Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion?
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.
Human Reproduction 01/2002; 17(5):1351-1357. DOI:10.1093/humrep/17.5.1351 · 4.59 Impact Factor
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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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ABSTRACT: To determine the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on trophoblast invasiveness. Laboratory investigation. Academic medical center. Placental tissues discarded after first-trimester terminations were obtained from patients with informed consent. A cell line, HTR-8/SVneo, established from first-trimester cytotrophoblast, and villous explants, was treated with or without sildenafil, guanosine 3',5'-cyclic monophosphate (cGMP) analog, cGMP inhibitor, or L-NAME (N(G)-nitro-L-arginine methyl ester hydrochloride) and cultured on fibronectin or Matrigel. Integrins α6β4 and α1β1 were detected by immunocytochemistry. Trophoblast outgrowth from villous tips, cytotrophoblast cell invasion, and integrin immunostaining were assessed in cytotrophoblast and explant cultures. Integrin expression in trophoblast cells ex vivo switched from α6 to α1, and invasiveness increased, when exposed to sildenafil or cGMP agonist. Either cGMP antagonist or L-NAME blocked integrin switching and invasion induced by sildenafil. Elevation of nitric oxide pharmacologically induced invasion, but not when cGMP antagonist was present. Sildenafil altered trophoblast phenotype through a process dependent on nitric oxide availability and cGMP accumulation. In addition to its vasoactivity, sildenafil directly stimulates trophoblast extravillous differentiation, which would be favorable for implantation and reduce risk for adverse pregnancy outcomes. Published by Elsevier Inc.Fertility and sterility 03/2015; DOI:10.1016/j.fertnstert.2015.02.025 · 4.30 Impact Factor