Decidual vascularization during organogenesis after perigestational alcohol ingestion

in Reproduction
Correspondence should be addressed to E Cebral; Email: ecebral@hotmail.com
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Perigestational alcohol consumption up to early organogenesis can produce abnormal maternal vascularization via altered decidual VEGF/receptor expression. CF-1 female mice were administered with 10% ethanol in drinking water for 17 days prior to and up to day 10 of gestation. Control females received water without ethanol. Treated females had reduced frequency of implantation sites with expanded vascular lumen (P < 0.05), α-SMA-immunoreactive spiral arteries in proximal mesometrial decidua, reduced PCNA-positive endothelial cells (P < 0.01) and diminished uterine NK cell numbers (P < 0.05) in proximal decidua compared to controls. The VEGF expression (laser capture microscopy, RT-PCR, western blot and immunohistochemistry) was reduced in decidual tissue after perigestational alcohol consumption (P < 0.05). The uNK-DBA+ cells of treated females had reduced VEGF immunoexpression compared to controls (P < 0.01). Very low decidual and endothelial cell KDR immunoreactivity and reduced decidual gene and protein KDR expression was found in treated females compared to controls (P < 0.001). Instead, strong FLT-1 immunoexpression was detected in decidual and uNK cells (P < 0.05) in the proximal decidua from treated females compared to controls. In conclusion, perigestational alcohol ingestion induces the reduction of lumen expansion of spiral arteries, concomitant with reduced endothelial cell proliferation and uNK cell population, and uncompleted remodeling of the artery smooth muscle. These effects were supported by low decidual VEGF and KDR gene and protein expression and increased FLT-1 expression, suggesting that VEGF and KDR reduction may contribute, in part, to mechanisms involved in deficient decidual angiogenesis after perigestational alcohol consumption in mouse.

 

    Society for Reproduction and Fertility

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    Histology of mesometrial decidua and vascular endothelial proliferation in control and treated females. Analysis of proximal mesometrial decidua in E10-implantation sites by hematoxylin-eosin (A and B), PAS-hematoxylin (C and D) and endothelial cell proliferation assessed by PCNA-immunohistochemistry (E, F and G). (A) Representative histological H-E-image section of E10-implantation site from control females (CF), showing lateral vascularized areas in proximal mesometrial decidua (pMD) and wide lumen of maternal blood vessels (asterisks) (inset in A). (B) Representative histological H-E image section of E10-implantation site from treated females (TF), showing reduced lateral lacunae of blood vessels (arrows and asterisks, inset B). (C) Representative histological PAS-stained image section of decidual vascular area from CF, showing regular alignment and attachment of endothelial cells (arrow) to the basement membrane, mature decidual cells (short arrows) and PAS-uNK-positive cells (arrowheads) located near the blood vascular lumen (asterisks). (D) Representative histological PAS-stained image section of decidual vascular area from TF, showing disorganized endothelium with few endothelial cells (arrow) attached to the basement membrane and many cells free in the lumen of maternal blood vessel (asterisk). (E and F) Representative image section of decidual vascular area from CF (E) and treated females (F), showing PCNA-positive cells (arrow) or PCNA-negative endothelial cells (arrowhead). AMD, antimesometrial decidua; dMD, distal mesometrial decidua; End, non-decidualized endometrium; pMD, proximal mesometrial decidua; TZ, trophoblastic zone. Scale bars: A and B: 500 µm, C and F and insets A and B: 20 μm. (G) Quantitative analysis of endothelial proliferation in decidual vascular area, expressed as the mean number of PCNA+ cells over the total endothelial cell number, and standard deviation. (**P < 0.01, Student’s t-test, between groups. Number of implantation sites used for each control and treated group: 6.)

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    Smooth muscle remodeling in maternal vascular wall of control and treated females. Immunohistochemistry for α-smooth muscle actin (α-SMA) of smooth muscle wall of spiral arteries in non-decidualized endometrium (End), distal (dMD) and proximal decidua (pMD) from control (CF) (A, C and E) and treated females (TF) (B, D and F). (A) Representative image section of End from CF, showing arteries (asterisk) with the typical wall with smooth muscle actin-positive media lamina (arrow). (B) Representative image section of End from TF, showing α-SMA-positive immunoreactivity in the vascular arterial wall. (C) Representative image section of distal mesometrial decidua (dMD) from CF, showing spiral arteries with some few α-SMA-positive cells. (D) Representative image section of dMD from TF showing positive α-SMA-immunoreactive cells around the arteries. (E) Representative image section of proximal mesometrial decidua (pMD) from CF, without smooth muscle cells in spiral arteries. (F) Representative image section of pMD from TF showing α-SMA-positive cells (arrow) in decidual spiral arteries. Number of implantation sites analyzed in each group: 6 (derived from six control and six treated females). Scale bar: 50 μm.

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    uNK cells in mesometrial decidua in control and treated females. DBA lectin-positive uNK cells in non-decidualized mesometrial endometrium (End), distal (dMD) and proximal (pMD) mesometrial decidua. (A) DBA lectin-positive uNK cells in implantation site from CF. (B) DBA lectin-positive uNK cells in implantation site from treated females. Inserts: implantation site without DBA lectin-cell reaction (negatives). dMD, distal decidua; End, endometrium; pMD, proximal decidua. Scale bars A, B: 500 μm. (C) Quantitative analysis of DBA lectin-positive uNK cell between pMD areas from control (■) and treated (□) females (mean number and standard deviation). (**P < 0.001, Student’s t-test, number of implantation sites used in each group: 5, derived from five control and five treated females.)

