title: Thyroid Hormone, Hormone Analogs, and Angiogenesis.
abstract: Modulation by thyroid hormone and hormone analogs of angiogenesis in the heart after experimental infarction, and in other organs, has been appreciated for decades. Description of a plasma membrane receptor for thyroid hormone on the extracellular domain of integrin αvβ3 on endothelial cells has revealed the complexity of the nongenomic regulation of angiogenesis by the hormone. From αvβ3, the hormone directs transcription of specific vascular growth factor genes, regulates growth factor receptor/growth factor interactions and stimulates endothelial cell migration to a vitronectin cue; these actions are implicated experimentally in tumor-relevant angiogenesis and angioproliferative pulmonary hypertension. Derived from L-thyroxine (T4), tetraiodothyroacetic acid (tetrac) can be covalently bound to a polymer and as Nanotetrac acts exclusively at the hormone receptor on αvβ3 to block actions of T4 and 3,5,3'-triiodo-L-thyronine (T3) on angiogenesis. Other antiangiogenic actions of Nanotetrac include disruption of crosstalk between integrin αvβ3 and adjacent cell surface vascular growth factor receptors, resulting in disordered vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF; FGF2) actions at their respective plasma membrane receptors. From αvβ3, Nanotetrac also downregulates expression of VEGFA and epidermal growth factor receptor (EGFR) genes, upregulates transcription of the angiogenesis suppressor gene, thrombospondin 1 (THBS1; TSP1) and decreases cellular abundance of Ang-2 protein and matrix metalloproteinase-9. Existence of this receptor provides new insights into the multiple mechanisms by which thyroid hormone and hormone analogs may regulate angiogenesis at the molecular level. The receptor also offers pharmacological opportunities for interruption of pathological angiogenesis via integrin αvβ3.
authors.affiliation: Department of Medicine, Albany Medical College, Albany, New York, USA.|Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, New York, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Davis
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, New York, USA.
authors.forename: Thangirala
authors.initials: T
authors.lastname: Sudha
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, New York, USA.|Institute of Cancer Biology and Drug Discovery, School of Medical Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hung-Yun
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, New York, USA.
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D013974:Thyroxine / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D043925:Angiogenesis Inducing Agents; D013974:Thyroxine