Authors: Zhen-Yan Chen and Ying Yao
Date: July 18, 2017
From: PLoS ONE(Vol. 12, Issue 7)
Publisher: Public Library of Science
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Smoking increases the risk of pregnancy complications such as spontaneousabortion and low birth weight (LBW). By cigarette smoke exposure (gestationalday, GD3-17), normal-litter-size pregnancy with low birth weight (NP-LBW) andsmall-litter-size pregnancy with normal birth weight (SP-NBW) in rats wereinduced. The placental weight in SP-NBW was twice the weight of the normal incontrast with the smaller placenta in NP-LBW. Compared with the normal,placental efficiency (expressed as fetus-to-placenta weight ratio) andplacental vascularisation were significantly decreased in smoke exposedplacentas with more obvious decrease in SP-NBW. For NP-LBW, decreasedplacental vascularisation was due to decreased labyrinth vascularisationwhich was caused by both decreased number density and diameter of fetalcapillary. For SP-NBW, decreased placental vascularisation was due to reducedproportion of labyrinth in placenta and decreased labyrinth vascularisationwhich was caused by decreased fetal capillary number density. Real timeRT-PCR analysis showed a tendency for decreased placental mRNA level ofvascular endothelial growth factor (VEGF), angiopoietin-1 (Ang1) and tyrosinekinase receptor-2 (Tie2) in NP-LBW(P<0.1), and the tendency became obviousin SP-NBW(P<0.05). A tendency for decreased placental mRNA level offms-like tyrosine kinase-1(Flt1) and angiopoietin-2 (Ang2) was also observedin SP-LBW(P<0.1). Our data demonstrated the synergistic negative effect ofgestational smoke-exposure and small litter size on placental efficiency,placental vascularisation and placental angiogenic growth factor mRNAexpression in rat.
Author(s): Zhen-Yan Chen, Ying Yao *
Smoking during pregnancy is associated with adverse pregnancy outcomesincluding spontaneous pregnancy loss and low birth weight. It has beenreported that smoke exposure during pregnancy increased the risk ofmiscarriage by nearly 11% and reduced birth weight by nearly 10.75% .Placental vascularisation is essential for normal pregnancy and determinesthe transport of oxygen and nutrients from the maternal blood circulation tothe fetal blood circulation. Impaired placental vascularisation is thought tobe associated with adverse pregnancy outcomes. However, findings on theeffects of maternal smoking on the structure of human placental vasculatureare inconsistent [2-10]. Several studies had demonstrated reduced placentalvascularisation in smokers [2,3,7,8,9] in marked contrast to the adaptivechanges seen in placenta associated with other types of preplacental hypoxia, while others used scanning electron microscopy on casts of thecapillaries or by 3D microscopy observed an adaptive response of the villouscapillaries in placentas of heavy smokers with increased branching [6,10].Animal model of fetal growth restriction triggered by constituents ofcigarette smoke revealed extensive branching and enlargement of vesselswithin the small placental labyrinth was also observed . Vascularisationis controlled by angiogenic factors. Vascular endothelial growth factor(VEGF) and its receptors, fms-like tyrosine kinase-1(Flt1, also namedVEGFR-1) and fetal liver kinase-1 (Flk1, also named VEGFR-2) are essentialfor vasculogenesis. Angiopoietin-1(Ang1), Angiopoietin-2(Ang2), and theirreceptor (Tie2) are essential for vascular remodeling. VEGF, Flt1 and Flk1are essential for endothelial cell proliferation, migration and tube-likestructure formation, while Ang1 promotes the association of endothelial cellswith periendothelial cells to mature and stabilize newly formed bloodvessels. Ang2 loosens the vessel wall, rendering endothelial cells accessibleto VEGF to further promote angiogenesis . So far, studies investigatedthe alterations of VEGF/VEGFR and Ang/Tie2 expression on placenta frommaternal smoking are seldom and limited to VEGF and VEGFR-1 on the assumptionthat maternal smoking is associated with a decreased risk of preeclampsiathrough reduced soluble form of VEGFR-1 which acts as a negative regulator ofVEGF . However, the results are inconsistent. Some study showed nochanged VEGF and VEGF receptor 1 mRNA in human placenta of smoking mothers offirst trimester [15,16], while increased placental VEGF mRNA  and protein of smokers of first trimester, and decreased soluble VEGF receptor 1 were also reported.
