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 (T-4) and 3,5,3'-triiodo-L-thyronine (T-3) in the chick chorioallantoic membrane (CAM) model. Tetraiodothyroacetic acid (tetrac) blocks T-4 binding to plasma membranes and its pro-angiogenic effect. T-4/T-3 stimulates expression of fibroblast growth factor 2 (FGF2) in endothelial cells. Thyroid hormone (T-4/T-3) is principally responsible for transcriptional activation mediated by nuclear thyroid hormone receptors TR beta and TR alpha. In contrast, the hormone analogue GC-1 also stimulates transcriptional activation via TR beta 1. In the present study, we have defined the effect of GC-1, compared with T-4 and T-4-agarose, on angiogenesis in the CAM assay. GC-1 demonstrated a proangiogenic effect similar to that of T4 and T4-agarose. Tetrac inhibited GC-1- and T-4-induced angiogenesis, indicating dependence on T-4 and GC-1 binding to plasma membranes. The effects of GC-1, T-4-agarose, and FGF2 were blocked by PD 98059, a mitogen-activated protein kinase (MAPK) pathway inhibitor. Additionally, the alpha v beta 3 integrin antagonist XT199 inhibited angiogenesis induced by T4-agarose, GC-1, or FGF2. Thus, the proangiogenic effects of GC-1 and T4 are initiated at the plasma membrane, require interaction with alpha v beta 3 integrin receptor, and are dependent on MAPK activation.