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Biomedical subjects

K Norrby

Publications and source records attributed to K Norrby.

At least 19 recordsLinked to original sources
PubMed1995

Evidence of a dual role of endogenous histamine in angiogenesis.

The specific activation of mast cells in situ causes vigorous local mast-cell mediated angiogenesis (MCMA). The mast cell is a major source of histamine and, as recently reported, specific histamine H1- and H2-membrane receptor antagonists are able individually to significantly suppress MCMA in rats, as assessed using the mesenteric window angiogenesis assay (MWAA). In addition to membrane receptors for histamine, a type of intracellular histamine receptors, designated Hic, has been described. It is now demonstrated that the potent Hic-receptor antagonist DPPE (N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl), administered parenterally, stimulates MCMA significantly in rats, as quantified by the MWAA. Although the target cell(s) are not known, there are several ways by which their Hic receptors could be activated: uptake of histamine released from mast cells, mobilization from preformed cytoplasmic and nuclear stores, and production of de novo histamine by histidine decarboxylase activity. The fact that the occupancy by histamine of H1- and H2-membrane receptors stimulates MCMA and the occupancy by histamine of Hic inhibits MCMA suggests that endogenous histamine is capable of regulating angiogenesis by a dual mode of action. This is apparently the first report ascribing a dual role of this type in angiogenesis to a single molecule.

Animals↗
PubMed1994

Basic fibroblast growth factor and de novo mammalian angiogenesis.

Using the rat mesenteric-window assay, the de novo angiogenic effect of basic fibroblast growth factor (bFGF) in the intact, adult, normally vascularized test tissue was analyzed using quantitative microscopy including image analysis. Basic FGF was injected ip at doses of 10, 100, and 1000 ng twice daily for 4.5 days and the animals, which were not subjected to surgery, were sacrificed in groups every week for 6 consecutive weeks. The scale and dynamics of the angiogenic response were measured in terms of variables related to microvascular spatial expansion and density. The growth factor-induced angiogenesis in a dose-dependent, nonlinear manner and the angiogenesis displayed distinctly dose-dependent kinetics. The middle dose thus caused angiogenesis that peaked already at Day 7, thereby suggesting a direct effect. The high dose caused angiogenesis that peaked at Day 14, which also appears to be compatible with a direct effect. The low dose caused a more prolonged angiogenic response which did not peak until Day 21 or 28, depending on which variable was measured, which is indicative of an indirect effect. Clearly, the findings suggest that the molecular and cellular mechanisms of bFGF-mediated angiogenesis are dose-dependent.

Animals↗
PubMed1994

Mast-cell histamine is angiogenic through receptors for histamine1 and histamine2.

The activation of mast-cells in situ induces angiogenesis in normally vascularized, adult mammalian tissue. Since the secreting mast-cell characteristically releases histamine, we studied the possible role of histamine in the outcome of mast-cell mediated angiogenesis using the rat mesenteric window assay. One H1-receptor antagonist, brompheniramine maleate (BPA), and one H2-receptor antagonist, metiamide, were separately administered systemically (s.c.) at non-toxic doses during the period of angiogenesis induction. Angiogenesis was effected by i.p. injections of the mast-cell secretagogue compound 48/80 for 5 consecutive days. The animals were killed 14 days after the start of the i.p. and s.c. treatment, close to the middle of the expanding angiogenic phase of the angiogenic reaction studied. Angiogenesis was quantified in terms of (a) the number of vessel profiles per unit tissue length (No/UL), which reflects mainly the degree of branching and/or tortuosity, (b) the relative vascularized area (VA), which is a measure of spatial extension, and (c) the vascular density (VD), a measure of vessel density per unit area of vascularized tissue. Whereas BPA significantly suppressed No/UL, metiamide significantly reduced No/UL and VD in statistical terms suggesting that endogenous mast-cell histamine is angiogenic through both H1- and H2-receptors. This appears to be the first paper to report that the occupancy of H2-receptors is angiogenic.