Placental efficiency (fetus-to-placenta weight ratio) was positivelycorrelated with placental vessel density and placental VEGF mRNA as allincreased progressively as gestation proceeds [19-21]. However, comparativestudies failed to demonstrate this positive relationship between differentplacental efficiency groups of the same gestational stage [20-22]. Incontrast with the consistent finding of reduced birth weight by passivesmoking, placental weight was reported to be decreased , increased[6,10,23] and no change with cigarette smoke [2,3,4,7,8]. In many of thesestudies, placental efficiency was smaller in smokers than in nonsmokers, butthis conclusion has not been established. Distinct individual difference ofplacental efficiency existed even in the same litter. So the aim of thisstudy was to determine the alterations of placental efficiency, placentalvascularisation and angiogenic factors expression in placenta with smokeexposure and the interaction between them.
Materials and methods
Specific pathogen free grade, Sprague Dawley rats were purchased from HunanSlac Jingda Laboratory Animal Co., Ltd. (China). Animals were housed andmaintained in the Laboratory Animal Care center of Tongji Medical College andkept in a controlled environment at a temperature of 24 ± 3°C, a humidityof 50 ±10% and a 12-h light/12-h dark cycle, and given free access to astandard diet and distilled water. Female rats aged between 8-12 wk withsperms present in vaginal smears following mating (designated as gestationday, GD 0) were subjected to cigarette smoke in a chamber measuring 50 cmx28cmx20 cm (4 rats per chamber) for five periods of 30 min, with 1.5 hourinterval between exposures from gestation day 3 till gestation day 17 inmodel group (five cigarettes lit for each exposure, the tar and nicotineyields of commercial cigarettes were 15 and 1.2 mg per cigaretterespectively), non-smoke-exposed normal pregnant rats served as controls. Allanimal experiments were performed according to the institutional guidelinesestablished by the Animal Care and Use Committee of Tongji Medical College,Huazhong University of Science and Technology with Permit Number:TJ-A20130901.
On GD17, pregnant rats were anesthetized with pentobarbital (dosage ofanesthetics was 50mg/kg), each feto-placental unit was removed quickly fromthe uterus, and the fetuses and placentas were weighed. Three placentasrandomly selected from each pregnancy were used for analysis as one sampleand then the dams were euthanized by cervical dislocation. Before furtherprocessing, placenta was placed flat, rotated at random, bisected with avertical cut through the insertion of the umbilical cord to expose across-section of the labyrinth and non-labyrinth areas which paralleled tothe mesometrial-fetal axis, and then was halved. The three halves of theplacentas were homogenized and preserved at -80°C for RNA extraction as onesample, while the other halves were fixed with 4% polyoxymethylene and thenembedded in paraffin with the cutting area faced to a surface of paraffinblock ensuring standardization of sections. Tissues were then sectioned at4[mu]m for fetal capillaries staining.
