the patient whom the physician judges to be at high risk for imminent delivery. In such patients, the knowledge of a negative fetal fibronectin may shorten the hospital stay.

Adult↗

PubMed1990

Effects of class I heparin binding growth factor and fibronectin on platelet adhesion and aggregation.

Fibronectin and heparin binding growth factor-type 1 have been affixed to vascular graft surfaces to enhance the attachment and the proliferation of transplanted endothelial cells, respectively. The current study examines the effect of fibronectin and heparin binding growth factor-type 1 on platelet adhesion and activation in vivo and on platelet aggregation in vitro. Expanded polytetrafluoroethylene prostheses (5 cm x 4 mm internal diameter) were treated either with fibronectin (n = 9), fibronectin/heparin/heparin binding growth factor-type 1/heparin (n = 12), or neither (n = 13) and were interposed into canine aortoiliac systems bilaterally. Autogenous radiolabeled (Indium 111 oxine, 650 microCi) platelets were injected intravenously before reestablishment of circulation. Perfusion was maintained for 30 minutes, and prostheses were removed with segments of native aorta and distal iliac arteries bilaterally. Specimens were examined for thrombus-free surface area, by gamma well counting for adherent radiolabeled platelets, and by light microscopy and transmission and scanning electron microscopic techniques. Results showed that both the fibronectin and fibronectin/heparin/heparin binding growth factor-type 1/heparin pretreated prostheses contained significantly greater numbers of platelets and adherent radioactivity than did control graft segments when normalized to their ipsilateral iliac arteries. Fibronectin/heparin/heparin binding growth factor-type 1/heparin pretreated prostheses contained 27 +/- 16 times more radioactivity per square millimeter than ipsilateral iliac arteries, fibronectin pretreated prostheses had 13 +/- 8 times more radioactivity per square millimeter than ipsilateral iliac arteries, and untreated expanded polytetrafluoroethylene had 4 +/- 3 times more radioactivity per square millimeter than ipsilateral iliac arteries. Fibronectin/heparin/heparin binding growth factor-type 1/heparin was more radioactive than fibronectin alone (p = 0.056). Histologic evaluation and thrombus-free surface area determinations corroborated the gamma well counting data. Platelet aggregation in vitro was not activated by either fibronectin (1 to 100 micrograms/100 microliters) or heparin binding growth factor-type 1 (25 to 2500 ng/100 microliters). These data suggest that fibronectin and heparin binding growth factor-type 1 promote platelet adhesion not aggregation.

Animals↗

PubMed2004

Regulation of fibronectin splicing in sinusoidal endothelial cells from normal or injured liver.

Fn containing an extra type III domain (EIIIA in the rat, ED1 or EDA in humans) is commonly termed "fetal" fibronectin, but it is prominent during the injury response of adult tissues and mediates important early events in the response. This form is particularly apparent in acute liver injury, where it has been shown that sinusoidal endothelial cells produce EIIIA-fibronectin. This fibronectin isoform arises by alternative splicing of the primary transcript. In the present experiments, we have studied the regulation of fibronectin splicing in primary sinusoidal endothelial cells by transfecting a minigene containing the EIIIA exon and its flanking introns, driven by various promoters. The results indicate that fibronectin splicing in endothelial cells from normal liver is in part promoter-dependent. However, in cells from injured liver in which expression of both total and EIIIA-fibronectin is strikingly increased, promoter effects disappear. Because fibronectin splicing is known to be regulated in part by TGFbeta, we also examined the effect of a soluble inhibitor of the TGFbeta type 2 receptor. This agent had no effect on splicing by normal endothelial cells. By contrast, for endothelial cells from the injured liver, the splicing pattern reverted to that of normal cells, i.e., it became promoter-dependent. We conclude that, in the setting of injury in vivo, TGFbeta overrides the promoter dependence of fibronectin splicing in normal cells. The data suggest that TGFbeta modifies the spliceosome, if not through its known signaling intermediates, then through the products of genes regulated by this cytokine.

Alternative Splicing↗

PubMed1981

Augmentation of human monocyte opsonin-independent phagocytosis by fragments of human plasma fibronectin.

