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. 1995 Sep;96(3):1295–1302. doi: 10.1172/JCI118164

Stimulation by thyroid-stimulating hormone and Grave's immunoglobulin G of vascular endothelial growth factor mRNA expression in human thyroid follicles in vitro and flt mRNA expression in the rat thyroid in vivo.

K Sato 1, K Yamazaki 1, K Shizume 1, Y Kanaji 1, T Obara 1, K Ohsumi 1, H Demura 1, S Yamaguchi 1, M Shibuya 1
PMCID: PMC185751  PMID: 7657804

Abstract

To elucidate the pathogenesis of thyroid gland hypervascularity in patients with Graves' disease, we studied the expression of mRNAs for vascular endothelial growth factor (VEGF) and its receptor, Flt family, using human thyroid follicles in vitro and thiouracil-fed rats in vivo. Human thyroid follicles, cultured in the absence of endothelial cells, secreted de novo-synthesized thyroid hormone in response to thyroid-stimulating hormone (TSH) and Graves' IgG. The thyroid follicles produced VEGF mRNA but not flt-1 mRNA. The expression of VEGF mRNA was enhanced by insulin, tumor-promoting phorbol ester, calcium ionophore, dibutyryl cAMP, TSH, and Graves' IgG. When rats were fed thiouracil for 4 wk, their serum levels of TSH were increased at day 3. VEGF mRNA was also increased on day 3, accompanied by an increase in flt family (flt-1 and KDR/ flk-1) mRNA expression. These in vitro and in vivo findings suggest that VEGF is produced by thyroid follicles in response to stimulators of TSH receptors, via the protein kinase A and C pathways. VEGF, a secretable angiogenesis factor, subsequently stimulates Flt receptors on endothelial cells in a paracrine manner, leading to their proliferation and producing hypervascularity of the thyroid gland, as seen in patients with Graves' disease.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  2. Claffey K. P., Wilkison W. O., Spiegelman B. M. Vascular endothelial growth factor. Regulation by cell differentiation and activated second messenger pathways. J Biol Chem. 1992 Aug 15;267(23):16317–16322. [PubMed] [Google Scholar]
  3. Conn G., Soderman D. D., Schaeffer M. T., Wile M., Hatcher V. B., Thomas K. A. Purification of a glycoprotein vascular endothelial cell mitogen from a rat glioma-derived cell line. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1323–1327. doi: 10.1073/pnas.87.4.1323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Connolly D. T., Heuvelman D. M., Nelson R., Olander J. V., Eppley B. L., Delfino J. J., Siegel N. R., Leimgruber R. M., Feder J. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest. 1989 Nov;84(5):1470–1478. doi: 10.1172/JCI114322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cullinan-Bove K., Koos R. D. Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth. Endocrinology. 1993 Aug;133(2):829–837. doi: 10.1210/endo.133.2.8344219. [DOI] [PubMed] [Google Scholar]
  6. Dumont J. E., Lamy F., Roger P., Maenhaut C. Physiological and pathological regulation of thyroid cell proliferation and differentiation by thyrotropin and other factors. Physiol Rev. 1992 Jul;72(3):667–697. doi: 10.1152/physrev.1992.72.3.667. [DOI] [PubMed] [Google Scholar]
  7. Emoto N., Isozaki O., Arai M., Murakami H., Shizume K., Baird A., Tsushima T., Demura H. Identification and characterization of basic fibroblast growth factor in porcine thyroids. Endocrinology. 1991 Jan;128(1):58–64. doi: 10.1210/endo-128-1-58. [DOI] [PubMed] [Google Scholar]
  8. Ericson L. E., Wollman S. H. Ultrastructural aspects of capillary fusion during the development of thyroid hyperplasia. J Ultrastruct Res. 1980 Sep;72(3):300–315. doi: 10.1016/s0022-5320(80)90066-0. [DOI] [PubMed] [Google Scholar]
  9. Ericson L. W., Wollman S. H. Increase in the rough endoplasmic reticulum in capillary endothelial cells and pericytes in hyperplastic rat thyroid glands. Endocrinology. 1980 Sep;107(3):732–737. doi: 10.1210/endo-107-3-732. [DOI] [PubMed] [Google Scholar]
  10. Ferrara N., Houck K., Jakeman L., Leung D. W. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev. 1992 Feb;13(1):18–32. doi: 10.1210/edrv-13-1-18. [DOI] [PubMed] [Google Scholar]