Fetal capillaries staining and image analysis
Rat placenta consists of three morphologically distinct zones, decidua,junction and labyrinth. Junction zone is the major secreting zone with nofetal capillary located in it. Labyrinth, major site of nutrient and gasexchange, is composed of fetal capillaries and maternal blood sinusoids.Fixed tissue sections were immunostained with biotinylated lectin BS-1(cat#L3759, Sigma, UAS) which could specifically combined with vascularendothelial cells to identify fetal capillaries in labyrinth as described inour previous work . Three placentas per pregnancy with one section perplacenta were used for analysis. Images were taken by the Canon Micro-imagingSystem (Canon 350 D, Japan) and analyzed by Image-Pro Plus version 6.0 (MediaCybernetics, Silver Spring, MD, USA) incorporated with a scale formeasurement. To determine proportion of labyrinth in placenta (proportion ofplacental sectional area that was occupied by labyrinth), non-overlappingfields of view with each placental section being fully covered were capturedat 4x(objective) magnification. Running the Grid mask program of theImage-Pro Plus software, an 111-point grid superimposed on each field of thesection, proportion of labyrinth in placenta was then calculated by dividingthe total numbers of points falling on labyrinth by the total numbers ofpoints falling on placenta. Labyrinth was studied in more detail at40x(objective) magnification to determinate the maternal blood sinusoids(MBS) area density (proportion of labyrinth sectional area that was occupiedby maternal blood sinusoids), fetal capillaries (FC) area density, FC numberdensity and FC diameter in labyrinth. Observed the hierarchical character oflabyrinth, 1 to 2 fields each from the center (chorionic plate side) and theperiphery (junction zone side) were selected per placenta, yielding a totalof 5-6 fields for the center and the periphery within labyrinth each perpregnancy. MBS area density was calculated by dividing the total numbers ofpoints falling on maternal blood sinusoids area in the 5-6 fields by thetotal numbers of points falling on labyrinth in the 5-6 fields. FC areadensity was calculated in the same way. FC number density in labyrinth wascalculated by dividing the total numbers of fetal capillary in the 5 fieldsby the total area of labyrinth of the 5-6 fields (mm2). FC diameter meant theshortest distance that was perpendicular to the longest aspect of vessel andall fetal capillaries in the selected fields were measured.
VEGF, Flt1, Flk1, Ang1, Ang2, and Tie2 mRNAs levels were analyzed by thequantitative RT-PCR method. All reagents for the quantitative RT-PCR werepurchased from TaKaRa (Japan). Total RNA was extracted using Trizol reagent.RNA purity and concentration were measured using a nucleic acid/proteinanalyzer (Beckman Coulte DU730, USA). One microgram of RNA was reversetranscribed using a PrimeScript RT Reagent Kit with gDNA Eraser. The volumeof the reaction mixture for mRNA amplification was 20[mu]L and contained 2[mu]L of transcribed cDNA, 0.4 [mu]L forward primer (10 [mu]mol/L), 0.4 [mu]Lreverse primer (10 [mu]mol/L), 0.4 [mu]L passive reference dye, 7.8 [mu]Lsterile water and 10 [mu]L 2xSYBR Premix Ex Taq. Reactions were performed in48-well optical PCR plates using an Applied Biosystems StepOne Real-Time PCRSystem (Applied Biosystems, USA). Each sample was assayed in triplicate. Theprimer sequences for VEGF, Flt1, Flk1, Ang1, Ang2, and Tie2 mRNA weredetailed in Table 1. All data were normalized to GDPAH, and the expression ofone placental in normal group was assumed to be 1 and used as a reference. 2-[DELTA][DELTA]CT method was used to calculate the relative amounts of the target genes.
Categorical variables were expressed as percentage and continuous variableswere presented as mean±standard deviation. General linear model with smokeexposure and litter size (normal or small, small defined as<5) as fixedeffects was used to test their effects on fetal weight, placental weight,placental efficiency and placental vascular variables. Test batch was addedas another main effect in angiogenic factors mRNA analysis of general linearmodel. All data analyses were performed using SPSS 17.0. P<0.05 was considered statistically significant and P<0.1 a trend.
Effects of smoke exposure on litter size, birth weight, placentalweight and placental efficiency
Litter size was an index of a combination of embryo implantation andabortion, while birth weight was an index of fetal growth. In thesmoking-exposed group, 17% (5/29) pregnant rats had the fetuses be completelyaborted, 17% (5/29) pregnant rats had small litter size (3 rats gestatingsingle fetus and 2 rats gestating 3 to 4 fetuses). Neither completely abortedpregnancy nor small-litter-size pregnancy was observed in normal group. By amixed effects analysis of variance, smoke exposure had a negative effect onfetal weight (F = 138.5, P = 0.000), placental weight (F = 11.2, P = 0.001) and placental efficiency (F = 45.9, P = 0.001). Smoke exposure yielded 18% reduction in fetal weight, 6.8%reduction in placental weight and 15% reduction in placental efficiency. Asexpected, small litter size had a positive effect on fetal weight (F = 8.6, P = 0.004), placental weight (F = 456.5, P = 0.000), and a synergistic negative effect (F = 42.1, P = 0.001) with smoke exposure on placental efficiency. Placental weight wasincreased by 111% and placental efficiency was decreased by 56% in smalllitters compared to the corresponding normal pregnancy. Detailed results oflitter size, birth weight, placental weight and placental efficiency werepresent in Table 2.
