Steroid Therapy of a Proliferating Hemangioma: Histochemical and Molecular Changes

Hasan, Qurratulain; Tan, Swee T.; Gush, Jason; Peters, Sue G.; Davis, Paul F.

doi:10.1542/peds.105.1.117

Cited by 110 publications

(77 citation statements)

References 26 publications

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“…Folkman et al described the angiostatic effects of pharmacological glucocorticoids in vitro Ͼ20 years ago (11), and these effects have been confirmed in vivo (3,10). Here, we show that the angiostatic effect occurs at physiological concentrations of glucocorticoids and is mediated by glucocorticoid receptors, and that endogenous glucocorticoids tonically repress angiogenic responses.…”

Section: Discussionsupporting

confidence: 73%

“…1) and incubated at 37°C in serum-free MCDB 131, with heparin, ascorbic acid, and GA1000 (Cambrex Biosciences) in the presence and absence of corticosterone (3,30,300, and 600 nM), 11-dehydrocorticosterone (300 and 600 nM), the glucocorticoid receptor antagonist RU38486 (10 Ϫ6 M), the mineralocorticoid receptor antagonist spironolactone (10 Ϫ6 M), and͞or the nonselective 11␤HSD inhibitor carbenoxolone (10 Ϫ6 M). All drugs (Sigma-Aldrich) were dissolved in ethanol and diluted in aqueous solution; final ethanol concentration 1-3% vol͞vol.…”

Section: Methodsmentioning

confidence: 99%

“…ngiogenesis, the formation of new vessels from existing ones, is a key factor in many common diseases (1)(2)(3)(4), and manipulation of angiogenesis is an important therapeutic target (5,6). Supraphysiological concentrations of glucocorticoids have been used in vitro and in vivo to inhibit angiogenesis (7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

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Preventing local regeneration of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 enhances angiogenesis

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Hadoke

Sharif

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

109

155

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Angiogenesis restores blood flow to healing tissues, a process that is inhibited by high doses of glucocorticoids. However, the role of endogenous glucocorticoids and the potential for antiglucocorticoid therapy to enhance angiogenesis is unknown. Using in vitro and in vivo models of angiogenesis in mice, we examined effects of (i) endogenous glucocorticoids, (ii) blocking endogenous glucocorticoid action with the glucocorticoid receptor antagonist RU38486, and (iii) abolishing local regeneration of glucocorticoids by the enzyme 11␤-hydroxysteroid dehydrogenase type 1 (11␤HSD1). Glucocorticoids, administered at physiological concentrations, inhibited angiogenesis in an in vitro aortic ring model and in vivo in polyurethane sponges implanted s.c. RU38486-enhanced angiogenesis in s.c. sponges, in healing surgical wounds, and in the myocardium of mice 7 days after myocardial infarction induced by coronary artery ligation. 11␤HSD1 knockout mice showed enhanced angiogenesis in vitro and in vivo within sponges, wounds, and infarcted myocardium. Endogenous glucocorticoids, including those generated locally by 11␤HSD1, exert tonic inhibition of angiogenesis. Inhibition of 11␤HSD1 in liver and adipose has been advocated to reduce cardiovascular risk in the metabolic syndrome: these data suggest that 11␤HSD1 inhibition offers a previously uncharacterized therapeutic approach to improve healing of ischemic or injured tissue. myocardial infarction ͉ wound healing

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Section: Discussionsupporting

confidence: 73%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Preventing local regeneration of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 enhances angiogenesis

Small

Hadoke

Sharif

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

109

155

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“…The cellular and biochemical events that initiate and regulate its proliferation and natural regression are unknown. Rudimentary knowledge of the pathogenesis of hemangioma has led to empirical and unsatisfactory therapies (22)(23)(24). Identification of the molecular trigger for hemangioma is of great interest both clinically and biologically.…”

Section: Discussionmentioning

confidence: 99%

A Novel In Vitro Human Model of Hemangioma

Tan¹,

Hasan²,

Velickovic³

et al. 2000

Modern Pathology

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Hemangioma, the most common tumor of infancy, is characterized by a proliferation of capillary endothelial cells with multilamination of the basement membrane and accumulation of cellular elements, including mast cells. The initial rapid growth is followed by an inevitable but slow involution. The currently available therapies are empirical and unsatisfactory because what is known of the cellular and molecular basis of hemangioma development is rudimentary. Advances in the understanding of its programmed biologic behavior has been hampered by the lack of a valid human model.We report here a novel in vitro culture system that is a useful human model of hemangioma. A small fragment of hemangioma biopsy is embedded in fibrin gel in a well of culture plates and incubated in a serum-free, buffered-salt, minimal medium. A complex network of microvessels grows out from the tissue fragments. Biopsies taken from all three phases of hemangioma development were cultured successfully; proliferative phase samples developed microvessels in 1 to 4 days, involuting phase in 5 to 7 days, and involuted phase in 7 to 12 days. The relative growth rates of the microvessels in the culture of biopsies taken from different stages of hemangioma development reflect the growth patterns seen clinically. This model has been validated using histochemistry, immunohistochemistry, and reverse transcriptase-polymerase chain reaction. Comparison of the number, localization, and phenotype of endothelial and mast cells and the distribution of basement membrane constituents (type IV collagen, perlecan, and laminins) and growth factors (basic fibroblast growth factor, vascular endothelial growth factor, transforming growth factor-␤s) in the biopsy and the tissue after culture shows that many of the characteristics of the original tissues were retained in culture.This in vitro human model of hemangioma overcomes some of the deficiencies associated with earlier models. It offers an opportunity for studying the precise cellular, biochemical, and molecular basis of hemangioma. It may also help to elucidate the mechanisms of action of existing therapies and may lead to the identification of novel treatments for hemangioma.

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“…The mechanism of action in IH remains unclear, but increased mast cell number, decreased transcription of cytokines and enhanced transcription of the mitochondrial cytochrome b gene have been noted following steroid treatment (6). Our study observed a decrease in height percentile in children treated with steroids.…”

Section: Discussionmentioning

confidence: 43%

Propranolol therapy for infantile hemangioma is less toxic but longer in duration than corticosteroid therapy

Sawa¹,

Yazdani²,

Rieder³

et al. 2014

CAN J PLAST SURG

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Steroid Therapy of a Proliferating Hemangioma: Histochemical and Molecular Changes

Abstract: The regression of this hemangioma subsequent to steroid therapy was accompanied by a significant increase in mast cell density, reduced transcription of several cytokines, and an enhanced expression of the mitochondrial cytochrome b gene.

Cited by 110 publications

References 26 publications

Preventing local regeneration of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 enhances angiogenesis

Preventing local regeneration of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 enhances angiogenesis

A Novel In Vitro Human Model of Hemangioma

Propranolol therapy for infantile hemangioma is less toxic but longer in duration than corticosteroid therapy

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