A New Class of Steroids Inhibits Angiogenesis in the Presence of Heparin or a Heparin Fragment

Crum, Rosa M.; Szabó, Sándor; Folkman, Judah

doi:10.1126/science.2416056

Cited by 465 publications

(163 citation statements)

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“…17a-hydroxyprogesterone was reported to inhibit the growth of new capillary blood vessels in the chick embryo, in the rabbit cornea, and in some mouse tumors [15]. In the present study, it was In the rat, after PMSG treatment, the serum concentration of 17a-hydroxyprogesterone increased significantly, but fell markedly after the additional administration of hCG [27].…”

Section: Discussionsupporting

confidence: 51%

“…In our study, we have demonstrated that the glycosaminoglycans (GAGs) from ovarian extracts induced capillary proliferation, and also that GAGs from ovarian extracts potentiated the angiogenic activity of epidermal growth factor (EGF) in mice [11]. On the other hand, steroids such as hydrocortisone, 11a-epihydrocortisol and 17a-hydroxyprogesterone showed high anti-angiogenic (angiostatic) activities in the chorioallantoic membrane of the 6-day shell-less chick embryo [15]. Among these steroids, 17a-hydroxyprogesterone is present as a metabolite in the ovaries [16].…”

mentioning

confidence: 89%

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17.ALPHA.-Hydroxyprogesterone Suppresses Neovascularization Induced by HPLC-Purified Ovarian Hyaluronic Acid-Like Glycosaminoglycan in Mice.

et al. 1995

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Abstract. HPLC-purified glycosaminoglycans (hpGAG) prepared from extracts of non-luteal mouse (JcL: ICR strain) ovaries were assayed for neovascularization by implanting Elvax films, containing test samples, on the lateral wall of the sheath of m. rectus abdominis in adult female mice of the same strain. Neovascularization occurred in a dose-dependent manner, and was characterized by capillary outgrowth extending into the tissue surrounding the implant. The single major peak of purified GAG on a column of TSK gel DEAE got out of order after treatment with streptococcal hyaluronidase or nitrous acid. The activity of this fraction was also greatly reduced when treated with streptococcal hyaluronidase or nitrous acid. When hpGAG was embedded in the implant with 17a-hydroxyprogesterone at a dose of 20 gig/film, neovascularization induced by means of hpGAGs was suppressed. Progesterone at a dose of 50 µg/film did not suppress the neovascularization induced by ovarian hpGAG. These findings suggest that 17a-hydroxyprogesterone suppresses the angiogenic activity of hyaluronic acid-like hpGAG in the ovary.

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Section: Discussionsupporting

confidence: 51%

mentioning

confidence: 89%

17.ALPHA.-Hydroxyprogesterone Suppresses Neovascularization Induced by HPLC-Purified Ovarian Hyaluronic Acid-Like Glycosaminoglycan in Mice.

et al. 1995

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“…Chicken chorioallantoic membrane (CAM) assays were performed as described (9,10) and the effects on the developing vasculature were recorded at 48 h after implantation of the 0.5% carboxymethylcellulose pellet containing various drugs. Corneal neovascularization was induced by an implanted pellet of poly(hydroxyethyl methacrylate) (Hydron; Interferon Sciences, New Brunswick, NJ) containing 650 ng ofthe potent angiogenic protein basic fibroblast growth factor (bFGF) bound to sucralfate (sucrose aluminum sulfate; Bukh Meditec, Copenhagen) (11).…”

