title: Involvement of mTOR and Regulation by AMPK in Early Iodine Deficiency-Induced Thyroid Microvascular Activation.
abstract: Iodine deficiency (ID) induces TSH-independent microvascular activation in the thyroid via the reactive oxygen species/nitric oxide-hypoxia-inducible factor-1α/vascular endothelial growth factor (VEGF) pathway. We hypothesized the additional involvement of mammalian target of rapamycin (mTOR) as a positive regulator of this pathway and AMP-activated protein kinase (AMPK) as a negative feedback regulator to explain the transient nature of ID-induced microvascular changes under nonmalignant conditions. mTOR and AMPK involvement was investigated using an in vitro model (human thyrocytes in primary cultures) and 2 murine models of goitrogenesis (normal NMRI and RET-PTC mice [a papillary thyroid cancer model]). In NMRI mice, ID had no effect on the phosphorylation of ribosomal S6 kinase (p70S6K), a downstream target of mTOR. However, rapamycin inhibited ID-induced thyroid blood flow and VEGF protein expression. In the RET-PTC model, ID strongly increased the phosphorylation of p70S6K, whereas rapamycin completely inhibited the ID-induced increase in p70S6K phosphorylation, thyroid blood flow, and VEGF-A expression. In vitro, although ID increased p70S6K phosphorylation, the ID-stimulated hypoxia-inducible factor/VEGF pathway was inhibited by rapamycin. Activation of AMPK by metformin inhibited ID effects both in vivo and in vitro. In AMPK-α1 knockout mice, the ID-induced increase in thyroid blood flow and VEGF-A protein expression persisted throughout the treatment, whereas both parameters returned to control values in wild-type mice after 4 days of ID. In conclusion, mTOR is required for early ID-induced thyroid microvascular activation. AMPK negatively regulates this pathway, which may account for the transient nature of ID-induced TSH-independent vascular effects under benign conditions.
authors.affiliation: Pôle de Morphologie (J.C., B.D.J., B.L., M.-C.M., I.M.C., A.-C.G.), de Pharmacologie et Thérapeutique (V.J., P.S.), de Recherche Cardiovasculaire (S.H., L.B.), Institut de Recherche Expérimentale et Clinique, Laboratoire de Biologie Cellulaire, and Institut des Sciences de la Vie (A.-C.G.), Université Catholique de Louvain, Louvain-La-Neuve, Brussels 1200, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Craps
authors.affiliation: Pôle de Morphologie (J.C., B.D.J., B.L., M.-C.M., I.M.C., A.-C.G.), de Pharmacologie et Thérapeutique (V.J., P.S.), de Recherche Cardiovasculaire (S.H., L.B.), Institut de Recherche Expérimentale et Clinique, Laboratoire de Biologie Cellulaire, and Institut des Sciences de la Vie (A.-C.G.), Université Catholique de Louvain, Louvain-La-Neuve, Brussels 1200, Belgium.
authors.forename: V
authors.initials: V
authors.lastname: Joris
authors.affiliation: Pôle de Morphologie (J.C., B.D.J., B.L., M.-C.M., I.M.C., A.-C.G.), de Pharmacologie et Thérapeutique (V.J., P.S.), de Recherche Cardiovasculaire (S.H., L.B.), Institut de Recherche Expérimentale et Clinique, Laboratoire de Biologie Cellulaire, and Institut des Sciences de la Vie (A.-C.G.), Université Catholique de Louvain, Louvain-La-Neuve, Brussels 1200, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: De Jongh
authors.affiliation: Pôle de Morphologie (J.C., B.D.J., B.L., M.-C.M., I.M.C., A.-C.G.), de Pharmacologie et Thérapeutique (V.J., P.S.), de Recherche Cardiovasculaire (S.H., L.B.), Institut de Recherche Expérimentale et Clinique, Laboratoire de Biologie Cellulaire, and Institut des Sciences de la Vie (A.-C.G.), Université Catholique de Louvain, Louvain-La-Neuve, Brussels 1200, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Sonveaux
authors.affiliation: Pôle de Morphologie (J.C., B.D.J., B.L., M.-C.M., I.M.C., A.-C.G.), de Pharmacologie et Thérapeutique (V.J., P.S.), de Recherche Cardiovasculaire (S.H., L.B.), Institut de Recherche Expérimentale et Clinique, Laboratoire de Biologie Cellulaire, and Institut des Sciences de la Vie (A.-C.G.), Université Catholique de Louvain, Louvain-La-Neuve, Brussels 1200, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Horman
authors.affiliation: Pôle de Morphologie (J.C., B.D.J., B.L., M.-C.M., I.M.C., A.-C.G.), de Pharmacologie et Thérapeutique (V.J., P.S.), de Recherche Cardiovasculaire (S.H., L.B.), Institut de Recherche Expérimentale et Clinique, Laboratoire de Biologie Cellulaire, and Institut des Sciences de la Vie (A.-C.G.), Université Catholique de Louvain, Louvain-La-Neuve, Brussels 1200, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Lengelé
authors.affiliation: Pôle de Morphologie (J.C., B.D.J., B.L., M.-C.M., I.M.C., A.-C.G.), de Pharmacologie et Thérapeutique (V.J., P.S.), de Recherche Cardiovasculaire (S.H., L.B.), Institut de Recherche Expérimentale et Clinique, Laboratoire de Biologie Cellulaire, and Institut des Sciences de la Vie (A.-C.G.), Université Catholique de Louvain, Louvain-La-Neuve, Brussels 1200, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Bertrand
authors.affiliation: Pôle de Morphologie (J.C., B.D.J., B.L., M.-C.M., I.M.C., A.-C.G.), de Pharmacologie et Thérapeutique (V.J., P.S.), de Recherche Cardiovasculaire (S.H., L.B.), Institut de Recherche Expérimentale et Clinique, Laboratoire de Biologie Cellulaire, and Institut des Sciences de la Vie (A.-C.G.), Université Catholique de Louvain, Louvain-La-Neuve, Brussels 1200, Belgium.
authors.forename: M-C
authors.initials: MC
authors.lastname: Many
authors.affiliation: Pôle de Morphologie (J.C., B.D.J., B.L., M.-C.M., I.M.C., A.-C.G.), de Pharmacologie et Thérapeutique (V.J., P.S.), de Recherche Cardiovasculaire (S.H., L.B.), Institut de Recherche Expérimentale et Clinique, Laboratoire de Biologie Cellulaire, and Institut des Sciences de la Vie (A.-C.G.), Université Catholique de Louvain, Louvain-La-Neuve, Brussels 1200, Belgium.
authors.forename: I M
authors.initials: IM
authors.lastname: Colin
authors.affiliation: Pôle de Morphologie (J.C., B.D.J., B.L., M.-C.M., I.M.C., A.-C.G.), de Pharmacologie et Thérapeutique (V.J., P.S.), de Recherche Cardiovasculaire (S.H., L.B.), Institut de Recherche Expérimentale et Clinique, Laboratoire de Biologie Cellulaire, and Institut des Sciences de la Vie (A.-C.G.), Université Catholique de Louvain, Louvain-La-Neuve, Brussels 1200, Belgium.
authors.forename: A-C
authors.initials: AC
authors.lastname: Gérard
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007455:Iodine / Q000172:deficiency*; D008297:Male; D008687:Metformin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013961:Thyroid Gland / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D008687:Metformin; D007455:Iodine; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D020123:Sirolimus