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    VEGF gene and protein expression in mesometrial decidua from control and treated females. VEGF expression in proximal mesometrial decidua assessed by immunohistochemistry, western blot and RT-PCR. (A) Representative image of VEGF immunoreactive area section of vascular decidua from control females, showing VEGF immunoexpression in decidual (arrowhead) and endothelial cells (arrow). (B) VEGF immunoexpression in proximal decidua of treated females, showing low VEGF immunoreactivity in decidual cells and negative VEGF immunoexpression in endothelial cells. (Number of implantation sites used for each group: 6, derived from six females for each). Asterisk: lumen of decidual blood vessel. Scale bars: A, B: 20 μm. (C) Representative immunoblot of VEGF expression in control and treated-derived decidual samples, showing VEGF-positive protein bands corresponding to molecular weight of 21 kDa. (D) Densitometric analysis of VEGF protein bands, normalized to β-actin and expressed as the mean AU and standard deviation, of three independent experiments performed with a total of seven samples for each groups, derived from seven control and seven treated females. (E) Quantitative analysis of Vegf mRNA levels assessed by laser capture microdissection of proximal decidual area per implantation site, and Real-Time-PCR. Values were calculated as the mean of 2−ΔCt and standard deviation, and expressed as level of mRNA. (Number of implantation site used for each groups: 5, derived from five control and five treated females.) ***P < 0.001, Student’s t-test, between control and treated females.

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    VEGF expression in DBA-uNK cells from control and treated females. Uterine NK-VEGF expression was determined by confocal VEGF immunofluorescence analysis (A and D), DBA lectin-fluorescence staining (B and E) and merges (C and F). Upper panel: representative image section of control-derived proximal decidual area tissue. Lower panel: representative image section of treated-derived proximal decidual area tissue. Asterisk: lumen of decidual blood vessel. Scale bar: 50 μm. Graphic represents the semiquantitative analysis of VEGF fluorescence signal in uNK cells (DBA-positive cells), expressed as the mean arbitrary units (AU) of CTCF Ln and standard deviation, in control and treated females. **P < 0.01, Student’s t-test, between control and treated females. Number of implantation sites used in each group: 5.

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    KDR and FLT-1 immunoexpression in decidual and uNK cells in control and treated females. Immunohistochemical localization and expression of KDR and FLT-1 in proximal mesometrial decidua of control (A, C, E and G) and treated females (B, D, F and H). (A) Representative image section of decidual vascular area of control females, showing localization and immunoexpression of KDR in decidual cells (short arrows) and in some endothelial cells (large arrows) of maternal vessel (mv). (B) Representative image section of decidual vascular area of treated females, showing low or negative KDR immunoreaction in decidual cells and almost no KDR-positive endothelial cells. (C) Detailed representative image of KDR immunoreactive-PAS counterstained decidua of control females, showing punctuate and strong KDR immunoexpression in decidual cells (short arrow) and absence in uNK cells (arrowhead). (D) Detailed representative image of KDR-immunoreactive PAS counterstained from treated females, showing very low KDR immunoreactivity in decidual cells. (E) Representative image section of decidual vascular area of control females, showing slightly moderate FLT-1 immunoreactivity in decidual (short arrows) and endothelial cells (large arrows). (F) Representative image section of decidual vascular area of treated females, showing strong FLT-1 immunoreactivity in many decidual and endothelial cells. (G) Detailed representative image of FLT-1 immunoreactive-PAS counterstained decidual vascular area of control females, showing punctuate and slightly moderate FLT-1 immunoexpression in decidual cells (short arrows), uNK (arrowheads) and in some endothelial cells (large arrow). (H) Detailed representative image of FLT-1 immunoreactive-PAS counterstained decidual vascular area of treated females, showing FLT-1 immunoexpression in the same cells as controls. Number of implantation sites used in each group: 5, derived from five control and five treated females. Scale bars: 20 μm.

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    KDR and FLT-1 gene and protein expression in decidua from control and treated females. Quantitative analysis of protein and mRNA expression of KDR and FLT-1 in decidual tissue. (A) Representative immunoblotting bands of KDR and FLT-1 protein expression of control and treated-derived decidual tissue samples, corresponding to the molecular weight 210-230 kDa and 180 kDa, respectively. (B) Densitometry analysis of KDR and FLT-1 protein bands normalized to β-actin and expressed as the mean arbitrary units (AU) and standard deviation, of three independent experiments performed with 12 tissue samples derived from six control and six treated females. (C) Quantitative analysis of Kdr and Flt-1 mRNA levels, assessed by laser capture microdissection of proximal decidual area per implantation site and real-time PCR. Values were calculated as the mean of 2−ΔCt and standard deviation, and expressed as level of mRNA. Number of samples used in each group: 5, derived from five implantation sites per each group. *P < 0.05, ***P < 0.001, Student’s t-test, between control and treated females.

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