Involvement of nitric oxide in iodine deficiency-induced microvascular remodeling in the thyroid gland: role of nitric oxide synthase 3 and ryanodine receptors
| Autor: | Jessica Vanderstraeten, Patrick Gilon, Anne Catherine Gérard, Marie-Christine Many, Julie Craps, B. De Jongh, Pierre Sonveaux, Ides M. Colin, Jean-Luc Balligand, Cindy Wilvers, Virginie Joris, Irina Lobysheva |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A medicine.medical_specialty Thapsigargin Nitric Oxide Synthase Type III medicine.medical_treatment Thyroid Gland Nitric Oxide Ryanodine receptor 2 Nitric oxide Cell Line chemistry.chemical_compound Mice Endocrinology In vivo Internal medicine medicine Animals Humans RYR1 biology Ryanodine receptor Growth factor Ryanodine Receptor Calcium Release Channel Hypoxia-Inducible Factor 1 alpha Subunit Rats Nitric oxide synthase chemistry cardiovascular system biology.protein Calcium Female Reactive Oxygen Species Iodine |
| Zdroj: | Endocrinology. 156(2) |
| ISSN: | 1945-7170 |
| Popis: | Iodine deficiency (ID) induces microvascular changes in the thyroid gland via a TSH-independent reactive oxygen species-hypoxia inducible factor (HIF)-1α-vascular endothelial growth factor (VEGF) pathway. The involvement of nitric oxide (NO) in this pathway and the role of calcium (Ca(2+)) and of ryanodine receptors (RYRs) in NO synthase 3 (NOS3) activation were investigated in a murine model of goitrogenesis and in three in vitro models of ID including primary cultures of human thyrocytes. ID activated NOS3 and the production of NO in thyrocytes in vitro and increased the thyroid blood flow in vivo. Using bevacizumab (a blocking antibody against VEGF-A) in mice, it appeared that NOS3 is activated upstream of VEGF-A. L-nitro arginine methyl ester (L-NAME, a NOS inhibitor) blocked the ID-induced increase in thyroid blood flow in vivo and NO production in vitro, as well as ID-induced VEGF-A mRNA and HIF-1α expression in vitro, while S-nitroso-acetyl-penicillamine (SNAP, a NO donor) did the opposite. Ca(2+) is involved in this pathway as intracellular Ca(2+) flux increased after ID, and thapsigargin activated NOS3 and increased VEGF-A mRNA expression. Two of the three known mammalian RYR isoforms (RYR1 and RYR2) were shown to be expressed in thyrocytes. RYR inhibition using ryanodine at 10 μ M decreased ID-induced NOS3 activation, HIF-1α and VEGF-A expression, while RYR activation with ryanodine at 1nM increased NOS3 activation and VEGF-A mRNA expression. In conclusion, during the early phase of TSH-independent ID-induced microvascular activation, ID sequentially activates RYRs and NOS3, thereby supporting ID-induced activation of the NO/HIF-1α/VEGF-A pathway in thyrocytes. |
| Databáze: | OpenAIRE |
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