title: 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.
authors.affiliation: Department of Stomatology, University of California San Francisco, San Francisco, California 94143-0512, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Michael
authors.initials: M
authors.lastname: McMaster
authors.forename: Kirstin
authors.initials: K
authors.lastname: Woo
authors.forename: Mary
authors.initials: M
authors.lastname: Janatpour
authors.forename: Jean
authors.initials: J
authors.lastname: Perry
authors.forename: Terhi
authors.initials: T
authors.lastname: Karpanen
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Caroline
authors.initials: C
authors.lastname: Damsky
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Fisher
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D015536:Down-Regulation; D016228:Endothelial Growth Factors / Q000378:metabolism*; D005260:Female; D017359:HELLP Syndrome / Q000503:physiopathology*; D006801:Humans; D008024:Ligands; D008222:Lymphokines / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000503:physiopathology*; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor; D012995:Solubility; D014327:Trophoblasts / Q000166:cytology / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008024:Ligands; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1