Regulation of Uterine Spiral Artery Remodeling: a Review


Extravillous trophoblast remodeling of the uterine spiral arteries is essential for promoting blood flow to the placenta and fetal development, but little is known about the regulation of this process. A defect in spiral artery remodeling underpins adverse conditions of human pregnancy, notably early-onset preeclampsia and fetal growth restriction, which result in maternal and fetal morbidity and mortality. Many in vitro studies have been conducted to determine the ability of growth and other factors to stimulate trophoblast cells to migrate across a synthetic membrane. Clinical studies have investigated whether the maternal levels of various factors are altered during abnormal human pregnancy. Animal models have been established to assess the ability of various factors to recapitulate the pathophysiological symptoms of preeclampsia. This review analyzes the results of the in vitro, clinical, and animal studies and describes a nonhuman primate experimental paradigm of defective uterine artery remodeling to study the regulation of vessel remodeling.


During early human pregnancy, extravillous trophoblast (EVT) migrates to, invades, and replaces the vascular smooth muscle cells (VSMC), endothelial cells, and elastic lamina within, thereby remodeling the uterine spiral arteries [1,2,3,4]. Consequently, these arteries change from high-resistance/low-capacity to low-resistance/high-capacity vessels, and thus, uterine artery blood flow increases with advancing gestation to enhance placental perfusion and promote fetal development. Defective uterine artery remodeling (UAR) underpins the etiology of certain pregnancy disorders that comprise the syndrome of placental ischemia [5, 6], notably early-onset preeclampsia, defined as premature delivery prior to week 34 of gestation and associated with a high rate of fetal growth restriction [7,8,9,10,11,12,13]. The term preeclampsia is used throughout this review to refer to early onset since in contrast to late-onset preeclampsia, i.e., delivery after 34 weeks, it is underpinned by defective UAR. Preeclampsia is associated with maternal systemic vascular endothelial inflammation-activation-dysfunction, hypertension, renal glomerular endotheliosis, and proteinuria, as well as maternal and neonatal morbidity/mortality [14,15,16,17,18,19,20]. It has been proposed that as a consequence of impaired UAR and placental perfusion, the placenta exhibits oxidative stress and the release of anti-angiogenic factors, cytokines, and/or syncytial extracellular vesicles which, along with predisposing maternal factors such as obesity and hypertension, elicit the pathophysiological manifestations of preeclampsia (reviewed in [16, 20]). Excessive trophoblast invasion and UAR are also deleterious because they result in impaired uterine artery vasomotor tone and hemorrhaging after delivery, a pregnancy complication known as placenta accreta [21, 22]. Despite the fundamental importance of UAR to successful pregnancy and fetal development, relatively little is known about the regulation of this process primarily because the majority of studies have focused on the pathophysiological consequences of adverse conditions of pregnancy and not on UAR. The present review describes the results of the in vitro and in vivo studies and a nonhuman primate model to study the regulation of UAR.

In Vitro Studies

Numerous in vitro studies have been conducted to investigate the ability of primary or immortalized trophoblasts cultured in two or three dimensions to pass across a synthetic permeable membrane coated with matrigel or decellularized extracellular matrix or to form endothelial-like tubes as indices of cell migration and invasion. Collectively, these studies have shown that several factors known to be produced by the placenta and/or decidua, including vascular endothelial growth factor-A (VEGF), placental growth factor (PlGF), insulin-like growth factor (IGF), epidermal growth factor (EGF), heparin-binding EGF (HB-EGF), activin, and human chorionic gonadotrophin (hCG), stimulated HTR-8/SV neo, trophoblast, or choriocarcinoma JEG-3 cell migration or endothelial-like tube formation [23,24,25,26,27,28,29,30,31,32,33]. Moreover, transcription and cell signaling molecules, including the Rac1 member of the Rho family of GTPases, the elastin-derived matrikine VGVAPG, the ephrin-B2 ligand of the Eph receptor, and Notch-2, also increased trophoblast migratory capacity in vitro [34,35,36,37,38]. However, in other in vitro studies, several of these factors did not alter EVT migration [39,40,41]. In contrast, transforming growth factor (TGFβ)-1, TGFβ-2, and TGFβ-3 and endocrine gland VEGF (EG-VEGF), as well as microRNA-93 and microRNA-135 which decrease CXCL12 gene expression, inhibited migration/invasive capacity of trophoblasts [42,43,44,45,46,47], while inhibition of TGFβ3 restored invasive capacity of trophoblasts obtained in late gestation from placentas of women with preeclampsia [48]. Additional in vitro studies using placental explants showed that elastin-derived peptides increased and endothelin-1 decreased trophoblast overgrowth [35, 49]. The underlying causes of the divergent effects of these factors on trophoblast migration are unclear, although use of different culture conditions, including oxygen and hypoxia-inducible factor levels and transformed versus primary trophoblasts, may be involved.

The presence of uterine natural killer (uNK) cells and macrophages, which are sources of VEGF-A and VEGF-C, angiopoietins, interleukins, and matrix metalloproteinases (MMPs) [50], was associated with VSMC and endothelial cell disruption in decidual tissue obtained in early human pregnancy [51], while the addition of uNK cell-conditioned medium to cultures of human term chorionic plate arteries caused VSMC and extracellular matrix breakdown [52]. The addition of EVT-conditioned medium to cultures of vascular endothelial cells increased expression of the chemokines CCL14 and CXCL6, which induced chemotaxis of decidual NK cells and macrophages, and the authors proposed that there was crosstalk between EVT, endothelial cells, and decidual immune cells in spiral artery remodeling [53]. NK cells also enhanced migration of and tube formation by primary trophoblast cells from placental villous tips, an effect that was prevented in cultures containing NK cells pretreated with sphingosine FTY720 to suppress NK cell function and VEGF production [54]. Moreover, recent studies suggest that additional processes, including invasion of uterine veins and lymph vessels by endo-venous and endo-lymphatic trophoblast cells, respectively, may also be involved in uterine artery remodeling [55, 56]. Based on these studies, it has been proposed that the immune system plays a role in uterine vessel transformation, although it has been suggested that the role of the immune system is more established in mouse than in human pregnancy (reviewed in [57,58,59]).

Clearly, the in vitro studies are significant in showing that a multitude of factors have the capacity to alter migratory and invasive capacity of trophoblast cells. However, considering the highly complex interplay of different cell types, molecular events, and spatio-temporal cell interactions that occur in vivo during spiral artery transformation, it is unclear whether trophoblast migration and endothelial tube formation as assessed in vitro validly mirror the process of UAR as it occurs in vivo. Thus, in vivo animal studies are needed to ascertain the applicability and physiological role of the candidate factors shown in vitro either operating alone or in conjunction with each other in regulating UAR.

Clinical Studies

Human clinical studies have shown that placental expression and/or maternal serum levels of many growth factors, including VEGF, IGF-I, EGF, HB-EGF, TGFβ, soluble endoglin, and other peptides, as well as Notch-2, endothelial colony-forming cells, tyrosine kinase-like orphan receptor, and microRNA-93, are either elevated, decreased, or unaltered in mid to late gestation in women who develop preeclampsia [23, 26, 60,61,62,63,64,65,66,67,68,69,70]. Additional studies have shown that maternal serum levels of PlGF are decreased, and the levels of the sFlt-1 soluble truncated VEGF receptor that binds to and suppresses VEGF bioavailability and endoglin were increased, preceding or coinciding with onset of the complications, e.g., maternal vascular dysfunction, of preeclampsia [71,72,73,74,75,76,77,78]. Consequently, it has been suggested that an imbalance in the levels of anti-angiogenic and angiogenic proteins and other factors may serve as biomarkers that are predictive for early detection of preeclampsia (reviewed in [19, 79, 80]).

Studies have also shown either an increase, no change, or a decrease in maternal serum estradiol levels at mid to late gestation in women exhibiting preeclampsia [81,82,83,84,85,86,87]. However, the role of estradiol in early human pregnancy with respect to UAR and onset of the pathophysiological conditions associated with preeclampsia has not been investigated.

