Roles of endothelin-1 and nitric oxide in the paracrine/autocrine regulation of the thyroid gland

Abstract

The biological importance of the thyroid gland has been recognized for centuries. For instance, the discovery in the late 19th century that cretinism results from thyroid dysfunction led to the identification of thyroid hormones (T3 and T4) in early years of our century. Thyroid hormones play a vital role in fetal development, and throughout life, they influence major metabolic processes in almost all organs. Their synthesis depends primarily upon the regular availability of a trace element, iodine, present in the human body in minute amounts. The adequate uptake of iodide by the thyroid follicular cells represents not only a limiting step in the thyroid hormone synthesis, but also a prerequisite to insure the near constancy of the rate of thyroid hormone synthesis and secretion. To face wide fluctuations in the supply of iodine, adaptive autoregulatory mechanisms are activated within the gland. One may, thus, consider endemic goiter as an adaptive process that occurs in response to insufficient supply of dietary iodine. The thyroid enlargement characterized by the typical hyperplastic picture including all cellular compartments (epithelial and stromal), as it is observed at the early stages of goiter formation (before the appearance of nodules), represents an examples of a coordinated nonneoplastic growth. The proliferation of stromal cells is mainly reflected in increased vascularity and blood flow secondary to the expansion of the capillary bed. Besides the obvious influx of nutrients, changes in the thyroid micro-vasculature can also modulate the availability of iodide load to epithelial cells, hence their ability to synthesize thyroid hormones and highlights the role of the thyroid vascular compartment on the maintenance of the general thyroid hormone economy. The mechanisms underlying the integrated processes leading to the coordinated growth between parenchyma and stromal cells are being to be elucidated. Although TSH is classically considered as the main trophic factor of the gland, it clearly appeared during the last 10-15 years that growing processes imply local cross-talks between the different thyroid cell populations mediated by a highly intricated network of locally-released factors acting on a paracrine and/or autocrine mode of action. Although some factors were already identified when we started the project, other candidates appeared of interest. Thus, we hypothesized that newly discovered vasoactive factors; endothelins, and nitric oxide, could play an important role in the control of the thyroid microvasculature and secondarily on several aspects of thyroid function and growth. In the present thesis, we present evidences for their local production and propose potential roles in the thyroid gland. The first chapter contains background informations about thyroid hormones synthesis and peripheral mode of action, about TSH- and non TSH-dependent control of thyroid gland and function. The role of iodine is specifically emphasized, based on personal results. The main morphological and physiological aspects of vascular changes occurring during goiter formation and involution are reviewed. In the second chapter, the specific aims of the study are exposed, based on data of the literature available at the time we started the project, as well as on the rationale that led us to propose that endothelins and nitric oxide could be endogenously synthesized factors regulating the thyroid vasculature. In the third chapter, general informations related to the endothelins and their roles in endocrine organs other than the thyroid gland are reviewed. We also present our personal data related to the identification of endothelin-related proteins and gene expression in the rat thyroid gland and their modifications in an experimental model of goiter formation and involution. The involvement of endothelins in the maintenance of thyroid growth and function is then proposed. The fourth chapter is built on the same template than the third chapter (a review on the general properties of nitric oxide and on its roles in diverse endocrine organs), but we aim to present evidences for the local production of nitric oxide in the thyroid gland (human and rat) by locally active nitric oxide synthases. We then propose at the end of this chapter a theory based on the assumption that increased production of nitric oxide at the early stages or goiter formation could be the initial step leading to the expansion if the thyroid vasculature. In the last chapter, our main findings are summarized, and new perspectives for this project are presentedThèse d'agrégation de l'enseignement supérieur (faculté de médecine) -- UCL, 199