Animals↗
PubMed1994

Endotoxin is angiogenic.

The formation of new blood vessels, angiogenesis, is an important event in inflammation, wound healing and tumour growth. Mediators produced by various cells when exposed to endotoxin include cytokines (tumour necrosis factor, interleukins 1 and 6, and basic fibroblast growth factor) which, it has been suggested, stimulate angiogenesis. The angiogenic effect of endotoxin (lipopolysaccharide, LPS) was studied in rats using the quantitative mesenteric window assay. Adult rats were injected intraperitoneally with Escherichia coli LPS (5 pg/ml-20,000 ng/ml) twice daily for 4.5 consecutive days and were sacrificed 14 days after the start of this treatment. An angiogenic response was observed at concentrations of > 2 ng/ml in a dose-dependent manner. No inflammatory cellular exudate was seen in the test tissue at the time of angiogenesis analysis. Suppressed body-weight gain, a marker of the systemic effect of LPS in the rat, was significant only at the highest dose tested. The data suggest that endotoxin-mediated neovascularization could be a component of inflammation and wound healing.

Animals↗
PubMed1994

A morphometric method to evaluate angiogenesis kinetics in the rat mesentery.

The mesenteric window angiogenesis assay permits the objective determination of a number of angiogenesis parameters in peritoneal connective tissue. The time-course of the angiogenic response that follows activation of endogenous connective tissue mast cells in situ in normal adult rats was investigated using a set of quantitative variables. A method developed to quantify angiogenesis kinetics by evaluation of microvascular ramification and elongation is presented. The angiogenic process was found to proceed long after the termination of the inducing selective mast-cell activation and was thus to a large extent self-perpetuating. The angiogenesis also continued long after the maximum level of the ingrowth of vessels from adjacent tissues, the vessel density, and ramification within the vascularized areas was reached. The whole angiogenic phase lasted as long as 5-6 weeks and the total vessel density, i.e. the vascular area multiplied by the vessel density, remained elevated over controls throughout the course of the 99-day experiment. It appears that angiogenesis kinetics based on truly quantitative assessment of relevant parameters, as in the present study, will be a useful means in elucidating how positive and negative angiogenic factors, individually or in combination, influence the microvascular arborization.

Animals↗
PubMed1993

Heparin and angiogenesis: a low-molecular-weight fraction inhibits and a high-molecular-weight fraction stimulates angiogenesis systemically.

The systemic effect of 2.4-, 8-, 15- and 22-kDa heparin fractions on saline-mediated angiogenesis in rats was compared with the systemic effect of an unfractionated Na-standard heparin (UFH), which had a mean molecular weight of about 15 kDa. Using the mesenteric-window assay in adult rats, the relative vascularized area was quantified morphometrically. The angiogenic response was strictly related to the mean molecular weight of the saccharides (r = 0.97); the 2.4-kDa fraction suppressed angiogenesis by 46% (p < or = 0.001), whereas the 22-kDa fraction stimulated angiogenesis by 123% (p < or = 0.01), as compared with the UFH. The UFH, thus, contained chain-length-related fragments that induced systemic antiangiogenic and angiogenic activity.

Animals↗
PubMed1993

Two potentially angiostatic factors, a steroid and L-azetidine-2-carboxylic acid, antagonize one another.

The proline analogue L-azetidine-2-carboxylic acid (LACA) systemically suppressed mast-cell-mediated angiogenesis, as measured by the rat mesenteric-window method. Dexamethasone and methylprednisolone at very low and non-toxic s.c. doses also somewhat inhibited the angiogenesis. Most interestingly, the co-administration of either of these steroids with LACA paradoxically stimulated angiogenesis. These findings suggest that in the future search for candidates for clinically-useful systemic angiostatic remedies, one may have to focus not only on the effect of individual drugs or agents, but also on the effect of such putative anti-angiogenic agents when co-administered. The fact that two potentially angiostatic agents can antagonize one another has not previously been reported.