Clinical studies have also shown that the number of immune cells, notably uNK cells, macrophages, and dendritic cells is either increased [88,89,90,91,92,93,94], decreased [95,96,97], or not altered [98,99,100] in decidua/placental bed obtained in late gestation before (e.g., biopsies) or after parturition in patients with preeclampsia. Studies also indicate that women with preeclampsia primarily express the inhibitory and not the stimulatory KIR receptors for uNK cells and that women with a KIR AA genotype, i.e., predictive of expression of the inhibitory KIRs KIR2DL-1, KIR2DL-2, KIR2DL-3, and KIR2DL-5, are at increased risk for developing preeclampsia [101]. Macrophages are also differently activated in preeclampsia [102,103,104,105,106], which may reflect a decrease in M2 macrophages and a concomitant increase in M1 macrophages [92] in the placental bed of preeclamptic women. Such a change would be consistent with increased placental production of pro-inflammatory cytokines [107] and decreased formation of anti-inflammatory cytokines [108, 109] that occur in preeclampsia. Interestingly the levels of mRNAs for immune-associated genes, notably IL-6 and macrophages, as well as markers for expression of M2 macrophages [110] are greater in biopsies of decidua from women in early gestation who subsequently developed pregnancy-induced hypertension compared with those who remained normotensive.

The human studies have been important in correlating the levels of the various factors with the pathophysiological features of preeclampsia. However, it is difficult to test cause and effect and the alterations in the various factors at mid-late gestation in preeclampsia patients may result from and not underpin the pathophysiological conditions elicited by preeclampsia. Importantly, since UAR was not simultaneously examined in these clinical studies, the regulatory role of these factors on UAR has not been established in normal or adverse human pregnancy.

Animal Studies

As presented in recent reviews [16, 19, 20, 111], early-onset preeclampsia is considered a two-stage disorder, stage 1 reflecting reduced placental perfusion and dysfunction due to impaired UAR and stage 2 the maternal syndrome induced by inadequate placental perfusion and deportation into the maternal blood of placental factors and syncytial particles produced in response to placental hypoxia and oxidative stress (Fig. 1). Although the maternal disorder including organ system involvement can vary greatly in complexity and severity [16, 111], maternal systemic vascular dysfunction and hypertension are hallmark features of preeclampsia. These manifestations appear to result from vascular endothelial inflammation, oxidative stress and dysfunction, notably impaired ability to produce the vasodilators nitric oxide (NO) and prostacyclin I2, increased production of vasoconstrictors such as endothelin, and hyper-sensitivity of VSMC to vasoconstrictors within the vascular bed (Fig. 2) [12, 14, 16,17,18, 20, 112,113,114,115,116,117,118,119,120,121].

Fig. 1

The two-stage placental model of preeclampsia in which it has been proposed [111] that impaired remodeling of uterine spiral arteries (“poor placentation”) is the pathway to stage 1 preeclampsia (placental dysfunction) and the preclinical stage before development of the maternal clinical syndrome (stage 2). Reprinted from Staff [20]

Fig. 2

Hypothetical scheme depicting how abnormal trophoblast invasion and spiral artery remodeling result in placental ischemia, endothelial dysfunction, and hypertension in preeclampsia. Reprinted from Palei et al. [17]

It is well established that VEGF plays a pivotal role in promoting vascular endothelial cell integrity, stability, and function, including NO production [122,123,124]. Therefore, it has been hypothesized [19, 75, 117] that in preeclampsia the placental ischemia induced by defective UAR causes an increase in placental expression and maternal serum levels of sFlt-1, which decreases VEGF bioavailability and elicits maternal vascular dysfunction (Fig. 2). Accordingly, animal models have been developed to examine this hypothesis and ascertain the possibility of achieving a therapeutic approach to overcome or prevent the vascular dysfunction elicited by decreased bioavailability of VEGF. Thus, key manifestations of preeclampsia, i.e., maternal hypertension, fetal growth restriction, and/or maternal vascular endothelial dysfunction, were induced in mice or rats in which levels of sFlt1 and/or endoglin were elevated by systemic adenoviral delivery of these proteins [74, 125,126,127,128,129,130,131]. Systemic administration to mice of an antibody which neutralized both Flt-1 and sFlt-1 decreased uterine artery length as an index of arterial transformation in this species [132]. The clinical manifestations of preeclampsia elicited in several of these animal models were prevented by adenoviral delivery of VEGF121 [133,134,135,136,137,138]. Symptoms of preeclampsia were also overcome in lentiviral sFlt1-treated mice by concomitant administration of the drug pravastatin [139] and in BPH/5 mice by injection of the drug celecoxib at the time of embryo implantation, which apparently acted by restoring the levels of Cox 2, VEGF, and related angiogenic factors [140]. Mice defective for PlGF, a member of the VEGF family, also exhibit preeclampsia-like symptoms, notably maternal endothelial dysfunction, as well as cognitive function of the offspring [141, 142]. Moreover, an experimental increase in sFlt-1 levels or decrease in VEGF and PlGF levels induced in rats and sheep by aortic or uterine artery ligation to elicit placental ischemia caused maternal hypertension, proteinurea, and vascular dysfunction, effects reversed by VEGF or PlGF administration [135, 138, 143,144,145]. Uterine spiral arteriole remodeling and MMP-2 and MMP-9 were decreased in the rat reduced uterine perfusion pressure model [146].

Inhibition of NO synthase [147], as well as administration of tumor necrosis factor-α [143] or interleukin [148], also induced preeclampsia-like symptoms in mice and rats. Interestingly, uterine artery diameter and length were reduced in endothelial NO synthase-null mice [149], whereas nanoparticle-mediated delivery of the NO donor SE175 to mice at mid-late gestation increased spiral artery diameter [150]. Roles for the Notch signaling pathway and the storkhead box 1 (STOX 1) transcription factor have also been suggested since Notch 2-null mice exhibited a decrease in spiral artery diameter and placental perfusion [151], while overexpression of STOX 1 in mice led to a preeclampsia phenotype of hypertension [152].

The role of immune cells in the process of vessel transformation has been proposed. Thus, studies in uNK cell-immunodeficient mice indicate that uNK cells, via the formation of interferon gamma, promote modification (i.e., luminal area) of spiral arteries [153,154,155,156]. Moreover, T lymphocyte regulatory cell (Tregs)-deficient mice show impaired uterine artery remodeling and flow [157, 158], suggesting that Tregs impair inflammatory responses that cause a defect in uterine vessel transformation [159].

Evidence for involvement of the renin-angiotensin (AT)-aldosterone system in preeclampsia has also emerged from rodent models. Thus, administration of antibodies to AT1 beginning at midgestation to mice or rats elicited hypertension, proteinuria, glomerular endotheliosis, and placental abnormalities [160, 161]. Moreover, AT1-deficient mice exhibited impaired placentation [162], and angiotensinogen transgenic mice exhibited deeper endovascular trophoblast invasion and spiral artery remodeling [163]. Upregulation of VSMC AT1 expression elicited hypertension, proteinuria, increased sFlt-1 expression, and decreased placental labyrinth growth in mice, effects prevented by administration of β-arrestin, a G protein that causes AT1 receptor desensitization [164].

The rodent models have been valuable in recapitulating the clinical symptoms of pregnancy disorders such as preeclampsia. However, in most instances, UAR was not examined, experimental interventions used to induce preeclampsia-like symptoms were often applied after the time of placentation, and many of the clinical features of preeclampsia were also induced in nonpregnant rodents, and thus, these models were not specific for pregnancy. Moreover, there are significant differences in placental morphology and development, the process and impact of spiral artery remodeling, uterine and placental vascular anatomy, and the maternal-placenta-fetal endocrine inter-relationships between rodents and humans [58, 59, 165,166,167,168,169,170,171]. For example, in the mouse and rat, trophoblast invasion is temporally restricted to late gestation [58, 172] and the role of UAR on maternal vascular function may be equivocal. Thus, although NK-defective mice exhibit impaired UAR, maternal resting blood pressure remains normal throughout gestation and maternal proteinuria does not develop [155], while trophoblast arterial invasion is more extensive and uterine artery resistance lower in the rat BHP/5 model of preeclampsia [163]. Collectively, these differences between rodents and humans make translation of findings on UAR in the rodent to the human uncertain.

Although rodents have been extensively used to recapitulate the pathophysiological features of preeclampsia, relatively few studies have employed nonhuman primates in this area of perinatal biology. Placental morphology, the process of uterine spiral artery transformation, uterine and placental vascular anatomy, and maternal-placental-fetal endocrine inter-relationships are similar in human and baboon pregnancy [58, 165, 173]. Although remodeling of the spiral arteries in the baboon does not extend into the inner myometrium, as in human pregnancy, the qualitative nature of placentation and UAR are alike [58, 174]. In addition to these important considerations, humans and baboons exhibit similar anatomy, physiology, and ontogeny of the fetal-placental unit [165] and share > 96% DNA/genetic homology [175, 176], and thus, the baboon provides an excellent nonhuman primate model for the study of human placental and fetal development.

