The Proangiogenic Action of Thyroid Hormone Analogue GC-1 Is Initiated at an Integrin

Our early reported investigations have demonstrated potent proangiogenic effects of L-thyroxine (T4) and 3,5,3′-triiodo-L-thyronine (T3) in the chick chorioallantoic membrane (CAM) model. Tetraiodothyroacetic acid (tetrac) blocks T4binding to plasma membranes and its pro-angiogenic effect. T4/T3stimulates expression of fibroblast growth factor 2 (FGF2) in endothelial cells. Thyroid hormone (T4/T3) is principally responsible for transcriptional activation mediated by nuclear thyroid hormone receptors TRβ and TRα. In contrast, the hormone analogue GC-1 also stimulates transcriptional activation via TRβ1. In the present study, we have defined the effect of GC-1, compared with T4and T4-agarose, on angiogenesis in the CAM assay. GC-1 demonstrated a proangiogenic effect similar to that of T4and T4-agarose. Tetrac inhibited GC-1- and T4-induced angiogenesis, indicating dependence on T4and GC-1 binding to plasma membranes. The effects of GC-1, T4-agarose, and FGF2 were blocked by PD 98059, a mitogen-activated protein kinase (MAPK) pathway inhibitor. Additionally, the αvβ3 integrin antagonist XT199 inhibited angiogenesis induced by T4-agarose, GC-1, or FGF2. Thus, the proangiogenic effects of GC-1 and T4are initiated at the plasma membrane, require interaction with αvβ3 integrin receptor, and are dependent on MAPK activation.