Effects of smoke exposure and litter size on proportion oflabyrinth in placenta and labyrinth vascularisation
Image analysis revealed that small litter size (F = 30.2, P = 0.000) but notsmoke exposure (F = 0.9, P = 0.342) reduced proportion of labyrinth inplacenta. Reduced proportion of labyrinth in placenta by 21% was onlyobserved in SP-NBW in compared with normal placentas (Fig 1). Based on theimmunohistochemical staining with BS-1lectin, images of maternal bloodsinusoids and fetal capillaries in labyrinth were obtained. Image analysisrevealed hierarchical structure of placental vertical section. Fetalcapillary number density, area density, diameter, and maternal bloodsinusoids area density in the periphery were approximately 115.5%, 61.2%,79.4% and 135.7% of those in the center of labyrinth in normal placentasrespectively (P<0.05). For fetal capillaries number density, smoke exposure and smalllitter size had synergistic negative effects on it, leading to more obviouslyreduced fetal capillaries number density in SP-NBW placentas. For fetalcapillary diameter, small litter size had enlarged effect in contrast withthe constricting effect of smoke exposure. Consequently, fetal capillariesarea density was equally decreased and maternal blood sinusoids area densitywas equally increased in SP-NBW and NP-LBW. For SP-NBW, decreased placentalvascularisation was due to reduced proportion of labyrinth in placenta anddecreased labyrinth vascularisation which was caused by decreased fetalcapillary number density. For NP-LBW, decreased placental vascularisation wasdue to decreased labyrinth vascularisation which was caused by both decreasednumber density and diameter of fetal capillary (Table 3, Fig 2).
Fig 1. Comparison of proportion of labyrinth in placenta betweenthe groups. The figure showed mid-line sections of placentas on GD17 that were subjectedto hematoxylin staining with magnification 4x (objective) from normal group(A), NP-LBW group (B) and SP-NBW group (C). Placental tissue on the rightside of red boundary line represented labyrinth. Note that proportion oflabyrinth in placenta was reduced in SP-NBW than that in normal placenta.[see PDF for image]
Fig 2. Comparison of fetal capillary number density, area density,diameter, and maternal blood sinusoids area density between the groups. The figure showed mid-line sections of labyrinths on GD17 that weresubjected to histochemistry staining by BS-1 lectin with magnification 40x(objective) from normal group (A, D), NP-LBW group (B, E) and SP-NBW group (C, F). A, B, C were from central part of labyrinth and D, E, F were from theperiphery of labyrinth. Clay bank rings represent fetal capillaries. [see PDFfor image]
Table 3. Comparisons of proportion of labyrinth in placenta andvascularisation of the labyrinth. [see PDF for image]
Effects of smoke exposure and litter size on placental angiogenicfactors mRNA expression
By a mixed effects analysis of variance, these were trends of decreased VEGFmRNA by 25%, Ang1 mRNA by 43%, and Tie2 mRNA by 55% with smoke exposure (P<0.1). When combined with small litter size, significantly decreased VEGFmRNA by 60%, Ang1 mRNA by 71%, and Tie2 mRNA by 70% were observed (P<0.05). The synergistic effect of smoke exposure and small litter sizelead to trends of decreased Flt1 mRNA by 60% and decreased Ang2 mRNA by 71% (P<0.1). The expression level of Flk1 did not get significant differencebetween the groups (Table 4).
