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PubMed1990

Cytochemical evidence for a proteoglycan-associated filamentous network in ligament extracellular matrix.

The purpose of this investigation was to examine the extracellular matrix of rabbit ligament before and after digestion with glycosaminoglycan degrading enzymes. In order to preserve and enhance the visibility of negatively charged tissue components, particularly the glycosaminoglycan-containing proteoglycans, the cationic stains ruthenium red (RR) and ruthenium hexamine trichloride (RHT) were used. Cross-sections of the midsubstance of 10-month-old (mature) rabbit medial collateral ligaments fixed using conventional procedures revealed a sparse population of stellate-shaped cells that did not appear to be interconnected. Similar tissue fixed in either RR or RHT showed an extensive network of thin, electron-dense "seams" that interconnected cells and appeared to irregularly subdivide the extracellular matrix (ECM). These seams mainly consisted of a meshwork of microfilaments throughout which small granules were dispersed. Numerous 14-nm microfibrils, as well as mature elastic fibers were also present within the seams. The size and shape of the microfilaments, together with their threadlike, beaded appearance suggested that they could be Type VI collagen. The seam granules were easily removed with chondroitinase ABC, chondroitinase AC II, and mild (0.18 M) salt treatment. Only chondroitinase ABC succeeded in removing additional granules, tentatively identified as proteodermatan sulphate molecules, that were periodically located at d band sites along the Type I collagen fibrils. These results suggest that the seam granules are not dermatan sulphate containing proteoglycans, and further, that these proteoglycans may be sequestered into specific zones within the ECM through loose association with the seam microfilaments. While the functional significance of the seams remains unknown and their specific composition clearly requires further study, it is likely that they represent important functional (e.g., viscoelastic) or biological (e.g., nutritional) subdivisions of ligament substance.

Animals↗

PubMed1998

Metal-catalyzed oxidation of extracellular matrix increases macrophage nitric oxide generation.

BACKGROUND: Oxygen radicals are believed to play a significant role in glomerular disease. In part this may be due to oxidation of lipids, but protein oxidation may play a contributory role as well. We have demonstrated that the mesangial extracellular matrix is susceptible to metal-catalyzed oxidation and that this increases scavenger receptor-mediated adhesion of macrophages, cells which appear to be important participants in glomerular injury via their secretory products. As other scavenger receptor ligands can increase macrophage nitric oxide generation, we examined whether oxidation of matrix could increase the activity of macrophage inducible nitric oxide synthase (iNOS). METHODS: Extracellular matrix was oxidized using a metal-catalyzed oxidation system. Matrix oxidation was measured using carbonyl analysis, and iNOS activity in macrophages seeded onto the matrix was measured by nitrite determination and Western and Northern analyses for iNOS. RESULTS: Macrophages exposed to oxidized matrix demonstrated a significant enhancement of iNOS activity. This enhancement could be antagonized by cotreatment of matrix with the radical spin trap N-tert-butyl-a-phenylnitrone, resulting in a corresponding decrease in protein carbonyl content, a measure of protein oxidation. Seeding macrophages onto oxidized matrix and adding the scavenger receptor ligand polyinosinic acid further augmented iNOS activity, suggesting that additional scavenger receptors were available to bind ligand and that further augmentation of iNOS activity did not require an additional change in cell shape. Western blot analysis revealed an increase in iNOS protein expression as a consequence of interaction with the oxidized matrix, but there was no difference in iNOS mRNA expression by Northern analysis suggesting a post-transcriptional mechanism for enhanced iNOS activity. CONCLUSION: These data demonstrate that oxidation of extracellular matrix enhances macrophage nitric oxide generation, and suggest a previously undescribed role for extracellular matrix modification in the regulation of cellular function and possibly the mediation of glomerular injury.

Animals↗

PubMed1999

Growth of rat mesangial cells on oxidized extracellular matrix increases inducible nitric oxide synthase activity.

