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(Circulation Research. 2004;94:1500.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Proangiogenic Action of Thyroid Hormone Is Fibroblast Growth Factor–Dependent and Is Initiated at the Cell Surface

Faith B. Davis, Shaker A. Mousa, Laura O’Connor, Seema Mohamed, Hung-Yun Lin, H. James Cao, Paul J. Davis

From the Department of Veterans Affairs Medical Center (F.B.D, H.-Y.L., P.J.D.); Albany College of Pharmacy (S.A.M., L.O., S.M.); Ordway Research Institute, Inc. (F.B.D., H.-Y.L., H.J.C., 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.

Correspondence to Faith B. Davis, MD, Ordway Research Institute, Inc., Center for Medical Science, 150 New Scotland Ave, Albany, NY 12208. Email fdavis{at}ordwayresearch.org

The effects of thyroid hormone analogues on modulation of angiogenesis have been studied in the chick chorioallantoic membrane model. Generation of new blood vessels from existing vessels was increased 3-fold by either L-thyroxine (T₄; 10^–7 mol/L) or 3,5,3'-triiodo-L-thyronine (10^–9 mol/L). T₄–agarose reproduced the effects of T₄, and tetraiodothyroacetic acid (tetrac) inhibited the effects of both T₄ and T₄–agarose. Tetrac itself was inactive and is known to block actions of T₄ on signal transduction that are initiated at the plasma membrane. T₄ and basic fibroblast growth factor (FGF2) were comparably effective as inducers of angiogenesis. Low concentrations of FGF2 combined with submaximal concentrations of T₄ produced an additive angiogenic response. Anti-FGF2 inhibited the angiogenic effect of T₄. The proangiogenic effects of T₄ and FGF2 were blocked by PD 98059, a mitogen-activated protein kinase (MAPK) pathway inhibitor. Endothelial cells (ECV304) treated with T₄ or FGF2 for 15 minutes demonstrated activation of MAPK, an effect inhibited by PD 98059 and the protein kinase C inhibitor CGP41251. Reverse transcription–polymerase chain reaction of RNA extracted from endothelial cells treated with T₄ revealed increased abundance of FGF2 transcript at 6 to 48 hours, and after 72 hours, the medium of treated cells showed increased FGF2 content, an effect inhibited by PD 98059. Thus, thyroid hormone is shown to be a proangiogenic factor. This action, initiated at the plasma membrane, is MAPK dependent and mediated by FGF2.

Key Words: angiogenesis • thyroxine • basic fibroblast growth factor • mitogen-activated protein kinase • endothelial cell

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