Decreased expression of the angiogenic regulators CYR61 (CCN1) and NOV (CCN3) in human placenta is associatedwith pre-eclampsia

Abstract

The pregnancy disorder pre-eclampsia (PE) is thought to be caused in part by shallow invasion of the extravillous trophoblast (EVT) leading to uteroplacental insufficiency and hypoxia. Here, we focused on the expressions of cysteine-rich 61 (CYR61, CCN1) and nephroblastoma overexpressed (NOV, CCN3), members of the CCN family of angiogenic regulators, in human placenta during normal pregnancy compared with pre-eclamptic and HELLP placentae using quantitative RT-PCR, western blotting and immunocytochemistry. During normal pregnancy, both proteins showed increasing expression levels and were strongly coexpressed in endothelial cells of vessels, stromal cells and interstitial EVT giant cells. However, NOV showed an earlier onset of expression in villous endothelial cells during gestation compared with CYR61, which may signify distinct roles of these proteins in placental angiogenesis. In early-onset pre-eclamptic placentae, both CYR61 and NOV were expressed at a significantly lower level compared with normal matched controls. This decrease of CYR61 and NOV in pre-eclamptic placentae is not associated with a decrease of the endothelial marker CD34 or vimentin. No obvious changes in the localization of CYR61 and NOV in pre-eclamptic placentae were detected but a change in the intracellular distribution in trophoblast giant cells. Our data point to a potential role of both molecules in the pathogenesis of early-onset PE.

CCN1 (CYR61) and CCN3 (NOV) signaling drives human trophoblast cells into senescence and stimulates migration properties

“…35,36 The results of previous experiments using the choriocarcinoma cell line Jeg3 suggested that CCN3 causes an imbalance between the proliferation and migration of human trophoblast cells. 13,14,22 In the present study we found that both glycosylation forms of CCN1 and CCN3 proteins reduce the numbers of benign SGHPL-5 trophoblast cells, whereas in Jeg3 cells only CCN3 seems to regulate proliferation. Comparing the effect of CCNs on migration properties in both cell lines showed that Jeg3 trophoblast cells and SGHPL-5 cells are mostly stimulated by non-glycosylated CCN1 and CCN3.…”

“…However, lower levels of CCN1 and CCN3 were detected in the sera of pregnant women with early-onset preeclampsia, a disease that is associated with insufficient trophoblast invasion. 22,23 These findings indicate that CCNs are involved in the regulation of cell biological events at the feto-maternal interface.…”

“…Previous studies showed that CCN1 and CCN3 are expressed at high levels in the human placenta during pregnancy, with expression in interstitial EVT cells, in endothelial cells of vessels, and in stromal cells. 22 The levels of both CCN proteins are consistently high in the sera of non-pregnant and pregnant women. However, lower levels of CCN1 and CCN3 were detected in the sera of pregnant women with early-onset preeclampsia, a disease that is associated with insufficient trophoblast invasion.…”

“…14,21 In the human placenta, CCN1 and CCN3 are expressed in endothelial cells of placental vessels, stromal cells, and interstitial EVT giant cells, and their expression levels increase during pregnancy. 22 In the placentas of women with early-onset preeclampsia, CCN1 and CCN3 protein levels are significantly lower than in gestation-matched control placentas. 23 We have already demonstrated that in the malignant trophoblast cell line Jeg3, a model of invasive EVT, CCN3 reduces cell proliferation and enhances migration properties.…”

Impaired A2A adenosine receptor/nitric oxide/VEGF signaling pathway in fetal endothelium during late- and early-onset preeclampsia

“…Moreover, EOPE exhibits placental histological changes related with reduced perfusion [10][11][12][13] as well as the anomalous structure of the peripheral villi and vasculature compared to respective controls identified by stereological analysis following EOPE, but not LOPE [13]. In addition, low placental levels of several pro-angiogenic factors have been reported in EOPE compared to LOPE or age-matched controls [14,15]. In particular, microarray analysis has described the lower expression of at least two angiogenesis-associated transcripts (Egfl7 and Acvrl1) in EOPE compared to LOPE or agematched controls [15].…”