As in the rodent studies, uterine artery ligation has been employed as an experimental paradigm in pregnant baboons. Uteroplacental ischemia elicited by uterine artery ligation in the second half of baboon pregnancy resulted in hypertension, proteinuria, and renal endotheliosis, effects reversed by administration of sFlt-1 siRNA or PlGF [177,178,179,180]. Thus, the latter primate studies focused on recapitulating the symptoms of adverse human pregnancy but not on UAR.

In contrast to the latter approach, the authors have published a series of studies in which they have established an experimental paradigm of prematurely elevating estradiol levels in the first trimester of baboon pregnancy to study the regulation of UAR [181,182,183]. Slightly elevating maternal estradiol levels resulted in a 3-fold increase in placental expression and maternal serum levels of sFlt-1 and decrease in extravillous trophoblast expression of VEGF in early pregnancy (Fig. 3). The increase in sFlt-1/decrease in VEGF was associated with a 75% reduction in the level of UAR, quantified as the percent of uterine spiral arteries invaded and remodeled by extravillous trophoblasts, at the end of the first trimester (Fig. 4). Concomitant administration of estradiol and delivery of the VEGF gene selectively to the maternal aspect of the placenta, but not the fetus, by contrast-enhanced ultrasonography/microbubble technology restored VEGF protein levels and prevented the decrease in UAR (Fig. 4, [184]).

Fig. 3

(a) sFlt-1 levels in uterine vein and (b) VEGF protein quantified by proximity ligation assay (signals/nuclear area × 104) in the anchoring villi on day 60 in untreated and estradiol (E2)-treated baboons. *P < 0.05

Fig. 4

Percent remodeling of uterine spiral arteries (i.e., number of vessels exhibiting trophoblast invasion divided by total number of vessels counted) on day 60 of gestation in baboons untreated, treated with estradiol (E2), or treated with E2 plus VEGF DNA. *Different (P < 0.01) from values in other two groups

The decline in extravillous trophoblast VEGF expression in estradiol-treated baboons was associated with a decrease in expression of the α1β1 and α5β1 integrins [182] that promote trophoblast migration and remodeling and are increased by VEGF in vitro [185,186,187]. This suggests that these integrins may mediate the stimulatory effect of VEGF on UAR during early baboon pregnancy. Coinciding with the decrease in UAR, uterine artery blood flow was reduced by 30% and maternal blood pressure increased by 25% near term, suggesting an impairment of maternal systemic vascular function [183]. Although it has been suggested that the alteration in expression of pro- and anti-angiogenic growth factors is simply the result and not the cause of placental dysfunction in preeclampsia [20], the prevention of the decrease in UAR by VEGF delivery in early baboon pregnancy is consistent with VEGF having a pivotal role in promoting UAR.


UAR is vital to successful pregnancy; however, the regulation of this fundamentally important process has not been established. The in vitro studies are important in having identified a multitude of factors that have the ability to alter migratory and invasive capacity of trophoblast cells. However, it is unclear whether trophoblast migration and endothelial tube formation as assessed in vitro validly mirror the process of UAR as it occurs in vivo. The clinical studies have been significant in showing that maternal serum levels of certain factors are altered, particularly sFlt-1 which is increased and PlGF which is decreased, preceding or coinciding with onset of the complications, e.g., maternal vascular dysfunction, emanating from preeclampsia. However, it is difficult to test cause and effect in human pregnancy studies, and thus, the alteration in circulating levels of the various factors may be a consequence of and not underpin the pathophysiological conditions elicited by adverse pregnancy. The rodent and a few primate studies have been valuable in recapitulating, and showing the ability of certain growth factors to mitigate, the clinical manifestations of pregnancy disorders such as preeclampsia, but have not focused on UAR. This review has described the results of in vitro, clinical, and rodent studies and also a novel experimental model of defective UAR in a nonhuman primate that allows study of the regulation of spiral artery transformation and the potential to develop therapeutic modalities to manage or prevent the maternal pathophysiological consequences of adverse pregnancy arising from defective UAR.


  1. 1.

    Hamilton WJ, Boyd JD. Development of the human placenta in the first three months of gestation. J Anat. 1960;94:297–328.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Ramsey EM, Houston ML, Harris JW. Interactions of the trophoblast and maternal tissues in three closely related primate species. Am J Obstet Gynecol. 1976;124:647–52.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Pijnenborg R, Dixon G, Robertson WB, Brosens I. Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy. Placenta. 1980;1:3–19.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Enders AC, King BF. Early stages of trophoblastic invasion of the maternal vascular system during implantation in the macaque and baboon. Am J Anat. 1991;192:329–46.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Ananth CV. Ischemic placental disease: a unifying concept for preeclampsia, intrauterine growth restriction, and placental abruption. Semin Perinatol. 2014;38:131–2.

    PubMed  Article  Google Scholar 

  6. 6.

    Heazell AE, Worton SA, Higgins LE, Ingram E, Johnstone ED, Jones RL, et al. IFPA Gábor Than Award Lecture: recognition of placental failure is key to saving babies’ lives. Placenta. 2015;36:S20–8.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Brosens I. A study of the spiral arteries of the decidua basalis in normotensive and hypertensive pregnancies. J Obstet Gynaecol Br Commonw. 1964;71:222–30.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol. 1986;93:1049–59.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Pijnenborg R, Vercruysse L, Hanssens M. The uterine spiral arteries in human pregnancy: facts and controversies. Placenta. 2006;27:939–58.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Lyall F, Robson SC, Bulmer JN. Spiral artery remodeling and trophoblast invasion in preeclampsia and fetal growth restriction: relationship to clinical outcome. Hypertension. 2013;62:1046–54.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Brosens I, Puttemans P, Benagiano G. Placental bed research: I. The placental bed: from spiral arteries remodeling to the great obstetrical syndromes. Am J Obstet Gynecol. 2019;221(5):437–56.

    PubMed  Article  Google Scholar 

  12. 12.

    Myatt L, Roberts JM. Preeclampsia: syndrome or disease? Curr Hypertens Rep. 2015;17(11):83.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Burton GJ, Jauniaux E. Pathophysiology of placental-derived fetal growth restriction. Am J Obstet Gynecol. 2018;218:S745–61.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Roberts JM, Taylor RN, Goldfien A. Clinical and biochemical evidence of endothelial cell dysfunction in the pregnancy syndrome preeclampsia. Am J Hypertens. 1991;4:700–8.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Gilbert JS, Ryan MJ, LaMarca BB, Sedeek M, Murphy SR, Granger JP. Pathophysiology of hypertension during preeclampsia: linking placental ischemia with endothelial dysfunction. Am J Physiol Heart Circ Physiol. 2008;294:H541–50.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Roberts JM, Bell MJ. If we know so much about preeclampsia, why haven’t we cured the disease? J Reprod Immunol. 2013;99:1–9.

    PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Palei AC, Spradley FT, Warrington JP, George EM, Granger JP. Pathophysiology of hypertension in pre-eclampsia: a lesson in integrative physiology. Acta Physiol. 2013;208:224–33.

    CAS  Article  Google Scholar 

  18. 18.

    Granger JP, Spradley FT, Bakrania BA. The endothelin system: a critical player in the pathophysiology of preeclampsia. Curr Hypertens Rep. 2018;20:32.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 19.

    Rana S, Lemoine E, Granger J, Karumanchi SA. Preeclapmsia. Circ Res. 2019;124:1094–112.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Staff AC. The two-stage placental model of preeclampsia: an update. J Reprod Immunol. 2019;134–135:1–10.

    PubMed  Article  Google Scholar 

  21. 21.

