Elsevier

Medical Hypotheses

Volume 84, Issue 1, January 2015, Pages 72-77
Medical Hypotheses

A putative role for telocytes in placental barrier impairment during preeclampsia

https://doi.org/10.1016/j.mehy.2014.11.019Get rights and content

Abstract

Preeclampsia (PE) is a major health problem occurring in pregnant women and the principal cause of maternal morbidity and perinatal mortality. It is characterized by alteration of the extravilli trophoblast cell migration toward the endometrial spiral arteries with a concomitant reduction in maternal blood flow in the placenta. This result in a state of ischemia–hypoxia which triggers an oxidative stress stage with production of reactive oxygen species. A cascade of cellular and molecular events leads then to endothelial dysfunction, transduction pathway signal disruption and induction of apoptosis and necrosis mechanisms and therefore a significant reduction in the amount of nutrients required for normal fetal development. Placental anchoring chorionic and stem villi present a skeleton of myofibroblasts arranged in parallel disposition to its longitudinal axis. The intraplacental blood volume is controlled by the contraction/relaxation of these myofibroblasts, promoting the delivery of nutrients and metabolites to the fetus. Recently, a new mesodermal originated cell type has been described in the villous stroma, the so named “telocytes”. These cells are strategically located between the smooth muscle cells of the blood vessel wall and the myofibroblasts, and it is reasonable to hypothesize that they may play a pacemaker role, as in the intestine. This study provide new information supporting the notion that the occurrence of oxidative stress in PE is not only related to endothelial dysfunction and apoptosis of the trophoblast cells, but also involves telocytes and its putative role in the regulation of fetal blood flow and the intra-placental blood volume. Some ideas aimed at dilucidating the relationship between placental failure and the behavior of telocytes in pathological organs in adulthood, are also discussed.

Introduction

It is widely known that PE is a clinical syndrome that represents one of the major causes of maternal morbidity and fetal mortality in pregnancy. The incidence of this condition varies between 4% and 6% of the world population of pregnant women [1]. Affected women also present hypertension, proteinuria and edema [2], and those who have shown no previous signs of hypertension, develop this symptoms by the 20th week of pregnancy. These signs disappear after childbirth and the delivery of the placenta and, so far, the only treatment for PE consists in the termination of pregnancy [3], [4]. The pathogenesis of PE has not been determined with certainty, although it is currently accepted that the syndrome would be triggered by some factors produced by the placenta [2].

PE is associated with a reduction of the utero-placental perfusion pressure, which leads to ischemia/hypoxia in the organ, which develops from the third trimester of pregnancy. The ischemia/hypoxia would be consequence of a failure in the migration of the extravilli trophoblast (EVT), during placentation, an event that takes place in the first trimester of pregnancy. EVT migration allows the replacement of both the endothelium and the muscle layer of the spiral arteries in the endometrium. By this mechanism, these vessels acquire high capacitance and low resistance, thus favoring flow of maternal blood to the placenta intervillous space [5], [6], [7]. Failure in EVT migration can increase the resistance of the blood vessels [8], [9], [10] producing placental ischemia/hypoxia that induces the release, towards the intervillous space, of a number of placental factors that will activate a cascade of cellular and molecular events that ultimately will produce dysfunctions in the endothelial wall and the smooth muscle cells of the blood vessel walls [11]. The same endothelial dysfunction has been described in cases of fetal growth restriction (IUGR), a fact that supports the hypotheses that both PE and IUGR share a common vascular etiology [9], [12].

Section snippets

Placental oxidative stress

Oxidative stress is consequence of an imbalance between excessive generation of reactive oxygen species (ROS) and the reduction of the antioxidant capacity; in other words, biological systems develop an inability to neutralize these molecules [13], [14]. The production of ROS in the placenta [13], [15], [16] is particularly relevant since this is a highly vascular organ with large numbers of mitochondria [17], adding the presence of organ-specific macrophages or Hofbauer cells [18]. The

Hypotheses

In this context, we propose that the apoptosis experienced by placental telocytes in PE would be related to the failure of its pacemaker function that modulates the contraction/relaxation of chorionic villi in the intervillous space as well as the blood flow to the fetus.

