Preeclampsia Is Associated with Defects in CTB Pseudovasculogenesis

Pre-eclampsia (PE) is a serious complication that affects 7 percent of first-time pregnancies in the United States (reviewed in Ref. [9]). The mother shows signs of widespread alterations in endothelial function, such as high blood pressure, proteinuria, and edema. In some cases the fetus stops growing, resulting in intrauterine growth restriction. Compounding the dangers of this condition is the fact that the maternal and fetal signs can appear suddenly at any time from mid-second trimester until term—hence the name preeclampsia, derived from the Greek eklampsis, meaning "sudden flash or development."

The PE syndrome reveals the significance of CTB pseudovasculogenesis. Floating chorionic villi in PE placentas are relatively unaffected. However, anchoring villi and the invasive CTBs they spawn show distinct anomalies. The extent of interstitial invasion by CTBs is variable, but frequently shallow. Endovascular invasion is consistently rudimentary, making it extremely difficult to find any maternal vessels that contain CTBs [10]. These anatomical defects suggested to us that in PE, CTB differentiation along the invasive pathway is abnormal. Biopsies of the uterine wall of women with this syndrome showed that invasive CTBs retain expression of adhesion receptors characteristic of the progenitor population and fail to turn on receptors that promote invasion and/or assumption of an endothelial phe-notype [11].

In addition to adhesion defects, immunolocalization on tissue sections of placentas obtained from the most severely affected patients showed that CTB VEGF-A (Figure 3) and VEGFR-1 staining decreased; staining for PlGF was unaffected. Cytotrophoblast secretion of the soluble form of VEGFR-1 (sFlt-1) in vitro also increased [4], an interesting observation in light of the recent discovery that excess sFlt-1 contributes to a pre-eclampsia-like syndrome in mice [12].

Figure 2 PlGF, VEGF-C, and Ang2 in cytotrophoblast-conditioned medium stimulate angiogenesis in vivo. The angiogenic effects of factors in cytotrophoblast-conditioned medium were assessed by using the chick chorioallantoic membrane assay. (A) The membranes were photographed after exposure to the samples for 48 hours. Cytotrophoblast-conditioned medium (a) and medium treated with a control CD6-Fc protein (b) induced a robust angiogenic response that was comparable to the response induced by basic FGF (data not shown). Removal of PlGF (c), VEGF-C (d), or Ang2 (e) diminished this effect by 70 to 80 percent. (f) Depletion of all three factors produced no further decrease in the angiogenic capacity of cytotrophoblast-conditioned medium. (B) The data were quantified by counting the number of new capillary sprouts. Data are expressed as means and standard deviations of seven experiments. The significance of the data from four separate experiments was determined by analysis of variance (ANOVA). (Reproduced with permission from Developmental Biology.) (see color insert)

Figure 2 PlGF, VEGF-C, and Ang2 in cytotrophoblast-conditioned medium stimulate angiogenesis in vivo. The angiogenic effects of factors in cytotrophoblast-conditioned medium were assessed by using the chick chorioallantoic membrane assay. (A) The membranes were photographed after exposure to the samples for 48 hours. Cytotrophoblast-conditioned medium (a) and medium treated with a control CD6-Fc protein (b) induced a robust angiogenic response that was comparable to the response induced by basic FGF (data not shown). Removal of PlGF (c), VEGF-C (d), or Ang2 (e) diminished this effect by 70 to 80 percent. (f) Depletion of all three factors produced no further decrease in the angiogenic capacity of cytotrophoblast-conditioned medium. (B) The data were quantified by counting the number of new capillary sprouts. Data are expressed as means and standard deviations of seven experiments. The significance of the data from four separate experiments was determined by analysis of variance (ANOVA). (Reproduced with permission from Developmental Biology.) (see color insert)

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