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Biomedical subjects

M Ziche

Publications and source records attributed to M Ziche.

At least 91 records · Page 5Linked to original sources
PubMed1990

Synergism between gangliosides and basic fibroblastic growth factor in favouring survival, growth, and motility of capillary endothelium.

The experiments reported were motivated by the observation that in vivo gangliosides promoted angiogenesis when the dose of the angiogenic factor was too low to be effective (Ziche et al.: Laboratory Investigation 61:629-634, 1989). As an approach to understanding the mechanism of this modulatory effect, we analysed the influence that gangliosides have on survival, growth, and migration of capillary endothelium when an angiogenesis factor like basic fibroblast growth factor (bFGF) was present in the culture medium. Clones of bovine capillary endothelium were cultivated in media unable to sustain survival over a 72 h period. With this experimental approach, cell survival was evaluated after addition of either bFGF or gangliosides or both to the medium. The Boyden chamber procedure was utilized to measure the influence of bFGF or gangliosides on cell mobilization across a micropore filter. Low doses of both molecules, ineffective when added singly to the culture media, improved all three parameters when added in combination. A synergic effect between bFGF and the gangliosides (GM1, GD1b, GT1b) was observed for the improvement of survival or growth and for the acceleration of endothelial cell migration. The removal of sialic acid from the ganglioside molecule prevented any effect on all three parameters. The addition of sialic acid alone to cultures was also totally ineffective. In the adult organism most angiogenic events occur under conditions of tissue damage. The synergism between gangliosides and bFGF can be interpreted as the initial phase of a process for which endothelial cell survival is the indispensable first step in the formation of a new vascular network.

Animals↗
PubMed1990

Gangliosides, copper ions and angiogenic capacity of adult tissues.

The report summarizes the work of our laboratory aimed at improving the understanding of the angiogenic response of adult tissues, an event that transforms a micro-embolus of neoplastic cells into a growing metastasis. Attention has been focused on tumor-induced angiogenesis. The following aspects of the subject are discussed: (a) relationship between size of vascular network and tumor growth rate or tumor cell population; (b) angiogenic capacity of tumors and role that prostaglandin E1 may have as an angiogenesis factor; (c) relationship between acquisition of angiogenic capacity and neoplastic transformation of a cell population; (d) modification of tissue composition at the onset of angiogenesis; (e) behaviour of copper ions and copper carriers in the course of the angiogenic response; (f) the influence of gangliosides on endothelial cell motility, survival and growth in vitro; (g) modulation of the angiogenic response by gangliosides (GM1, GT1b) in vivo.

Alprostadil↗
PubMed1990

Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells.

We have investigated the possible effect of substance P (SP), a main mediator of neurogenic inflammation, on the growth of capillary vessels in vivo, and on the proliferation of cultured endothelial cells in vitro. Slow release preparations of SP were implanted into the avascular cornea of New Zealand White rabbits and vessel growth was monitored daily through a slit lamp stereomicroscope. SP (1-5 micrograms/pellet) induced a marked neovascularization. A selective NK-1 receptor agonist [beta-Ala4, Sar9, Met(O2)11]-SP(4-11) also induced neovascularization. The addition of SP to serum-free cultured endothelial cells, isolated from bovine adrenals (BACE) and from human umbilical cord veins (HUVE), increased proliferation of both cell lines in a concentration-dependent manner with maximal activity at 10(-8) M (BACE) and 10(-10) M (HUVE). The selective NK-1 receptor agonist induced a similar proliferative action on both cell lines, while the selective NK-2 receptor agonist [beta-Ala8]-NKA(4-10) and the selective NK-3 receptor agonist [MePhe7]-NKB had no significant effect. Two different SP antagonists [D-Pro2, D-Trp7,9]-SP and [D-Pro4, D-Trp7,9,Phe11]-SP (4-11) blocked the response to SP. These findings indicate that SP can directly stimulate the process of neovascularization, probably through induction of endothelial cell proliferation. This hitherto unraveled activity of SP could play a key role in the trophic action produced by activation of the efferent function of peripheral endings of primary sensory neurons.

Animals↗
PubMed1990

Interleukin 1 is an autocrine regulator of human endothelial cell growth.

