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EMBO Mol Med. 2017 Jun;9(6):750-769. doi: 10.15252/emmm.201607341.

VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis.

Author information

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 minhos@cnu.ac.kr gykoh@kaist.ac.kr.
13
Center for Vascular Research, Institute of Basic Science (IBS), Daejeon, Korea minhos@cnu.ac.kr 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.

KEYWORDS:

VEGFR2; thyroid angiofollicular unit; thyroid goitrogenesis; vascular remodeling

PMID:
28438786
PMCID:
PMC5452036
DOI:
10.15252/emmm.201607341
[Indexed for MEDLINE]
Free PMC Article

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