Vascular Endothelial Growth Factor Ligands and Receptors That Regulate Human Cytotrophoblast Survival Are Dysregulated in Severe Preeclampsia and Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome

Abstract

Human placental development combines elements of tumorigenesis and vasculogenesis. The organ's specialized epithelial cells, termed cytotrophoblasts, invade the uterus where they reside in the interstitial compartment. They also line uterine arteries and veins. During invasion, ectodermally derived cytotrophoblasts undergo pseudovasculogenesis, switching their adhesion molecule repertoire to mimic that of vascular cells. Failures in this transformation accompany the pregnancy complication preeclampsia. Here, we used a combination of in situ and in vitro analyses to characterize the cell's expression of vascular endothelial growth factor (VEGF) family ligands and receptors, key regulators of conventional vasculogenesis and angiogenesis. Cytotrophoblast differentiation and invasion during the first and second trimesters of pregnancy were associated with down-regulation of VEGF receptor (VEGFR)-2. Invasive cytotrophoblasts in early gestation expressed VEGF-A, VEGF-C, placental growth factor (PlGF), VEGFR-1, and VEGFR-3 and, at term, VEGF-A, PlGF, and VEGFR-1. In vitro the cells incorporated VEGF-A into the surrounding extracellular matrix; PlGF was secreted. We also found that cytotrophoblasts responded to the VEGF ligands they produced. Blocking ligand binding significantly decreased their expression of integrin alpha1, an adhesion molecule highly expressed by endovascular cytotrophoblasts, and increased apoptosis. In severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome, immunolocalization on tissue sections showed that cytotrophoblast VEGF-A and VEGFR-1 staining decreased; staining for PlGF was unaffected. Cytotrophoblast secretion of the soluble form of VEGFR-1 in vitro also increased. Together, the results of this study showed that VEGF family members regulate cytotrophoblast survival and that expression of a subset of family members is dysregulated in severe forms of preeclampsia.

New Aspects in the Pathophysiology of Preeclampsia

“…Invasive trophoblasts express VEGF, placental growth factor (PlGF), and VEGF-C and their receptors. Furthermore, blocking their signaling pathways decreases the expression of marker of pseudovasculogenesis in vitro (18).…”

Expression of vascular endothelial growth factor receptor types 1, 2 and 3 in placenta from pregnancies complicated by hypertensive disorders

“…Several studies have been undertaken investigating the expression of the VEGF family and its receptors in placental tissues of women with normal pregnancies (Cooper et al 1995;Clark et al 1996;Cheung 1997;Shore et al 1997;Dunk and Ahmed 2001;Demir et al 2004) and pregnancies complicated by hypertensive disorders (Cooper et al 1996;Lyall et al 1997;Cheng et al 2001;El-Salahy et al 2001;Helske et al 2001;Ranheim et al 2001;Kumazaki et al 2002;Zhou et al 2002;Tsatsaris et al 2003). However, there are some discrepancies in the data reported.…”

The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age

“…This state appears to result from an imbalance in the production and circulating concentrations of angiogenic factors such as placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) and anti-angiogenic factors such as soluble VEGF receptor-1 (sVEGFR-1) and soluble endoglin (sEng). Elevated serum and plasma concentrations of sVEGFR-1 and s-Eng have been observed after the diagnosis of PE [1][2][3][7][8][9]11,12,15,18,19,[21][22][23] and before the recognition of clinical disease [4][5][6]10,13,14,16,17,20,30,32].…”