Mechanisms of angiogenic suppression in uteri exposed to diethylstilbestrol neonatally in the mouse

Shuji Yamashita, Akihiko Kudo, Hayato Kawakami, Yasunori Okada

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Perinatal estrogen exposure elicits a wide range of abnormalities in the female genital tract. Since angiogenesis is essential for morphogenesis, we investigated the vascular density, integrity of vasculatures, and expression of angiogenic factors and their receptors in the uteri of mice treated with diethylstilbestrol (DES) neonatally (DES-mice); the uteri were collected from Day 4 to Day 20. DES treatment reduced the number and density of vasculatures immunostained with PECAM1 (platelet and endothelial cell adhesion molecule 1) in the stroma. Horseradish peroxidase injected into the left ventricle leaked into the endometrium and myometrium on Day 10 in the DES-mice but not in the controls. Electron microscopy confirmed the immaturity of the capillaries, which had an incomplete basal lamina and fewer pericytes. Immunohistochemical studies demonstrated that VEGFA (vascular endothelial growth factor A) expression and ANGPT1 (angiopoietin 1) expression were down-regulated in the stromal cells until Days 20 and 10, respectively. The number of vasculatures with ANGPT2 immunoreaction was reduced in the DES-mice. DES treatment suppressed the expression of VEGFR2 (VEGF receptor 2) and the co-receptor NRP1 (neuropilin 1) as well as TEI2 in the vasculatures. The results of RT-PCR and Western blotting supported the down-regulation of the expression of angiogenic factors and their receptors in DES-mice, whereas the VEGFR1 protein expression was up-regulated. These results suggested that the low concentration of angiogenic factors in the stroma was primarily responsible for the low vascular density in the stroma of the DES-mice, and that the low vascular density and immature vasculatures resulted in uterine malformations

Original languageEnglish
Article numberArticle 116
JournalBiology of Reproduction
Volume88
Issue number5
DOIs
Publication statusPublished - 2013

Fingerprint

Diethylstilbestrol
Uterus
Angiogenesis Inducing Agents
Blood Vessels
Neuropilin-1
Angiopoietin-1
CD31 Antigens
Pericytes
Vascular Endothelial Growth Factor Receptor
Myometrium
Horseradish Peroxidase
Stromal Cells
Endometrium
Morphogenesis
Basement Membrane
Vascular Endothelial Growth Factor A
Heart Ventricles
Electron Microscopy
Estrogens
Down-Regulation

Keywords

  • ANGPT1
  • ANGPT2
  • DES
  • NRP1
  • TIE2
  • Uterus
  • Vascular density
  • VEGFA
  • VEGFR1
  • VEGFR2

ASJC Scopus subject areas

  • Cell Biology

Cite this

Mechanisms of angiogenic suppression in uteri exposed to diethylstilbestrol neonatally in the mouse. / Yamashita, Shuji; Kudo, Akihiko; Kawakami, Hayato; Okada, Yasunori.

In: Biology of Reproduction, Vol. 88, No. 5, Article 116, 2013.

Research output: Contribution to journalArticle

Yamashita, Shuji ; Kudo, Akihiko ; Kawakami, Hayato ; Okada, Yasunori. / Mechanisms of angiogenic suppression in uteri exposed to diethylstilbestrol neonatally in the mouse. In: Biology of Reproduction. 2013 ; Vol. 88, No. 5.
@article{adebf3d381ba48c2aa10e7175e635a64,
title = "Mechanisms of angiogenic suppression in uteri exposed to diethylstilbestrol neonatally in the mouse",
abstract = "Perinatal estrogen exposure elicits a wide range of abnormalities in the female genital tract. Since angiogenesis is essential for morphogenesis, we investigated the vascular density, integrity of vasculatures, and expression of angiogenic factors and their receptors in the uteri of mice treated with diethylstilbestrol (DES) neonatally (DES-mice); the uteri were collected from Day 4 to Day 20. DES treatment reduced the number and density of vasculatures immunostained with PECAM1 (platelet and endothelial cell adhesion molecule 1) in the stroma. Horseradish peroxidase injected into the left ventricle leaked into the endometrium and myometrium on Day 10 in the DES-mice but not in the controls. Electron microscopy confirmed the immaturity of the capillaries, which had an incomplete basal lamina and fewer pericytes. Immunohistochemical studies demonstrated that VEGFA (vascular endothelial growth factor A) expression and ANGPT1 (angiopoietin 1) expression were down-regulated in the stromal cells until Days 20 and 10, respectively. The number of vasculatures with ANGPT2 immunoreaction was reduced in the DES-mice. DES treatment suppressed the expression of VEGFR2 (VEGF receptor 2) and the co-receptor NRP1 (neuropilin 1) as well as TEI2 in the vasculatures. The results of RT-PCR and Western blotting supported the down-regulation of the expression of angiogenic factors and their receptors in DES-mice, whereas the VEGFR1 protein expression was up-regulated. These results suggested that the low concentration of angiogenic factors in the stroma was primarily responsible for the low vascular density in the stroma of the DES-mice, and that the low vascular density and immature vasculatures resulted in uterine malformations",
keywords = "ANGPT1, ANGPT2, DES, NRP1, TIE2, Uterus, Vascular density, VEGFA, VEGFR1, VEGFR2",
author = "Shuji Yamashita and Akihiko Kudo and Hayato Kawakami and Yasunori Okada",
year = "2013",
doi = "10.1095/biolreprod.112.106443",
language = "English",
volume = "88",
journal = "Biology of Reproduction",
issn = "0006-3363",
publisher = "Society for the Study of Reproduction",
number = "5",

