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. 2008 Oct;149(10):5078-87.
doi: 10.1210/en.2008-0116. Epub 2008 Jun 19.

Suppression of extravillous trophoblast vascular endothelial growth factor expression and uterine spiral artery invasion by estrogen during early baboon pregnancy

Thomas W Bonagura  1 , Gerald J Pepe, Allen C Enders, Eugene D Albrecht
Affiliations

Suppression of extravillous trophoblast vascular endothelial growth factor expression and uterine spiral artery invasion by estrogen during early baboon pregnancy

Thomas W Bonagura et al. Endocrinology. 2008 Oct.

Abstract

We have shown that advancing the increase in maternal serum estrogen levels from the second to the first third of baboon pregnancy suppressed extravillous cytotrophoblast (EVT) spiral artery invasion. Because vascular endothelial growth factor (VEGF) promotes EVT invasion, the present study determined whether EVT VEGF expression is altered by prematurely elevating estrogen in early pregnancy. Placental basal plate was obtained on d 60 of gestation (term is 184 d) from baboons treated daily on d 25-59 with estradiol (0.35 mg/d sc), which increased maternal peripheral serum estradiol levels 3-fold above normal. Overall percentage of uterine arteries (25 to more than 100 microm in diameter) invaded by EVT assessed by image analysis in untreated baboons (29.11+/-5.78%) was decreased 4.5-fold (P<0.001) by prematurely elevating estrogen (6.55+/-1.83%). VEGF mRNA levels in EVT isolated by laser capture microdissection from the anchoring villi of untreated baboons (6.77+/-2.20) were decreased approximately 5-fold (P<0.05, ANOVA) by estradiol (1.37+/-0.29). Uterine vein serum levels of the truncated soluble fms-like receptor, which controls VEGF bioavailability, in untreated baboons (403+/-37 pg/ml) were increased 3-fold (P<0.01) by estrogen treatment (1127+/-197 pg/ml). Thus, placental EVT expression of VEGF mRNA was decreased and serum soluble truncated fms-like receptor levels increased in baboons in which EVT invasion of the uterine spiral arteries was suppressed by advancing the rise in estrogen from the second to the first third of pregnancy. We suggest that VEGF mediates the decline in EVT vessel invasion induced by estrogen in early primate pregnancy.

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Figures

Figure 1
Figure 1
Maternal peripheral serum estradiol levels (means ±se) in baboons untreated (n = 9) or treated daily on d 25–59 of gestation (term is 184 d) with estradiol benzoate (0.35 mg/d sc, n = 10). Serum estradiol levels on each of the days between d 27 and 60 are greater (P < 0.01) in estradiol-treated than untreated animals.
Figure 2
Figure 2
Photomicrographs of histology of the placental basal plate and chorionic villi on d 60 of gestation in baboons untreated (A and B) and treated daily on d 25–59 with estradiol (C and D). Magnifications, ×200 (A and C) and ×400 (B and D). FV, Floating villi; AV, anchoring villi; V, vessel wall with trophoblast cells and fibrinoid; CS, cytotrophoblastic shell; DB, decidua basalis; SA, spiral artery.
Figure 3
Figure 3
Percent invasion (A) and number invaded per square micrometer decidua (B) of uterine spiral arterioles/arteries grouped by vessel diameter on d 60 in baboons untreated (n = 9) or treated daily on d 25–59 with estradiol benzoate (n = 10). *, Values different (P < 0.01) from untreated animals for each arterial diameter as analyzed by the generalized estimating equation and Genmod procedure (Table 3).
Figure 4
Figure 4
Immunocytochemical localization (brown precipitate) of cytokeratin (A), vimentin (B), and CD68 (C) in the placental basal plate on d 60 of baboon pregnancy. D, Vimentin primary antibody replaced with immunoglobulin control. AV, Anchoring villi; CS, cytotrophoblastic shell; DB, decidua basalis: MC, mesenchymal core. Magnification scale bar, 100 μm.
Figure 5
Figure 5
Placental histology on d 60 of baboon pregnancy before (A) and after (B) LCM of cells from anchoring villi (AV) and cytotrophoblastic shell (CS). C, Isolated cells in LCM cap. LCM, area of cell isolation; MC, mesenchymal core; DB, decidua basalis; VS, venous sinusoid.
Figure 6
Figure 6
VEGF mRNA levels (means ± se) in cells isolated by LCM from the anchoring villi, cytotrophoblastic shell, and floating villi of the placenta on d 60 in baboons untreated (n = 5) or treated daily on d 25–59 with estradiol (n = 5). *, Different (P < 0.05) from values in untreated animals (ANOVA and Newman-Keuls multiple statistic).
Figure 7
Figure 7
Serum sFLT1 levels (means ±se) in uterine vein (mean of left and right, A) and sFLT1 mRNA levels in cells isolated by LCM from the cytotrophoblastic shell (B) and anchoring villi (C) on d 60 in baboons untreated (n = 4) or treated daily on d 25–59 of gestation with estradiol (n = 5). *, Different (P < 0.01) from value in untreated animals (Student’s t test).
Figure 8
Figure 8
Representative photomicrographs of placental immunocytochemical localization (brown precipitate) on d 60 of gestation of VEGF (A), estrogen receptor-β (C), estrogen receptor-α (D), and cytokeratin (E) in untreated baboons and VEGF (B) and cytokeratin (F) in baboons treated with estradiol on d 25–59. Preabsorption of VEGF antibody with recombinant VEGF protein (G) and replacement of primary antibody for estrogen receptor-β with immunoglobulin (H). Insets in A–D represent higher magnification of anchoring villi region illustrating immunocytochemistry for each respective protein. FV, Floating villi; AV, anchoring villi; CS, cytotrophoblastic shell; DB, decidua basalis. Magnification bar (G), 250 μm.
Figure 9
Figure 9
Immunocytochemical localization of cytokeratin (A), VEGF (B), estrogen receptor-β (C), and estrogen receptor-α (D) within cells of the wall of a remodeled spiral artery in an untreated baboon on d 60 of gestation. Magnification scale bar, 100 μm.
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