Human plasma fibronectin isolated by gelatin-affinity chromatography increases in a dose-dependent fashion the number of human monocytes that ingest particulate activators of the human alternative complement pathway in a fully synthetic medium. The fibronectin effect is selective for these particulate activators, does not extend to particles whose ingestion is dependent upon opsonization with IgG, and is not observed with pretreatment of the monocytes. Affinity chromatography with monoclonal antibody to plasma fibronectin of 440,000 daltons reveals that only 12-53% of the protein in a phagocytically active gelatin-affinity-purified fibronectin preparations is bound to the antibody. The protein eluted after affinity chromatography with monoclonal antibody of active preparations, which represented 10-43% of the protein applied, exhibits a 2- to 10-fold increment of activity per microgram of protein above the starting gelatin-affinity-purified material. Thus, the activity that augments the percent of human monocytes ingesting particulate activators of the alternative pathway is antigenically defined as plasma fibronectin. Preparations containing only intact 440,000-dalton fibronectin are also bound to and eluted from the monoclonal antibody, but they fail to augment phagocytosis. When inactive 440,000-dalton plasma fibronectin is subjected to limited trypsin cleavage, phagocytosis-enhancing activity develops that is bound to and elutes from the affinity column prepared with monoclonal antibody, thereby indicating that the enhancing activity of plasma fibronectin resides in cleavage fragments.

Clone Cells↗

PubMed1985

On the origin of species of fibronectin.

Multiple different subunits of fibronectin are known to occur and their origin has been unclear. Recent results showing that a single fibronectin gene can give rise to several different mRNAs by alternative splicing suggested an explanation for some of this diversity of fibronectin subunits. Because the alternative splicing events occur within the coding region, the mRNAs differ in coding potential. We have prepared recombinant phage containing a rat fibronectin cDNA segment that is present in some fibronectin mRNAs and not in others. This segment was inserted in the beta-galatosidase gene of lambda gt11, and fusion protein produced by lysogens of the recombinant phage was purified and used as immunogen. The resulting antisera recognized some subunits of rat and hamster fibronectins but not others, indicating that inclusion or removal of this segment gives rise to mRNAs that encode different fibronectin subunits. In particular, presence or absence of a 95 amino acid segment appears to account for differences in size among the subunits of plasma fibronectin, whose origin is therefore explained by alternative patterns of RNA splicing.

Animals↗

PubMed1987

Efficient and stable expression of recombinant fibronectin polypeptides.

We describe retroviral expression vectors containing cDNAs encoding part of fibronectin preceded by the signal and "pro" sequences of parathyroid hormone. The recombinant retroviruses were used to generate NIH 3T3 cell lines stably producing functionally active fragments of fibronectin. The recombinant fibronectins (deminectins) are processed and secreted by the cells and form disulfide-bonded dimers with themselves and with endogenous fibronectin subunits. The fibronectin-deminectin heterodimers are incorporated into the extracellular matrix. We describe cell lines producing six variant forms of deminectin corresponding to variant forms of fibronectin produced by alternative splicing. In constructing fibronectin cDNAs encoding the six variant forms, we also made use of the ability of retroviral vectors to generate cDNAs by accurate splicing of cloned genomic segments. These constructs should be valuable in analyses of the structure-function relationships of fibronectins.

Animals↗

PubMed1995

Extracellular matrix binding properties of recombinant fibronectin type II-like modules of human 72-kDa gelatinase/type IV collagenase. High affinity binding to native type I collagen but not native type IV collagen.

72-kDa gelatinase/type IV collagenase is an important matrix metalloproteinase in the degradation of basement membranes and denatured collagens (gelatin). These proteolytic processes are required for pathologic tissue destruction and physiologic tissue remodeling. To investigate the molecular determinants of substrate specificity of this enzyme, a 21-kDa domain of 72-kDa gelatinase, consisting of three tandem fibronectin type II-like modules, was expressed in Escherichia coli. Similar to full-length 72-kDa gelatinase and the type II modules in fibronectin, the recombinant (r) fibronectin-like domain of this proteinase bound denatured type I collagen with an apparent Kd in the micromolar range. This domain, designated the collagen-binding domain (rCBD123), possesses at least two collagen-binding sites that can each be simultaneously occupied. rCBD123 also avidly bound elastin and denatured types IV and V collagens, but neither native types IV and V collagens nor fibronectin, all of which are substrates of the enzyme. Although 72-kDa gelatinase is involved in basement membrane degradation, rCBD123 also did not bind reconstituted basement membrane, laminin, or SPARC. Native type I collagen, which is not degraded by 72-kDa gelatinase, competed with gelatin for a shared binding site on rCBD123. rCBD123 also displaced full-length 72-kDa gelatinase bound to native type I collagen, further demonstrating that the collagen binding properties of the recombinant domain closely mimicked those of the full-length enzyme. Since rCBD123 showed reduced binding to pepsin-cleaved type I collagen, either or both of the collagen telopeptide ends contain recognition sites for the 72-kDa gelatinase fibronectin-like domain. This was confirmed by the avid binding of rCBD123 to the alpha 1(I) collagen cyanogen bromide fragment CB2 from the NH2-terminal telopeptide. rCBD123 also bound alpha 1(I)-CB7, which encompasses the fibronectin-binding site, and to alpha 1(I)-CB8, a fragment not bound by fibronectin. Thus, type I collagen contains multiple binding sites for rCBD123 which are partially masked by the triple helical conformation of native collagen and fully exposed upon unfolding of the triple helix. The potential of the fibronectin-like collagen binding domain of 72-kDa gelatinase to bind extracellular matrix proteins may facilitate enzyme localization in connective tissue matrices.