Biochemical modification of extracellular matrix (ECM) proteins can alter the function in overlying cells. We tested the hypothesis that metal-catalyzed oxidation of native ECM and individual matrix proteins modulates the activity of inducible nitric oxide synthase (iNOS) in cultured rat mesangial cells (RMC). Oxidized modification of native ECM resulted in a 32% increase in iNOS activity (P<0.01) without influencing the response to supplemental L-arginine or to the addition of the iNOS inhibitor, L-NAME. Immunoblot analysis indicated that enhanced iNOS activity was not associated with a parallel rise in the cytosolic content of iNOS. Synthesis of type IV collagen was unaffected by growth of RMC on oxidized native ECM. Oxidation of three normal constituents of the mesangial matrix - type IV collagen, laminin, and fibronectin - also stimulated iNOS activity in overlying RMC by 18-32% (P<0.05). Growth of RMC on oxidized type I collagen or Vitrogel had no effect on NO production. We conclude that oxidized modification of the mesangial matrix promotes increased iNOS activity and NO production by mesangial cells. Further work is required to determine whether this response limits glomerular injury or promotes damage to the mesangium in oxygen free radical-mediated diseases such as chronic renal failure, atherosclerosis and diabetes.

Animals↗

PubMed1987

Development of the electromotor system of Torpedo marmorata: distribution of extracellular matrix and cytoskeletal components during acetylcholine receptor focalization.

A combination of direct fluorescence and indirect immunofluorescence microscopy has been used to compare the distribution of the acetylcholine receptor with the distribution of major cytoskeletal and extracellular matrix components during electrocyte differentiation in the electric organs of Torpedo marmorata. Laminin, fibronectin and extracellular matrix proteoglycan are always more extensively distributed around the differentiating cell than the acetylcholine receptor-rich patch that forms on the ventral surface of the cell. The distribution of acetylcholinesterase within the ventral surface of the differentiating electrocyte closely resembles the distribution of the acetylcholine receptor. Areas of apparently high acetylcholine receptor density within the ventrally forming acetylcholine receptor-rich patch are always areas of apparently high extracellular matrix proteoglycan density but are not always areas of high laminin or fibronectin density. Desmin levels appear to increase at the onset of differentiation and desmin initially accumulates in the ventral pole of each myotube as it begins to form an electrocyte. During differentiation F-actin-positive filament bundles are observed that extend from the nuclei down to the ventrally forming acetylcholine receptor-rich patch. Most filament bundles terminate in the acetylcholine receptor-rich region of the cell membrane. Electron-microscopic autoradiography suggests that the filament bundles attach to the membrane at sites where small acetylcholine receptor clusters are found. The results of this study suggest that, out of the four extracellular matrix components studied, only the distribution of acetylcholinesterase (which may be both matrix- and membrane-bound at this stage) closely parallels that of the acetylcholine receptor, and that F-actin filament bundles terminate in a region of the cell that is becoming an area of high acetylcholine receptor density.

Acetylcholinesterase↗

PubMed1996

Regulatory role of eicosanoids in extracellular matrix overproduction induced by long-term exposure to high glucose in cultured rat mesangial cells.

Accumulation of extracellular matrix in the mesangium and altered renal eicosanoid synthesis are two prominent features of diabetic glomerular disease. We investigated the relationship between eicosanoid and extracellular matrix production in rat mesangial cells cultured under high glucose vs normal glucose conditions. Long-term exposure of rat mesangial cells to high glucose, but not to iso-osmolar mannitol, significantly increased extracellular matrix accumulation and gene expression and transforming growth factor-beta (TGF-beta) mRNA levels, and decreased prostaglandin (PG) E2 synthesis without affecting production of either thromboxane (TX) B2 or PGF2 alpha, with respect to cells incubated in normal glucose. Addition of exogenous PGE2 resulted in a dose-dependent reduction of matrix protein and mRNA levels and TGF-beta gene expression in cells cultured in either normal or high glucose conditions, whereas exposure to exogenous PGF2 alpha produced a significant increment in matrix production and matrix and TGF-beta gene expression in cells grown in normal glucose, but only a slight increase in those cultured in high glucose. Stimulation of endogenous endoperoxide metabolism towards PGE2 and PGF2 alpha synthesis with FCE-22,178, a drug originally developed as TXA2 synthase inhibitor, resulted in a dose-dependent decrease in matrix accumulation and matrix and TGF-beta gene expression which was suppressed by coincubation with the cyclo-oxygenase inhibitor fenoprofen blocking the FCE-22,178-enhanced PG production. In both cell lines, the rate of synthesis of TXA2 was very low and the selective blockade of its synthesis (by two other TXA2 synthase inhibitors, OKY-046 and Ridogrel) or action (by the TXA2 receptor antagonist BM-13,177) did not alter matrix production or TGF-beta mRNA levels. These results suggest that the cyclo-oxygenase pathway is involved in the regulation of matrix changes induced by high glucose in rat mesangial cells; the reduced production of PGE2 may enhance the synthesis or potentiate the effect of stimulators of ECM formation such as TGF-beta, whereas TXA2 does not appear to be involved. These data also indicate that glucose-enhanced mesangial matrix accumulation may be prevented by exogenous PGE2 or by drugs capable of increasing endogenous PGE2 synthesis.

