Heparin and Growth Control of Vascular Cellsa

Thompson, Robert W.; Orlidge, Alicia; D’Amore, Patricia A.

doi:10.1111/j.1749-6632.1989.tb22508.x

Cited by 17 publications

(9 citation statements)

References 49 publications

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“…The presence of mast-cell derived heparin might also prolong the FGF half-life by protecting it against protease actions [32,33]. A similar mechanism may act in the induction of collateralization as we have shown that heparin is effective in increasing the levels of FGF-like molecules released from myocardial tissue [42].…”

Section: Fgf Is Localized On Cell Surfaces In Vitro and In Vivomentioning

confidence: 81%

Modes of FGF release in vivo and in vitro

D’Amore

1990

Cancer Metast Rev

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150

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The fibroblast growth factors (FGFs) are a family of polypeptide growth regulators. The prototypes of this family are acidic and basic FGF. Unusual among their characteristics are a high affinity for the glycosaminoglycan heparin and the lack of a signal sequence for secretion. Other members of the FGF family include a number of oncogene products that also display heparin affinity but do possess signal sequences. Results from early tissue culture studies were consistent with the prediction that acidic and basic FGF would not be secreted. Investigators found that virtually no FGF was secreted into conditioned media, instead it remained cell-associated and was deposited into the basement membrane. More recently, however, a number of studies have indicated that a small amount of FGF is 'released' from cells where it is postulated to act as an autocrine regulator. Acidic and basic FGF have been localized in basement membranes both in vivo and in vitro. The mode of release to this site is also unclear but may be secondary to the mechanisms cited above with soluble FGF becoming bound to heparan sulfate molecules in the extracellular matrix. A number of observations have indicated that matrix-bound FGF is biologically active in vitro. There are no data to indicate whether the same is true for FGF bound to basement membranes in vivo. In addition to its apparent sequestration in the basement membrane, FGF has also been localized to the surface of a variety of normal and tumor cell types. In particular, endothelial cells have been shown to possess two classes of FGF-binding sites: low abundance, high-affinity receptors that mediate the biological activity as well as high abundance, low affinity binding sites. The physiologic relevance of FGF binding to these low affinity sites is not clear. The possibility of locally high concentrations of heparin released by mast cells, as well as the presence of heparan sulfate-degrading enzymes, suggests that this glycosaminoglycan bound FGF might be released from these binding sites under some circumstances. Cell surface binding of FGF has also been demonstrated in vivo; in rabbits plasma levels of the growth factor were shown to be dramatically elevated following intravenous heparinization. Since the FGFs were first noted to lack a signal sequence, cell injury has been suspected to be the most likely route for FGF release in vivo. A number of studies using different models of cell injury, including endotoxins and irradiation, have revealed that damaged cells do release FGF.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Fgf Is Localized On Cell Surfaces In Vitro and In Vivomentioning

confidence: 81%

Modes of FGF release in vivo and in vitro

D’Amore

1990

Cancer Metast Rev

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150

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“…Thus, in the heart NG2 is expressed by cardiac myocytes, 2 in large vessels it is expressed by smooth muscle cells (8,10), and in capillaries it is expressed by pericytes (4, 5, 7). The intimate relationship between endothelial cells and their mural cell companions (62-64) allows for extensive cross-talk, and evidence exists for signaling in both directions between the two cell types (65)(66)(67)(68)(69)(70). As a cell surface component of mural cells, NG2 is in position to sequester angiostatin, which otherwise would be available to inhibit proliferation and migration of endothelial cells.…”

Section: Ng2 Interactions With Angiostatin and Plasmin(ogen)mentioning

confidence: 99%

Binding of the NG2 Proteoglycan to Kringle Domains Modulates the Functional Properties of Angiostatin and Plasmin(ogen)

