Abstract
Angiogenesis, the process involving the growth of new blood vessels from pre-existing vessels, may be a target for combating diseases characterized by either poor vascularisation or abnormal vasculature as in cardiovascular diseases. Thyroid hormones (THs) are strong proangiogenic factors whose action starts at the plasma membrane integrin αvβ3 protein transducing rapid nongenomic signals on tumor thyroid cells. The tetraiodothyroacetic acid (Tetrac) inhibits the binding of TH to integrin receptor αVs3 blocking angiogenesis. Growing evidences suggest that, also in heart, Triiodothyronine (T3) and Thyroxine (T4) triggered nongenomic pathways through their binding to integrin receptor αVβ3 inducing capillary proliferation. The angiogenic activity of T3 and T4 has been studied by the chick choriallontoic endothelial cell microtubule assay and the human dermal microvascular endothelial cells microtubule assay. The aim of this work was to evaluate the direct stimulative activity of T3 and T4 on human cardiac microvascular endothelial cell (HMVEC-C) proliferation, migration and tube formation, employing Tetrac as inhibitor. Our in vitro study indicates that T3 and T4 directly stimulate angiogenesis in HMVEC-C observed as capillary density, cell proliferation and cell migration. In all models, Tetrac (5 μM) inhibited the proangiogenic effect of T3 and T4 suggesting its integrin-mediated action. Sq RT-PCR assay revealed that T3, and in less extent T4, increased the expression of angiogenic genes such as angiopoietin-1 (Angpt-1), angio-associated migratory cell protein (AAMP) and vascular endothelial growth factor (VEGF), whereas when the cells were pre-incubated with Tetrac this effect was abolished. In conclusion, our results show that THs stimulate angiogenesis, suggesting a potential therapeutic role aimed at increasing capillary density in cardiac diseases.
Highlights
Angiogenesis is considered a physiological process involving the growth of new blood vessels from pre-existing vessels
Thyroid hormones (THs) are strong proangiogenic factors whose action starts at the plasma membrane integrin αvβ3 protein [7,8,9], that belongs to a family of heterodimer receptors very important for interaction with extracellular matrix proteins [10,11,12]
Treatment with T3 or T4 in presence or absence of tetraiodothyroacetic acid (Tetrac) did not change the integrin β3 expression compared to cells in basal condition (Figure 1)
Summary
Angiogenesis is considered a physiological process involving the growth of new blood vessels from pre-existing vessels. It is a fundamental step in the transition of tumors from a benign to a malignant condition, anti-angiogenic therapies are employed to fight cancer and malignancies [1,2]. Thyroid hormones (THs) are strong proangiogenic factors whose action starts at the plasma membrane integrin αvβ protein [7,8,9], that belongs to a family of heterodimer receptors very important for interaction with extracellular matrix proteins [10,11,12]. It has been reported that the plasma membrane integrin receptor αVß3 is widely expressed on tumor thyroid cells trasducing rapid nongenomic
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