Animals↗

PubMed1985

Extracellular matrix microfibrils are composed of core proteins coated with fibronectin.

Extracellular proteins of cultured calf aortic smooth muscle cells consist predominantly of microfibrils 10-20 nm in diameter typical of "elastin-associated" microfibrils described in many tissues. Chemical and immunochemical evidence is presented that microfibrils consist of at least two proteins: core protein and fibronectin. Insoluble proteins of the microfibrils were obtained in the form of a pellet and antibodies raised in rabbits against these components. The antisera reacted with the insoluble microfibrillar proteins and with soluble fibronectin in enzyme-linked immunosorbent assay, and immunostained the extracellular microfibrils in cultured cells. An immunoglobulin (Ig) fraction was prepared and absorbed with fibronectin. The absorbed IgG retained its reactivity with the microfibrillar proteins but was no longer reactive with soluble fibronectin. Immunofluorescence studies were carried out using the absorbed IgG and IgG to soluble fibronectin. Both antibodies showed immunoreactive microfibrils in the extracellular matrix of cells in log phase. However, with increasing time in culture, as the cells reached confluence, the immunofluorescence of microfibrils reacting with the absorbed IgG became less intense, whereas that of microfibrils reacting with IgG to fibronectin increased; in confluent cells, essentially no staining was detected with the absorbed IgG, and a dense network of intensely stained microfibrils was seen with IgG to fibronectin. Treatment of these cultures with urea led to partial dissociation of the fibronectin and increased visualization of the microfibrils with the absorbed IgG; double-label immunofluorescence showed that both proteins occurred on the same microfibrils. The localization of immunoreactive sites to the extracellular microfibrils was confirmed by immunoelectron microscopy. Nearly quantitative cleavage with CNBr failed to dissociate the antigenically active fragments of fibronectin from the CNBr fragments of the core proteins of the microfibrils. It was concluded that microfibrils contain core proteins and fibronectin that are codistributed in insoluble, possibly covalently cross-linked, aggregates. The core proteins are first deposited by the cell and, as a function of time in culture, fibronectin gradually coats their surface.

Animals↗

PubMed1998

Binding to human extracellular matrix by Neisseria meningitidis.

Adhesion of Neisseria meningitidis strains to extracellular matrix (ECM) and purified matrix components was examined. Most strains bound to subendothelial ECM as well as to immobilized fibronectin and types I, III, and V collagen. Strains from healthy carriers adhered significantly better than isolates from patients. The binding site was localized to the central 75-kDa cell-binding domain of the fibronectin molecule. This domain has not been described previously to interact with bacterial structures.

Bacterial Adhesion↗

PubMed1993

Influence of extracellular matrix on the proliferation and differentiation of adrenocortical cells in culture.

Extracellular matrix is indispensable for cell differentiation in vivo. The aim of this study is to examine effects of extracellular matrix on adrenocortical cells embedded in collagen gel in terms of cellular proliferation and differentiation. Dissociated human or bovine adrenocortical cells were embedded in collagen gel; the gel was then immediately thin-coated on the bottom of culture dishes. The cortical cells were thus trapped in collagen and cultured in monolayer, a suitable means for observation of culture cells. To the authors' best knowledge, this "collagen gel-embedded" monolayer culture is described here for the first time. Cortical cells were spherical in shape and had the activities of proliferation and steroid production in collagen gel matrix of this culture method. Aldosterone production in particular tended to be maintained much longer than in conventional monolayer culture. This method seems to provide a physiological environment in which to study the differentiation of cortical cells.

Adrenal Cortex↗

PubMed1991

Characterization of a novel heparan sulfate proteoglycan found in the extracellular matrix of liver sinusoids and basement membranes.

