THE EFFECT OF ESTROGEN-RELATED RECEPTOR alpha ON THE REGULATION OF ANGIOGENESIS AFTER SPINAL CORD INJURY

Estrogen receptor-related receptor-alpha (ERR alpha) is an orphan member of the nuclear receptor superfamily that interacts with peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) to stimulate vascular endothelial growth factor (VEGF) expression and angiogenesis in a hypoxia-inducible factor-1 alpha-independent pathway. Although it is not regulated by any natural ligand, the action of ERR alpha can be blocked by the synthetic molecule XCT790. In the present study, Sprague-Dawley rats were randomly allocated to a sham group, injury-saline group or injury-XCT90 group. A modified Allen's weight-drop method was applied to induce the acute traumatic spinal cord injury (SCI) model in these rats, and an injection of XCT790 was administered every 24 h, starting half an hour after the SCI contusion. Histological analyses revealed that XCT790 significantly aggravated tissue damage and decreased the number of ERR alpha-positive cells at 1, 3 and 7 days after SCI. Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) analyses also indicated that XCT790 dramatically repressed the expression of ERR alpha, thus reducing the expression of VEGF and angiopoietin-2 (Ang-2) throughout the duration of the experiment, but the expression of PGC-1 alpha was not affected. Immunofluorescence analyses indicated that vascular density and endothelial cell proliferation were decreased in the injury-XCT90 group compared with the injury-saline group. These results suggest that ERR alpha is involved in mediating angiogenesis after SCI in the rat traumatic SCI model. (C) 2015 The Authors. Published by Elsevier Ltd. on behalf of IBRO.