Gérard Anne-Catherine, Poncin Sylvie, Caetano Bertrand, Sonveaux Pierre, Audinot Jean-Nicolas, Feron Olivier, Colin Ides M, Soncin Fabrice
CNRS UMR8161, Institut de Biologie de Lille, 1, rue Calmette, 59021 Lille Cedex, France.
Am J Pathol. 2008 Mar;172(3):748-60. doi: 10.2353/ajpath.2008.070841. Epub 2008 Feb 14.
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.
甲状腺微血管扩张是甲状腺肿形成过程中最早出现的事件，总是发生在甲状腺细胞增殖之前；然而，调控这种生理性血管生成的精确机制尚未完全明确。我们利用逆转录聚合酶链反应和免疫组织化学来测量基因表达，并使用激光多普勒测量甲状腺肿发生动物模型中的血流，结果表明甲状腺血管生成分为两个连续阶段。第一阶段持续一周，涉及血管激活；这个过程不依赖促甲状腺激素（TSH），一旦细胞内碘含量降低，甲状腺细胞表达血管内皮生长因子（VEGF）就会直接触发该过程。这一早期反应之后是甲状腺血流增加和内皮细胞增殖，二者均由VEGF介导，并被VEGF阻断抗体抑制。第二个血管生成阶段依赖TSH，并随着TSH水平升高而激活。这个阶段涉及主要促血管生成因子VEGF-A、成纤维细胞生长因子-2、血管生成素1和NG2及其受体Flk-1/VEGFR2、Flt-1/VEGFR1和Tie-2的大量上调。总之，甲状腺肿相关的血管生成促进甲状腺适应碘缺乏。具体而言，一旦碘供应受限，甲状腺细胞就会产生促血管生成信号，引发早期不依赖TSH的微血管激活；如果碘缺乏持续存在，血浆TSH水平就会升高，触发支持甲状腺细胞增殖的第二个血管生成阶段。
