Upregulation of the angiogenic factors PlGF, VEGF and their receptors (Flt-1, Flk-1/KDR) by TSH in cultured thyrocytes and in the thyroid gland of thiouracil-fed rats suggest a TSH-dependent paracrine mechanism for goiter hypervascularization.
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.
Viglietto
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Istituto Nazionale dei Tumori Fondazione Senatore Pascale, Naples, Italy.
Romano
A
A
Manzo
G
G
Chiappetta
G
G
Paoletti
I
I
Califano
D
D
Galati
M G
MG
Mauriello
V
V
Bruni
P
P
Lago
C T
CT
Fusco
A
A
Persico
M G
MG
D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology; D006042:Goiter / Q000503:physiopathology*; D006111:Graves Disease / Q000378:metabolism; D006801:Humans; D008222:Lymphokines / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009389:Neovascularization, Pathologic; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger; D051381:Rats; D011919:Rats, Inbred Strains; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D013889:Thiouracil / Q000494:pharmacology*; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013972:Thyrotropin / Q000378:metabolism* / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D013956:Antithyroid Agents; D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; D008222:Lymphokines; C000608036:PGF protein, human; C000608038:Pgf protein, rat; D011257:Pregnancy Proteins; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000072483:Placenta Growth Factor; D013889:Thiouracil; D013972:Thyrotropin; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1