    Tantbirojn P, Crum CP, Parast MM. Pathophysiology of placenta creta: the role of decidua and extravillous trophoblast. Placenta. 2008;29:639–45.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Hannon T, Innes BA, Lash GE, Bulmer JN, Robson SC. Effects of local decidua on trophoblast invasion and spiral artery remodeling in focal placenta creta – an immunohistochemical study. Placenta. 2012;33:998–1004.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen T, et al. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol. 2002;160:1405–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Lala PK, Chakraborty C. Factors regulating trophoblast migration and invasiveness: possible derangements contributing to pre-ecclampsia and fetal injury. Placenta. 2003;24:575–87.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Anteby EY, Greenfield C, Natanson-Yaron S, Goldman-Wohl D, Hamani Y, Khudyak V, et al. Vascular endothelial growth factor, epidermal growth factor and fibroblast growth factor-4 and -10 stimulate trophoblast plasminogen activator system and metalloproteinase-9. Mol Hum Reprod. 2004;10:229–35.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Leach RE, Kilburn B, Wang J, Liu Z, Romero R, Armant DR. Heparin-binding EGF-like growth factor regulates human extravillous cytotrophoblast development during conversion to the invasive phenotype. Dev Biol. 2004;266:223–37.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Lyall F. Priming and remodelling of human placental bed spiral arteries during pregnancy - a review. Placenta. 2005;26:S31–6.

    PubMed  Article  Google Scholar 

  28. 28.

    Rao CV, Lei ZM. The past, present and future of nongonadal LH/hCG actions in reproductive biology and medicine. Mol Cell Endocrinol. 2007;269:2–8.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Harris LK. Review: Trophoblast-vascular cell interactions in early pregnancy: how to remodel a vessel. Placenta. 2010;31:S93–8.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Knöfler M, Pollheimer J. IFPA Award in Placentology lecture: molecular regulation of human trophoblast invasion. Placenta. 2012;33:S55–62.

    PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Lala N, Girish GV, Cloutier-Bosworth A, Lala PK. Mechanisms in decorin regulation of vascular endothelial growth factor-induced human trophoblast migration and acquisition of endothelial phenotype. Biol Reprod. 2012;87(59):1–14.

    Google Scholar 

  32. 32.

    Li Y, Zhu H, Klausen C, Peng B, Leung PC. Vascular endothelial growth factor-A (VEGF-A) mediates activin A-induced human trophoblast endothelial-like tube formation. Endocrinology. 2015;156:4257–68.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Evans J, Salamonsen LA, Menkhorst E, Dimitradis E. Dynamic changes in hyperglycosylated human chorionic gonadotrophin throughout the first trimester of pregnancy and its role in early placentation. Hum Reprod. 2015;30:1029–38.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Luo Q, Liu X, Zheng Y, Zhao Y, Zhu J, Zou L. Ephrin-B2 mediates trophoblast-dependent maternal spiral artery remodeling in first trimester. Placenta. 2015;36:567–74.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Deforges M, Harris LK, Alpin JD. Elastin-derived peptides stimulate trophoblast migration and invasion: a positive feedback loop to enhance spiral artery remodelling. Mol Hum Reprod. 2015;21:95–104.

    Article  CAS  Google Scholar 

  36. 36.

    Fan M, Xu Y, Hong F, Gao X, Xin G, Hong H, et al. Rac1/β-catenin signalling pathway contributes to trophoblast cell invasion by targeting snail and MMP9. Cell Physiol Biochem. 2016;38:1319–32.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Zhao WX, Zhuang X, Huang TT, Feng R, Lin JH. Effects of Notch2 and Notch3 on cell proliferation and apoptosis of trophoblast cell lines. Int J Med Sci. 2015;12:867–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    McNally R, Alqudah A, Obradovic D, McClements L. Elucidating the pathogenesis of pre-eclampsia using in vitro models of spiral uterine artery remodelling. Curr Hypertens Rep. 2017;19:93.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Athanassiades A, Hamilton GS, Lala PK. Vascular endothelial growth factor stimulates proliferation but not migration or invasiveness in human extravillous trophoblast. Biol Reprod. 1998;59:643–54.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Fitzpatrick TE, Lash GE, Yanaihara A, Charnock-Jones DS, Macdonald-Goodfellow SK, Graham CH. Inhibition of breast carcinoma and trophoblast cell invasiveness by vascular endothelial growth factor. Exp Cell Res. 2003;283:247–55.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Dubinsky V, Poehlmann TG, Suman P, Gentile T, Markert UR, Gutierrez G. Role of regulatory and angiogenic cytokines in invasion of trophoblastic cells. Am J Reprod Immunol. 2010;63:193–9.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Forbes K, Westwood M. Maternal growth factor regulation of human placental development and fetal growth. J Endocrinol. 2010;207:1–16.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Jones RL, Findlay JK, Farnworth PG, Robertson DM, Wallace E, Salamonsen LA. Activin A and inhibin A differentially regulate human uterine matrix metalloptoteinases: potential interactions during decidualization and trophoblast invasion. Endocrinology. 2006;147:724–32.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Hu XQ, Zhang L. MicroRNAs in uteroplacental vascular dysfunction. Cells. 2019;8(11):1344.

    CAS  PubMed Central  Article  Google Scholar 

  45. 45.

    Hoffman P, Saoudi Y, Benharouga M, Graham CH, Schaal JP, Mazouni C, et al. Role of EG-VEGF in human placentation: physiological and pathological implications. J Cell Mol Med. 2009;13:2224–35.

    Article  Google Scholar 

  46. 46.

    Tamaru S, Mizuno Y, Tochigi H, Kajihara T, Okazaki Y, Okagaki R, et al. MicroRNA-135b suppresses extravillous trophoblast-derived HTR-7/SVneo cell invasion by directly down regulating CXCL12 under low oxygen conditions. Biochem Biophys Res Commun. 2015;461:421–6.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Pan Q, Niu HY, Cheng LF, Li XQ, Zhang QG, Ning Y. Invasion of trophoblast cell lines is inhibited by miR-93 via MMP-2. Placenta. 2017;53:48–53.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Caniggia I, Grisaru-Gravnosky S, Kuliszewsky M, Post M, Lye SJ. Inhibition of TFG-beta 3 restores the invasive capability of extravillous trophoblasts in preeclamptic pregnancies. J Clin Invest. 1999;103:1641–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Majali-Martinez A, Velicky P, Pollheimer J, Knöfler M, Yung HW, Burton GJ, et al. Endothelin-1 down-regulates matrix metalloproteinase 14 and 15 expression in human first trimester trophoblasts via endothelin receptor type B. Hum Reprod. 2017;32:46–54.

    CAS  PubMed  Google Scholar 

  50. 50.

    Lash GE, Pitman H, Morgan HL, Innes BA, Agwu CN, Bulmer JN. Decidual macrophages: key regulators of vascular remodeling in human pregnancy. J Leukoc Biol. 2016;100:315–25.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Smith SD, Dunk CE, Aplin JD, Harris LK, Jones RL. Evidence for immune cell involvement in decidual spiral arteriole remodeling in early human pregnancy. Am J Pathol. 2009;174:1959–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Robson A, Harris LK, Innes BA, Lash GE, Aljunaidy MM, Aplin JD, et al. Uterine natural killer cells initiate spiral artery remodeling in human pregnancy. FASEB J. 2012;26:4876–85.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Choudhury RH, Dunk CE, Lye SJ, Aplin JD, Harris LK, Jones RL. Extravillous trophoblast and endothelial cell crosstalk mediates leukocyte infiltration to the early remodeling decidual spiral arteriole wall. J Immunol. 2017;198(10):4115–28.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Zhang J, Dunk CE, Lye SJ. Sphingosine signalling regulates decidual NK cell angiogenic phenotype and trophoblast migration. Hum Reprod. 2013;28:3026–37.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Pollheimer J, Vondra S, Baltayeva J, Beristain AG, Knöfler M. Regulation of placental extravillous trophoblasts by the maternal uterine environment. Front Immunol. 2018;9:1–18.

    Article  CAS  Google Scholar 

  56. 56.

    Moser G, Windsperger K, Pollheimer J, de Sousa Lopes SC, Huppertz B. Human trophoblast invasion: new and unexpected routes and functions. Histochem Cell Biol. 2018;150:361–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Harris LK, Benagiano M, D’Elios MM, Brosens I, Benagiano G. Placental bed research: 2. Functional immunological investigations of the placental bed. Am J Obstet Gynecol. 2019;221(5):457–69.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Carter AM. Animal models of human placentation – a review. Placenta. 2007;28(Suppl A):S41–7.

    PubMed  Article  Google Scholar 

  59. 59.

    Moffet A, Loke C. Immunology of placentation in eutherian mammals. Nat Rev Immunol. 2006;6:584–94.

    Article  CAS  Google Scholar 

  60. 60.

