Abstract
Placenta growth factor (PlGF) and vascular endothelial growth factor (VEGF) represent two closely related angiogenic growth factors active as homodimers or heterodimers. Since goiters of the thyroid gland are extremely hypervascular, we investigated the expression of PlGF, VEGF and their receptors, Flt-1 and Flk-1/KDR, in a small panel of human goiters from patients with Graves's disease, in an animal model of thyroid goitrogenesis and in in vitro cultured thyroid cells. Here we report that the mRNA expression of PlGF, VEGF and their receptors is markedly enhanced in biopsies of goiters resected from Graves's patients. In vivo studies demonstrated that in the thyroid gland of thiouracil-fed rats, increased mRNA and protein expression of PIGF, VEGF, Flt-1 and Flk-1/KDR occurred subsequent to the rise in the serum thyroid stimulating hormone (TSH) levels and in parallel with thyroid capillary proliferation. In vitro studies confirmed the existence of such TSH-dependent paracrine communication between thyroid epithelial cells and endothelium since the conditioned medium collected from TSH-stimulated thyrocytes acquired mitogenic activity for human umbilical vein endothelial (HUVE) cells. Altogether, these data suggest that PlGF and VEGF, released by thyrocytes in response to the chronic activation of the TSH receptor pathway, may act through a paracrine mechanism on thyroid endothelium.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antithyroid Agents / pharmacology
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Cells, Cultured
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Culture Media, Conditioned / pharmacology
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Endothelial Growth Factors / genetics
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Endothelial Growth Factors / metabolism*
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Endothelial Growth Factors / pharmacology
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Endothelium, Vascular / cytology
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Goiter / physiopathology*
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Graves Disease / metabolism
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Humans
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Lymphokines / drug effects
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Lymphokines / genetics
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Lymphokines / metabolism*
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Lymphokines / pharmacology
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Neovascularization, Pathologic
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Placenta Growth Factor
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Pregnancy Proteins / drug effects
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Pregnancy Proteins / genetics
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Pregnancy Proteins / metabolism*
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Protein Synthesis Inhibitors / pharmacology
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / immunology
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Proto-Oncogene Proteins / metabolism
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RNA, Messenger
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Rats
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Rats, Inbred Strains
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Receptor Protein-Tyrosine Kinases / drug effects
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Receptor Protein-Tyrosine Kinases / immunology
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptors, Growth Factor / drug effects
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Receptors, Growth Factor / immunology
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Receptors, Growth Factor / metabolism
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Receptors, Vascular Endothelial Growth Factor
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Thiouracil / pharmacology*
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Thyroid Gland / cytology
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Thyroid Gland / drug effects
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Thyroid Gland / metabolism
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Thyrotropin / metabolism*
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Thyrotropin / pharmacology
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Umbilical Veins / cytology
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Up-Regulation
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factors
Substances
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Antithyroid Agents
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Culture Media, Conditioned
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Endothelial Growth Factors
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Lymphokines
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PGF protein, human
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Pgf protein, rat
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Pregnancy Proteins
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Protein Synthesis Inhibitors
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Proto-Oncogene Proteins
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RNA, Messenger
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Receptors, Growth Factor
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Placenta Growth Factor
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Thiouracil
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Thyrotropin
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Receptor Protein-Tyrosine Kinases
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Receptors, Vascular Endothelial Growth Factor
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Vascular Endothelial Growth Factor Receptor-1