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.

Flurbiprofen in the treatment of corneal neovascularization induced by contact lenses.

Cellulose acetate butyrate extended-wear contact lenses were fitted bilaterally on ten New Zealand albino rabbits. We administered flurbiprofen 0.03% solution topically to the experimental eyes and vehicle solution to the contralateral control eyes four times a day in a random, masked fashion beginning 24 hours before the contact lens was fitted. Corneal neovascularization, which developed in all eyes by the 25th day of contact lens wear, was significantly suppressed by flurbiprofen treatment (mean vessel length was 1.5 +/- 0.4 mm for the treated eyes and 3.0 +/- 0.3 mm for the control eyes; P less than .005). Topical administration of a noncorticosteroidal anti-inflammatory agent may be an effective treatment for corneal neovascularization induced by contact lenses.

Effect of a deproteinized blood extract on the recovery of blood circulation in an ischaemic skin lesion.

An experimental model was used to study the revascularization of an ischaemic skin lesion and the effect on this process of the blood extract Solcoseryl. Under the conditions given in the experiment, restoration of the circulation was by 2 modes--re-flow in the original vessels, and neovascularization. Solcoseryl given daily i.p. encouraged the re-flow phenomenon and therefore, by improving the microcirculation and nutrition, the healing of the ischaemic lesions.

Plasminogen activator (urokinase) causes vascularization of the cornea.

The presence of a peripheral zone of (presumed intracellular) plasminogen activator in the normal rabbit cornea has suggested that activator, once released, might regulate the permeability of limbal vessels and angiogenesis, by plasmin-dependent pathways. Plasminogen activator (urokinase [UK]) in rabbit serum albumin (RSA) was injected once (20 microliter, 3.7 CTA U) into the corneal stroma, 2 mm from the limbus. Sprouts arose from the engorged circumlimbal vessels (16 of 20 corneas) beginning on the third day and grew into the cornea over the next several days. Histologically, PMNs were observed in association with growing vessels. Contralateral corneas injected with UK (in RSA) previously inactivated by 99.7% with the specific active site inhibitor, Phe-Ala-Arg-chloromethyl ketone showed minimal vessel engorgement or stromal edema and no vascularization (0 to 20 corneas). Injuries to the so-called (plasminogen activator-containing)"critical zone" of the cornea which elicit neovascularization possibly do so by causing extracellular release of endogenous plasminogen activator. Thus, in addition to initiating the destructive events of ulceration, activator might initiate increases in vessel permeability and also neovascularization, which would result in the eventual arrest of ulceration.

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.

Suppression of corneal allograft rejection by cyclosporin A.

Corneal allografts can elicit a host immune response that results in their destruction as functional tissues. Just as with other types of tissue allografts, effective, safe methods are needed to prevent corneal allograft rejection in patients undergoing penetrating keratoplasty. In this study, cyclosporin A, a compound of fungal origin, was tested for its capacity to suppress corneal allograft rejection in rabbits. Corneal allografts were exchanged between pairs of randomly bred albino rabbits. Some animals received retrobulbar injections and others received similar injections of the drug vehicle only. Cyclosporin A significantly prolonged corneal allograft survival. All the allografts in untreated eyes were rejected within 40 days; four (45%) of the nine allografts in treated eyes survived more than 70 days. Cyclosporin A alone was less effective in suppressing allograft rejection in heavily vascularized, inflamed graft sites. No adverse side effects were seen when it was injected locally into the rabbit eye. We conclude that in the acute graft model in this study, cyclosporin A is a safe, potent immunosuppressive agent.

Regulation of wound-healing angiogenesis-effect of oxygen gradients and inspired oxygen concentration.

Tissue hypoxia is a well-known stimulus to angiogenesis. The central dead space in healing wounds has been shown to be hypoxic (PO2 = 1 to 10). Angiogenesis is a necessary component of all healing wounds. Rabbit ear chambers were used to explore the contribution of O2 gradients and various inspired oxygen concentrations on wound healing and angiogenesis. These experiments demonstrate that: (1) A hypoxic tissue gradient is mandatory for wound-healing angiogenesis, (2) when the hypoxic gradient is destroyed capillary growth cases, and (3) inspired oxygen concentrations affect the rate and density of capillary growth.

Influence of tranexamic acid on tumour vascularization. An experimental microangiographic study.

Administration of tranexamic acid given from tumour transplantation up to sacrifice 5 days later, inhibited the early vascularization of an intramuscularly transplanted rat sarcoma. A marked reduction of angiographically demonstrated vascular connections between tumour and normal muscle was observed. In older, larger tumours an increased frequency of small non-vascularized and probably necrotic tumour areas was suggested after administration of tranexamic acid. An inhibiting effect of tranexamic acid on tumour growth rate has been earlier reported in both experimental and clinical studies. This effect may be explained by an influence of tranexamic acid on tumour vascularization.

Inhibition of tumour vascularization by tranexamic acid. Experimental studies on possible mechanisms.

The vascularization of an intramuscularly transplanted rat sarcoma was studied by microangiography. Administration of tranexamic acid as well as of indomethacin reduced the vascular connections between tumour and surrounding normal muscle. These drugs also reduced tumour growth rate irrespective of whether they were administered early or late during tumour growth. An electron microscopy study of tumour specimens from animals given tranexamic acid did not reveal any degenerative vascular changes. One explanation of the inhibition of tumour growth and vascularization by tranexamic acid and by indomethacin may be reduction of a local inflammatory reaction induced by tumour transplantation and stimulating tumour vascularization.

Mechanism of the induction of angiogenesis by human neoplastic lymphoid tissue: studies on the chorioallantoic membrane (CAM) of the chick embryo.

The angiogenic activity of various neoplastic and control tissues, cells and extracts has been tested on the chorioallantoic membrane of the chick (CAM). The vascular response was assessed macroscopically and also by histological examination. Angiogenesis was induced by a number of neoplastic implants the most potent being derived from Hodgkin's disease, histiocytic lymphoma or glioma tissue. Boiled tumour tissue was ineffective. Lymphocytes extracted from human lymphomas, activated normal peripheral blood lymphocytes and established lymphoid cell lines of neoplastic origin were generally effective in inducing neovascularisation through millipore membranes as were 90,000-100,000 MW fractions of human tumour tissue. In all cases examined histologically a mononuclear cell infiltrate in the CAM mesoderm accompanied a positive vascular response. These results implicate host monocytes in the generation of neovascularisation by neoplastic tissue.

Resolution of optic disk neovascularization associated with intraocular inflammation.

Three cases of optic disk neovascularization associated with intraocular inflammation demonstrated progressive regression of the neovascularization with resolution of the inflammation, suggesting a causal relationship. These are the first reported cases, to the best of our knowledge, of regression of optic disk neovascularization in this situation.