    Baker PN, Krasnow J, Roberts JM, Yeo KT. Elevated serum levels of vascular endothelial growth factor in patients with preeclampsia. Obstet Gynecol. 1995;86:815–21.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Cooper JC, Sharkey AM, Charnock-Jones DS, Palmer CR, Smith SK. VEGF mRNA levels in placentae from pregnancies complicated by pre-eclampsia. Br J Obstet Gynaecol. 1996;103:1191–6.

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Sharkey AM, Cooper JC, Balmforth JR, McLaren J, Clark DE, Charnock-Jones DS, et al. Maternal plasma levels of vascular endothelial growth factor in normotensive pregnancies and in pregnancies complicated by pre-eclampsia. Eur J Clin Investig. 1996;26:1182–5.

    CAS  Article  Google Scholar 

  63. 63.

    Lyall F, Greer IA, Boswell F, Fleming R. Suppression of serum vascular endothelial growth factor immunoreactivity in normal pregnancy and in pre-eclampsia. Br J Obstet Gynaecol. 1997;104:223–8.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Chung JY, Song Y, Wang Y, Magness RR, Zheng J. Differential expression of vascular endothelial growth factor (VEGF), endocrine gland derived-VEGF, and VEGF receptors in human placentas from normal and preeclamptic pregnancies. J Clin Endocrinol Metab. 2004;89:2484–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Hamilton GS, Lysiak JJ, Han VK, Lala PK. Autocrine-paracrine regulation of human trophoblast invasiveness by insulin-like growth factor (IGF)-II and IGF-binding protein (IGFBP)-1. Exp Cell Res. 1998;244:147–56.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Armant DR, Fritz R, Kilburn BA, Kim YM, Nien JK, Maihle NJ, et al. Reduced expression of the epidermal growth factor signaling system in preeclampsia. Placenta. 2015;6:270–8.

    Article  CAS  Google Scholar 

  67. 67.

    Fragkiadaki P, Soulitzis N, Sifakis S, Koutroulakis D, Gourvas V, Vrachnis N, et al. Downregulation of notch signaling pathway in late preterm and term placentas from pregnancies complicated by preeclampsia. PLoS One. 2015;10:e0126163.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. 68.

    Muñoz-Hernandez R, Miranda ML, Stiefel P, Lin RZ, Praena-Fernández JM, Dominguez-Simeon MJ, et al. Decreased level of cord blood circulating endothelial colony-forming cells in preeclampsia. Hypertension. 2014;64:165–71.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  69. 69.

    Travaglino A, Raffone A, Saccone G, Migliorini S, Maruotti GM, Esposito G, et al. Placental morphology, apoptosis, angiogenesis and epithelial mechanisms in early-onset preeclampsia. Eur J Obstet Gynecol Reprod Biol. 2019;234:200–6.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Chen J, Yue C, Xu J, Zhan Y, Zhao H, Li Y, et al. Downregulation of receptor tyrosine kinase-like orphan receptor 1 in preeclampsia placenta inhibits human trophoblast cell proliferation, migration, and invasion by PI3K/AKT/mTOR pathway accommodation. Placenta. 2019;82:17–24.

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Torry DS, Wang HS, Wang TH, Caudle MR, Torry RJ. Preeclampsia is associated with reduced serum levels of placenta growth factor. Am J Obstet Gynecol. 1998;179:1539–44.

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Taylor RN, Grimwood J, Taylor RS, McMaster MT, Fisher SJ, North RA. Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies. Am J Obstet Gynecol. 2003;188:177–82.

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Tsatsaris V, Goffin F, Munaut C, Brichant JF, Pignon MR, Noel A, et al. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab. 2003;88:5555–63.

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111:649–58.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350:672–83.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Chaiworapongsa T, Romero R, Kim YM, Kim GJ, Kim MR, Espinoza J, et al. Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia. J Matern Fetal Neonatal Med. 2005;17:3–18.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Wathén KA, Tuutti E, Stenman UH, Alfthan H, Halmesmäki E, Finne P, et al. Maternal serum-soluble vascular endothelial growth factor receptor-1 in early pregnancy ending in preeclampsia or intrauterine growth retardation. J Clin Endocrinol Metab. 2006;91:180–4.

    PubMed  Article  CAS  Google Scholar 

  78. 78.

    Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med. 2006;355:992–1005.

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Myatt L, Clifton RG, Roberts JM, Spong CY, Hauth JC, Varner MW, et al. First-trimester prediction of preeclampsia in nulliparous women at low risk. Obstet Gynecol. 2012;119:1234–42.

    PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Kenny LC, Black MA, Poston L, Taylor R, Myers JE, Baker PN, et al. Early pregnancy prediction of preeclampsia in nulliparous women, combining clinical risk and biomarkers: the screening for pregnancy endpoints (SCOPE) international cohort study. Hypertension. 2014;64:644–52.

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Serin IS, Kula M, Başbuğ M, Unlühizarci K, Güçer S, Tayyar M. Androgen levels of preeclamptic patients in the third trimester of pregnancy and six weeks after delivery. Acta Obstet Gynecol Scand. 2001;80:1009–13.

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Zeisler H, Jirecek S, Hohlagschwandtner M, Knöfler M, Tempfer C, Livingston JC. Concentrations of estrogens in patients with preeclampsia. Wien Klin Wochenschr. 2002;114:458–61.

    CAS  PubMed  Google Scholar 

  83. 83.

    Miller NR, Garry D, Cohen HW, Figueroa R. Serum androgen markers in preeclampsia. J Reprod Med. 2003;48:225–9.

    PubMed  Google Scholar 

  84. 84.

    Salas SP, Marshall G, Gutiérrez BL, Rosso P. Time course of maternal plasma volume and hormonal changes in women with preeclampsia or fetal growth restriction. Hypertension. 2006;47:203–8.

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Hertig A, Liere P, Chabbert-Buffet N, Fort J, Pianos A, Eychenne B, et al. Steroid profiling in preeclamptic women: evidence for aromatase deficiency. Am J Obstet Gynecol. 2010;203:477.e1–9.

    Article  CAS  Google Scholar 

  86. 86.

    Berkane N, Liere P, Oudinet JP, Hertig A, Lefèvre G, Pluchino N, et al. From pregnancy to preeclampsia: a key role for estrogens. Endocr Rev. 2017;38:123–44.

    PubMed  Article  Google Scholar 

  87. 87.

    Jobe SO, Tyler CT, Magness RR. Aberrant synthesis, metabolism, and plasma accumulation of circulating estrogens and estrogen metabolites in preeclampsia implications for vascular dysfunction. Hypertension. 2013;61:480–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Faas MM, De Vos P. Innate immune cells in the placental bed in healthy pregnancy and preeclampsia. Placenta. 2018;29:125–33.

    Article  CAS  Google Scholar 

  89. 89.

    Stallmach T, Hebisch G, Orban P, Lu X. Aberrant positioning of trophoblast and lymphocytes in the feto-maternal interface with pre-eclampsia. Virchows Arch. 1999;434(3):07–211.

    Article  Google Scholar 

  90. 90.

    Bachmayer N, Rafik Hamad R, Liszka L, Bremme K, Sverremark-Ekstrom E. Aberrant uterine natural killer (NK)-cell expression and altered placental and serum levels of the NK-cell promoting cytokine interleukin-12 in pre-eclampsia. Am J Reprod Immunol. 2006;56(5–6):292–301.

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Wilczyński JR, Tchórzewski H, Banasik M, Głowacka E, Wieczorek A, Lewkowicz P, et al. Lymphocyte subset distribution and cytokine secretion in third trimester decidua in normal pregnancy and preeclampsia. Eur J Obstet Gynecol Reprod Biol. 2003;109(1):8–15.

    PubMed  Article  CAS  Google Scholar 

  92. 92.

    Schonkeren D, van der Hoorn ML, Khedoe P, Swings G, van Beelen E, Claas F, et al. Differential distribution and phenotype of decidual macrophages in preeclamptic versus control pregnancies. Am J Pathol. 2011;178(2):709–17.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Reister F, Frank HG, Kingdom JC, Heyl W, Kaufmann P, Rath W, et al. Macrophage-induced apoptosis limits endovascular trophoblast invasion in the uterine wall of preeclamptic women. Lab Investig. 2001;81(8):1143–52.

