Pro-angiogenic activity of thyroid hormone analogues: Mechanisms, physiology and clinical prospects

Thyroid hormone and analogues have demonstrated potent pro-angiogenic activity in various in vitro and in vivo model systems. These pro-angiogenic effects of thyroid hormone are initiated nongenomically at a receptor on integrin αvβ3 on receptor blood vessel endothelial cells, but may culminate in genomic responses. This receptor on the cell surface may direct gene transcription and regulate activity of plasma membrane vascular growth factor receptors. Promotion of hormonal angiogenic activity can be blocked by tetrac and nanoparticulate tetrac that inhibit binding of T₄ and T₃ to αvβ3, and also block activities of endogenous vascular growth factors. Endogenous or prescribed thyroid hormone appears to support tumor-relevant angiogenesis. It may also support pathologic skin neovascularization. In the absence of malignancy, however, the angiogenic activity of the hormone has exhibited experimental utility in wound-healing and tissue ischemia. Clinical applications of the hormone may be optimized by a nanoparticulate to which the hormone is covalently bound. Nanoparticulate thyroid hormone does not gain access to the intracellular space and acts exclusively at the hormone receptor on integrin αvβ3. Restriction of the hormone to the extracellular space avoids unwanted hormonal effects on cellular respiration, on protein synthesis and on protein turnover and specific organ effects, such as cardiac tachyarrhythmias. Needed are more extensive preclinical data on the actions of thyroid hormone, T₄ and T₃ on, respectively, wound-healing and revascularization of limb or cardiac ischemic tissues.