Base Sequence↗

PubMed1996

Identification of a novel binding site to the integrin alphaIIbbeta3 located in the C-terminal heparin-binding domain of human plasma fibronectin.

Fibronectin has been shown to bind to integrin alphaIIbbeta3 in Arg-Gly-Asp (RGD)-dependent and -independent manners. A recent study has indicated that a 29-kDa dispase-digestive fragment from the C-terminal heparin-binding domain of human plasma fibronectin (lacking RGD sequence) inhibits binding of fibronectin to thrombin-stimulated platelets and ADP-induced aggregation (Tanabe, J. , Fujita, H., Iwamatsu, A., Mohri, H., and Ohkubo, T.(1993) J. Biol. Chem. 268, 27143-27147). We provide here the evidence that a peptide corresponding to residues from Ala1704 to Glu1718 (designated F1) from this fragment inhibited binding of 125I-labeled 29-kDa fragment of fibronectin to thrombin-stimulated platelets and ADP-induced aggregation. The F1 peptide bound directly to alphaIIbbeta3 integrin receptor. These results indicate that a novel binding site in the C-terminal heparin-binding region of fibronectin is localized within the residues from Ala1704 to Glu1718. Binding of 125I-labeled 29-kDa fragment of fibronectin to thrombin-stimulated platelets was not inhibited by RGDS peptide and the 12-residue peptide from the cell-binding domain of fibronectin, suggesting that binding site in the C-terminal heparin-binding domain may be different from those of RGDS and the 12-residue peptide. This additional alphaIIbbeta3-binding domain(s) in fibronectin may also play some role for prevention of thrombus formation by direct interaction with alphaIIbbeta3.

Adenosine Diphosphate↗

PubMed1999

Inhibition of fibronectin matrix assembly by the heparin-binding domain of vitronectin.

The deposition of fibronectin into the extracellular matrix is an integrin-dependent, multistep process that is tightly regulated in order to ensure controlled matrix deposition. Reduced fibronectin deposition has been associated with altered embryonic development, tumor cell invasion, and abnormal wound repair. In one of the initial steps of fibronectin matrix assembly, the amino-terminal region of fibronectin binds to cell surface receptors, termed matrix assembly sites. The present study was undertaken to investigate the role of extracellular signals in the regulation of fibronectin deposition. Our data indicate that the interaction of cells with the extracellular glycoprotein, vitronectin, specifically inhibits matrix assembly site expression and fibronectin deposition. The region of vitronectin responsible for the inhibition of fibronectin deposition was localized to the heparin-binding domain. Vitronectin's heparin-binding domain inhibited both beta(1) and non-beta(1) integrin-dependent matrix assembly site expression and could be overcome by treatment of cells with lysophosphatidic acid, an agent that promotes actin polymerization. The interaction of cells with the heparin-binding domain of vitronectin resulted in changes in actin microfilament organization and the subcellular distribution of the actin-associated proteins alpha-actinin and talin. These data suggest a mechanism whereby the heparin-binding domain of vitronectin regulates the deposition of fibronectin into the extracellular matrix through alterations in the organization of the actin cytoskeleton.

Animals↗

PubMed2000

Molecular mechanism of fibronectin gene activation by cyclic stretch in vascular smooth muscle cells.

Fibronectin plays an important role in vascular remodeling. A functional interaction between mechanical stimuli and locally produced vasoactive agents is suggested to be crucial for vascular remodeling. We examined the effect of mechanical stretch on fibronectin gene expression in vascular smooth muscle cells and the role of vascular angiotensin II in the regulation of the fibronectin gene in response to stretch. Cyclic stretch induced an increase in vascular fibronectin mRNA levels that was inhibited by actinomycin D and CV11974, an angiotensin II type 1 receptor antagonist; cycloheximide and PD123319, an angiotensin II type 2 receptor antagonist, did not affect the induction. In transfection experiments, fibronectin promoter activity was stimulated by stretch and inhibited by CV11974 but not by PD123319. DNA-protein binding experiments revealed that cyclic stretch enhanced nuclear binding to the AP-1 site, which was partially supershifted by antibody to c-Jun. Site-directed mutation of the AP-1 site significantly decreased the cyclic stretch-mediated activation of fibronectin promoter. Furthermore, antisense c-jun oligonucleotides decreased the stretch-induced stimulation of the fibronectin promoter activity and the mRNA expression. These results suggest that cyclic stretch stimulates vascular fibronectin gene expression mainly via the activation of AP-1 through the angiotensin II type 1 receptor.

Angiotensin II↗