A novel heparan sulfate proteoglycan (HSPG) present in the extracellular matrix of rat liver has been partially characterized. Proteoglycans were purified from a high salt extract of total microsomes from rat liver and found to consist predominantly (approximately 90%) of HSPG. A polyclonal antiserum raised against this fraction specifically recognized HSPG by immunoprecipitation and immunoblotting. The intact, fully glycosylated HSPG migrated as a broad smear (150-300 kD) by SDS-PAGE, but after deglycosylation with trifluoromethanesulfonic acid only a single approximately 40-kD band was seen. By immunocytochemistry this HSPG was localized in the perisinusoidal space of Disse associated with irregular clumps of basement membrane-like extracellular matrix material, some of which was closely associated with the hepatocyte sinusoidal cell surface. It was also localized in biosynthetic compartments (rough ER and Golgi cisternae) of hepatocytes, suggesting that this HSPG is synthesized and deposited in the space of Disse by the hepatocyte. The anti-liver HSPG IgG also stained basement membranes of hepatic blood vessels and bile ducts as well as those of kidney and several other organs (heart, pancreas, and intestine). An antibody that recognizes the basement membrane HSPG found in the rat glomerular basement membrane did not precipitate the 150-300-kD rat liver HSPG. We conclude that the liver sinusoidal space of Disse contains a novel population of HSPG that differs in its overall size, its distribution and in the size of its core protein from other HSPG (i.e., membrane-intercalated HSPG) previously described in rat liver. It also differs in its core protein size from HSPG purified from other extracellular matrix sources. This population of HSPG appears to be a member of the basement membrane HSPG family.

Animals↗

PubMed2001

Human corneal epithelial extracellular matrix perlecan serves as a site for Pseudomonas aeruginosa binding.

PURPOSE: Previous data has shown that basement membrane associated perlecan serves as a binding site for Pseudomonas aeruginosa in the wounded mouse cornea. The current study determined whether it also provides a binding site for Pseudomonas aeruginosa in transformed human corneal epithelium. METHODS: Bacterial adherence to transformed human corneal epithelial cells grown in normal or in media containing various inhibitors of glycosaminoglycan synthesis was tested. Bacterial binding was similarly tested in wild-type and in mutant Chinese hamster ovary cell lines naturally deficient in glycosaminoglycan synthesis. Transformed human corneal epithelial extracellular matrix also was tested before and after treatment with anti-proteoglycan monoclonal antibodies or heparinase III before bacterial inoculation. Scanning electron microscopy was used to quantitate adherent bacteria. Intact transformed human corneal epithelial cells or extracellular matrix, the latter either treated or not treated with heparinase III or chondroitin ABC lyase were stained to localize perlecan. RESULTS: Examination of the binding of bacteria to transformed human corneal epithelial cells (normal media vs with inhibitors) and Chinese hamster ovary cell lines suggested that bacterial binding was not associated with the surface of either cell type. In contrast, anti-perlecan antibody, as well as heparinase III decreased the binding of bacteria to corneal extracellular matrix. Fluorescence staining localized perlecan to the extracellular matrix beneath the corneal epithelial cells. CONCLUSIONS: Perlecan localized to the extracellular matrix but not the apical surface of transformed human corneal epithelial cells, provides a binding site for Pseudomonas aeruginosa.

Animals↗

PubMed1987

Schwann cell myelination in a chemically defined medium: demonstration of a requirement for additives that promote Schwann cell extracellular matrix formation.

Primary cultures of embryonic rat Schwann cells and sensory nerve cells can be grown in the serum-free defined medium N2, but the Schwann cells fail to deposit extracellular matrix and do not ensheath or myelinate axons. Previously these functions could be induced only in media supplemented with serum and chick embryo extract. Here we show that supplementing N2 medium with ascorbic acid and a commercial preparation of the glycoprotein fetuin or purified bovine serum albumin in the absence of serum or other undefined media components leads to increased production of Schwann cell extracellular matrix and extensive myelin formation by Schwann cells. Ascorbic acid is required for production of collagen type IV. Both ascorbic acid and one of the proteins are required for optimal extracellular matrix formation and myelination. These results lend support to the hypothesis that production of extracellular matrix by Schwann cells is necessary for myelination of nerve fibers.

Animals↗

PubMed1998

Identification, characterization, and mapping of Ecm1, a locus affecting extracellular matrix production and lesion size in Cochliobolus heterostrophus.