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Kim JS, Romero R, Cushenberry E, Kim YM, Erez O, Nien JK, et al. Distribution of CD14+ and CD68+ macrophages in the placental bed and basal plate of women with preeclampsia and preterm labor. Placenta. 2007;28(5–6):571–6.

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Williams PJ, Bulmer JN, Searle RF, Innes BA, Robson SC. Altered decidual leucocyte populations in the placental bed in pre-eclampsia and foetal growth restriction: a comparison with late normal pregnancy. Reproduction. 2009;138(1):177–84.

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Eide IP, Rolfseng T, Isaksen CV, Mecsei R, Roald B, Lydersen S, et al. Serious foetal growth restriction is associated with reduced proportions of natural killer cells in decidua basalis. Virchows Arch. 2006;448(3):269–76.

    PubMed  Article  Google Scholar 

  97. 97.

    Bürk MR, Troeger C, Brinkhaus R, Holzgreve W, Hahn S. Severely reduced presence of tissue macrophages in the basal plate of pre-eclamptic placentae. Placenta. 2001;22(4):309–16.

    PubMed  Article  Google Scholar 

  98. 98.

    Rieger L, Segerer S, Bernar T, Kapp M, Majic M, Morr AK, et al. Specific subsets of immune cells in human decidua differ between normal pregnancy and preeclampsia–a prospective observational study. Reprod Bio Endocrino: RBE (Rev Bras Entomol). 2009;7:132.

    Article  CAS  Google Scholar 

  99. 99.

    Hsu P, Santner-Nanan B, Dahlstrom JE, Fadia M, Chandra A, Peek M, et al. Altered decidual DC-SIGN+ antigen-presenting cells and impaired regulatory T-cell induction in preeclampsia. Am J Pathol. 2012;181(6):2149–60.

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Huang SJ, Chen CP, Schatz F, Rahman M, Abrahams VM, Lockwood CJ. Pre-eclampsia is associated with dendritic cell recruitment into the uterine decidua. J Pathol. 2008;214(3):328–36.

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Hiby SE, Walker JJ, O’Shaughnessy KM, Redman CW, Carrington M, Trowsdale J, et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med. 2004;200(8):957–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Reister F, Frank HG, Heyl W, Kosanke G, Huppertz B, Schröder W, et al. The distribution of macrophages in spiral arteries of the placental bed in pre-clampsia differs from that in healthy patients. Placenta. 1999;20((2–3)):229–33.

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Katabuchi H, Yih S, Ohba T, Matsui K, Takahashi K, Takeya M, et al. Characterization of macrophages in the decidual atherotic spiral artery with special reference to the cytology of foam cells. Med Electron Microsc. 2003;36(4):253–62.

    PubMed  Article  Google Scholar 

  104. 104.

    Haeger M, Unander M, Norder-Hansson B, Tylman M, Bengtsson A. Complement, neutrophil, and macrophage activation in women with severe preeclampsia and the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol. 1992;79(1):19–26.

    CAS  PubMed  Google Scholar 

  105. 105.

    Benyo DF, Smarason A, Redman CW, Sims C, Conrad KP. Expression of inflammatory cytokines in placentas from women with preeclampsia. J Clin Endocrinol Metab. 2001;86(6):2505–12.

    CAS  PubMed  Google Scholar 

  106. 106.

    Wang Y, Walsh SW. TNF alpha concentrations and mRNA expression are increased in preeclamptic placentas. J Reprod Immunol. 1996;32(2):157–69.

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Pang ZJ, Xing FQ. Comparative study on the expression of cytokine–receptor genes in normal and preeclamptic human placentas using DNA microarrays. J Perinat Med. 2003;31(2):153–62.

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Hennessy A, Pilmore HL, Simmons LA, Painter DM. A deficiency of placental IL-10 in preeclampsia. J Immunol. 1999;163(6):3491–5.

    CAS  PubMed  Google Scholar 

  109. 109.

    Rein DT, Breidenbach M, Hönscheid B, Friebe-Hoffmann U, Engel H, Göhring UJ, et al. Preeclamptic women are deficient of interleukin-10 as assessed by cytokine release of trophoblast cells in vitro. Cytokine. 2003;23(4–5):119–25.

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Prins JR, Faas MM, Melgert BN, Huitema S, Timmer A, Hylkema MN, et al. Altered expression of immune-associated genes in first-trimester human decidua of pregnancies later complicated with hypertension or foetal growth restriction. Placenta. 2012;33(5):453–5.

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Redman CW, Sargent IL, Staff AC. IFPA Senior Award Lecture: making sense of preeclampsia–two placental causes of preeclampsia? Placenta. 2014;35(Suppl):S20–5.

    PubMed  Article  Google Scholar 

  112. 112.

    Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, Mclaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 1989;161:1200–4.

    CAS  PubMed  Article  Google Scholar 

  113. 113.

    Barden A, Beilin LJ, Ritchie J, Walters BN, Michael CA. Plasma and urinary endothelin 1, prostacyclin metabolites and platelet consumption in pre-eclampsia and essential hypertensive pregnancy. Blood Press. 1994;3:38–46.

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Walsh SW. Maternal-placental interactions of oxidative stress and antioxidants in preeclampsia. Semin Reprod Endocrinol. 1998;16:93–104.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Myatt L, Webster RP. Vascular biology of preeclampsia. J Thromb Haemost. 2009;7:375–84.

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Cunningham FG, Roberts JM, Lindheimer MD. The clinical spectrum of preeclampsia. In: Lindheimer MD, Roberts JM, Cunningham FG, editors. Chesley’s hypertensive disorders in pregnancy. San Diego: Academic; 2009. p. 25–36.

    Google Scholar 

  117. 117.

    Redman CW, Sargent IL. Placental stress and pre-eclampsia: a revised view. Placenta. 2009;30(Suppl A):S38–42.

    PubMed  Article  CAS  Google Scholar 

  118. 118.

    Brennan LJ, Morton JS, Davidge ST. Vascular dysfunction in preeclampsia. Microcirculation. 2014;21:4–14.

    PubMed  Article  Google Scholar 

  119. 119.

    Goulopoulou S, Davidge ST. Molecular mechanisms of maternal vascular dysfunction in preeclampsia. Trends Mol Med. 2015;21:88–97.

    CAS  PubMed  Article  Google Scholar 

  120. 120.

    Khalil RA, Granger JP. Vascular mechanisms of increased arterial pressure in preeclampsia: lessons from animal models. Am J Physiol Regul Integr Comp Physiol. 2002;283:R29–45.

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Ilekis JV, Tsilou E, Fisher S, Abrahams VM, Soares MJ, Cross JC, et al. Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Am J Obstet Gynecol. 2016;215:S1–S46.

    PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Sladek SM, Magness RR, Conrad KP. Nitric oxide and pregnancy. Am J Phys. 1997;272:R441–63.

    CAS  Google Scholar 

  123. 123.

    Hood JD, Meininger CJ, Ziche M, Granger HJ. VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells. Am J Phys. 1998;274:H1054–8.

    CAS  Google Scholar 

  124. 124.

    Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–76.

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med. 2006;12(6):642–9 Epub 2006 Jun 4.

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    Lu F, Longo M, Tamayo E, Maner W, Al-Hendy A, Anderson GD, et al. The effect of over-expression of sFlt-1 on blood pressure and the occurrence of other manifestations of preeclampsia in unrestrained conscious pregnant mice. Am J Obstet Gynecol. 2007;196:396.e1–7.

    Article  CAS  Google Scholar 

  127. 127.

    Tang JR, Karumanchi SA, Seedorf G, Markham N, Abman SH. Excess soluble vascular endothelial growth factor receptor-1 in amniotic fluid impairs lung growth in rats: linking preeclampsia with bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol. 2012;302:L36–46.

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    LaMarca BD, Gilbert JS, Granger JP. Recent progress toward the understanding of the pathophysiology of hypertension during preeclampsia. Hypertension. 2008;51:982–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Suzuki H, Ohkuchi A, Matsubara S, Takei Y, Murakami M, Shibuyua M, et al. Effect of recombinant placental growth factor 2 on hypertension induced by full-length mouse soluble fms-like tyrosine kinase 1 adenoviral vector in pregnant mice. Hypertension. 2009;54:11291135.

    Article  CAS  Google Scholar 

  130. 130.