Evaluation of the hypotheses and results

In order to validate this hypotheses, we are analyzing a number of data already provided in the literature and complemented it with observations and findings from preliminary studies at immunohistochemical and transmission electron microscopy (TEM) level, performed at our lab.

Discussion and conclusions

Regarding the preliminary results communicated here, it is important to mention that Caspase 3 is implicated in the cleavage of various cellular components and the morphological changes associated to apoptosis [36]. In PE placenta we have found an intense immunohistochemical expression of the anti-active caspase-3 monoclonal antibody, displaying intense mark in the cytotrophoblast layer, endothelium and telocytes (Fig. 1A and B). This data are in the same direction of the study of Cobellis et

Conflict of interest statement

None.

Acknowledgments

This review was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT), grant 1090245.

References (74)

  • S.C. Smith et al.

    Placental apoptosis in normal human pregnancy

    Am J Obstet Gynecol

    (1997)
  • B. Huppertz et al.

    Apoptosis and its role in the trophoblast

    Am J Obstet Gynecol

    (2006)
  • A.D. Allaire et al.

    Placental apoptosis in preeclampsia

    Obstet Gynecol

    (2000)
  • A.E. Heazell et al.

    Live and let die – regulation of villous trophoblast apoptosis in normal and abnormal pregnancies

    Placenta

    (2008)
  • G.J. Burton et al.

    Syncytial knots, sprouts, apoptosis, and trophoblast deportation from the human placenta

    Taiwan J Obstet Gynecol

    (2009)
  • M.L. Tjoa et al.

    Trophoblastic oxidative stress and the release of cell-free feto-placental DNA

    Am J Pathol

    (2006)
  • C. Bosco et al.

    Ganglionar nervous cells and telocytes in the pancreas of Octodon degus

    Auton Neurosci

    (2013)
  • C. Bosco

    Alcohol and xenobiotics in placenta damage

  • L. Myatt et al.

    Inducible (type II) nitric oxide synthase in human placental villous tissue of normotensive, pre eclamptic and intrauterine growth-restricted pregnancies

    Placenta

    (1997)
  • F. Lyall et al.

    Placental expression of vascular endothelial growth factors in placentae from pregnancies complicated by pre-eclampsia and intrauterine growth restriction does not support placental hypoxia at delivery

    Placenta

    (1997)
  • V.S. Ratts et al.

    Expression of BCL-2, BAX and BAK trophoblast layer of the term human placenta: a unique model of apoptosis within a syncytium

    Placenta

    (2000)
  • P.J. Meiss et al.

    The preterm prediction study: risk factor for indicated preterm births

    Am J Obstet Gynecol

    (1998)
  • M. Parra-Cordero et al.

    Prediction of early and late pre-eclampsia from maternal characteristics, uterine artery Doppler and markers of vasculogenesis during first trimester of pregnancy

    Ultrasound Obstet Gynecol

    (2013)
  • Y. Zhou et al.

    Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblast

    J Clin Invest

    (1993)
  • R.A. Khalil et al.

    Vascular mechanisms of increased arterial pressure in preeclampsia: lessons from animal models

    Am J Physiol Regul Integr Comp Physiol

    (2002)
  • M. Parra-Cordero et al.

    Immunohistochemical expression of von Willebrand factor in the preeclamptic placenta

    J Mol Histol

    (2011)
  • C. Bosco et al.

    Increased immunohistochemical expression of thrombomodulin at placental perivascular myofibroblast in severe preeclampsia (PE)

    Histol Histopathol

    (2005)
  • K.A. Wathén 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)
  • R.S. Bowen et al.

    Oxidative stress in pre-eclampsia

    Acta Obstet Gynecol Scand

    (2001)
  • L. Myatt et al.

    Oxidative stress in the placenta

    Histochem Cell Biol

    (2004)
  • S.T. Davidge

    Oxidative stress and altered endothelial cell function in preeclampsia

    Semin Reprod Endocrinol

    (1998)
  • S.W. Walsh et al.

    Placental isoprostane is significantly increased in preeclampsia

    FASEB J

    (2000)
  • Y. Wang et al.

