Vascular Endothelial Growth Factor Ligands and Receptors ThatRegulate Human Cytotrophoblast Survival Are Dysregulated in SeverePreeclampsia and Hemolysis Elevated Liver Enzymes and Low PlateletsSyndrome

摘要

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. Invitro the cells incorporated VEGF-A into the surroundingextracellular matrix; PlGF was secreted. We also found thatcytotrophoblasts responded to the VEGF ligands they produced. Blockingligand binding significantly decreased their expression of integrinα1, an adhesion molecule highly expressed by endovascularcytotrophoblasts, and increased apoptosis. In severepreeclampsia and hemolysis, elevated liver enzymes, andlow platelets syndrome, immunolocalization on tissue sectionsshowed that cytotrophoblast VEGF-A and VEGFR-1 staining decreased;staining for PlGF was unaffected. Cytotrophoblast secretion of thesoluble form of VEGFR-1 in vitro also increased.Together, the results of this study showed that VEGF familymembers regulate cytotrophoblast survival and that expression ofa subset of family members is dysregulated in severe forms ofpreeclampsia.