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

The Pharmaceutical Research Institute and Albany College of Pharmacy (S.A.M., L.O.), Ordway Research Institute, Inc. (F.B.D., P.J.D.), Wadsworth Center of the New York State Department of Health (P.J.D.), and Albany Medical College (P.J.D.), Albany, New York 12208

Address all correspondence and requests for reprints to: Faith B. Davis, M.D., Ordway Research Institute, 150 New Scotland Avenue, Albany, New York 12208. E-mail: fdavis{at}ordwayresearch.org.

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 vß3. 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 vß3 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 vß3, and are MAPK dependent.

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