Beside intrauterine growth restriction which is the best documented among thevariety of adverse outcomes by cigarette smoke exposure in utero, humanepidemiological study revealed that tobacco use was independently associatedwith an increased risk of spontaneous abortion (odds ratio 1.8)  andsecondhand tobacco smoke exposure was associated with increased risk offailed implantation and reduced IVF success (odds ratio 1.5) .Gestational day 6 is the peri-implantation stage in rat. In theory, smokeexposure initiated on GD3 is possible to induced abortion. However, animalmodel of cigarette smoke-induced abortion was rare reported and effect ofperi-implantation smoke exposure on litter size was not found in previousstudies [26-28]. The negative results might due to the low occurrence rate ofsmoke induced abortion. Compensatory mechanisms are sufficiently robust toresist the damage of smoking and allow pregnancy to continue, althoughplacental function is impaired, and ultimately, lead to intrauterine growthrestriction. If the damage intensified and outstrips potential repairmechanisms, abortion will occur. The insult might be not intense enough forabortion induction in previous studies. Emily R et al exposed pregnant miceto cigarette smoke during pre-/peri-implantation (GD1-5), throughoutgestation (GD 1-17) and post-implantation (GD6-18) . He found no effectof cigarette smoke on litter size on GD18, and smoke exposure duringpre-/peri-implantation (GD1-5) or throughout gestation (GD 1-17) resulted inlow birth weight whereas smoke exposure during post-implantation (GD6-18) didnot . However, our preliminary experiment found that low birth weightcould be successfully induced by post-implantation smoke when the insultintensified. In Emily R et al study, smoke exposure (GD1-17) reduced birthweight by 6.1% whereas reduction was 18% in this study which might indicatemore intensified insult in our study. However, abortion seemed to beall-or-none with smoke exposure in this study. Inter-individual difference insensibility to the toxic substances might contribute to the differentoutcomes.
Reduced placental weight and efficacy in maternal smoking was reported in2014 by R.H.F. van Oppenraaij et al who conducted a large humanepidemiological sample study (n = 7945) with multivariable linear regressionmodels adjusting for potential confounder . Our study firstlydemonstrated reduced placental efficacy with smoke exposure in animal model.Inconsistent reports before would caused by small multitude of the placentalweight change that could be easily confounded by other factors when theinsult is not intense enough. Histomorphometric studies on human placentas ofsmokers show contrasting effects of smoking on placental vascularisation[2-11]. Beside variance of preparations, sampling and analysis thatcontribute to the inconsistent results, compensatory response related to thestart time, duration and magnitude of insult, and individual difference alsoaffects the results. Our study examined placenta of late-gestation while theprevious studied term (when placenta was degenerated) [2,3,4,6,7,8] or firsttrimester placenta (would before the onset of vascular density reduction)[5,9,10]. Compensatory response would have occurred in previous studies thatreported increased villous capillaries. Unlike other types of preplacentalhypoxia (maternal anemia or pregnancies at high altitude) which adaptivechanges with increased capillary volume fractions are confirmed ,decreased capillary volume fraction in cigarettes smoke during pregnancy wasreported [2,3,7,8,9], indicated that other influences suppress thecompensatory response (eg, a toxic effect).
Except increased placental VEGF mRNA  and protein  were reported,alterations of VEGF system and angiopoietin system gene expression levels insmoking pregnant women placenta were seldom reported. Akihiko Sekizawa et alreported increased placental VEGF mRNA in first trimester placentas ofsmokers , however, when number of samples increased, no difference wasfound . Previously, we found decreased Tie2/Ang1 in smoke exposed ratplacentas of GD17 . We increased the number of samples in this study andstill found decreased trend of VEGF/tie2/Ang1 in smoke exposed placentas.Trophoblast cells respond to reduced oxygen tensions by activation of theVEGF system and stimulate angiogenesis , cigarette smoke extracts wasdemonstrated to inhibit hypoxia-induced angiogenesis of human umbilical veinendothelial cells via reduced expression of HIF-1 and VEGF in hypoxicconditions . VEGF are up-regulated in several inflammatory conditions,smoking can cause inflammation . We hypothesized that the inconsistentresults might be caused by the contrasting effect of hypoxia, inflammationand toxic effect of ingredients of tobacco. Compensatory response would bedetermined by the combined effect of the contrasting factors. Except onepregnancy, compensatory response was not observed with smoke exposure andseemed to be all-or-none in this study. Placental efficacy and vessel densitydecreased in smoke exposed in association with decreased placenta angiogenicfactors mRNA. The consistent change supports the hypothesis that smokingcauses anti-angiogenic status and leads to reduced placental angiogenicfactors mRNA expression, placental vascularisation is reduced, andultimately, reduced placental efficiency.