  11. Folkman J., Shing Y. Angiogenesis. J Biol Chem. 1992 Jun 5;267(16):10931–10934. [PubMed] [Google Scholar]
  12. Gospodarowicz D., Abraham J. A., Schilling J. Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7311–7315. doi: 10.1073/pnas.86.19.7311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Greil W., Rafferzeder M., Bechtner G., Gärtner R. Release of an endothelial cell growth factor from cultured porcine thyroid follicles. Mol Endocrinol. 1989 May;3(5):858–867. doi: 10.1210/mend-3-5-858. [DOI] [PubMed] [Google Scholar]
  14. Harada S., Nagy J. A., Sullivan K. A., Thomas K. A., Endo N., Rodan G. A., Rodan S. B. Induction of vascular endothelial growth factor expression by prostaglandin E2 and E1 in osteoblasts. J Clin Invest. 1994 Jun;93(6):2490–2496. doi: 10.1172/JCI117258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jakeman L. B., Armanini M., Phillips H. S., Ferrara N. Developmental expression of binding sites and messenger ribonucleic acid for vascular endothelial growth factor suggests a role for this protein in vasculogenesis and angiogenesis. Endocrinology. 1993 Aug;133(2):848–859. doi: 10.1210/endo.133.2.7688292. [DOI] [PubMed] [Google Scholar]
  16. Jakeman L. B., Winer J., Bennett G. L., Altar C. A., Ferrara N. Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J Clin Invest. 1992 Jan;89(1):244–253. doi: 10.1172/JCI115568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Keck P. J., Hauser S. D., Krivi G., Sanzo K., Warren T., Feder J., Connolly D. T. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989 Dec 8;246(4935):1309–1312. doi: 10.1126/science.2479987. [DOI] [PubMed] [Google Scholar]
  18. Kosugi S., Okajima F., Ban T., Hidaka A., Shenker A., Kohn L. D. Mutation of alanine 623 in the third cytoplasmic loop of the rat thyrotropin (TSH) receptor results in a loss in the phosphoinositide but not cAMP signal induced by TSH and receptor autoantibodies. J Biol Chem. 1992 Dec 5;267(34):24153–24156. [PubMed] [Google Scholar]
  19. Kriss J. P., Konishi J., Herman M. Studies on the pathogenesis of Graves' ophthalmopathy (with some related observations regarding therapy). Recent Prog Horm Res. 1975;31:533–566. doi: 10.1016/b978-0-12-571131-9.50018-9. [DOI] [PubMed] [Google Scholar]
  20. Leung D. W., Cachianes G., Kuang W. J., Goeddel D. V., Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989 Dec 8;246(4935):1306–1309. doi: 10.1126/science.2479986. [DOI] [PubMed] [Google Scholar]
  21. Millauer B., Wizigmann-Voos S., Schnürch H., Martinez R., Møller N. P., Risau W., Ullrich A. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell. 1993 Mar 26;72(6):835–846. doi: 10.1016/0092-8674(93)90573-9. [DOI] [PubMed] [Google Scholar]
  22. Miyazaki T., Sato M., Murata Y., Maeda K., Seo H. Factor(s) present in sera from patients on long-term hemodialysis increase(s) mRNAs for collagenase and stromelysin in synovial cells. Am J Nephrol. 1995;15(1):48–56. doi: 10.1159/000168801. [DOI] [PubMed] [Google Scholar]
  23. Nitsch L., Wollman S. H. Suspension culture of separated follicles consisting of differentiated thyroid epithelial cells. Proc Natl Acad Sci U S A. 1980 Jan;77(1):472–476. doi: 10.1073/pnas.77.1.472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nohtomi K., Sato K., Shizume K., Yamazaki K., Demura H., Hosoda K., Murata Y., Seo H. Stimulation of interleukin-4 of cell proliferation and mRNA expression of alkaline phosphatase and collagen type I in human osteoblast-like cells of trabecular bone. Bone Miner. 1994 Oct;27(1):69–79. doi: 10.1016/s0169-6009(08)80188-2. [DOI] [PubMed] [Google Scholar]
  25. Plate K. H., Breier G., Weich H. A., Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 1992 Oct 29;359(6398):845–848. doi: 10.1038/359845a0. [DOI] [PubMed] [Google Scholar]
