[Expression of hypoxia-inducible factor-1alpha, vascular endothelial growth factor and sFlt-1 in preeclampsia placenta].

To investigate the expression and correlation of hypoxia-inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF) and sFlt-1 in the preeclampsia placenta, and discuss their significance in the pathogenesis of preeclampsia. Placentas were collected from 20 pregnant women with preeclampsia as study group and 15 normal pregnant women as control group. The expressions of HIF-1alpha, VEGF and sFlt-1 protein were semi-quantitatively analyzed with immunohistochemical assay and mRNA level was determined using reverse transcription polymerase chain reaction (RT-PCR) technique. (1) the expression of HIF-1alpha and sFlt-1 protein in preeclampsia group obviously increased. Strong (+++) positive expression was observed in 9 and 11 cases respectively, significantly higher than in control group (2 and 3 cases) (P < 0.05), however, VEGF expression obviously reduced in preeclampsia group (P < 0.01). (2) the level of HIF-1alpha and sFlt-1 mRNA in preeclamptic placenta was 0.604 +/- 0.013, 0.898 +/- 0.041, significantly higher than 0.208 +/- 0.007 and 0.559 +/- 0.244 in normal placenta (P < 0.05). Although the level of VEGF mRNA increased in preeclampsia placenta, it was not significantly different from that in normal placenta (P > 0.05). The ratio of VEGF mRNA/sFlt-1mRNA obviously reduced in preeclampsia group and was significantly lower than in control group (P < 0.05). (3) in preeclampsia group, HIF-1alpha mRNA expression was positively correlated with the expression of sFlt-1 mRNA (r = 0.577, P < 0.05), and negatively correlated with the ratio of VEGF mRNA/sFlt-1 mRNA (r = -0.376, P < 0.05). Abnormal high HIF-1alpha expression in preeclampsia placenta indicates that HIF-1alpha might play an important role in the pathogenesis of preeclampsia, possibly through affecting the cytotrophoblastic invasion and placental vascular reconstruction via the modulation of VEGF and sFlt-1 gene transcription.

Sun SG ，Shen N ，Zheng YH ，Shang T ... -  《-》

[Expression and significance of soluble fms-like tyrosine kinase 1 in preeclampsia placenta].

To investigate the expression and significance of serum soluble fms-like tyrosine kinase 1 (sFlt-1) in preeclampsia placenta. Immunohistochemistry and semi-quantitative RT-PCR were used to investigate the expression of sFlt-1 and sFlt-1 mRNA in placenta of 30 women with preeclampsia (including mild and moderate preeclampsia 11 cases, severe preeclampsia 19 cases) and 45 normal pregnant women (including first trimester pregnancy 18 cases, 2nd trimester pregnancy 12 cases, and 3rd trimester pregnancy 15 cases). The levels of vascular endothelial growth factor (VEGF) and sFlt-1 in serum were detected by enzyme linked immunosorbent assay. (1) The expression of sFlt-1 mRNA was significantly higher in preeclampsia group (0.90 +/- 0.11) compared with the third trimester group (0.80 +/- 0.06; P < 0.01), and was higher in the severe preeclampsia group (0.93 +/- 0.12) than that in the mild group (0.85 +/- 0.05; P < 0.05). (2) The mean density of sFlt-1 in preeclampsia placenta (0.156 +/- 0.008) was significantly higher than that in the third trimester group (0.143 +/- 0.009, P < 0.01), and was higher in the severe group (0.159 +/- 0.008) than in the mild group (0.151 +/- 0.005; P < 0.05). (3) The level of VEGF in serum of the preeclampsia group (19.3 +/- 2.9) ng/L was significantly lower than that of the third trimester group [(30.2 +/- 3.1) ng/L, P < 0.01]. The level of sFlt-1 in serum of the preeclampsia group (30.2 +/- 13.7) microg/L was significantly higher than that of the third trimester group [(7.4 +/- 3.1) microg/L, P < 0.01]. (4) There was significant correlation between the serum level of sFlt-1 and the expression of sFlt-1 mRNA or sFlt-1 in placenta of normal pregnancy group (r = 0.314, P < 0.05; r = 0.439, P < 0.01) and preeclampsia groups (r = 0.372, r = 0.383; P < 0.05). Upregulation of sFlt-1mRNA and excess expression of sFlt-1 in placenta may induce higher level of sFlt-1 in serum, which may be involved in the pathophysiological processes of preeclampsia.

Ye YH ，Liu L ，Zhan Y ，Peng W ... -  《-》

Extra-placental expression of vascular endothelial growth factor receptor-1, (Flt-1) and soluble Flt-1 (sFlt-1), by peripheral blood mononuclear cells (PBMCs) in normotensive and preeclamptic pregnant women.

