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Int J Clin Exp Pathol 2013;6(11):2441-2450

Original Article
Cyclosporin A enhances the ability of trophoblasts to displace the activated human
umbilical vein endothelial cell monolayers

Chuanling Tang, Limei Chen, Weirong Gu, Meirong Du, Mingqing Li, Qi Chen, Dajin Li

Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College,
Shanghai 200011, China; Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, The University of Auckland,
Auckland 1001, New Zealand

Received September 8, 2013; Accepted October 12, 2013; Epub October 15, 2013; Published November 1, 2013

Abstract: Transformation of the spiral arteries including the displacement of vascular endothelial cells by extravillous trophoblasts is an
essential prerequisite to normal placentation. However, the activated endothelial cells resist the invasion of trophoblasts, which contributes to
the pathologies of some pregnant disorders. Our previous studies have demonstrated that Cyclosporin A (CsA) promotes the migration and
invasion of human first-trimester trophoblasts. In the present study, we further investigated whether CsA could promote the ability of
trophoblasts to displace the activated human umbilical vein endothelial cell (HUVEC) monolayers and the possible molecular mechanisms.
Human choriocarcinoma Jar cells were used as a model of invasive trophoblasts. CsA pretreated JAR cells (red) were added to HUVEC
monolayers (green) activated with either necrotic JAR cells or tumor necrosis factor alpha (TNFα). The ability of JAR cells to displace HUVECs
from the monolayers was examined by confocal microscopy. The effects of CsA on Titin and E-cadherin expression, matrix metalloproteinases
(MMPs) activity and CXCL12 secretion of JAR cells were evaluated by western blot, gelatin zymography and enzyme-linked immunosorbent
assay (ELISA), respectively. We found that CsA pretreatment increased the ability of JAR cells to displace activated HUVECs from the
monolayers. However, the displacement was reduced by untreated JAR cells. Moreover, CsA pretreatment up-regulated Titin expression, down-
regulated E-cadherin expression, improved MMP2 and MMP9 activity, and increased the CXCL12 secretion in JAR cells. These results indicate
that CsA may improve the trophoblast invasion to activated HUVEC monolayers through different downstream targets, and ultimately, improve
the transformation and remodeling of spiral arteries. (IJCEP1309025).

Keywords: CsA, trophoblast, invasion, HUVEC, activation, remodelling

Address correspondence to: Dr. Dajin Li, Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics & Gynecology,
Shanghai Medical School, Fudan University, 419 Zhao Zhou Road, Shanghai, 200011, China. Tel: +86-21-63457331; Fax: +86-21-63457331; E-
mail: djli@shmu.edu.cn; Dr. Qi Chen, Department of Obstetrics and Gynecology, Faculty of Medical and Health Sciences, The University of
Auckland, 85 Park Road, Grafton, Auckland 1001, New Zealand. Tel: +64-9- 3737599x89519; Fax: +64-9-3035969. E-mail: q.chen@auckland.ac.
nz