Proliferation of endothelial cells is regulated through the autocrine production of growth factors and the expression of cognate surface receptors. In this study, we demonstrate that interleukin 1 (IL-1) is an inhibitor of endothelial growth in vitro and in vivo. IL-1 arrested growing, cultured endothelial cells in G1 phase; inhibition of proliferation was dose dependent and occurred in parallel with occupancy of endothelial surface IL-1 receptors. In an angiogenesis model, IL-1 could inhibit fibroblast growth factor-induced vessel formation. The autocrine nature of the IL-1 effect on endothelial proliferation was demonstrated by the observation that occupancy of cell-surface receptors by endogenous IL-1 depressed cell growth. The potential significance of this finding was emphasized by the detection of IL-1 in the native endothelium of human umbilical veins. A mechanism by which IL-1 may exert its inhibitory effect on endothelial cell growth was suggested by studies showing that IL-1 decreased the expression of high-affinity fibroblast growth factor binding sites on endothelium. These results point to a potentially important role of IL-1 in regulating blood vessel growth and suggest that autocrine production of inhibitory factors may be a mechanism controlling proliferation of normal cells.

Animals↗
PubMed1990

NK1-receptors mediate the proliferative response of human fibroblasts to tachykinins.

1. The effect of synthetic tachykinin selective receptor agonists was studied on the growth of cultured human skin fibroblasts (HF). 2. Human fibroblasts were grown in serum-free conditions in the presence of natural tachykinins (substance P and neurokinin A) and of three synthetic agonists, [beta-Ala4, Sar9, Met(O2)11]-SP(4-11), [beta-Ala8]-NKA(4-10) and [MePhe7]-NKB selective for NK1-, NK2- and NK3-receptors respectively. Cell proliferation was measured by percentage increase in cell number and by [3H]-thymidine uptake following 48 h exposure to agents compared to baseline condition. 3. Neurokinin A (NKA) and substance P (SP) significantly increased cell proliferation the threshold concentrations being 10(-12) and 10(-11) M, respectively. Addition of thiorphan to culture conditions enhanced the effect of SP but not of NKA. 4. The selective NK1-receptor agonist produced a dose-dependent increase in cell proliferation as judged by total cell number and [3H]-thymidine uptake. No significant effect was observed with NK2- and NK3-receptor agonists. 5. These data indicate that the effect of SP on fibroblast proliferation is mediated by interaction with a NK1-receptor type and local metabolism can interfere with the full expression of this effect of SP on cell proliferation.

Autoradiography↗
PubMed1989

Gangliosides promote the angiogenic response.

Formation of new capillaries was induced in rabbit corneas by optimal doses of prostaglandin E1 (PGE1) or basic fibroblastic growth factor. Suboptimal doses of either of these angiogenesis inducers were unable to elicit corneal angiogenesis. However, the addition of gangliosides (GM1 or GT1b) to the insufficient dose of the angiogenic inducer, not only promoted neovascularization but strongly enhanced the number and growth rate of the newly formed capillaries as compared with the effect of an optimal dose of the angiogenesis inducer alone. Removal of the ganglioside stimulation led to the disappearance of the newly formed capillaries. Re-establishment of the ganglioside stimulation renewed the appearance of a conspicuous vascular network. Removal of sialic acid from the ganglioside molecule nullified its stimulatory effect on angiogenesis. GMI or GT1b or sialic acid were not angiogenic by themselves. Corneas ready to be invaded by newly formed capillaries induced by an optimal dose of an angiogenesis factor such as PGE1 had a ganglioside content about twice that of unstimulated corneas. The results are interpreted to indicate that ganglioside molecules influence capillary formation not as angiogenesis inducers but as promoters of vessel morphogenesis. The data support the hypothesis that in vivo the level of gangliosides in the tissue milieu could influence the evolution of pathologic processes in which new formation of capillaries is a critical event.

Alprostadil↗
PubMed1988

Interaction of urokinase with specific receptors stimulates mobilization of bovine adrenal capillary endothelial cells.

