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This version published online on December 29, 2005
Endocrinology, doi:10.1210/en.2005-1390
A more recent version of this article appeared on April 1, 2006
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Submitted on November 2, 2005
Accepted on December 19, 2005

PRO-ANGIOGENESIS ACTION OF THE THYROID HORMONE ANALOG 3, 5-DIIODOTHYROPROPIONIC ACID (DITPA) IS INITIATED AT THE CELL SURFACE AND IS INTEGRIN-MEDIATED

Shaker A. Mousa, Laura O'Connor, Faith B. Davis*, and Paul J. Davis

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, NY

* To whom correspondence should be addressed. E-mail: fdavis{at}ordwayresearch.org.

We have recently described the pro-angiogenesis effects of thyroid hormone in the chick chorioallantoic membrane (CAM) model. Generation of new blood vessels from existing vessels was promoted 2-3-fold by either L-thyroxine (T4) or 3,5,3'-triiodo-L-thyronine (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 pro-angiogenic activity that was comparable to that obtained with T3 and T4 in both the CAM model and in an in vitro 3-dimensional human microvascular endothelial sprouting assay. The pro-angiogenesis effect of DITPA was inhibited by tetraiodothyroacetic (tetrac), a thyroid hormone analog that competes with T4 and T3 for a novel cell surface hormone receptor site on integrin {alpha}v{beta}3. The thyroid hormone analogs DITPA, T4, and T4-agarose, as well as basic fibroblast growth factor (b-FGF) and vascular endothelial cell growth factor (VEGF), demonstrated comparable proangiogenic effects in the CAM model and in the 3-dimensional human microvascular endothelial sprouting model. The pro-angiogenesis effect of either DITPA or b-FGF was blocked by PD 98059, an inhibitor of the mitogen-activated protein kinase (MAPK; ERK1/2) signal transduction cascade. Additionally, a specific integrin {alpha}v{beta}3 small molecule antagonist, XT199, effectively inhibited the pro-angiogenesis effect of DITPA and b-FGF. Thus, the pro-angiogenesis actions of thyroid hormone and its analog DITPA are initiated at the plasma membrane, apparently at integrin {alpha}v{beta}3, and are MAPK-dependent.
Key words: angiogenesis • thyroid hormone • diiodothyropropionic acid • basic fibroblast growth factor • mitogen-activated protein kinase • integrin {alpha}v{beta}3




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