Animals↗
PubMed1993

The proline analog L-azetidine-2-carboxylic acid modifies the neovascularization pattern by inhibiting branching or tortuosity and stimulating spatial expansion in the rat mesentery.

The L-proline analog L-azetidine-2-carboxylic acid, LACA, systemically inhibited autogenous mast-cell-mediated angiogenesis in normal rats. LACA was injected s.c. at a dose of 100 mg/kg/day and the angiogenic response was assessed in the mesenteric windows. Angiogenesis was induced by the i.p. injection of a highly-selective activator of the mast cells in situ. At these concentrations, LACA appeared to be non-toxic since it affected neither the physiologic body-weight gain nor the mast-cell secretory capacity in the test tissue. The LACA-treatment markedly reduced (p < or = 0.01) microvascular formation in terms of the number of vessels per unit length of tissue (No/mm) but, at the same time, tended to stimulate the spatial expansion of the newly-formed vasculature in terms of the vascularized area (VA). Since No/mm is a measure that reflects the degree of branching, the degree of tortuosity and VA, the findings suggest that LACA inhibited branching/tortuosity and simultaneously stimulated the spatial expansion of the new microvasculature. The difference in response to LACA in terms of No/mm and VA was highly statistically-significant (p < or = 0.0001). The fact that an agent may affect neovascular branching/tortuosity and spatial extension in a distinctly contradictory fashion has not been reported previously.

Animals↗
PubMed1992

Cyclosporine is angiostatic.

The systemic effect of the immunosuppressive drug cyclosporine (CS) on formation of new blood vessels was studied quantitatively in rats using the mesenteric-window assay. Angiogenesis was induced by i.p. injection of saline. CS at a s.c. dose of 4 mg/kg/day, which is in the range used clinically, suppressed angiogenesis (inhibiting branching or tortuosity more than spatial expansion), and appeared to be non-toxic. This is the first report on an apparently selective angiostatic effect of CS. The finding is likely to have implications for the clinical use of CS, not only in certain types of organ transplantation but possibly also in psoriasis and other angiogenesis-dependent diseases.

Animals↗
PubMed1992

On the quantitative rat mesenteric-window angiogenesis assay.

The rodent mesenteric-window angiogenesis assay permits the quantitative assessment of angiogenesis in adult, normally-vascularized mammalian tissue in the intact animal. Using appropriate optical magnifications, even very small, newly-formed vessels are recorded. The ultimate value of the model will, of course, depend on how pertinent it is to the features which govern angiogenesis in the tissues that are involved in clinically-relevant, angiogenesis-related diseases.

Allantois↗
PubMed1992

Heparin enhances angiogenesis by a systemic mode of action.

A systemically-administered standard sodium heparin, but not an oligosaccharide fraction derived from the heparin, significantly potentiated angiogenesis induced by saline in normal rats, as assessed by the quantitative mesenteric window angiogenesis assay. This is the first unambiguous evidence that any single specific mast-cell product can potentiate angiogenesis in normally vascularized mammalian tissue. Whether systemic treatment with a heparin-like substance may be useful for stimulating neoangiogenic formation of collaterals in situations of relative microvascular insufficiency, such as coronary collaterals in patients suffering from ischaemic heart disease, is briefly discussed.

Animals↗
PubMed1990

Increased angiogenesis in diabetes.

Rats with streptozotocin-induced diabetes mellitus showed a 3.4-4.5 times increased angiogenic response following mast-cell activation in situ as compared with age-matched normal controls. The test tissue used was the mesenteric window, which we have previously exploited as a quantitative angiogenesis assay. In the present study two independent techniques for quantifying the angiogenic response showed essentially the same result. The finding of a pathologically increased angiogenic reaction in the diabetic animals is noteworthy since some of the most harmful complications of diabetes in man relate to proliferative vascular lesions.

Animals↗
PubMed1990

On mast-cell-mediated angiogenesis in the rat mesenteric-window assay.

