title: The proangiogenic action of thyroid hormone analogue GC-1 is initiated at an integrin.
abstract: 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 T4 binding to plasma membranes and its pro-angiogenic effect. T4/T3 stimulates 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 TRbeta and TRalpha. In contrast, the hormone analogue GC-1 also stimulates transcriptional activation via TRbeta1. In the present study, we have defined the effect of GC-1, compared with T4 and T4-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 T4-induced angiogenesis, indicating dependence on T4 and 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 alphavbeta3 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 alphavbeta3 integrin receptor, and are dependent on MAPK activation.
authors.affiliation: Pharmaceutical Research Institute at Albany and Albany College of Pharmacy, Albany, New York 12208, USA. mousas@acp.edu
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
authors.forename: Laura J
authors.initials: LJ
authors.lastname: O'Connor
authors.forename: Joel J
authors.initials: JJ
authors.lastname: Bergh
authors.forename: Faith B
authors.initials: FB
authors.lastname: Davis
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Scanlan
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Davis
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D007202:Indicators and Reagents; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010636:Phenols / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D037042:Thyroid Hormone Receptors beta / Q000187:drug effects; D013974:Thyroxine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000085:Acetates; C413355:GC 1 compound; D007202:Indicators and Reagents; D039302:Integrin alphaVbeta3; D010636:Phenols; D037042:Thyroid Hormone Receptors beta; D016222:Fibroblast Growth Factor 2; D020928:Mitogen-Activated Protein Kinases; C011126:tetraiodothyroacetic acid; D013974:Thyroxine