On the basis of 125I-labeled plasminogen activator binding analysis we have found that bovine adrenal capillary endothelial cells have specific receptors for human urinary-type plasminogen activator on the cell membrane. Each cell exposes about 37,000 free receptors with a Kd of 0.8958 x 10(-9) M [corrected]. A monoclonal antibody against the 17,500 proteolytic fragment of the A chain of the plasminogen activator, not containing the catalytic site of the enzyme, impaired the specific binding, thus suggesting the involvement of a sequence present on the A chain in the interaction with the receptor, as previously shown in other cell model systems. Both the native molecule and the A chain are able to stimulate endothelial cell motility in the Boyden chamber, when used at nanomolar concentrations. The use of the same monoclonal antibody that can inhibit ligand-receptor interaction can impair the plasminogen activator and A-chain-induced endothelial cell motility, suggesting that under the conditions used in this in vitro model system, the motility of bovine adrenal capillary endothelial cells depends on the specific interaction of the ligand with free receptors on the surface of endothelial cells.

Adrenal Glands↗
PubMed1986

Cooperation of heparin with other angiogenetic effectors.

The heterogeneous variety of factors involved in the induction of vessels to proliferate is briefly reviewed in connection with the possible cooperative role of heparin, a compound indicated by many kinds of evidence to be basically involved in angiogenesis.

Adenosine Diphosphate↗
PubMed1985

Effects of cortisone with and without heparin on angiogenesis induced by prostaglandin E1 and by S180 cells, and on growth of murine transplantable tumours.

Cortisone acetate, locally applied in sustained-release pellets, is effective in inhibiting angiogenesis induced by prostaglandin E1 in the rabbit cornea. The inhibitory effect of cortisone is not increased by addition of heparin. Similar results were obtained with angiogenesis induced by S180 cells. The effects of cortisone with and without heparin were also studied on 5 transplantable murine tumours: 3 variants of B16 melanoma, Lewis lung carcinoma and fibrosarcoma M4. The effect of cortisone in slowing the growth rate of tumours was modestly potentiated by heparin, but no regression of the tumour mass occurred.

Alprostadil↗
PubMed1985

Pyridoxamine as inhibitor of the blood plasma benzylamine oxidase and other copper-containing amine oxidases.

Pyridoxamine inhibits rabbit and pig plasma benzylamine oxidase (BAO), the diamine oxidase of pig kidney and the lysyloxidase of pig aorta in-vitro. In-vivo in the rabbit, the inhibitory activity of pyridoxamine on plasma BAO is antagonized by an increase in the level of this enzyme that is dependent on an increase in rate of synthesis, there being no variation in the degradation rate constant.

Animals↗
PubMed1982

Role of prostaglandin E1 and copper in angiogenesis.

The interstitial fluid of MTW9A and Walker carcinomas and their ethanol extract induced strong angiogenic response in the rabbit (New Zealand White) corneal test. The fluid collected in vivo was rich in E-type prostaglandins, and prostaglandin E1 (PGE1) in particular was strongly angiogenic at the lowest dose as compared with the angiogenic responses of prostaglandins E2, I2, and F2 alpha. Neoplastic fibroblasts also induced a strong angiogenic response, but in indomethacin-treated rabbits neovascularization failed to occur. Copper was concentrated in the cornea during PGE1-induced neovascularization, and copper-deficient rabbits were unable to mount an angiogenic response in the corneal test. Ceruloplasmin, the copper carrier of plasma, was found to be angiogenic at high doses. In indomethacin-treated rabbits, however, ceruloplasmin at the same high doses failed to induce angiogenesis. The experiments are interpreted to indicate that angiogenesis is the end result of a sequence of events, two of which are PGE1 production and copper mobilization in the tissue where neovascularization occurs.

Alprostadil↗
PubMed1982

Angiogenesis and neoplastic progression in vitro.

In vivo cell populations at high risk of neoplastic transformation have been shown to acquire the ability to induce new formation of vessels. The present experiments tested whether the same change occurred during neoplastic transformation in vitro. In four cell populations (human HBL 100 mammary epithelium, BALB/c fibroblasts, C57BL-MG epithelium, and Syrian golden hamster embryo cells), angiogenic capacity appeared during their cultivation in vitro and was evident long before a neoplastic transformation could be recognized. The data were interpreted to support the hypothesis that acquisition of angiogenic capacity by a cell population normally devoid of this capacity indicates an increased risk of neoplastic transformation.

Animals↗
PubMed1982

Ceruloplasmin, copper ions, and angiogenesis.

