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

Jeon Yeob Jang, Sung Yong Choi, Intae Park, Do Young Park, Kibaek Choe, Pilhan Kim, Young Keum Kim, Byung Joo Lee, Masanori Hirashima, Yoshiaki Kubota, Jeong Won Park, Sheue Yann Cheng, Andras Nagy, Young Joo Park, Kari Alitalo, Minho Shong, Gou Young Koh

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)750-769
Number of pages20
JournalEMBO Molecular Medicine
Volume9
Issue number6
DOIs
Publication statusPublished - 1 Jun 2017
Externally publishedYes

Keywords

  • thyroid angiofollicular unit
  • thyroid goitrogenesis
  • vascular remodeling
  • VEGFR2

Cite this

Jang, Jeon Yeob ; Choi, Sung Yong ; Park, Intae ; Park, Do Young ; Choe, Kibaek ; Kim, Pilhan ; Kim, Young Keum ; Lee, Byung Joo ; Hirashima, Masanori ; Kubota, Yoshiaki ; Park, Jeong Won ; Cheng, Sheue Yann ; Nagy, Andras ; Park, Young Joo ; Alitalo, Kari ; Shong, Minho ; Koh, Gou Young. / VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis. In: EMBO Molecular Medicine. 2017 ; Vol. 9, No. 6. pp. 750-769.
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title = "VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis",
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 = "thyroid angiofollicular unit, thyroid goitrogenesis, vascular remodeling, VEGFR2",
author = "Jang, {Jeon Yeob} and Choi, {Sung Yong} and Intae Park and Park, {Do Young} and Kibaek Choe and Pilhan Kim and Kim, {Young Keum} and Lee, {Byung Joo} and Masanori Hirashima and Yoshiaki Kubota and Park, {Jeong Won} and Cheng, {Sheue Yann} and Andras Nagy and Park, {Young Joo} and Kari Alitalo and Minho Shong and Koh, {Gou Young}",
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doi = "10.15252/emmm.201607341",
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Jang, JY, Choi, SY, Park, I, Park, DY, Choe, K, Kim, P, Kim, YK, Lee, BJ, Hirashima, M, Kubota, Y, Park, JW, Cheng, SY, Nagy, A, Park, YJ, Alitalo, K, Shong, M & Koh, GY 2017, 'VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis' EMBO Molecular Medicine, vol. 9, no. 6, pp. 750-769. https://doi.org/10.15252/emmm.201607341

VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis. / Jang, Jeon Yeob; Choi, Sung Yong; Park, Intae; Park, Do Young; Choe, Kibaek; Kim, Pilhan; Kim, Young Keum; Lee, Byung Joo; Hirashima, Masanori; Kubota, Yoshiaki; Park, Jeong Won; Cheng, Sheue Yann; Nagy, Andras; Park, Young Joo; Alitalo, Kari; Shong, Minho; Koh, Gou Young.

In: EMBO Molecular Medicine, Vol. 9, No. 6, 01.06.2017, p. 750-769.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis

AU - Jang, Jeon Yeob

AU - Choi, Sung Yong

AU - Park, Intae

AU - Park, Do Young

AU - Choe, Kibaek

AU - Kim, Pilhan

AU - Kim, Young Keum

AU - Lee, Byung Joo

AU - Hirashima, Masanori

AU - Kubota, Yoshiaki

AU - Park, Jeong Won

AU - Cheng, Sheue Yann

AU - Nagy, Andras

AU - Park, Young Joo

AU - Alitalo, Kari

AU - Shong, Minho

AU - Koh, Gou Young

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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.

KW - thyroid angiofollicular unit

KW - thyroid goitrogenesis

KW - vascular remodeling

KW - VEGFR2

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DO - 10.15252/emmm.201607341

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