Section: Methodsmentioning

confidence: 99%

Thalidomide Is an Inhibitor of Angiogenesis

Amato¹,

Loughnan²,

Flynn³

et al. 1996

Retina

204

240

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Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of aniogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antaniogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization ofthafidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally adminsered drug for the treatment of many diverse dease dependent on angiogenesis.Thalidomide is a potent teratogen. It was developed by Chemie Grunenthal in the 1950s as a sedative that appeared so nontoxic in rodent models that a LD50 could not be established. In 1961, McBride (1) and Lenz (2) described the association between limb defects in babies and maternal thalidomide usage. Although humans are exquisitely sensitive to the teratogenic effects of thalidomide, experiments in rodents failed to reveal similar effects (3, 4). Teratogenic effects could be experimentally reproduced by the administration of thalidomide to pregnant rabbits at an oral dose of 100-300 mg per kg per day (5, 6). Over the past 30 years, the mechanism of thalidomide's teratogenicity has been extensively studied but has remained unsolved (7).We now postulate that the limb defects seen with thalidomide were secondary to an inhibition of blood vessel growth in the developing fetal limb bud. The limb bud is unique in requiring a complex interaction of both angiogenesis and vasculogenesis during development (8). Vasculogenesis is the formation of a capillary bed from endothelial cells that have differentiated from mesenchymal precursors. Angiogenesis is the formation of new blood vessels from sprouts ofpreexisting vessels. Therefore, the limb bud would be a particularly vulnerable target to a teratogen that inhibited endothelial cell function. We chose to examine the effect of thalidomide on growing vasculature in the chicken chorioallantoic membrane and in the rabbit cornea. MATERIALS AND METHODSChicken chorioallantoic membrane (CAM) assays were performed as described (9, 10) and the effects on the developing vasculature were recorded at 48 h after implantation of the 0.5% carboxymethylcellulose pellet containing various drugs. Corneal

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“…Antiangiogenic therapy may prove a promising direction to reduce graft failure (21). Various chemical compounds and drugs, such as steroids (22), methotrexate (23), heparin (24), and thalidomide (25), are reported to inhibit corneal neovascularization. Recently, anti-VEGF therapy targeting corneal angiogenesis showed successful results in animal experiments and clinical trials (26).…”

mentioning

confidence: 99%

Immunological Disruption of Antiangiogenic Signals by Recruited Allospecific T Cells Leads to Corneal Allograft Rejection

Tan

Cruz-Guilloty

Medina-Mendez

et al. 2012

The Journal of Immunology

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Corneal transplantation is the most common solid organ transplantation. The immunologically privileged nature of the cornea results in high success rates. However, T cell-mediated rejection is the most common cause of corneal graft failure. Using antiangiogenesis treatment to prevent corneal neovascularization, which revokes immune privilege, prevents corneal allograft rejection. Endostatin is an antiangiogenic factor that maintains corneal avascularity. In this study, we directly test the role of antiangiogenic and immunological signals in corneal allograft survival, specifically the potential correlation of endostatin production and T cell recruitment. We report that 75% of the corneal allografts of BALB/c mice rejected after postoperative day (POD) 20, whereas all syngeneic grafts survived through POD60. This correlates with endogenous endostatin, which increased and remained high in syngeneic grafts but decreased after POD10 in allografts. Immunostaining demonstrated that early recruitment of allospecific T cells into allografts around POD10 correlated with decreased endostatin production. In Rag−/− mice, both allogeneic and syngeneic corneal grafts survived; endostatin remained high throughout. However, after T cell transfer, the allografts eventually rejected, and endostatin decreased. Furthermore, exogenous endostatin treatment delayed allograft rejection and promoted survival secondary to angiogenesis inhibition. Our results suggest that endostatin plays an important role in corneal allograft survival by inhibiting neovascularization and that early recruitment of allospecific T cells into the grafts promotes destruction of endostatin-producing cells, resulting in corneal neovascularization, massive infiltration of effector T cells, and ultimately graft rejection. Therefore, combined antiangiogenesis and immune suppression will be more effective in maintaining corneal allograft survival.

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A New Class of Steroids Inhibits Angiogenesis in the Presence of Heparin or a Heparin Fragment

Cited by 465 publications

References 5 publications

17.ALPHA.-Hydroxyprogesterone Suppresses Neovascularization Induced by HPLC-Purified Ovarian Hyaluronic Acid-Like Glycosaminoglycan in Mice.

17.ALPHA.-Hydroxyprogesterone Suppresses Neovascularization Induced by HPLC-Purified Ovarian Hyaluronic Acid-Like Glycosaminoglycan in Mice.

Thalidomide Is an Inhibitor of Angiogenesis

Immunological Disruption of Antiangiogenic Signals by Recruited Allospecific T Cells Leads to Corneal Allograft Rejection

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