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27 March 2013 Mechanisms of Angiogenic Suppression in Uteri Exposed to Diethylstilbestrol Neonatally in the Mouse
Shuji Yamashita, Akihiko Kudo, Hayato Kawakami, Yasunori Okada
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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.

Shuji Yamashita, Akihiko Kudo, Hayato Kawakami, and Yasunori Okada "Mechanisms of Angiogenic Suppression in Uteri Exposed to Diethylstilbestrol Neonatally in the Mouse," Biology of Reproduction 88(5), (27 March 2013). https://doi.org/10.1095/biolreprod.112.106443
Received: 20 November 2012; Accepted: 1 March 2013; Published: 27 March 2013
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KEYWORDS
ANGPT1
ANGPT2
DES
NRP1
TIE2
uterus
vascular density
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