Precocity of the endothelial proliferation during a course of rapid goitrogenesis

Many, Marie‐Christine; Denef, Jean‐François; Haumont, Stanislas

doi:10.1530/acta.0.1050487

Cited by 34 publications

(24 citation statements)

References 5 publications

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“…Autoradiographies were performed on 1-m-thick sections from Epon-embedded lobes as previously described. 4,5 Ultrathin sections were prepared and stained with uranyl acetate and lead citrate and examined with an electron microscope Zeiss EM169 (Carl Zeiss, Oberkochem, Germany). The second thyroid lobe was fixed in paraformaldehyde [4% in phosphatebuffered saline (PBS)] for 36 hours and embedded in paraffin.…”

Section: Preparation Of Tissue Samples For Microscopymentioning

confidence: 99%

Iodine Deficiency Induces a Thyroid Stimulating Hormone-Independent Early Phase of Microvascular Reshaping in the Thyroid

Gérard

Poncin

Caetano

et al. 2008

The American Journal of Pathology

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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.

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Section: Preparation Of Tissue Samples For Microscopymentioning

confidence: 99%

Iodine Deficiency Induces a Thyroid Stimulating Hormone-Independent Early Phase of Microvascular Reshaping in the Thyroid

Gérard

Poncin

Caetano

et al. 2008

The American Journal of Pathology

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“…Goitre formation is associated with enlargement of capillaries and mitosis of endothelial cells (Wollman et al 1978) and in experimental models of iodine-deficient goitre endothelial proliferation occurs before thyroid epithelial cell growth (Wollman et al 1978, Denef et al 1981, Smeds & Wollman 1983, Many et al 1984). Many pro-angiogenic growth factors are produced by thyroid follicular cells, including insulin-like growth factor (Bachrach et al 1988), vascular endothelial growth factor (Sato et al 1995), fibroblast growth factor (FGF) (Thompson et al 1998) and angiopoietin-1 (Cocks et al 2000, Ramsden et al 2001, and the conditioned medium of thyroid cells stimulates endothelial cell growth (Goodman & Rone 1987).…”

Section: Introductionmentioning

confidence: 99%

Thyroid follicular cells secrete plasminogen activators and can form angiostatin from plasminogen

Ramsden¹,

Yarram²,

Mathews³

et al. 2002

Journal of Endocrinology

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Angiostatin, a 38 kDa fragment of plasminogen, potently inhibits the growth of blood vessels. Angiostatin is generated from plasminogen by urokinase-type (uPA) and tissue-type (tPA) plasminogen activators in the presence of free sulphydryl donors. Angiogenesis inhibitors may be important in regulating angiogenesis in developing goitre. We have examined angiostatin formation in human primary thyrocyte cultures and a rat thyrocyte cell line (FRTL-5). We found that human thyroid cells in culture secrete plasminogen activators (both tPA and uPA) as well as matrix metalloproteinase 2 into the medium. When human thyrocyte conditioned medium was incubated with plasminogen (10 µg/ml) and N-acetylcysteine (100 µM) for 24 h, a 38 kDa fragment of plasminogen, which is consistent with angiostatin, was generated. The appearance of the 38 kDa fragment was increased by agents that increase cAMP (forskolin and 8 BrcAMP). FRTL-5 cells, which do not secrete uPA or tPA, did not generate angiostatin. Thyroid cells produce several angiogenic growth factors, and human thyrocyte conditioned medium stimulated growth of endothelial cells. When the conditioned medium was incubated with plasminogen and N-acetylcysteine, this stimulatory effect was lost, consistent with the production of a growth inhibitory factor. We conclude that thyroid cells can produce angiostatin from plasminogen in vitro, and this may play a role in vivo in limiting goitre size.

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“…In animal models of thyroid hypertrophy, the mitotic activity of the thyroid endothelial cells increases before thyrocyte proliferation (4). Moreover, during involution of experimentally induced goitre, the thyroid vasculature regresses much earlier than the thyroid epithelium (22).…”

Section: Discussionmentioning

confidence: 99%

“…Thyroid hypertrophy is commonly associated with prominent neovascularization and increased thyroid blood flow (2,3). In such situations, endothelial cell proliferation occurs before the proliferation of follicular cells (4), suggesting that vascularization is necessary to sustain thyroid growth.…”

Section: Introductionmentioning

confidence: 99%

Thyrocyte release of asymmetric dimethylarginine does not account for human thyrocyte inhibition of endothelial cell cyclic GMP

Millatt

Johnstone²,

Nussey³

et al. 2000

European Journal of Endocrinology

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Background: The thyroid gland produces and responds to the signalling molecule nitric oxide (NO). The activity of NO synthase (NOS) may be regulated by endogenous NOS inhibitors such as asymmetric dimethylarginine (ADMA). Objective: To investigate whether human thyrocytes are capable of regulating NOS activity via the production of ADMA. Design: Human thyrocytes were incubated with human umbilical vein endothelial cells (HUVEC) in order to determine the effect on HUVEC NOS activity. HUVEC cGMP production over a 3-h period was measured as an indicator of NOS activity in the absence and presence of thyrocytes. To determine thyrocyte production of ADMA, samples of conditioned media were analysed by HPLC. Results: The presence of primary human thyrocytes or immortalized human thyrocyte SGHTL-189 cells caused a significant inhibition of both basal (approximately 57% inhibition) and thrombinstimulated (approximately 42% inhibition) HUVEC cGMP production. Both primary human thyrocytes and SGHTL-189 cells released ADMA (approximately 0.28 mg per 10 6 thyrocytes over a 3-day period). However, excess L-arginine, the natural substrate for NOS, was unable to overcome thyrocyte inhibition of HUVEC cGMP production. Conclusion: These data indicate that human thyrocytes potently reduce endothelial cell cGMP concentrations, and that thyrocytes produce the endogenous NOS inhibitor, ADMA. However, the inhibition of endothelial cGMP is not mediated via thyrocyte production of a competitive NOS inhibitor.

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Precocity of the endothelial proliferation during a course of rapid goitrogenesis

Cited by 34 publications

References 5 publications

Iodine Deficiency Induces a Thyroid Stimulating Hormone-Independent Early Phase of Microvascular Reshaping in the Thyroid

Iodine Deficiency Induces a Thyroid Stimulating Hormone-Independent Early Phase of Microvascular Reshaping in the Thyroid

Thyroid follicular cells secrete plasminogen activators and can form angiostatin from plasminogen

Thyrocyte release of asymmetric dimethylarginine does not account for human thyrocyte inhibition of endothelial cell cyclic GMP

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