  26. Sato K., Robbins J. Thyroid hormone metabolism in primary cultured rat hepatocytes. Effects of glucose, glucagon, and insulin. J Clin Invest. 1981 Aug;68(2):475–483. doi: 10.1172/JCI110278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sato K., Satoh T., Shizume K., Ozawa M., Han D. C., Imamura H., Tsushima T., Demura H., Kanaji Y., Ito Y. Inhibition of 125I organification and thyroid hormone release by interleukin-1, tumor necrosis factor-alpha, and interferon-gamma in human thyrocytes in suspension culture. J Clin Endocrinol Metab. 1990 Jun;70(6):1735–1743. doi: 10.1210/jcem-70-6-1735. [DOI] [PubMed] [Google Scholar]
  28. Sato K., Yamazaki K., Shizume K., Yamakawa Y., Satoh T., Demura H., Kanaji Y., Obara T., Fujimoto Y., Aiba M. Pathogenesis of autoimmune hypothyroidism induced by lymphokine-activated killer (LAK) cell therapy: in vitro inhibition of human thyroid function by interleukin-2 in the presence of autologous intrathyroidal lymphocytes. Thyroid. 1993 Fall;3(3):179–188. doi: 10.1089/thy.1993.3.179. [DOI] [PubMed] [Google Scholar]
  29. Seetharam L., Gotoh N., Maru Y., Neufeld G., Yamaguchi S., Shibuya M. A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. Oncogene. 1995 Jan 5;10(1):135–147. [PubMed] [Google Scholar]
  30. Senger D. R., Perruzzi C. A., Feder J., Dvorak H. F. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res. 1986 Nov;46(11):5629–5632. [PubMed] [Google Scholar]
  31. Shibuya M., Yamaguchi S., Yamane A., Ikeda T., Tojo A., Matsushime H., Sato M. Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene. 1990 Apr;5(4):519–524. [PubMed] [Google Scholar]
  32. Shweiki D., Itin A., Neufeld G., Gitay-Goren H., Keshet E. Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J Clin Invest. 1993 May;91(5):2235–2243. doi: 10.1172/JCI116450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Shweiki D., Itin A., Soffer D., Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992 Oct 29;359(6398):843–845. doi: 10.1038/359843a0. [DOI] [PubMed] [Google Scholar]
  34. Smeds S., Wollman S. H. 3H-thymidine labeling of endothelial cells in thyroid arteries, veins, and lymphatics during thyroid stimulation. Lab Invest. 1983 Mar;48(3):285–291. [PubMed] [Google Scholar]
  35. Tischer E., Mitchell R., Hartman T., Silva M., Gospodarowicz D., Fiddes J. C., Abraham J. A. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991 Jun 25;266(18):11947–11954. [PubMed] [Google Scholar]
  36. Wollman S. H., Herveg J. P., Zeligs J. D., Ericson L. E. Blood capillary enlargement during the development of thyroid hyperplasia in the rat. Endocrinology. 1978 Dec;103(6):2306–2314. doi: 10.1210/endo-103-6-2306. [DOI] [PubMed] [Google Scholar]
  37. Yamane A., Seetharam L., Yamaguchi S., Gotoh N., Takahashi T., Neufeld G., Shibuya M. A new communication system between hepatocytes and sinusoidal endothelial cells in liver through vascular endothelial growth factor and Flt tyrosine kinase receptor family (Flt-1 and KDR/Flk-1). Oncogene. 1994 Sep;9(9):2683–2690. [PubMed] [Google Scholar]
  38. Yamazaki K., Sato K., Shizume K., Kanaji Y., Ito Y., Obara T., Nakagawa T., Koizumi T., Nishimura R. Potent thyrotropic activity of human chorionic gonadotropin variants in terms of 125I incorporation and de novo synthesized thyroid hormone release in human thyroid follicles. J Clin Endocrinol Metab. 1995 Feb;80(2):473–479. doi: 10.1210/jcem.80.2.7852507. [DOI] [PubMed] [Google Scholar]
  39. Yeo K. T., Wang H. H., Nagy J. A., Sioussat T. M., Ledbetter S. R., Hoogewerf A. J., Zhou Y., Masse E. M., Senger D. R., Dvorak H. F. Vascular permeability factor (vascular endothelial growth factor) in guinea pig and human tumor and inflammatory effusions. Cancer Res. 1993 Jun 15;53(12):2912–2918. [PubMed] [Google Scholar]
  40. Zeligs J. D., Wollman S. H. Ultrastructure of cytokinesis in blood capillary endothelial cells in thyroid gland in vivo. J Ultrastruct Res. 1981 Jun;75(3):291–299. doi: 10.1016/s0022-5320(81)80086-x. [DOI] [PubMed] [Google Scholar]
  41. de Vries C., Escobedo J. A., Ueno H., Houck K., Ferrara N., Williams L. T. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 1992 Feb 21;255(5047):989–991. doi: 10.1126/science.1312256. [DOI] [PubMed] [Google Scholar]

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