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 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.
Mousa
Shaker A
SA
The Pharmaceutical Research Institute and Albany College of Pharmacy, New York 12208, USA.
O'Connor
Laura
L
Davis
Faith B
FB
Davis
Paul J
PJ
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D002642:Chick Embryo; D004104:Diiodothyronines / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011422:Propionates / Q000494:pharmacology*; D013974:Thyroxine / Q000031:analogs & derivatives / Q000494:pharmacology
D004104:Diiodothyronines; D039302:Integrin alphaVbeta3; D011422:Propionates; D016222:Fibroblast Growth Factor 2; C082182:3,5-diiodothyropropionic acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C011126:tetraiodothyroacetic acid; D013974:Thyroxine