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 T(4) or T(3) 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 T(3) and T(4) 
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 T(4) 
and T(3) for a novel cell surface hormone receptor site on integrin alphavbeta3. 
The thyroid hormone analogs DITPA, T(4), and T(4)-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 alphavbeta3 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 alphavbeta3, and are MAPK dependent.