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Published on: January 17, 2012
Adenoviral mediated expression of anti-inflammatory progranulin by placental explants modulates endothelial cell
Johannes Stubert1, Marlen Szewczyk1, Alf Spitschak2
1Department of Obstetrics and Gynecology, Rostock University Medical Center, Suedring 81, 18059, Rostock, Germany.
Introduction:
Functional disorders of the villous trophoblast may result in preeclampsia through the release of endothelial activating substances. Progranulin is an anti-inflammatory, pro-angiogenic cytokine with TNF-α antagonizing activity. The trophoblastic expression of progranulin is increased during preeclampsia. The aim of the study was to investigate the impact of placental progranulin synthesis on endothelial cell activation.
Methods:
Placental progranulin expression was modified by transduction of an adenoviral vector. Primary isolated human umbilical venous endothelial cells (HUVECs) were incubated with conditioned medium of first trimester placental explants. Functional studies on HUVECs included assays for proliferation, viability, cytotoxicity and analyzes of Intercellular adhesion molecule-1 (ICAM-1) and E-selectin expression.
Results:
Placental progranulin expression was more than 10-fold higher by using an adenoviral-mediated overexpression system (Ad.PGRN) compared to control vector (Ad.CTRL) and untreated controls. Incubation of HUVECs with conditioned placental medium revealed a dose-dependent increase of cytotoxicity, reduced cell proliferation and viability and resulted in an increase of ICAM-1 and E-selectin expression. Overexpression of progranulin (Ad.PGRN) antagonized the ICAM-1 expression induced by conditioned medium. However progranulin did not influence the effects on cell proliferation, viability, cytotoxicity and E-selectin expression in HUVECs.
Discussion:
Regulation of gene expression in human placental explants is possible by usage of an adenoviral vector system. The increase of endothelial ICAM-1 expression following the incubation with placental conditioned medium was partly reversed by overexpression of placental progranulin. It is suggested that up-regulation of the placental progranulin expression is an endogenous anti-inflammatory mechanism that partially antagonizes the endothelial cell activation during preeclampsia.
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