}

TY - JOUR

T1 - Mechanisms of angiogenic suppression in uteri exposed to diethylstilbestrol neonatally in the mouse

AU - Yamashita, Shuji

AU - Kudo, Akihiko

AU - Kawakami, Hayato

AU - Okada, Yasunori

PY - 2013

Y1 - 2013

N2 - Perinatal estrogen exposure elicits a wide range of abnormalities in the female genital tract. Since angiogenesis is essential for morphogenesis, we investigated the vascular density, integrity of vasculatures, and expression of angiogenic factors and their receptors in the uteri of mice treated with diethylstilbestrol (DES) neonatally (DES-mice); the uteri were collected from Day 4 to Day 20. DES treatment reduced the number and density of vasculatures immunostained with PECAM1 (platelet and endothelial cell adhesion molecule 1) in the stroma. Horseradish peroxidase injected into the left ventricle leaked into the endometrium and myometrium on Day 10 in the DES-mice but not in the controls. Electron microscopy confirmed the immaturity of the capillaries, which had an incomplete basal lamina and fewer pericytes. Immunohistochemical studies demonstrated that VEGFA (vascular endothelial growth factor A) expression and ANGPT1 (angiopoietin 1) expression were down-regulated in the stromal cells until Days 20 and 10, respectively. The number of vasculatures with ANGPT2 immunoreaction was reduced in the DES-mice. DES treatment suppressed the expression of VEGFR2 (VEGF receptor 2) and the co-receptor NRP1 (neuropilin 1) as well as TEI2 in the vasculatures. The results of RT-PCR and Western blotting supported the down-regulation of the expression of angiogenic factors and their receptors in DES-mice, whereas the VEGFR1 protein expression was up-regulated. These results suggested that the low concentration of angiogenic factors in the stroma was primarily responsible for the low vascular density in the stroma of the DES-mice, and that the low vascular density and immature vasculatures resulted in uterine malformations

AB - Perinatal estrogen exposure elicits a wide range of abnormalities in the female genital tract. Since angiogenesis is essential for morphogenesis, we investigated the vascular density, integrity of vasculatures, and expression of angiogenic factors and their receptors in the uteri of mice treated with diethylstilbestrol (DES) neonatally (DES-mice); the uteri were collected from Day 4 to Day 20. DES treatment reduced the number and density of vasculatures immunostained with PECAM1 (platelet and endothelial cell adhesion molecule 1) in the stroma. Horseradish peroxidase injected into the left ventricle leaked into the endometrium and myometrium on Day 10 in the DES-mice but not in the controls. Electron microscopy confirmed the immaturity of the capillaries, which had an incomplete basal lamina and fewer pericytes. Immunohistochemical studies demonstrated that VEGFA (vascular endothelial growth factor A) expression and ANGPT1 (angiopoietin 1) expression were down-regulated in the stromal cells until Days 20 and 10, respectively. The number of vasculatures with ANGPT2 immunoreaction was reduced in the DES-mice. DES treatment suppressed the expression of VEGFR2 (VEGF receptor 2) and the co-receptor NRP1 (neuropilin 1) as well as TEI2 in the vasculatures. The results of RT-PCR and Western blotting supported the down-regulation of the expression of angiogenic factors and their receptors in DES-mice, whereas the VEGFR1 protein expression was up-regulated. These results suggested that the low concentration of angiogenic factors in the stroma was primarily responsible for the low vascular density in the stroma of the DES-mice, and that the low vascular density and immature vasculatures resulted in uterine malformations

KW - ANGPT1

KW - ANGPT2

KW - DES

KW - NRP1

KW - TIE2

KW - Uterus

KW - Vascular density

KW - VEGFA

KW - VEGFR1

KW - VEGFR2

UR - http://www.scopus.com/inward/record.url?scp=84880970866&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880970866&partnerID=8YFLogxK

U2 - 10.1095/biolreprod.112.106443

DO - 10.1095/biolreprod.112.106443

M3 - Article

VL - 88

JO - Biology of Reproduction

JF - Biology of Reproduction

SN - 0006-3363

IS - 5

M1 - Article 116

ER -