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

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 PlGF, 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

Vascular Endothelial Growth Factors and Thyroid Disorders.

“…Our findings were confirmed by Viglietto et al [14], who found that, in addition to VEGF, production of a VEGF-related angiogenesis factor, placenta growth factor (P1GF), is also enhanced by TSH, and demonstrated that both angiogenesis fac- Thyroid follicles (TF) were prepared from thyroid tissues obtained from Graves' patients at subtotal thyroidectomy. TF were cultured in tissue culture dishes which had been coated with (left) or without agarose (right).…”

“…For unknown reasons, the expression levels of VEGF and VEGFR gradually decreased thereafter, although the hypervascularity of the thyroid gland persisted. In accordance with these experimental data, VEGF and its receptor (VEGFR-1) mRNA were shown to have increased in hyperplastic thyroid gland in Graves' disease [14,15]. Therefore, we speculate that when TSH receptor is stimulated by TSH or Graves' IgG, VEGF mRNA expression is increased via the adenylate kinase and protein kinase C pathways.…”

Modulation of in vivo growth of thyroid tumor-derived cell lines by sense and antisense vascular endothelial growth factor gene

“…We have previously reported that VEGF expression is upregulated in human goiters and in an animal model of thyroid goitrogenesis (Viglietto et al, 1997), as well as in thyroid carcinomas (Viglietto et al, 1995). In this study we have addressed the role of VEGF in the development of thyroid tumors by two complementary approaches.…”

“…VEGF and GAPDH probes were radiolabeled with a random prime synthesis kit (Multi-Prime, Amersham Inc.). Hybridization reactions were performed as described (Viglietto et al, 1997).…”

Combretastatin-A4 disrupts neovascular development in non-neoplastic tissue

“…We have no reason to suppose that vascular growth in the thyroid due to TSH stimulation differs in any fundamental aspect from angiogenesis in other tissues. During goitrogenesis vascular growth is coordinated, the thyroid endothelial cells responding to VEGF, as do endothelial cells of many other tissues, with VEGF being produced locally by follicular cells in response to TSH stimulation (Sato et al, 1995;Viglietto et al, 1997;Wang et al, 1998;Bidey et al, 1999). There is no evidence that the endothelial cells respond directly to TSH.…”