    Bridges JP, Gilbert JS, Colson D, Gilbert SA, Dukes MP, Ryan MJ, et al. Oxidative stress contributes to soluble fms-like tyrosine kinase-1 induced vascular dysfunction in pregnant rats. Am J Hypertens. 2009;22:564–8 Epub 2009 Mar 5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Szalai G, Romero R, Chaiworapongsa T, Xu Y, Wang B, Ahn H, et al. Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice. PLoS One. 2015;10(4):e0119547.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  132. 132.

    Khankin EV, Mandala M, Colton I, Karumanchi SA, Osol G. Hemodynamic, vascular, and reproductive impact of FMS-like tyrosine kinase 1 (FLT1) blockade on the uteroplacental circulation during normal mouse pregnancy. Biol Reprod. 2012;86:57,1–8.

    Article  CAS  Google Scholar 

  133. 133.

    Li Z, Zhang Y, Ying Ma J, Kapoun AM, Shao Q, Kerr I, et al. Recombinant vascular endothelial growth factor 121 attenuates hypertension and improves kidney damage in a rat model of preeclampsia. Hypertension. 2007;50:686–92.

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    Bergmann A, Ahmad S, Cudmore M, Gruber AD, Wittschen P, Lindenmaier W, et al. Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model. J Cell Mol Med. 2010;14:1857–67.

    CAS  PubMed  Article  Google Scholar 

  135. 135.

    Gilbert JS, Verzwyvelt J, Colson D, Arany M, Karumanchi SA, Granger JP. Recombinant vascular endothelial growth factor 121 infusion lowers blood pressure and improves renal function in rats with placental ischemia-induced hypertension. Hypertension. 2010;55:380–385.

  136. 136.

    Woods AK, Hoffmann DS, Weydert CJ, Butler SD, Zhou Y, Sharma RV, et al. Adenoviral delivery of VEGF121 early in pregnancy prevents spontaneous development of preeclampsia in BPH/5 mice. Hypertension. 2011;57:94–102.

    CAS  PubMed  Article  Google Scholar 

  137. 137.

    Mateus J, Bytautiene E, Lu F, Tamayo EH, Betancourt A, Hankins GD, et al. Endothelial growth factor therapy improves preeclampsia-like manifestations in a murine model induced by overexpression of sVEGFR-1. Am J Physiol Heart Circ Physiol. 2011;301:H1781–7.

    CAS  PubMed  Article  Google Scholar 

  138. 138.

    Carr DJ, Wallace JM, Aitken RP, Milne JS, Martin JF, Zachary IC, et al. Peri- and postnatal effects of prenatal adenoviral VEGF gene therapy in growth-restricted sheep. Biol Reprod. 2016;94:142,1–12.

    Article  CAS  Google Scholar 

  139. 139.

    Kumasawa K, Ikawa M, Kidoya H, Hasuwa H, Saito-Fujita T, Morioka Y, et al. Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model. Proc Natl Acad Sci U S A. 2011;108:1451–5.

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    Rejinders D, Liu CC, Xu X, Zhao AM, Olson KN, Butler SD, et al. Celecoxib restores angioogenic factor expression at the maternal-fetal interface in the BPH/5 mouse model of preeclampsia. Physiol Genomics. 2018;50(5):385–92.

    Article  CAS  Google Scholar 

  141. 141.

    Aasa KL, Zavan B, Luna RL, Wong PG, Ventura NM, Tse MY, et al. Placental growth factor influences maternal cardiovascular adaptation to pregnancy in mice. Biol Reprod. 2015;92:44.

    PubMed  Article  CAS  Google Scholar 

  142. 142.

    Kay VR, Rätsep MT, Figueiró-Filho EA, Croy BA. Preeclampsia may influence offspring neuroanatomy and cognitive function: a role for placental growth factor. Biol Reprod. 2019;101:271–83.

    PubMed  Article  Google Scholar 

  143. 143.

    LaMarca BB, Bennett WA, Alexander BT, Cockrell K, Granger JP. Hypertension produced by reductions in uterine perfusion in the pregnant rat: role of tumor necrosis factor–α. Hypertension. 2005;46:1022–5.

    CAS  PubMed  Article  Google Scholar 

  144. 144.

    Gilbert JS, Babcock SA, Granger JP. Hypertension produced by reduced uterine perfusion in pregnant rats is associated with increased soluble fms-like tyrosine kinase-1 expression. Hypertension. 2007;50:1142–7 Epub 2007 Oct 8.

    CAS  PubMed  Article  Google Scholar 

  145. 145.

    Walsh SK, English FA, Johns EJ, Kenny LC. Plasma-mediated vascular dysfunction in the reduced uterine perfusion pressure model of preeclampsia: a microvascular characterization. Hypertension. 2008;54:345–51.

    Article  CAS  Google Scholar 

  146. 146.

    Lin, C, He H, Cui N, Ren Z, Zhu M, Khalil RA. Decreased uterine vascularization and uterine arterial expansive remodeling with reduced matrix metalloproteinase-2 and -9 in hypertensive pregnancy. Am J Physiol Heart Circ Physiol. 2019;318(1):H165–H180.

  147. 147.

    Molnár M, Sütö T, Tóth T, Hertelendy F. Prolonged blockade of nitric oxide synthesis in gravid rats produces sustained hypertension, proteinuria, thrombocytopenia, and intrauterine growth retardation. Am J Obstet Gynecol. 1994;170:1458–66.

    PubMed  Article  Google Scholar 

  148. 148.

    Winship AL, Koga K, Menkhorst E, Van Sinderen M, Rainczuk K, Nagai M, et al. Interleukin–11 alters placentation and causes preeclampsia features in mice. Proc Natl Acad Sci U S A. 2015;112:15928–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. 149.

    Kulandavelu S, Whiteley KJ, Qu D, Mu J, Bainbridge SA, Adamson SL. Endothelial nitric oxide synthase deficiency reduces uterine blood flow, spiral artery elongation, and placental oxygenation in pregnant mice. Hypertension. 2012;60:231–8.

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Cureton N, Kortokova I, Baker B, Greenwood S, Wareing M, Kotamraju VR, et al. Selective targeting of a novel vasodilator to the uterine vasculature to treat impaired uteroplacental perfusion in pregnancy. Theronastics. 2017;7(15):3715–31 eCollection 2017.

    CAS  Article  Google Scholar 

  151. 151.

    Hunkapillar NM, Gasperowicz M, Kapidzic M, Plaks V, Maltepe E, Kitajewski J, et al. A role for Notch signaling in trophoblast endovascular invasion and in the pathogenesis of pre-eclampsia. Development. 2011;138:2987–98.

    Article  CAS  Google Scholar 

  152. 152.

    Doridot L, Passet B, Méhats C, Rigourd V, Barbaux S, Ducat A, et al. Preeclampsia-like symptoms induced in mice by fetoplacental expression of STOX1 are reversed by aspirin treatment. Hypertension. 2013;61:662–8.

    CAS  PubMed  Article  Google Scholar 

  153. 153.

    Greenwood JD, Minhas K, di Santo JP, Makita M, Kiso Y, Croy BA. Ultrastructural studies of implantation sites from mice deficient in uterine natural killer cells. Placenta. 2000;21:693–702.

    CAS  PubMed  Article  Google Scholar 

  154. 154.

    Ashkar AA, Di Santo JP, Croy BA. Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy. J Exp Med. 2000;192:259–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. 155.

    Croy BA, He H, Esadeg S, Wei Q, McCartney D, Zhang J, et al. Uterine natural killer cells: insights into their cellular and molecular biology from mouse modelling. Reproduction. 2003;126:149–60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. 156.

    Monk JM, Leonard S, McBey BA, Croy BA. Induction of murine spiral artery modification by recombinant human interferon-gamma. Placenta. 2005;26:835–8.

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Nadkarni S, Smith J, Sferruzzi-Perri AN, Ledwozyw A, Kishore M, Haas R, et al. Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy. Proc Natl Acad Sci U S A. 2016;113:E8415–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. 158.

    Care AS, Bourque SL, Morton JS, Hjartarson EP, Robertson SA, Davidge ST. Reduction in regulatory T cells in early pregnancy causes uterine dysfunction in mice. Hypertension. 2018;72:177–87.

    CAS  PubMed  Article  Google Scholar 

  159. 159.

    Robertson SA, Care AS, Moldenhauer LM. Regulatory T cells in embryo implantation and the immune response to pregnancy. J Clin Invest. 2018;128:4225–35.

    Article  Google Scholar 

  160. 160.