Testosterone propionate injected s.c. significantly reduced the mast-cell mediated angiogenic response occurring in prepubescent rats, thereby indicating that this angiogenic reaction can be influenced by hormonal stimuli. Since the newly-formed vessels are very small, one could expect that microscopic examination would be needed to quantify the vasculature. When studying the discernment of vessels at optical magnifications of between x 100 and x 1000 in sections of methacrylate-embedded mesenteric window, we found that the number of discernible vessels increased dramatically as the magnification increased. This not only underlines the genuine microvascular character of the reaction but also demonstrates the need for high-power magnification when truly quantifying an angiogenic reaction by optical means.

Animals↗
PubMed1990

Quantitative angiogenesis in spreads of intact rat mesenteric windows.

By introducing a new mode of the recently described mesenteric-window angiogenesis assay (K. Norrby, A. Jakobsson, and J. Sörbo, 1986, Virchows Arch. B. Cell Pathol. 52, 195-206) we measured the entire vascular tree in terms of the vascularized area and the vascular density in spreads of intact mesenteric windows in rats receiving a terminal iv infusion of an ink-gelatin solution to visualize the vessels. Adult and prepubescent rats given ip injections of the mast-cell secretagogue Compound 48/80 or the saline vehicle, as well as untreated litter mates, were used. Following mast-cell activation, both prepubescent and adult rats showed a significant angiogenesis taken as the vascularized area and the vascular density in spreads compared with those of the vehicle-treated animals. In fact the 48/80-treatment increased the vasculature 100-fold compared with the untreated controls. The finding of experimentally induced angiogenesis occurring in rats of all ages should make the assay useful in a wide range of angiogenesis experiments.

Aging↗
PubMed1990

Protamine and mast-cell-mediated angiogenesis in the rat.

Different doses of protamine sulphate (PS) given s.c. (at 12-h intervals) were tested for signs of non-specific toxicity measured as effect on body weight and small-gut proliferation as well as on mast-cell secretion and mast-cell-mediated mitogenesis in the mesenteric windows following i.p. injection of Compound 48/80, a potent mast cell secretagogue, in normal rats. In a non-toxic dose range, the effect of PS on mast-cell-mediated angiogenesis, effected by 48/80, was quantified as the number of vessels per mm of mesenteric window in histological sections at x 400. No intelligible dose-effect relationship was discernible between the dose of PS given and the effect on angiogenesis. Only in a tight interval, at 40 mg PS/kg but not at 20 or 60 mg PS/kg, was the angiogenesis statistically significantly suppressed. Hence, it was concluded that PS can be angiostatic but does not exert a more general angiostatic effect in the autogenous systems used.

Animals↗
PubMed1990

Increased angiogenesis during wound healing in rats with streptozotocin-diabetes.

The neovascularization that occurs during wound healing in the perforated mesenteric membrane was quantitatively studied in rats with streptozotocin induced diabetes. The virtually avascular mesenteric windows in both controls and diabetic rats were perforated with a scalpel during laparatomy. At designated intervals during days 1-63 postoperatively, the mesenteries were excised, fixed, and cut perpendicularly through the wound margin or the central part of a closed wound. An unperforated window from each animal served as an internal control. The numerical microvascular density of the healing tissue and the unperforated control mesentery was assessed by morphometry on photomicrographs with regard to number of vascular profiles per mm length of mesentery or mm2 sectioned tissue area. The vascularity in unperforated windows of both diabetics and age-matched healthy controls was unaffected by laparotomy whereas perforation significantly increased the numerical microvascular density of the mesentery. The onset of angiogenesis in the perforated mesenteries occurred on days 5-7 and in both diabetics and controls, wound areas retained an increased numerical microvascular density throughout the observation period. The numerical microvascular density of the wound areas was greater in diabetics than controls following closure of the wounds. A number of wounds healed without being vascularized. The number of vascularized wounds was significantly higher in diabetic animals than controls.

Animals↗