Tetraiodothyroacetic acid, a small molecule integrin ligand, blocks angiogenesis induced by vascular endothelial growth factor and basic fibroblast growth factor.
Thyroid hormone has been recently shown to induce tumor growth and angiogenesis via a plasma-membrane hormone receptor on integrin alphaVbeta3. The receptor is at or near the Arg-Gly-Asp (RGD) recognition site on the integrin that is important to extracellular matrix (ECM) protein and vascular growth factor interactions with the integrin. In the present study, we examined the possibility that tetraiodothyroacetic acid (tetrac), a deaminated, non-agonist thyroid hormone analog that binds to the integrin receptor, may modulate vascular growth factor-induced angiogenesis in the absence of thyroid hormone. Angiogenesis models were studied in which VEGF or FGF2 (1-2 microg/ml) induced tube formation in human dermal microvascular endothelial cells (HDMEC), stimulated new blood vessel branch formation in the chick chorioallantoic membrane (CAM) and induced angiogenesis in the mouse matrigel model. In all models, tetrac (1-10 microM) and at 10 microg in mouse matrigel inhibited the pro-angiogenesis activity of VEGF and FGF2 by more than 50%. RT-PCR revealed that tetrac (1-3 microM) decreased abundance of angiopoietin-2 mRNA, but not angiopoietin-1 mRNA, in VEGF-exposed endothelial cells, suggesting that specific angiogenic pathways are targeted by tetrac. Tetrac is a novel, inexpensive small molecule whose anti-angiogenic activity in the present studies is proposed to reflect inhibition, via the integrin RGD recognition/thyroid hormone receptor site, of crosstalk between plasma-membrane vascular growth factor receptors and integrin alphaVbeta3.
Mousa
Shaker A
SA
Albany College of Pharmacy, The Pharmaceutical Research Institute (PRI), 106 New Scotland Avenue, Albany, NY 12208, USA. mousas@acp.edu
Bergh
Joel J
JJ
Dier
Emie
E
Rebbaa
Abdelhadi
A
O'Connor
Laura J
LJ
Yalcin
Murat
M
Aljada
Ahmad
A
Dyskin
Evgeny
E
Davis
Faith B
FB
Lin
Hung-Yung
HY
Davis
Paul J
PJ
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004727:Endothelium / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013974:Thyroxine / Q000031:analogs & derivatives* / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D016023:Integrins; D008024:Ligands; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D020782:Matrix Metalloproteinases; C011126:tetraiodothyroacetic acid; D013974:Thyroxine