Research Article: Species-specific regulation of angiogenesis by glucocorticoids reveals contrasting effects on inflammatory and angiogenic pathways

Date Published: February 15, 2018

Publisher: Public Library of Science

Author(s): Ruth Morgan, John Keen, Daniel Halligan, Alan O’Callaghan, Ruth Andrew, Dawn Livingstone, Amber Abernethie, Giorgia Maltese, Brian Walker, Patrick Hadoke, Christina L Addison.


Glucocorticoids are potent inhibitors of angiogenesis in the rodent in vivo and in vitro but the mechanism by which this occurs has not been determined. Administration of glucocorticoids is used to treat a number of conditions in horses but the angiogenic response of equine vessels to glucocorticoids and, therefore, the potential role of glucocorticoids in pathogenesis and treatment of equine disease, is unknown. This study addressed the hypothesis that glucocorticoids would be angiostatic both in equine and murine blood vessels.The mouse aortic ring model of angiogenesis was adapted to assess the effects of cortisol in equine vessels. Vessel rings were cultured under basal conditions or exposed to: foetal bovine serum (FBS; 3%); cortisol (600 nM), cortisol (600nM) plus FBS (3%), cortisol (600nM) plus either the glucocorticoid receptor antagonist RU486 or the mineralocorticoid receptor antagonist spironolactone. In murine aortae cortisol inhibited and FBS stimulated new vessel growth. In contrast, in equine blood vessels FBS alone had no effect but cortisol alone, or in combination with FBS, dramatically increased new vessel growth compared with controls. This effect was blocked by glucocorticoid receptor antagonism but not by mineralocorticoid antagonism. The transcriptomes of murine and equine angiogenesis demonstrated cortisol-induced down-regulation of inflammatory pathways in both species but up-regulation of pro-angiogenic pathways selectively in the horse. Genes up-regulated in the horse and down-regulated in mice were associated with the extracellular matrix. These data call into question our understanding of glucocorticoids as angiostatic in every species and may be of clinical relevance in the horse.

Partial Text

Angiogenesis, the formation of new blood vessels from existing vasculature, is essential for tissue repair [1]. Aberrant angiogenesis is an important feature of several disease processes including the growth of tumours [2], diabetic retinopathy [3] and rheumatoid arthritis [4]. Glucocorticoids at supra-physiological levels and in the presence of heparin, are potent inhibitors of angiogenesis in the chick embryo and rabbit corneal models [5]. At physiological concentrations, glucocorticoids inhibit angiogenesis in rodent models, both in vitro and in vivo [6]. When first described, this angiostatic effect presented a potentially significant therapeutic breakthrough in the prevention of tumour metastasis and aberrant angiogenesis [5, 7]. In addition, reduced angiogenesis is described in circumstances of chronic exposure to excess endogenous or exogenous glucocorticoids [8–10]. There has, however, been limited use of glucocorticoids as angiogenesis inhibitors in human medicine [11–13].

New vessel growth from murine aortae was stimulated by foetal bovine serum (FBS; Fig 1). Cortisol inhibited both basal and FBS-induced growth of new vessels from murine aortae (Fig 1). This inhibitory effect was abolished by antagonism of glucocorticoid, but not mineralocorticoid, receptor (Fig 1).

In this study, we demonstrated that cortisol increased angiogenesis in equine vessels in contrast to its angiostatic effects in murine vessels. This unexpected cortisol-dependent induction of angiogenesis was mediated by glucocorticoid receptor (GR).




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