A mutant of Cochliobolus heterostrophus lacking the outer layer of extracellular matrix around its germ tubes and hyphae was obtained by mutagenizing protoplasts. The mutant not only lacks the outer matrix, but also produces much smaller lesions on corn leaves than nonmutant strains; the area of mutant lesions averages 0.6 mm2 compared with 5.8 mm2 for nonmutant lesions. Genetic analysis demonstrated that the failure to produce the outer matrix cosegregates with the reduced lesion size, indicating that the two traits are controlled by the same locus, designated Ecm1 (Extracellular Matrix Deficient). The mutant retains normal growth on media and normal abilities to germinate, form appressoria, and penetrate corn leaves. This indicates that the outer matrix is not necessary for infection prior to entrance of the fungus into the leaf. It also indicates that the pathogenicity defect in this mutant is manifested after penetration. To facilitate future tests of whether the pathogenicity defect is caused by the lack of the outer matrix, Ecm1 was mapped. Seven markers linked to Ecm1 were found by analysis of amplified fragment length polymorphisms. Ecm1 maps to chromosome 4; the closest markers to Ecm1 are 5 cM distant, which is estimated to represent about 115 kb.

Ascomycota↗

PubMed1990

Dermatitis herpetiformis and gluten sensitive enteropathy (including celiac disease)--increased subepithelial extracellular matrix viscosity due to gliadin.

It is now firmly established that dermatitis herpetiformis (DH) is associated with gluten sensitive enteropathy (GSE), although the GSE of DH is generally milder than that form which occurs in celiac disease. The toxic fraction of gluten is in the gliadin, a protein fraction. Gliadin is absorbed in GSE and antigliadin antibodies are present in both DH and celiac disease. There is a question of a cross reactivity between reticulin and gliadin. Gliadin is reported to bind to reticulin. Reticulin has a glycosaminoglycan component. Fibronectin, another component of ground substance, also binds to reticulin. Reticulin and fibronectin are important in basement membrane areas and play a role in basement membrane attachment. Gluten may also exert a lectin effect on gastrointestinal mucosa which contributes to the underlying extracellular matrix. DH and GSE have different pathologies because of their different anatomical sites. The pathomechanisms of both diseases can be explained by one mechanism. Gliadin, or a peptide fraction from it, enters or combines with the extracellular matrix and increases tissue viscosity. The protein fraction of glycosaminoglycans in the extracellular matrix is known to control viscosity. In DH the increased extracellular matrix viscosity would interfere with the diffusion of tissue fluid in the dermal papillae and leads to vesicle formation. The intestinal villi serve a very different function. In GSE the increased extracellular matrix viscosity would decrease adsorption from the intestinal tract producing villi with less volume (shortened or atrophic). The shortened villi decrease the production of digestive enzymes and the absorptive surface. The decreased movement of nutrient tissue fluid supplied to the intestinal epithelial cells also eliminates the microvilli.(ABSTRACT TRUNCATED AT 250 WORDS)

Celiac Disease↗

PubMed1990

Quantitation and relative distribution of extracellular matrix in Staphylococcus epidermidis biofilm.

The relationship between adherence of bacteria to foreign bodies and their deposition of extracellular matrix was examined on glass and suture material. To quantitate bacterial adherence, uptake of [3H]thymidine into bacterial DNA was analyzed. Corresponding amounts of extracellular matrix were measured by a new technique using [14C]glucose incorporation. This study shows that [14C]glucose preferentially labeled bacterial strains in proportion to biofilm production. The ratio of 3H14C in high biofilm producers was 0.9 and in low producers it was 3.7. Radioactive identification of organisms as high and low producers was confirmed by electron microscopy. The results presented here show that production and accumulation of biofilm over time is a stable characteristic in different strains of S. epidermidis. The use of ratios reflecting radiolabeling of bacteria and biofilm by [3H]thymidine and [14C]glucose, respectively, is a quantitative yet simple technique to assess extracellular matrix of different strains of S. epidermidis.

Animals↗

PubMed2006

Role of cathepsin K in the turnover of the dermal extracellular matrix during scar formation.

Cathepsins are a group of cysteine proteinases that are involved in various aspects of extracellular matrix turnover. The collagenolytic activity of cathepsin K plays a pivotal role in bone resorption and lung matrix homeostasis, but so far has not been described in skin. To study the role of cathepsin K in the turnover of the cutaneous extracellular matrix, we studied the expression of cathepsin K in human skin and in cultured primary neonatal skin fibroblasts. Normal skin exhibited only low levels or no expression of cathepsin K. In contrast, dermal fibroblasts in surgical scars showed strong cytoplasmic cathepsin K expression. Cathepsin K expression was most prominent in young scars and declined with time. Cultured neonatal primary fibroblasts showed strong cathepsin K staining in the perinuclear endosomal compartment, consistent with intracellular degradation of internalized collagen in lysosomes. Cathepsin K was also found to be strongly expressed in keloids and dermatofibromas, but not in sclerotic areas of morphea. Our data suggest that cathepsin K may play an important role in the homeostasis of the dermal extracellular matrix and the dynamic equilibrium between matrix synthesis and proteolytic degradation, by counteracting deposition of matrix proteins during scar formation with its matrix-degrading activity.

