Iodine deficiency induces a thyroid stimulating hormone-independent early phase of microvascular reshaping in the thyroid.
Expansion of the thyroid microvasculature is the earliest event during goiter formation, always occurring before thyrocyte proliferation; however, the precise mechanisms governing this physiological angiogenesis are not well understood. Using reverse transcriptase-polymerase chain reaction and immunohistochemistry to measure gene expression and laser Doppler to measure blood flow in an animal model of goitrogenesis, we show that thyroid angiogenesis occurred into two successive phases. The first phase lasted a week and involved vascular activation; this process was thyroid-stimulating hormone (TSH)-independent and was directly triggered by expression of vascular endothelial growth factor (VEGF) by thyrocytes as soon as the intracellular iodine content decreased. This early reaction was followed by an increase in thyroid blood flow and endothelial cell proliferation, both of which were mediated by VEGF and inhibited by VEGF-blocking antibodies. The second, angiogenic, phase was TSH-dependent and was activated as TSH levels increased. This phase involved substantial up-regulation of the major proangiogenic factors VEGF-A, fibroblast growth factor-2, angiopoietin 1, and NG2 as well as their receptors Flk-1/VEGFR2, Flt-1/VEGFR1, and Tie-2. In conclusion, goiter-associated angiogenesis promotes thyroid adaptation to iodine deficiency. Specifically, as soon as the iodine supply is limited, thyrocytes produce proangiogenic signals that elicit early TSH-independent microvascular activation; if iodine deficiency persists, TSH plasma levels increase, triggering the second angiogenic phase that supports thyrocyte proliferation.
Gérard
Anne-Catherine
AC
CNRS UMR8161, Institut de Biologie de Lille, 1, rue Calmette, 59021 Lille Cedex, France.
Poncin
Sylvie
S
Caetano
Bertrand
B
Sonveaux
Pierre
P
Audinot
Jean-Nicolas
JN
Feron
Olivier
O
Colin
Ides M
IM
Soncin
Fabrice
F
D000222:Adaptation, Physiological / Q000502:physiology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006042:Goiter / Q000139:chemically induced / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D007455:Iodine / Q000172:deficiency* / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010472:Perchlorates / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D013960:Thyroid Function Tests; D013961:Thyroid Gland / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D013972:Thyrotropin / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007211:Indoles; D010472:Perchlorates; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D005346:Fibroblast Growth Factors; C116890:Semaxinib; D013972:Thyrotropin; D007455:Iodine; D007453:Iodide Peroxidase; C494474:perchlorate