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Zhou, Y. et al. Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion? J. Clin. Invest. 99, 2139-2151

Department of Stomatology, University of California San Francisco, 94143-0512, USA.
Journal of Clinical Investigation (Impact Factor: 13.77). 06/1997; 99(9):2139-51. DOI: 10.1172/JCI119387
Source: PubMed

ABSTRACT Establishment of the human placenta requires that fetal cytotrophoblast stem cells in anchoring chorionic villi become invasive. These cytotrophoblasts aggregate into cell columns and invade both the uterine interstitium and vasculature, anchoring the fetus to the mother and establishing blood flow to the placenta. Cytotrophoblasts colonizing spiral arterioles replace maternal endothelium as far as the first third of the myometrium. We show here that differentiating cytotrophoblasts transform their adhesion receptor phenotype so as to resemble the endothelial cells they replace. Cytotrophoblasts in cell columns show reduced E-cadherin staining and express VE-(endothelial) cadherin, platelet-endothelial adhesion molecule-1, vascular endothelial adhesion molecule-1, and alpha-4-integrins. Cytotrophoblasts in the uterine interstitium and maternal vasculature continue to express these receptors, and, like endothelial cells during angiogenesis, also stain for alphaVbeta3. In functional studies, alphaVbeta3 and VE-cadherin enhance, while E-cadherin restrains, cytotrophoblast invasiveness. Cytotrophoblasts expressing alpha4 integrins bound immobilized VCAM-1 in vitro, suggesting that this receptor-pair could mediate cytotrophoblast-endothelium or cytotrophoblast-cytotrophoblast interactions in vivo, during endovascular invasion. In the pregnancy disorder preeclampsia, in which endovascular invasion remains superficial, cytotrophoblasts fail to express most of these endothelial markers (Zhou et al., 1997. J. Clin. Invest. 99:2152-2164.), suggesting that this adhesion phenotype switch is required for successful endovascular invasion and normal placentation.

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    • "Following implantation, human blastocyst-derived extravillous trophoblasts (EVTs) invade the underlying decidua composed primarily of resident decidual cells and an immune cell population dominated by decidual natural killer (dNK) cells (70%) with significant numbers of macrophages (20%) and regulatory T-cells (10% – 20%) [1] . As EVTs cross the decidua and the inner third of the myometrium they promote transformation of spiral arteries and arterioles into low-resistance high-capacity vessels that increase uteroplacental blood flow to the developing 2 Chedraui et al., Reduced ITAC and IP-10 levels in fetal circulation in severe preeclampsia fetal-placental unit [2] [3] . Preeclampsia (PE) is associated with shallow EVT invasion [4] [5] and reduced dNK cell infiltration [6] . "
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    ABSTRACT: Background: Higher 1 st trimester maternal serum levels of interferon-induced protein 10 (IP-10) and interferon inducible T-cell alpha chemoattractant (ITAC) are reported in gestations complicated with preeclampsia. However, parallel results in the fetal circulation are lacking. Objective: To compare IP-10 and ITAC levels in neonatal cord blood from gestations complicated by severe preeclampsia vs. gestational age-matched controls. Method: Umbilical cord vessels were sampled following delivery of women with severe preeclampsia (n = 30) ≥ 36 weeks to measure plasma IP-10 and ITAC levels and compared to corresponding controls matched for parity as well as maternal and gestational age. Chemokines were measured by specific ELISAs and expressed as pg/mL. Rho Spearman ’ s coefficients were calculated to establish correlations between chemokine values and various numeric variables. Results: Preeclamptic cases displayed significantly lower median plasma umbilical artery and vein levels of both chemokines when compared to controls (IP-10: 23.4 vs. 31.4 and 2.0 vs. 24.6 pg/mL, P < 0.05; and ITAC: 2.0 vs. 13.9 and 11.9 vs. 31.6 pg/mL, P < 0.05, in artery and vein, respectively). There was a significant correlation between levels of both chemokines (r 2 = 0.616, P = 0.0001), but not with other variables. Conclusion: In contrast to elevated 1 st trimester levels of IP-10 previously found in the maternal serum of women who later developed preeclampsia, this study found lower umbilical cord IP-10 and ITAC plasma levels in near-term gestations with established severe preeclampsia.
    Journal of Perinatal Medicine 05/2015; DOI:10.1515/jpm-2014-0371 · 1.43 Impact Factor
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    • "The profound changes that occur in the spiral arteries of the decidua favour local complement activation. The vascular changes are characterized by partial replacement of endothelial cells by a subpopulation of EVT that expresses endothelial-like adhesion molecules (Zhou et al., 1997). These cells adhere to endothelial cells and migrate through the interendothelial cell junctions reaching a subendothelial position without destroying the endothelial cells (Bulla et al., 2005). "
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    • "In our study alpha1-3(IV) and alpha5(IV) domains are present in CCC. Since EVT at the tip of CCC express integrin avb3, which binds to alpha2(IV) and alpha3(IV) NC1 domains, a direct interaction with trophoblast is possible [59] [61] [62]. The collagen XVIII NC1 domain (endostatin) is known to increase MMP-2 expression in trophoblast cells and the alpha(IV) NC1 domains might similarly affect MMP expression by EVT [56] [63]. "
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    ABSTRACT: Introduction Extracellular matrix proteins play a crucial role in influencing the invasion of trophoblast cells. However the role of collagens and collagen type IV (col-IV) in particular at the implantation site is not clear. Methods Immunohistochemistry was used to determine the distribution of collagen types I, III, IV and VI in endometrium and decidua during the menstrual cycle and the first trimester of pregnancy. Expression of col-IV alpha chains during the reproductive cycle was determined by qPCR and protein localisation by immunohistochemistry. The structure of col-IV in placenta was examined using transmission electron microscopy. Finally, the expression of col-IV alpha chain NC1 domains and collagen receptors was localised by immunohistochemistry. Results Col-IV alpha chains were selectively up-regulated during the menstrual cycle and decidualisation. Primary extravillous trophoblast cells express collagen receptors and secrete col-IV in vitro and in vivo, resulting in the increased levels found in decidua basalis compared to decidua parietalis. A novel expression pattern of col-IV in the mesenchyme of placental villi, as a three-dimensional network, was found. NC1 domains of col-IV alpha chains are known to regulate tumour cell migration and the selective expression of these domains in decidua basalis compared to decidua parietalis was determined. Discussion Col-IV is expressed as novel forms in the placenta. These findings suggest that col-IV not only represents a structural protein providing tissue integrity but also influences the invasive behaviour of trophoblast cells at the implantation site.
    Placenta 11/2014; 36(1). DOI:10.1016/j.placenta.2014.10.012 · 3.29 Impact Factor
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