Proangiogenesis Action of the Thyroid Hormone Analog 3,5-Diiodothyropropionic Acid (DITPA) Is Initiated at the Cell Surface and Is Integrin Mediated

We have recently described the proangiogenesis effects of thyroid hormone in the chick chorioallantoic membrane (CAM) model. Generation of new blood vessels from existing vessels was promoted 2- to 3-fold by either T4 or T3 at 10−8–10−7 m total hormone concentrations. In the present studies, nanomol...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 2006-04, Vol.147 (4), p.1602-1607
Main Authors: Mousa, Shaker A, O’Connor, Laura, Davis, Faith B, Davis, Paul J
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cell Membrane - drug effects
Chick Embryo
Diiodothyronines - pharmacology
Fibroblast Growth Factor 2 - physiology
Fundamental and applied biological sciences. Psychology
Humans
Integrin alphaVbeta3 - physiology
MAP Kinase Signaling System - physiology
Mitogen-Activated Protein Kinase 1 - physiology
Mitogen-Activated Protein Kinase 3 - physiology
Neovascularization, Physiologic - drug effects
Propionates - pharmacology
Thyroxine - analogs & derivatives
Thyroxine - pharmacology
Vertebrates: endocrinology
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Summary:We have recently described the proangiogenesis effects of thyroid hormone in the chick chorioallantoic membrane (CAM) model. Generation of new blood vessels from existing vessels was promoted 2- to 3-fold by either T4 or T3 at 10−8–10−7 m total hormone concentrations. In the present studies, nanomolar concentrations of 3,5-diiodothyropropionic acid (DITPA), a thyroid hormone analog with inotropic but not chronotropic properties, exhibited potent proangiogenic activity that was comparable to that obtained with T3 and T4 in both the CAM model and in an in vitro three-dimensional human microvascular endothelial sprouting assay. The proangiogenesis effect of DITPA was inhibited by tetraiodothyroacetic acid, a thyroid hormone analog that competes with T4 and T3 for a novel cell surface hormone receptor site on integrin αvβ3. The thyroid hormone analogs DITPA, T4, and T4-agarose, as well as basic fibroblast growth factor (b-FGF) and vascular endothelial cell growth factor, demonstrated comparable proangiogenic effects in the CAM model and in the three-dimensional human microvascular endothelial sprouting model. The proangiogenesis effect of either DITPA or b-FGF was blocked by PD 98059, an inhibitor of the ERK1/2 signal transduction cascade. Additionally, a specific integrin αvβ3 small molecule antagonist, XT199, effectively inhibited the proangiogenesis effect of DITPA and b-FGF. Thus, the proangiogenesis actions of thyroid hormone and its analog DITPA are initiated at the plasma membrane, apparently at integrin αvβ3, and are MAPK dependent.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2005-1390