Endovascular Trophoblast Invasion and Associated Structural Changes in Uterine Spiral Arteries of the Pregnant Rat

Caluwaerts, Silvia; Vercruysse, Lisbeth; Luyten, C; Pijnenborg, Robert

doi:10.1016/j.placenta.2004.09.007

Cited by 107 publications

(106 citation statements)

References 26 publications

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“…Interstitial trophoblast was present in the central basal zone, but proper evaluation of this invasion pathway (unpublished observation) will require a more quantitative approach. An unusual finding that we have not observed in placentas of normal Wistar rats, 10 and also not in the SD ϫ hRen cross of the present study, was the occasional occurrence of spiral arteries with focal necrosis of the vessel , and C3q showed glomerular staining in the female hAogen ϫ male hRen cross, but not in the other strains. C5b-9 was also present in these glomeruli and blood vessels as shown.…”

Section: Resultscontrasting

confidence: 56%

“…The sequence of vascular changes after trophoblast invasion in the rat has recently been described. 10 Normal vascular remodeling in the rat placental bed involves endothelial replacement by trophoblasts, fibrinoid deposition, and at least a partial breakdown of the vascular smooth muscle, followed by restoration of endothelium overlying the embedded trophoblast. We will next investigate whether the same sequence of events occurs in this model of preeclampsia.…”

Section: Discussionmentioning

confidence: 99%

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Agonistic Autoantibodies to the AT1 Receptor in a Transgenic Rat Model of Preeclampsia

et al. 2005

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Abstract-We used rats transgenic for the human angiotensinogen (hAogen) gene and the human renin (hRen) gene and crossed the strains to produce a model of preeclampsia in the dams. The female (nϭ9) hAogen ϫ male hRen cross had severe (telemetry-measured) hypertension and albuminuria, which developed during the last trimester of pregnancy and subsided after delivery. The converse cross (nϭ9) and control (nϭ9) SD rats did not. We demonstrated that the female hAogen ϫ male hRen cross had agonistic antibodies capable of activating the angiotensin (Ang) II AT1 receptor (AT1R-AA) and defined the epitope on the receptor's second extracellular loop. The phenomenon also occurs in humans with preeclampsia. The rats displayed renal histology reminiscent of preeclampsia, including fibrin deposition confined to the glomeruli. The complement system was activated in glomeruli and IgG deposits were present that may represent AT1R-AA. Finally, we observed an atherosis-like lesion in the spiral arteries of the placental bed, which we called placental-bed arteriolosclerosis. Our model may be relevant to preeclampsia in humans. Key Words: preeclampsia Ⅲ rats, transgenic Ⅲ antibodies Ⅲ immune systems Ⅲ renin-angiotensin system P reeclampsia, proteinuria, and severe hypertension in the latter part of pregnancy affects Ϸ3% of women in industrialized nations and a much higher percentage of women in underdeveloped countries. 1 In all countries, preeclampsia represents the major cause of maternal and fetal morbidity and mortality. Constructing a suitable animal model has been difficult. Takimoto et al described hypertension induced in pregnant mice by placental renin and maternal angiotensinogen. 2 Mice were generated transgenic for the human renin (hRen) and human angiotensinogen (hAogen) genes. The rodent and human renin-angiotensinogen systems do not interact and single transgenic animals are normotensive. Severe hypertension develops in double-transgenic offspring. The investigators observed that hypertension developed in the latter third of pregnancy in hAogen dams mated with hRen males. They showed that secreted active hRen of placental origin was capable of reacting with hAogen in the dams to produce angiotensin (Ang) II. Takimoto et al suggested that the transgenic mice might offer a unique model of "genetically induced" preeclampsia. 2 We showed that the same phenomenon exists in a rat transgenic model. 3 We used telemetric blood pressure measurements in that study to document the precise timing of the model; however, we presented no functional or histological data. 3 We have also studied preeclamptic women and found that they produce an agonistic antibody to the Ang II receptor (AT1R). 4,5 These autoantibodies (AT1-AA) activate the receptor. The activation sets into motion a chain of signaling events that could be responsible for the clinical disease. 6 We have now restudied our transgenic animal model and have observed that the rats also have these novel autoantibodies. MethodsSprague-Dawley (SD) rats harboring the human Aogen...