Kimberly A et al failed to demonstrate the hypothesis that with an increaseof fetal number within the uterus placental capillary vascularity will beenhanced to compensate for reduced placental weight per fetus, and theexpression of angiogenic factors in the placenta will depend on the number offetuses [20-22]. In this study, we confirmed this hypothesis by theconsistenly decreased placental efficiency, vascularity and angiogenicfactors mRNA in SP-NBW. Large litter size difference of ours might contributeto the positive results.
To our knowledge, this study is the first to provide consistent changes ofplacental efficiency, placental vascularisation and placental angiogenicfactors mRNA expression in smoke-exposed placenta. Decreased fetal capillarynumber density in smoke-exposed placenta was also firstly presented. Only oneprevious study reported reduced total villous capillaries number in smokers, other studies concluded that reduced capillary volume density was onlydue to capillaries diameter reduction [2,3,7,9]. The strengths of our studyinclude standardization of the orientation of placental section and thefields in center and periphery separated selected. Placental verticalcross-section showed that placenta vasculature was a tree-like structurewhere stem-vasculature lies in the center and microvasculature lies in theperiphery. Significant differences in vascular morphology exist between stemvasculature and microvasculature, so our study was one of the few studieswhich selected central and peripheral fields separately to better elucidatethe alterations. The limitation in our study is that we did not evaluate theexpression of VEGF family proteins which would have been beneficial incorrelating with the mRNA levels and detect the serum nicotine level tobetter explain the adverse outcomes. In SP-NBW, reduced placentalvascularisation was due to the reduced proportion of labyrinth in placentaand decreased labyrinth vascularisation which only caused by decreased fetalcapillary number density. In NP-LBW, reduced placental vascularisation wasonly due to decreased labyrinth vascularisation which caused by bothdecreased number density and diameter of fetal capillary. We could notexplain the mechanism of the different placental vascular changes betweenSP-NBW and NP-LBW. We also could not elucidate the exact mechanism ofangiogenic factors mRNA alteration by smoke exposure. Further studies areneeded to elucidate these mechanisms.
S1 Datesets Original data for the results of this experiment. Data for litter size,birth weight, placental weight, placental efficiency, proportion of labyrinthin placenta, labyrinth vascularisation, fetal capillary diameter andplacental angiogenic factors mRNA expression.
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Department of Nutrition, Tongji Hospital, Tongji Medical College, HuazhongUniversity Science and Technology, Wuhan, Hubei, China
Corresponding Author: * E-mail: email@example.com
Editor: Christopher Torrens, University of Southampton, UNITED KINGDOM
Received Date: 12/14/2016
Accepted Date: 6/14/2017
Published Date: 7/18/2017
Copyright: © 2017 Chen, Yao
This is an open access article distributed under the terms of the CreativeCommons Attribution License, which permits unrestricted use, distribution,and reproduction in any medium, provided the original author and source arecredited.
Data Availability: All relevant data are within the paper and its Supporting Information file.
Funding: This study was supported by the grants funded by National Natural ScienceFoundation of China (81300592) and general Program in Scientific ResearchFoundation of Health Department of Hubei Province (WJ2015MB011).
Competing interests: The authors declare no conflicts of interest.
Copyright: COPYRIGHT 2017 Public Library of Science
Gale Document Number: GALE|A498881480
- Gene expression
- Low birth weight
- Messenger RNA
- Smoking in pregnancy
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