[Freedom of choice and monopoly. When "my" patient goes to others].
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Family Practice↗
Biomedical subjects
K Norrby
Publications and source records attributed to K Norrby.
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↗
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↗
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↗
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↗
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↗
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↗
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↗
[A meeting of general practitioners in Jerusalem. Good physician-patient relations lead to higher quality of care].
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Clinical Competence↗
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↗
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↗
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↗
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↗
Evidence of an acquired increase in mitogenesis in streptozotocin-diabetic rats, apparently relating to some tissue factor.
We have previously reported that rats which have been suffering from streptozotocin-diabetes for 4 weeks show a supranormal mast cell mediated mitogenesis in mesenteric windows and in the skin; this late emerging, augmented mitogenic responsiveness appears, to be unaffected by insulin per se. To test whether this increased proliferogenic response is effected by some acquired quality within the tissue rather than a systemic factor in the blood, we studied mast cell mediated mitogenesis in organ-cultured intact mesenteric windows from rats with diabetes of 4 weeks' duration, using a biochemically-defined serum-free growth medium. Mast cells were activated by Compound 48/80 and their secretion was quantified biochemically in terms of histamine release. The mast cell-dependent mitogenic reaction in the predominant, morphologically discrete fibroblasts and mesothelial cells was quantified photometrically using Feulgen-absorption analysis of individual cell nuclei, and by determination of the mitotic index. Both types of target cell responded to a significantly greater degree mitogenically in diabetic compared with control tissue. This finding suggests that a considerable part of the increased mitogenic responsiveness previously observed in diabetic animals in vivo is causally related to some tissue-bound, i.e., cellular and/or extracellular factor(s) acquired during the course of the disease.
Animals↗
Mast-cell secretion and angiogenesis, a quantitative study in rats and mice.
The activation of the autogenous mast cells (MCs) in situ in intact mesenterial windows was elicited by the intraperitoneal injection of the MC secretagogue Compound 48/80 over a period of 1, 3 and 5 days in Sprague-Dawley rats and in C57 BL/6 and CBA/Ca mice. As a probe of MC secretion, the release of histamine was quantified fluorometrically at predetermined intervals during the treatment. Fourteen days after the start of the treatment, the angiogenic response was quantified histologically as the number of vessel profiles per unit length of mesenteric window. Both the MC-activating and the angiogenic effect of the 48/80-treatment was greater in the rats than in the mice. The occurrence of MC-mediated angiogenesis in the mouse is demonstrated here for the first time. In the rat, 48/80-induced MC mediated angiogenesis increased in a distinctly dose-dependent manner. Two daily doses of 48/80 was the most efficient angiogenic protocol tested; a single day's treatment increased the number of vessels almost fivefold. The remarkable potency of the angiogenic reaction following MC secretion supports our previous notion that MC-mediated angiogenesis may have therapeutic implications in poorly vascularized tissues.
Animals↗
On mast cell-mediated mitogenesis in normal and hyperplastic mesenterial windows in female rats.
The outcome of the mast cell-mediated mitogenesis in hyperplastic membranous mesenterial windows of lactating rats as well as in normal mesenterial windows of age-matched and young virgin female rats was studied quantitatively in vivo and in organ culture. Besides elucidating the effect of age and tissue hyperplasia on mitogenic responsiveness, this approach should provide some insight into the pathogenic mechanics of the previously reported supranormal mast cell-mediated mitogenic reaction that emerges in similarly hyperplastic mesenterial windows of diabetic rats. Mast cell secretion was elicited by Compound 48/80 and the histamine release, which was quantified fluorometrically, was unaffected by lactation. The young female rats showed a statistically significant mast cell-dependent mitogenesis taken as the mitotic index and the fraction of the predominating fibroblasts and mesothelial cells in the (S+G2) cell cycle phases after Feulgen-DNA absorption analysis of the cells in situ. Although there was an age-dependent decrease in mitogenesis, the older lactating and non-lactating virgin control rats also showed mast cell-mediated mitogenesis measured as the specific DNA activity. The hyperplastic mesenterial tissue of the lactating animals showed a virtually normal mitogenic reactivity following local mast cell secretion, but at a lower level than in the age-matched controls. This finding suggests that the supranormal mast cell-mediated mitogenesis previously found in the hyperplastic mesenterial windows of diabetic animals is causally related to the diabetic condition rather than to the hyperplastic state of the test tissue.
Animals↗
Molecular aspects of mast-cell-mediated mitogenesis in fibroblasts and mesothelial cells in situ.
Mast-cell-mediated mitogenesis in intact tissues is a paracrine reaction the molecular mechanisms of which still have to be elucidated. One strategy worth exploring is to study the mitogenic reaction under as defined conditions as possible. The present study demonstrates that in the virtually avascular rat mesentery, organ-cultured in a biochemically-defined medium, activation of mast cells induced a mitogenic reaction in fibroblasts and mesothelial cells, the two predominant, morphologically distinct neighboring cell types. Thus the system provides a means of studying the influence of defined molecules in the growth medium on the outcome of a mitogenic response in these two cell types in situ. It was further observed that exogenous platelet-derived growth factor (PDGF) was not essential for this mast-cell-mediated mitogenic reaction to occur in the tissue-bound fibroblasts and mesothelial cells.
Animals↗