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Thyroid Hormone, Hormone Analogs, and Angiogenesis

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Modulation by thyroid hormone and hormone analogs of angiogenesis in the heart after experimental infarction, and in other organs, has been appreciated for decades. Description of a plasma membrane receptor for thyroid hormone on the extracellular domain of integrin αvβ3 on endothelial cells has revealed the complexity of the nongenomic regulation of angiogenesis by the hormone. From αvβ3, the hormone directs transcription of specific vascular growth factor genes, regulates growth factor receptor/growth factor interactions and stimulates endothelial cell migration to a vitronectin cue; these actions are implicated experimentally in tumor‐relevant angiogenesis and angioproliferative pulmonary hypertension. Derived from L‐thyroxine (T4), tetraiodothyroacetic acid (tetrac) can be covalently bound to a polymer and as Nanotetrac acts exclusively at the hormone receptor on αvβ3 to block actions of T4 and 3,5,3′‐triiodo‐L‐thyronine (T3) on angiogenesis. Other antiangiogenic actions of Nanotetrac include disruption of crosstalk between integrin αvβ3 and adjacent cell surface vascular growth factor receptors, resulting in disordered vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF; FGF2) actions at their respective plasma membrane receptors. From αvβ3, Nanotetrac also downregulates expression of VEGFA and epidermal growth factor receptor (EGFR) genes, upregulates transcription of the angiogenesis suppressor gene, thrombospondin 1 (THBS1; TSP1) and decreases cellular abundance of Ang‐2 protein and matrix metalloproteinase‐9. Existence of this receptor provides new insights into the multiple mechanisms by which thyroid hormone and hormone analogs may regulate angiogenesis at the molecular level. The receptor also offers pharmacological opportunities for interruption of pathological angiogenesis via integrin αvβ3. © 2016 American Physiological Society. Compr Physiol 6:353‐362, 2016.

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Figure 1. Figure 1. Schematic diagram of mechanisms of integrin‐dependent, nongenomic actions of T4, T3, and a thyroid hormone antagonist, Nanotetrac, on angiogenesis. T4 and T3 are proangiogenic at the integrin of endothelial cells by amplifying vascular growth factor signals (VEGF, bFGF, PDGF, and EGF) at the growth factor receptors that are adjacent to αvβ3. Nanotetrac is antiangiogenic by multiple mechanisms. The agent (A) inhibits amplification by T4 and T3 of vascular growth factor signals and (B) disrupts specific growth factor interactions with growth factor receptor in the absence of T4 and T3. Nanotetrac also blocks the proangiogenic actions of bradykinin, Ang II, and LPS by mechanisms that appear to depend upon αvβ3. Local release of Ang‐2 and MMP‐9 is an anticipatory step in angiogenesis and is also decreased by Nanotetrac, but the mechanism is not yet known. Not shown is the antiangiogenic effect of Nanotetrac involving modulation of transcription of angiogenesis‐relevant genes; these genes are listed in Table .

Figure 1. Schematic diagram of mechanisms of integrin‐dependent, nongenomic actions of T4, T3, and a thyroid hormone antagonist, Nanotetrac, on angiogenesis. T4 and T3 are proangiogenic at the integrin of endothelial cells by amplifying vascular growth factor signals (VEGF, bFGF, PDGF, and EGF) at the growth factor receptors that are adjacent to αvβ3. Nanotetrac is antiangiogenic by multiple mechanisms. The agent (A) inhibits amplification by T4 and T3 of vascular growth factor signals and (B) disrupts specific growth factor interactions with growth factor receptor in the absence of T4 and T3. Nanotetrac also blocks the proangiogenic actions of bradykinin, Ang II, and LPS by mechanisms that appear to depend upon αvβ3. Local release of Ang‐2 and MMP‐9 is an anticipatory step in angiogenesis and is also decreased by Nanotetrac, but the mechanism is not yet known. Not shown is the antiangiogenic effect of Nanotetrac involving modulation of transcription of angiogenesis‐relevant genes; these genes are listed in Table .
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Paul J. Davis, Thangirala Sudha, Hung‐Yun Lin, Shaker A. Mousa. Thyroid Hormone, Hormone Analogs, and Angiogenesis. Compr Physiol 2015, 6: 353-362. doi: 10.1002/cphy.c150011