Our data support the idea that the intracellular signal responsible for this early angiogenic reaction is closely associated with intracellular levels of iodine. 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. Vascular supply is an absolute requirement for all organs that cannot solely rely on diffusion of oxygen and metabolites for their survival. In endocrine glands, in addition to allocating nutrient supply, the microvascular network is particularly well adapted to secretory functions. Among all endocrine glands, the thyroid is the most vascularized. The expansion and the shrinkage of the vascular bed are Rabbit Polyclonal to KITH_VZV7 dynamically coupled with its functional status.1,2,3 Microvascular adaptation is the earliest morphological event occurring during goiter formation, before any alteration in other tissue compartments.4,5 The vascular bed may expand up to twofold, along with an increase in microvessel density and blood flow to reach a plateau when a new equilibrium is achieved.6,7 Changes in vasculature are closely related to those in intraglandular iodine content. Hence, the thyroid blood flow sharply rises when iodine supply decreases and promptly falls when iodine supply is restored.8 Variations in blood flow likely participate in intraglandular autoregulatory mechanisms that keep thyroid hormone release constant.9 The maintenance of a steady iodide supply is one of the foremost steps in hormone synthesis. Hence, increasing vascular supply contributes to the optimization of iodide uptake. Of note, iodine may be hazardous for thyrocytes when it is overloaded in iodine-deficient glands. To limit this toxicity because of free radicals released in excess, a transient blockade in thyroid MC-Val-Cit-PAB-carfilzomib hormone synthesis occurs (Wolff-Chaikoff effect).10 In the meantime, iodide access to thyrocytes becomes strongly hindered, limiting iodine-induced deleterious effects and disables the Wolff-Chaikoff effect. This is achieved, at least in part, by a prompt vasoconstriction 11,12,13,14,15 and a down-regulation of the sodium-iodide symporter (NIS).16 Thus, thyroid angioarchitecture is perfectly adapted to bring iodine supply in line with thyrocyte demand and finely tuned to quickly react to adverse environmental conditions. Previous studies reported that each follicle is surrounded by its own capillary network that remains totally independent from neighboring follicles.17 The extent of each microvascular bed is closely related to the functional status and proliferation of nearby thyrocytes. Hence, the thyroid is composed of angio-follicular units that are independent from each other but able to react to thyrotropin (thyroid-stimulating hormone or TSH) stimulation on its own. This physiological process entirely relies on a permanent paracrine dialog between endothelial and epithelial cells.1,2,3 As for changes in the epithelial compartment, recent evidence suggests that changes affecting endothelium are also of utmost importance for the development of goiters. The development of hyperplastic goiter consecutive to iodine deficiency should therefore be considered as an adaptation involving angiogenic processes synchronized with adjustments in thyrocyte function and proliferation, events that evolve throughout the entire adult life. In contrast with the chaotic nature of malignant angiogenesis, thyroid-specific angiogenic processes are both tightly controlled and perfectly reproducible using animal models of goitrogenesis. This makes the thyroid gland an easily workable model MC-Val-Cit-PAB-carfilzomib to understand how epithelial and endothelial cells cooperate in physiological conditions to keep intact organ homeostasis. Numerous questions remain regarding the role of angiogenesis during goiter development. To answer them, we studied the early stages of angiogenesis in a mouse model of goiter formation. We analyzed the expression of the major proangiogenic factors vascular endothelial growth factor (VEGF)-A, fibroblast growth factor-2 (FGF2), and angiopoietin-1 (Ang-1) and their receptors, as well as the possible involvement of pericytes in this process. We found that two successive phases of vascular remodeling take place during goitrogenesis. The early one, which had not previously been described, involves vascular activation and occurs as an immediate response to dropping iodine supply. It is TSH-independent and is directly triggered by thyrocytes. The later angiogenic phase MC-Val-Cit-PAB-carfilzomib has been previously described, is fully TSH-dependent, and involves blood vessel growth along with thyroid hyperplasia. Our study brings new understanding to the processes that control angiogenesis in regulated growth. Materials and Methods Animals and Treatments Two-month-old NMRI mice received a low-iodine diet (LID) (0.1 g iodine/day; Animalabo, Brussels, Belgium) MC-Val-Cit-PAB-carfilzomib supplemented.