Thyroid hormone and angiogenesis.
In models of thyroid hormone-induced cardiac hypertrophy, there is appropriate, supportive angiogenesis. Twenty years ago in one such model, angiogenesis in response to the hormone was observed before hypertrophy developed and it is now understood that iodothyronines induce neovascularization in a variety of settings, including the heart, ischemic striated muscle and tumor beds. The molecular mechanism of the proangiogenic action of thyroid hormone is both nongenomic and genomic. It is initiated nongenomically at the cell surface receptor for the hormone on integrin alphavbeta3. Kinase transduction of the hormone signal and, ultimately, transcription of several anagiogenesis-relevant genes result. The genes include basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). In addition, the integrin receptor for thyroid hormone (l-thyroxine, T(4), and 3, 5, 3'-triiodo-l-thyronine, T(3)) engages in crosstalk with the VEGF and bFGF receptors. Occlusion with tetraiodothyroacetic acid (tetrac) of the hormone receptor on the integrin in the absence of T(4) and T(3) suppresses the angiogenic effects of VEGF and bFGF. Tetrac also blocks the proangiogenic actions of T(4) and T(3). Other thyroid hormone analogues that are angiogenic include diiodothyropropionic acid (DITPA) and the nuclear thyroid hormone receptor-beta-selective agonist, GC-1. Thyroid hormone sustains angiogenesis and coronary blood flow about infarcted heart tissue in experimental models and blocks deleterious heart remodeling that otherwise is predictable in such tissue. The hormone may also induce expression of the hypoxia-inducible factor 1alpha (HIF1alpha) gene, a transcription factor important to coronary artery collateralization in the setting of hypoxia. The hormone also causes transcription of the matrix Gla protein (MGP) gene that opposes vascular smooth muscle calcification.
Luidens
Mary K
MK
Signal Transduction Laboratory, Ordway Research Institute, Albany, NY 12208, USA.
Mousa
Shaker A
SA
Davis
Faith B
FB
Lin
Hung-Yun
HY
Davis
Paul J
PJ
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D006332:Cardiomegaly / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011956:Receptors, Cell Surface / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D013963:Thyroid Hormones / Q000494:pharmacology*; D013974:Thyroxine / Q000031:analogs & derivatives / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects
D043925:Angiogenesis Inducing Agents; D011956:Receptors, Cell Surface; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; C011126:tetraiodothyroacetic acid; D013974:Thyroxine