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Section: Resultscontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Agonistic Autoantibodies to the AT1 Receptor in a Transgenic Rat Model of Preeclampsia

et al. 2005

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“…4,5 The mechanisms underlying spiral artery remodeling are still yet to be elucidated, largely because of the difficulty in obtaining tissue and the scarcity of suitable animal models that mirror the highly invasive nature of human hemochorial placentation. 1,6 Much of the current understanding is derived from examination of histological specimens and studies of primate models. Trophoblast, derived from chorionic villi, migrate away from the placental villous tips forming a population termed extravillous trophoblast.…”

mentioning

confidence: 99%

Fetal-Derived Trophoblast Use the Apoptotic Cytokine Tumor Necrosis Factor-α–Related Apoptosis-Inducing Ligand to Induce Smooth Muscle Cell Death

Keogh

Harris

Freeman

et al. 2007

Circulation Research

111

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Abstract-Remodeling of the uterine spiral arteries during pregnancy transforms them from high to low resistance vessels that lack vasoconstrictive properties. This process is essential to meet the demand for increased blood flow imposed by the growing fetus. Loss of endothelial and smooth muscle cells (SMC) is evident in remodeled arteries but the mechanisms underlying this transformation remain unknown. This study investigated the hypothesis that fetal trophoblast invading from the placenta instigate remodeling by triggering cell death in vascular SMC. Specifically, a role for trophoblast-derived death inducing cytokine tumor necrosis factor-␣-related apoptosis-inducing ligand (TRAIL) was investigated. Expression of the activating TRAIL receptors R1 and R2 was detected by flow cytometry on human aortic SMC and by immunohistochemistry on spiral artery SMC. Recombinant human TRAIL induced human aortic SMC apoptosis, which was inhibited by antibodies against TRAIL-R1 or -R2. Perfusion of denuded spiral artery segments with recombinant human TRAIL also induced SMC apoptosis. Trophoblasts isolated from first trimester placenta expressed membrane-associated TRAIL and induced apoptosis of human aortic SMC; apoptosis was significantly inhibited by a recombinant human TRAIL-R1:Fc construct. Trophoblast within the first trimester placental bed also expressed TRAIL. These data show that: 1) TRAIL causes SMC death; 2) trophoblast produce the apoptotic cytokine TRAIL; and 3) trophoblast induce SMC apoptosis via a TRAIL-dependent mechanism. We conclude that TRAIL produced by trophoblast causes apoptosis of SMC and thus may contribute to SMC loss during spiral artery remodeling in pregnancy. (Circ Res. 2007;100:834-841.)

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“…In humans and rats, trophoblast cells invade the uterine interstitium 25,26 and the lumina of spiral arteries. 27,28 In rats, interstitial trophoblast cell invasion occurs after endovascular invasion. 25 This finding again supports our hypothesis that the observed vasculopathy occurred at the end of pregnancy, hampering physiological interstitial trophoblast cell invasion and a putative (according to Chakraborty et al 16 ) increased endovascular trophoblast cell invasion.…”

Section: Discussionmentioning

confidence: 99%

Natural Killer Cell Reduction and Uteroplacental Vasculopathy

et al. 2016

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Abstract-Uterine natural killer cells are important for uteroplacental development and pregnancy maintenance. Their role in pregnancy disorders, such as preeclampsia, is unknown. We reduced the number of natural killer cells by administering rabbit anti-asialo GM1 antiserum in an established rat preeclamptic model (female human angiotensinogen×male human renin) and evaluated the effects at the end of pregnancy (day 21), compared with preeclamptic control rats receiving normal rabbit serum. In 100% of the antiserum-treated, preeclamptic rats (7/7), we observed highly degenerated vessel cross sections in the mesometrial triangle at the end of pregnancy. This maternal uterine vasculopathy was characterized by a total absence of nucleated/living cells in the vessel wall and perivascularly and prominent presence of fibrosis. Furthermore, there were no endovascular trophoblast cells within the vessel lumen. In the control, normal rabbit serum-treated, preeclamptic rats, only 20% (1/5) of the animals displayed such vasculopathy. We confirmed the results in healthy pregnant wild-type rats: after anti-asialo GM1 treatment, 67% of maternal rats displayed vasculopathy at the end of pregnancy compared with 0% in rabbit serum-treated control rats. This vasculopathy was associated with a significantly lower fetal weight in wild-type rats and deterioration of fetal brain/liver weight ratio in preeclamptic rats. Anti-asialo GM1 application had no influence on maternal hypertension and albuminuria during pregnancy. Our results show a new role of natural killer cells during hypertensive pregnancy in maintaining vascular integrity. In normotensive pregnancy, this integrity seems important for fetal growth. (Hypertension. 2016;68:964-973.

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Endovascular Trophoblast Invasion and Associated Structural Changes in Uterine Spiral Arteries of the Pregnant Rat

Cited by 107 publications

References 26 publications

Agonistic Autoantibodies to the AT1 Receptor in a Transgenic Rat Model of Preeclampsia

Agonistic Autoantibodies to the AT1 Receptor in a Transgenic Rat Model of Preeclampsia

Fetal-Derived Trophoblast Use the Apoptotic Cytokine Tumor Necrosis Factor-α–Related Apoptosis-Inducing Ligand to Induce Smooth Muscle Cell Death

Natural Killer Cell Reduction and Uteroplacental Vasculopathy

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