The ability to induce new formation of capillaries in the cornea was tested for ceruloplasmin, the copper carrier of serum, for fragments of the ceruloplasmin molecule with and without copper, for heparin, and for glycyl-L-histidyl-L-lysine, bound or not bound to copper ions. Male or female 2- to 3-kg New Zealand White rabbits were used. These experiments were prompted by the previous observation of copper accumulation in the cornea during angiogenesis and by the inability of copper-deficient rabbits to mount an angiogenic response. The results showed that the three different molecules were all able to induce angiogenesis provided that they were bound to copper. Fragments of the ceruloplasmin molecule also induced angiogenesis but only when copper was bound to the peptides. The data are interpreted to indicate that copper ions are involved in the sequence of events leading to angiogenesis and that the carrier molecules may be of quite a different nature.

Animals↗
PubMed1981

Angiogenesis and prediction of sarcoma formation by plastic.

The capacity to induce new formation of capillaries was tested in cells attached to plastics. It is known that large plastic coverslips implanted s.c. in CBA mice produce sarcomas more rapidly and in a greater number than do small coverslips. We observed that within a few weeks after implantation the cells attached to the large coverslips showed an angiogenic capacity about 5-fold greater than that of the cells attached to the small coverslips. Months before a sarcoma was evident, angiogenesis induced by the cells attached to the large coverslips predicted the high risk of neoplastic transformation by large coverslips.

Animals↗
PubMed1980

Influence of lithium on mammary tumor growth in vivo.

The possibility that lithium ions stimulate growth of mammary tumors in vivo has been suggested by their mitogenic action in vitro on normal and neoplastic mammary epithelium [8] and their clinical use as stimulators of neutrophil production in tumor-bearing patients treated with cytotoxic drugs [14,15]. Three experiments were performed to assess this possibility. Buffalo/N female rats received a single injection of N-nitrosomethylurea (NMU) at a dose known to produce mammary carcinomas in about 50% of animals under standard conditions. Under lithium treatment, the incidence of tumors did not increase significantly. Sprague-Dawley female rats treated with a single dose of 7,12-dimethylbenz[alpha] anthracene (DMBA), but showing no mammary tumors after 4 months, received lithium in their drinking water for 3 additional months. The number of late-appearing tumors was not increased by lithium treatment. Buffalo/N females with NMU-induced tumors were castrated, and the subsequent changes in tumor volume were compared in lithium-treated and control animals. The regression-regrowth curves were not altered by lithium treatment. These results are in contrast to the growth stimulatory capacity of lithium on mammary epithelium observed in vitro [8] and indicate it is very unlikely that lithium ions have an undesirable growth stimulatory action on primary mammary carcinomas in vivo.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Nitric oxide and angiogenesis.

The steps required for new vessel growth are biologically complex and require coordinate regulation of contributing components, including modifications of cell--cell interactions, proliferation and migration of endothelial cells and matrix degradation. The observation that in vivo angiogenesis is accompanied by vasodilation, that many angiogenesis effectors possess vasodilating properties and that tumor vasculature is in a persistent state of vasodilation, support the existence of a molecular/biochemical link between vasodilation and angiogenesis. Several pieces of evidence converge in the indication of a role for nitric oxide (NO), the factor responsible for vasodilation, in physiological and pathological angiogenesis. Data originated in different labs indicate that NO can act both as an 'actor' of angiogenesis and as a 'director of angiogenesis', both functions being equally expressed during physiological and pathological processes. NO significantly contributes to the prosurvival/proangiogenic program of capillary endothelium by triggering and transducing cell growth and differentiation via endothelial-constitutive NO synthase (ec-NOS) activation, cyclic GMP (cGMP) elevation, mitogen activated kinase (MAPK) activation and fibroblast growth factor-2 (FGF-2) expression. Re-establishment of a balanced NO production in the central nervous system results in a reduction of cell damage during inflammatory and vascular diseases. Elevation of NOS activity in correlation with angiogenesis and tumor progression has been extensively reported in experimental and human tumors. In the brain, tumor expansion and edema formation are sensitive to NOS inhibition. On this basis, the nitric oxide pathway appears to be a promising target for consideration in pro- and anti-angiogenic therapeutic strategies. The use of NOS inhibitors seems appropriate to reduce edema, block angiogenesis and facilitate antitumor drug delivery.

Angiogenesis Inhibitors↗