    Antioxidant activities and mRNA expression of superoxide dismutase, catalase, and glutathione peroxidase in normal and preeclamptic placentas

    J Soc Gynecol Investig

    (1996)
  • I. Bae et al.

    BRCA1 induces antioxidant gene expression and resistance to oxidative stress

    Cancer Res

    (2004)
  • S. Qanungo et al.

    Ontogenic profile of some antioxidants and lipid peroxidation in human placental and fetal tissues

    Mol Cell Biochem

    (2000)
  • M.L. Jones et al.

    Antioxidant defenses in the rat placenta in late gestation: increased labyrinthine expression of superoxide dismutases, glutathione peroxidase 3, and uncoupling protein 2

    Biol Reprod

    (2010)
  • B. Das et al.

    Assessment of placental oxidative stress in pre-eclampsia

    J Obstet Gynaecol India

    (2012)
  • Cited by (35)

    • Roles and distribution of telocytes in tissue organization in health and disease

      2021, Tissue Barriers in Disease, Injury and Regeneration
    • Comprehensive analysis of oxidative stress markers and antioxidants status in preeclampsia

      2018, Taiwanese Journal of Obstetrics and Gynecology
      Citation Excerpt :

      It is proposed that oxidative stress, defined as oxidant-antioxidant imbalance, is implicated in the pathophysiology of preeclampsia. Various studies have focused on the role of oxidative stress in preeclamptic women, in whom placental tissue demonstrated to produce high levels of superoxide as compared to normal pregnant women [19,20]. Normally, oxidative stress occurs in normal healthy pregnant women compared with non-pregnant women, but reactive free radicals is further raised in preeclampsia.

    • Recently discovered interstitial cells “telocytes” as players in the pathogenesis of uterine leiomyomas

      2018, Medical Hypotheses
      Citation Excerpt :

      This disruption of normal telocytes physiology is commonly described in terms of their ultrastructure, quantitative changes and modification of their topographical relations with surrounding cells and extracellular components. Focusing on the female reproductive system, dysfunction of telocytes is associated with the pathogenesis of tubal infertility [3,4], endometriosis [5], premature ovarian failure [6], or preeclampsia [7,8]. Several works have been published recently, implying telocytes’ dysfunction as one of the key factors also in tumorigenesis [9–11].

    • Subsets of telocytes: Myocardial telocytes

      2017, Annals of Anatomy
      Citation Excerpt :

      A previous TEM study of the oral mucosa showed that telopodes of TCs and filopodia of ETCs are morphologically similar; are both located in the connective stroma; and should be carefully distinguished between (Rusu et al., 2013a); this is easy even in light microscopy; as we have shown in this study in which we found ETCs filopodia “embracing” muscle fibers (see inset in Fig. 5). Therefore; although TCs are considered to belong to the mesodermal/mesenchymal lineage (Bosco et al., 2015); this may not be exclusive; a subset of these belonging in fact to the endothelial lineage. A positive diagnosis for cardiac ETCs and filopodia in light microscopy is difficult.

    • Telocytes in the reproductive organs: Current understanding and future challenges

      2016, Seminars in Cell and Developmental Biology
      Citation Excerpt :

      Moreover, cells respecting TCs morphology in cell cultures were found to co-express c-kit, vimentin, and caveolin-1 (about 13%), whilst 70% of the c-kit-positive cells co-expressed CD34 and 12% co-expressed iNOS or VEGF [59]. In 2015, Bosco et al., postulated – based on previous assumption of Suciu et al. – that TCs might play a role in the regulation of foetal blood flow and intraplacental blood volume - that alteration of placental TCs in preeclampsia may be due to the shrinkage and shortening of Tps as a forerunner of apoptosis and as a consequence of oxidative stress, resulting in placental barrier impairment [60]. She also suggested that TCs as hypothetic care-takers of foetal vessels blood flow and of the shortening/lengthening of the chorionic villi, are exposed and affected to hypoxia developed during preeclampsia and as a consequence suffer apoptosis contributing to alteration of maternal-fetus metabolic exchanges [61].

    View all citing articles on Scopus

    Grants: This review was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT), Grant 1090245.

    View full text