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From the Departments of Stomatology,*Anatomy, Obstetrics, Gynecology, andReproductive Sciences, and PharmaceuticalChemistry,¶ University of California SanFrancisco, San Francisco, California; and the Molecular/Cancer BiologyLaboratory, Biomedicum Helsinki and LudwigInstitute for Cancer Research, University of Helsinki, Helsinki,Finland
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
1, 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.
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K. Fukushima, S. Miyamoto, K. Tsukimori, H. Kobayashi, H. Seki, S. Takeda, E. Kensuke, K. Ohtani, M. Shibuya, and H. Nakano Tumor Necrosis Factor and Vascular Endothelial Growth Factor Induce Endothelial Integrin Repertories, Regulating Endovascular Differentiation and Apoptosis in a Human Extravillous Trophoblast Cell Line Biol Reprod, July 1, 2005; 73(1): 172 - 179. [Abstract] [Full Text] [PDF]
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C. M. Anderson, F. Lopez, H.-Y. Zhang, K. Pavlish, and J. N. Benoit Reduced Uteroplacental Perfusion Alters Uterine Arcuate Artery Function in the Pregnant Sprague-Dawley Rat Biol Reprod, March 1, 2005; 72(3): 762 - 766. [Abstract] [Full Text] [PDF]
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 K. Y Lee and F. J DeMayo Animal models of implantation Reproduction, December 1, 2004; 128(6): 679 - 695. [Abstract] [Full Text] [PDF]
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S. A. Karumanchi and Y. Bdolah Hypoxia and sFlt-1 in Preeclampsia: The "Chicken-and-Egg" Question Endocrinology, November 1, 2004; 145(11): 4835 - 4837. [Full Text] [PDF]
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T. Nagamatsu, T. Fujii, M. Kusumi, L. Zou, T. Yamashita, Y. Osuga, M. Momoeda, S. Kozuma, and Y. Taketani Cytotrophoblasts Up-Regulate Soluble Fms-Like Tyrosine Kinase-1 Expression under Reduced Oxygen: An Implication for the Placental Vascular Development and the Pathophysiology of Preeclampsia Endocrinology, November 1, 2004; 145(11): 4838 - 4845. [Abstract] [Full Text] [PDF]
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S. Ahmad and A. Ahmed Elevated Placental Soluble Vascular Endothelial Growth Factor Receptor-1 Inhibits Angiogenesis in Preeclampsia Circ. Res., October 29, 2004; 95(9): 884 - 891. [Abstract] [Full Text] [PDF]
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J. M. Davison, V. Homuth, A. Jeyabalan, K. P. Conrad, S. A. Karumanchi, S. Quaggin, R. Dechend, and F. C. Luft New Aspects in the Pathophysiology of Preeclampsia J. Am. Soc. Nephrol., September 1, 2004; 15(9): 2440 - 2448. [Abstract] [Full Text] [PDF]
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J.-Y. Chung, Y. Song, Y. Wang, R. R. Magness, and J. Zheng Differential Expression of Vascular Endothelial Growth Factor (VEGF), Endocrine Gland Derived-VEGF, and VEGF Receptors in Human Placentas from Normal and Preeclamptic Pregnancies J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2484 - 2490. [Abstract] [Full Text] [PDF]
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E.Y. Anteby, C. Greenfield, S. Natanson-Yaron, D. Goldman-Wohl, Y. Hamani, V. Khudyak, I. Ariel, and S. Yagel Vascular endothelial growth factor, epidermal growth factor and fibroblast growth factor-4 and -10 stimulate trophoblast plasminogen activator system and metalloproteinase-9 Mol. Hum. Reprod., April 1, 2004; 10(4): 229 - 235. [Abstract] [Full Text] [PDF]
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 R. J. Levine, S. E. Maynard, C. Qian, K.-H. Lim, L. J. England, K. F. Yu, E. F. Schisterman, R. Thadhani, B. P. Sachs, F. H. Epstein, et al. Circulating Angiogenic Factors and the Risk of Preeclampsia N. Engl. J. Med., February 12, 2004; 350(7): 672 - 683. [Abstract] [Full Text] [PDF]
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R. Thadhani, W. P. Mutter, M. Wolf, R. J. Levine, R. N. Taylor, V. P. Sukhatme, J. Ecker, and S. A. Karumanchi First Trimester Placental Growth Factor and Soluble Fms-Like Tyrosine Kinase 1 and Risk for Preeclampsia J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 770 - 775. [Abstract] [Full Text] [PDF]
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 L. V. Parise JAM-1 Regulation of Endothelial Cell Migration: Implications for Angiogenesis Arterioscler Thromb Vasc Biol, December 1, 2003; 23(12): 2119 - 2120. [Full Text] [PDF]
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K. Hirtenlehner, J. Pollheimer, C. Lichtenberger, M. F. Wolschek, H. Zeisler, P. Husslein, and M. Knofler Elevated Serum Concentrations of the Angiogenesis Inhibitor Endostatin in Preeclamptic Women Reproductive Sciences, October 1, 2003; 10(7): 412 - 417. [Abstract] [PDF]
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D. S. Torry, D. Mukherjea, J. Arroyo, and R. J. Torry Expression and Function of Placenta Growth Factor: Implications for Abnormal Placentation Reproductive Sciences, May 1, 2003; 10(4): 178 - 188. [Abstract] [PDF]
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H. Sugimoto, Y. Hamano, D. Charytan, D. Cosgrove, M. Kieran, A. Sudhakar, and R. Kalluri Neutralization of Circulating Vascular Endothelial Growth Factor (VEGF) by Anti-VEGF Antibodies and Soluble VEGF Receptor 1 (sFlt-1) Induces Proteinuria J. Biol. Chem., April 4, 2003; 278(15): 12605 - 12608. [Abstract] [Full Text] [PDF]
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K. A. Longo, J. A. Kennell, M. J. Ochocinska, S. E. Ross, W. S. Wright, and O. A. MacDougald Wnt Signaling Protects 3T3-L1 Preadipocytes from Apoptosis through Induction of Insulin-like Growth Factors J. Biol. Chem., October 4, 2002; 277(41): 38239 - 38244. [Abstract] [Full Text] [PDF]
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