A culprit of thyroid diseases

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ineke
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Lid geworden op: 08 nov 2014, 17:53

A culprit of thyroid diseases

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A culprit of thyroid diseases
A research team has clarified a molecular mechanism of the thyroid and surrounding vascular system in the most common form of hyperthyroidism. Published in the EMBO Molecular Medicine journal, these findings provide a potential therapeutic target for thyroid diseases.

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VEGF-A (blue) in follicular cells of the thyroid. This study shows that the protein VEGF-A and its correspondent receptor VEGFR2 trigger two common hallmarks of thyroid diseases: enlargement of the thyroid and increase in density of the capillaries surrounding this gland. Credit: Institute for Basic Science


The thyroid is a highly vascularized organ found behind the Adam's apple. Some of the functions of the thyroid are regulated by a hormone called thyrotropin, produced in the brain. Graves' disease, the most common cause of hyperthyroidism in the United States, affects both the thyroid and the surrounding vascular network. In this disease, the thyroid produces an excessive amount of hormones and the capillaries become denser. "Previous studies show that abnormalities in thyroid glands and surrounding vasculature are interconnected, we wanted to understand how this happens, at the molecular level," explains Koh.

Using animal models that simulate Graves' disease, IBS scientists uncovered the biological pathway contributing to this disorder. They found that the culprit is the vascular endothelial growth factor A (VEGF-A). This protein is involved in forming new vessels around the thyroid. It also regulates the hormonal exchange between these vessels and the thyroid through very small pores called fenestrae.

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Thyrotropin affects the vascular diameter of capillaries surrounding the thyroid. Changes in vascular diameter with normal (left), less than normal (middle), and higher (right) levels of the hormone thyrotropin. Excess of thyrotropin stimulation is associated with human thyroidal diseases like hyperthyroidism, Graves' disease, goiter, and cancer. Credit: Institute for Basic Science

Upon stimulation with the thyrotropin hormone, VEGF-A is produced by the thyroid gland. As a result, the thyroid enlarges and the walls of the capillaries (constituted mainly by endothelial cells) increase the expression of VEGFR2, the receptor for VEGF-A.

By blocking VEGFR2, the scientists could inhibit enlargement of the thyroid and stop vascular remodeling. "Our findings identify VEGFR2 blockade as a novel therapeutic avenue for targeting thyroid disease associated with thyrotropin," explains Koh.

The research team could also exclude other molecular pathways. For example, they found that the angiopoietin-Tie2 pathway, fundamental in other tissues like the eyes and brain, does not play a major role in remodeling the vasculature of the thyroid gland. Finally, VEGFR3 was ruled out from the indispensable pool of proteins that maintain thyroid vascular integrity.

Bron: Med. Express



Open Access
Research Article
VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis

Jeon Yeob Jang1,2,3,†, Sung Yong Choi2,†, Intae Park1,2, Do Young Park1,2, Kibaek Choe4,
Pilhan Kim4, Young Keum Kim5, Byung‐Joo Lee3, Masanori Hirashima6, Yoshiaki Kubota7,
Jeong‐Won Park8, Sheue‐Yann Cheng8, Andras Nagy9, Young Joo Park10, Kari Alitalo11,
Minho Shong (minhos@cnu.ac.kr)*,12 and Gou Young Koh (gykoh@kaist.ac.kr)*,1,4
1 Center for Vascular Research, Institute of Basic Science (IBS), Daejeon, Korea
2 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
3 Department of Otorhinolaryngology‐Head and Neck Surgery and Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, Busan, Korea
4 Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
5 Department of Pathology, Pusan National University School of Medicine, Pusan National University Hospital, Busan, Korea
6 Department of Physiology and Cell Biology Graduate School of Medicine Kobe University, Kobe, Japan
7 Department of Vascular Biology, The Sakaguchi Laboratory, School of Medicine, Keio University, Shinjuku‐ku Tokyo, Japan
8 Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
9 Lunenfeld‐Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
10 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
11 Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
12 Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, Korea
↵* Corresponding author. Tel: +82 42 280 7161; Fax: +82 42 280 7995; E‐mail: minhos@cnu.ac.kr
Corresponding author. Tel: +82 42 350 2638; Fax: +82 42 350 2610; E‐mail: gykoh@kaist.ac.kr

Abstract
Thyroid gland vasculature has a distinguishable characteristic of endothelial fenestrae, a critical component for proper molecular transport. However, the signaling pathway that critically governs the maintenance of thyroid vascular integrity, including endothelial fenestrae, is poorly understood. Here, we found profound and distinct expression of follicular epithelial VEGF‐A and vascular VEGFR2 that were precisely regulated by circulating thyrotropin, while there were no meaningful expression of angiopoietin–Tie2 system in the thyroid gland. Our genetic depletion experiments revealed that VEGFR2, but not VEGFR3, is indispensable for maintenance of thyroid vascular integrity. Notably, blockade of VEGF‐A or VEGFR2 not only abrogated vascular remodeling but also inhibited follicular hypertrophy, which led to the reduction of thyroid weights during goitrogenesis. Importantly, VEGFR2 blockade alone was sufficient to cause a reduction of endothelial fenestrae with decreases in thyrotropin‐responsive genes in goitrogen‐fed thyroids. Collectively, these findings establish follicular VEGF‐A–vascular VEGFR2 axis as a main regulator for thyrotropin‐dependent thyroid angiofollicular remodeling and goitrogenesis.

The follicular VEGF‐A–vascular VEGFR2 axis regulates thyroid follicle integrity and is a key mediator of thyrotropin‐dependent angiofollicular remodeling and goitrogenesis.

Synopsis
◾Follicular VEGF‐A and vascular VEGFR2 expression are precisely regulated by thyrotropin stimulation in the thyroid gland.
◾Blockade of VEGF‐A or VEGFR2 induces thyroid vascular regression during the physiologic state and abrogates angiofollicular remodeling during goitrogenesis.
◾Microvessel densities and their VEGFR2 expression are increased in thyroid glands of patients with Graves' disease.
◾VEGFR2 inhibition reduces transcellular transport capacities of thyroid vasculatures and thyrotropin‐responsiveness of follicular cells, ultimately inhibiting goitrogenesis.

Figuren en gegevens:
http://embomolmed.embopress.org/content ... gures-only


Gehele artikel
http://embomolmed.embopress.org/content/9/6/750



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