Cathepsin K↗

PubMed1998

The extracellular matrix in multiple sclerosis lesions.

Receptor-mediated recognition of extracellular matrix (ECM) molecules transduces intracellular signals that determine many cellular behaviors under normal and pathological conditions. This review briefly describes the major central nervous system (CNS) white matter ECM molecules and their receptors, the mechanisms by which the ECM may be altered in multiple sclerosis (MS) lesions, and potential roles for inflammatory and CNS resident cell interactions with specific ECM molecules in these lesions. In acute lesions, ECM recognition and cell signaling contribute to leukocyte migration through blood vessel walls, and within the CNS, through leukocyte and CNS resident cell immune activation and demyelination. An abnormal ECM in chronic MS lesions may preclude ECM-dependent developmental processes that lead to remyelination and axon regeneration. Thus, the composition of the ECM and the cellular recognition of its individual components may be critical to the pathogenesis of all stages of MS. An understanding of these complex interactions may lead to additional strategies for intervention and the promotion of reparative processes in MS patients.

Axons↗

PubMed2002

Computer-assisted quantitative analysis of immunofluorescence staining of the extracellular matrix in rat dorsal and ventral spinal roots.

The endoneurial extracellular matrix (ECM) is produced by Schwann cells and fibroblasts under the control of axons. Dorsal and ventral spinal roots contain different types of axons, but information is not available on differences in the composition of their ECM. A comparison was made of the intensity of immunofluorescence staining of chondroitin sulfate proteoglycan, fibronectin, tenascin and thrombospondin in the endoneurial ECM of rat dorsal and ventral spinal roots. Sections of dorsal and ventral roots were incubated simultaneously for indirect immunofluorescence detection of the epitopes studied. Brightness of immunofluorescence staining was assessed by computer-assisted image analysis using interactive segmentation of digitized images to select areas to be analyzed. Our results revealed quantitative differences in the composition of endoneurial ECM of spinal dorsal and ventral roots, probably due to the presence of different types of axons. The ECM composition of the endoneurium in dorsal and ventral roots may be related with the creation of extrinsic conditions that support differential regeneration of afferent and motor axons after injury.

Animals↗

PubMed1996

Regulation of urokinase plasminogen activator production in implanting mouse embryo: effect of embryo interaction with extracellular matrix.

Embryo implantation in the mouse is an invasive process and requires the action of proteinases, including plasminogen activator (PA) and metalloproteinases. After the implanting embryo establishes close contact with the endometrium, the invasion process begins, at least in part, through interactions of the embryo with the extracellular matrix in the endometrium. This study determined whether embryo interaction with extracellular matrix components would affect the secretion of PA in vitro. PA in vitro. Mouse embryos were collected from the uterus on Day 3.5 of development, just before implantation, and were cultured dishes precoated with bovine serum, plasma fibronectin, or BSA (control). Embryos cultured on serum- or fibronectin-coated dishes secretes significantly more PA than those cultured on BSA. The effect of fibronectin was inhibited by hexapeptides that contained the integrin-recognizing Arg-Gly-Asp sequence. This indicates that the action of fibronectin in enhancing PA secretion is mediated through its receptor (integrins) in the embryo. Fibronectin fragments reproduced the effect of the whole fibronectin molecule, suggesting that the clustering of integrins by specific ligands is responsible, at least in part, for the increase PA secretion. The increase in PA secretion was a specific response to fibronectin rather than a reflection of increased total protein secretion, and was at least partially a result of the increased steady-state level of PA mRNA in the cultured embryos. Laminin was as effective as fibronectin in promoting PA secretion. Epidermal growth factor increased PA secretion, probably by promoting the interaction of the embryos with the extracellular matrix. In summary, our findings indicate that the interactions of the implanting embryos with their extracellular matrix may regulate trophoblast invasion by controlling PA secretion.

Amino Acid Sequence↗