    Zhou CC, Zhang Y, Irani RA, Zhang H, Mi T, Popek EJ, et al. Angiotensin receptor agnostic autoantibodies induce pre-eclampsia in pregnant mice. Nat Med. 2008;14:855–62 Epub 2008 Jul 27.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161.

    Parrish MR, Murphy SP, Rutland S, Wallace K, Wenzel K, Wallukat G, et al. The effect of immune factors, tumor necrosis factor-alpha, and agonistic autoantibodies to the angiotensin II type I receptor on soluble fms-like tyrosine-1 and soluble endoglin production in response to hypertension during pregnancy. Am J Hypertens. 2010;23:911–6 Epub 2010 Apr 29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. 162.

    Walther T, Jank A, Heringer-Walther S, Horn LC, Stepan H. Angiotensin II type 1 receptor has impact on murine placentation. Placenta. 2008;29:905–9.

    CAS  PubMed  Article  Google Scholar 

  163. 163.

    Geusens N, Hering L, Verlohren S, Luyten C, Drijkoningen K, Taube M, et al. Changes in endovascular trophoblast invasion and spiral artery remodelling at term in a transgenic preeclamptic rat model. Placenta. 2010;31:320–6.

    CAS  PubMed  Article  Google Scholar 

  164. 164.

    Quitterer U, Fu X, Pohl A, Bayoumy KM, Langer A, Abdalla S. Beta-arrestin 1 prevents preeclampsia by downregulation of mechanosensitive AT1-B2 receptor heteromers. Cell. 2019;176:318–333.e19.

    CAS  PubMed  Article  Google Scholar 

  165. 165.

    Albrecht ED, Pepe GJ. Endocrinology of pregnancy. In: Brans YW, Kuehl TJ, editors. Non-human primates in perinatal research. New York: John Wiley and Sons; 1988. p. 13–78.

    Google Scholar 

  166. 166.

    Malassine A, Frendo JL, Evain-Brion D. A comparison of placental development and endocrine functions between the human and mouse model. Hum Reprod Update. 2003;9:531–9.

    CAS  PubMed  Article  Google Scholar 

  167. 167.

    Osol G, Mandala M. Maternal uterine vascular remodeling during pregnancy. Physiology (Bethesda). 2009;24:58–71.

    Google Scholar 

  168. 168.

    McCarthy FP, Kingdom JC, Kenny LC, Walsh SK. Animal models of preeclampsia; uses and limitations. Placenta. 2011;32:413–9.

    CAS  PubMed  Article  Google Scholar 

  169. 169.

    Georgiades P, Ferguson-Smith AC, Burton GJ. Comparative developmental anatomy of the murine and human definitive placentae. Placenta. 2002;23:3–19.

    CAS  PubMed  Article  Google Scholar 

  170. 170.

    Silva JF, Serakides R. Intrauterine trophoblast migration: a comparative view of humans and rodents. Cell Adhes Migr. 2016;10:88–110.

    CAS  Article  Google Scholar 

  171. 171.

    Marshall SA, Hannan NJ, Jelinic M, Nguyen TPH, Girling JE, Parry LJ. Animal models of preeclampsia: translational failings and why. Am J Physiol Regul Integr Comp Physiol. 2018;314:R499–508.

    CAS  PubMed  Article  Google Scholar 

  172. 172.

    Adamson SL, Lu Y, Whiteley KJ, Homyard D, Hemberger M, Pfarrer C, et al. Interactions between trophoblast cells and the maternal and fetal circulation in the mouse placenta. Dev Biol. 2002;250(2):358–73.

    CAS  PubMed  Article  Google Scholar 

  173. 173.

    Schlabritz-Loutsevitch NE, Hubbard GB, Jenkins SL, Martin HC, Snider CS, Frost PA, et al. Ontogeny of hematological cell and biochemical profiles in maternal and fetal baboons (Papio species). J Med Primatol. 2005;34:193–200.

    CAS  PubMed  Article  Google Scholar 

  174. 174.

    Enders AC, Blankenship TN, Fazleabas AT, Jones CJ. Structure of anchoring villi and the trophoblastic shell in the human, baboon and macaque placenta. Placenta. 2001;22:284–303.

    CAS  PubMed  Article  Google Scholar 

  175. 175.

    VandeBerg JL, Williams-Blangero S. Advantages and limitations of nonhuman primates as animal models in genetic research on complex diseases. J Med Primatol. 1997;26:113–9.

    CAS  PubMed  Article  Google Scholar 

  176. 176.

    Cox LA, Mahaney MC, Vandeberg JL, Rogers J. A second-generation genetic linkage map of the baboon (Papio hamadryas) genome. Genomics. 2006;88:274–81.

    CAS  PubMed  Article  Google Scholar 

  177. 177.

    Cavanagh D, Rao PS, Tsai CC, O’Connor TC. Experimental toxemia in the pregnant primate. Am J Obstet Gynecol. 1977;128:75–85.

    CAS  PubMed  Article  Google Scholar 

  178. 178.

    Makris A, Thornton C, Thompson J, Thomson S, Martin R, Ogle R, et al. Uteroplacental ischemia results in proteinuric hypertension and elevated sFLT-1. Kidney Int. 2007;71:977–84.

    CAS  PubMed  Article  Google Scholar 

  179. 179.

    Makris A, Yeung KR, Lim SM, Sunderland N, Heffernan S, Thompson JF, et al. Placental growth factor reduces blood pressure in a uteroplacental ischemia model of preeclampsia in nonhuman primates. Hypertension. 2016;67:1263–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  180. 180.

    Turanov AA, Lo A, Hassler MR, Makris A, Ashar-Patel A, Alterman JF, et al. RNAi modulation of placental sFLT1 for the treatment of preeclampsia. Nat Biotechnol. 2018;36:1164–1173.

  181. 181.

    Bonagura TW, Pepe GJ, Enders AC, Albrecht ED. Suppression of extravillous trophoblast vascular endothelial growth factor expression and uterine spiral artery invasion by estrogen during early baboon pregnancy. Endocrinology. 2008;149:5078–87.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. 182.

    Bonagura TW, Babischkin JS, Aberdeen GW, Pepe GJ, Albrecht ED. Prematurely elevating estradiol in early baboon pregnancy suppresses uterine artery remodeling and expression of extravillous placental vascular endothelial growth factor and α1β1 and α5β1 integrins. Endocrinology. 2012;153:2897–906.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  183. 183.

    Aberdeen GW, Bonagura TW, Harman CR, Pepe GJ, Albrecht ED. Suppression of trophoblast uterine spiral artery remodeling by estrogen during baboon pregnancy: impact on uterine and fetal blood flow dynamics. Am J Physiol Heart Circ Physiol. 2012;302:H1936–44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. 184.

    Babischkin JS, Aberdeen GW, Lindner JR, Bonagura TW, Pepe GJ, Albrecht ED. Vascular endothelial growth factor delivery to placental basal plate promotes uterine artery remodeling in the primate. Endocrinology. 2019;160:1492–505.

    PubMed  PubMed Central  Article  Google Scholar 

  185. 185.

    Aplin JD, Haigh T, Jones CJ, Church HJ, Viovac L. Development of cytrophoblast columns from explanted first trimester human placental villi: role of fibronectin and integrin α5β1. Biol Reprod. 1999;60:828838.

    Article  Google Scholar 

  186. 186.

    Irving JA, Lala PK. Functional role of cell surface integrins on human trophoblast cell migration: regulation by TGFβ, IGF-II, and IGFBP-1. Exp Cell Res. 1995;217:419427.

    Article  Google Scholar 

  187. 187.

    Fukushima K, Miyamoto S, Tsukimori K, Kobayashi H, Seki H, Takeda S, et al. Tumor necrosis factor and vascular endothelial growth factor induce endothelial integrin repertories, regulating endovascular differentiation and apoptosis in a human extravillous trophoblast cell line. Biol Reprod. 2005;73:172–9.

    CAS  PubMed  Article  Google Scholar 

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The authors thank Irene Baranyk, B.A., and Sandra Huband for the computer-assisted preparation of this manuscript.


This work was supported by National Institutes of Health R01 HD 93070 and R01 HD 93946.

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Albrecht, E.D., Pepe, G.J. Regulation of Uterine Spiral Artery Remodeling: a Review. Reprod. Sci. (2020).

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  • Uterine artery remodeling
  • Preeclampsia
  • Animal models