Goretzki

Lombardo

Stallcup

2000

Journal of Biological Chemistry

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Interactions of the developmentally regulated chondroitin sulfate proteoglycan NG2 with human plasminogen and kringle domain-containing plasminogen fragments have been analyzed by solid-phase immunoassays and by surface plasmon resonance. In immunoassays, the core protein of NG2 binds specifically and saturably to plasminogen, which consists of five kringle domains and a serine protease domain, and to angiostatin, which contains plasminogen kringle domains 1-3. Apparent dissociation constants for these interactions range from 12 to 75 nM. Additional evidence for NG2 interaction with kringle domains comes from its binding to plasminogen kringle domain 4 and to miniplasminogen (kringle domain 5 plus the protease domain) with apparent dissociation constants in the 18 -71 nM range. Inhibition of plasminogen and angiostatin binding to NG2 by 6-aminohexanoic acid suggests that lysine binding sites are involved in kringle interaction with NG2. The interaction of NG2 with plasminogen and angiostatin has very interesting functional consequences. 1) Soluble NG2 significantly enhances the activation of plasminogen by urokinase type plasminogen activator. 2) The antagonistic effect of angiostatin on endothelial cell proliferation is inhibited by soluble NG2. Both of these effects of NG2 should make the proteoglycan a positive regulator of the cell migration and proliferation required for angiogenesis.

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“…On the other hand, laminin and fibronectin could exert an indirect effect on cell differentiation via their binding to hepa-rin or heparan sulfate proteoglycans (Ruoslahti, 1988;Sasaki et al, 1988). This is intriguing because of the ability of these latter compounds to bind fibroblast growth factor and transforming growth factor (Martin and Timpl, 1987;Ruoslahti, 1988;Thompson et al, 1989), whose analogs apparently participate in the regulation of mesodermal differentiation (see Smith, 1989, for review). The morphogenetic significance of these binding affinities will have to be determined for each developmental system independently.…”

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confidence: 99%

Extracellular matrix of the developing heart in normal and cardiac lethal mutant axolotls, Ambystoma mexicanum

Fransen

Lemanski

1991

Anat. Rec.

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As part of an ongoing study of heart development in normal and cardiac lethal mutant axolotls (Mexican salamanders) we examined the extracellular matrix (ECM) by microscopical methods. With scanning electron microscopy we are unable to detect ECM on the apical surface of cells of the early cardiogenic mesoderm. During the period of lateral plate migration, which coincides with the period of cardiogenic induction of mesoderm by anterior endoderm, there is little ECM, aside from some microfibrils, on the basal surface of the endoderm or mesoderm of the pharyngeal region. Later, a basal lamina (BL) is found on the endoderm and along portions of the developing endocardial and myocardial tubes. By the time of heartbeat initiation the BLs are complete and invested with striated collagen-like fibrils that are sparsely distributed in the "cardiac jelly" of normal and mutant hearts. Striated fibril deposition, which increases with time, is generally random in orientation, with the exception of some regions where there is a preferred directionality. During the post-hatching period striated fibrils appear in the subepicardial space. In addition, branching fibers that are probably elastin appear in the bulbus arteriosus. In these later stages the density of fibrils in the cardiac lethal mutant heart is much less than normal. Indirect immunofluorescent microscopy reveals laminin and fibronectin in the basal laminae of the endocardial and myocardial tubes of both normal and cardiac lethal mutant hearts. In addition, punctate and fibrillar staining for fibronectin, and punctate staining for laminin are found in the cardiac jelly. These matrix proteins are not abundant at the apical (exterior) surface of the myocardium until the epicardium appears.(ABSTRACT TRUNCATED AT 250 WORDS)

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Heparin and Growth Control of Vascular Cellsa

Cited by 17 publications

References 49 publications

Modes of FGF release in vivo and in vitro

Modes of FGF release in vivo and in vitro

Binding of the NG2 Proteoglycan to Kringle Domains Modulates the Functional Properties of Angiostatin and Plasmin(ogen)

Extracellular matrix of the developing heart in normal and cardiac lethal mutant axolotls, Ambystoma mexicanum

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