The soluble VEGF receptor, sFlt-1 (otherwise referred to as sVEGFR-1), has been implicated in the pathogenesis of preeclampsia. The preeclamptic placenta has been previously demonstrated to produce high levels of the soluble VEGF receptor. Here we tested the hypothesis that peripheral blood mononuclear cells (PBMCs) may also represent an additional source for circulating sFlt-1 during normal and preeclamptic pregnancies. We first demonstrate that preeclamptic placentae show five-fold increased Flt-1 and sFlt-1 mRNA levels. We also show that the Flt-1 and sFlt-1 levels are eight-fold higher in preeclamptic placentae if we collect biopsies without rinsing them in saline to remove excess blood. Cultured villous explants from women with preeclampsia failed to show the increased amount of Flt-1 and sFlt-1 mRNA that was observed in the placental biopsies of normal pregnancy and preeclampsia. Under normoxic conditions the Flt-1 and sFlt-1 mRNA levels in the explants were 3.11+/-0.6 fold in normal pregnancy and 3.6+/-0.4 fold in women with preeclampsia (p = NS by ANOVA). However, the same villous explants showed hypoxic induction of Flt-1 mRNA (NP 3.96+/-0.4 fold, p = NS and PE 5.24+/-0.6 fold, p < 0.05 by ANOVA). We analyzed Flt-1 and sFlt-1 protein levels in the peripheral blood mononuclear cells (PBMCs) to analyze the possibility of an extra-placental sFlt-1 source. Our results indicate that PBMCs of pregnant women are capable of expressing variable amounts of Flt-1 proteins. PBMCs from pregnant women exposed to hypoxia show up-regulation of HIF-1alpha and Flt-1 proteins. PBMCs obtained from women with preeclampsia (n = 9) produced significantly higher amounts of sFlt-1 under normal tissue culture conditions (104.6+/-14.3 pg/ml vs. 46.23+/-5.03 pg/ml, p < 0.05 by ANOVA) and much higher concentrations under hypoxia (196.74+/-26.3pg/ml vs. 83.3+/-13.6pg/ml, p < 0.05 by ANOVA) than PBMCs from normal pregnant women (n = 11). Moreover, analysis of PBMCs from a different group of women with a history of preeclampsia showed persistent abnormality of Flt-1 women one year post-partum. The present study indicates that Flt-1 dysregulation in PBMCs of pregnant women resulting in over-expression of sFlt-1 could be an additional (extra-placental) source of sFlt-1 that contributes to the pathogenesis of preeclampsia.

Rajakumar A ，Michael HM ，Rajakumar PA ，Shibata E ，Hubel CA ，Karumanchi SA ，Thadhani R ，Wolf M ，Harger G ，Markovic N ... -  《PLACENTA》

[Relationship of hypoxia-inducible factor-1alpha expression and vascular endothelial growth factor in SKOV-3 ovarian cancer model].

Jiang HY ，Feng YJ 《-》

[Alteration and potential role of soluble fms-like tyrosine kinase receptor 1 in preeclampsia].

To investigate the alteration of serum soluble fms-like tyrosine kinase receptor 1 (sFlt-1) and the possible source in preeclampsia, and the relationship between sFlt-1 and the pathogenesis of preeclampsia. (1) Semi-quantitative RT-PCR was carried out to detect the level of sFlt-1 mRNA in placental tissue of 10 preeclampsia (preeclampsia group) and 10 normotensive pregnancies (normotensive pregnancy group). (2) Enzyme linked immunosorbent assay (ELISA) was used to detect the serum level of sFlt-1 in peripheral venous blood in preeclampsia group 1 (n = 35) and normotensive pregnancies group 1 (n = 35); the serum level of sFlt-1 of uterine vein blood in preeclampsia group 2 (n = 20) and normotensive pregnancies group 2 (n = 20); and the volume of peripheral venous blood sFlt-1 in 10 early (early pregnancy group) and 10 middle pregnancies (middle pregnancy group). (1) sFlt-1 mRNA of placental tissue was significantly higher in preeclampsia group (0.95 +/- 0.04) than that in normal pregnancy group (0.64 +/- 0.15). (2) The serum level of sFlt-1 of peripheral vein in preeclampsia group 1 (5640 +/- 3191) ng/L was higher than that in normal pregnancy group 1 (2194 +/- 635) ng/L. (3) The serum sFlt-1 of uterine vein in preeclampsia group 2 (7673 +/- 2296) ng/L was higher than that in normotensive pregnancy group 2 (3057 +/- 785) ng/L, indicating that the volume of sFlt-1 of uterine vein blood was significantly higher than that of peripheral venous blood (P < 0.01). (4) The serum levels of sFlt-1 in early and middle pregnancy groups were (32 +/- 20) ng/L and (994 +/- 302) ng/L, respectively, showing that the level of sFlt-1 in peripheral venous blood increasingly elevated with the development of pregnancy. (1) The placenta may be the major source of elevated sFlt-1. (2) The serum level of sFlt-1 is related with the development of pregnancy. The alteration of sFlt-1 may contribute to the pathogenesis of preeclampsia.

Li Y ，Li DH ，Yao YQ ，Min BH ，Zhang CL ，Hou XH ，Huang L ，Zhao HX ... -  《-》