A putative role for telocytes in placental barrier impairment during preeclampsia☆
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)
- et al.
Pathogenesis and genetics of preeclampsia
Lancet
(2001) Current topic: pre-eclampsia and the placenta
Placenta
(1991)- et al.
Preeclampsia is associated with widespread apoptosis of placental cytotrophoblasts within the uterine wall
Am J Pathol
(1999) - et al.
Invasive cytotrophoblasts manifest evidence of oxidative stress in preeclampsia
Am J Pathol
(2000) - et al.
Screening test for preeclampsia through assessment of uteroplacental blood flow and biochemical markers of oxidative stress and endothelial dysfunction
Am J Obstet Gynecol
(2005) Vitamin E and C in preeclampsia
Eur J Obstet Gynecol Reprod Biol
(2000)- et al.
Pathophysiological basis for the prophylaxis of preeclampsia through early supplementation with antioxidant vitamins
Pharmacol Ther
(2005) - et al.
Placental and decidual lipid peroxidation and antioxidant defenses in preeclampsia. Lipid peroxidation in preeclampsia
Pathophysiology
(2002) - et al.
How does superoxide dismutase protect against tumor necrosis factor: a hypothesis informed by effect of superoxide on “free” iron
Free Radic Biol Med
(1997) - et al.
Hypoxia favours necrotic versus apoptotic shedding of placental syncytiotrophoblast into the maternal circulation
Placenta
(2003)
Placental apoptosis in normal human pregnancy
Am J Obstet Gynecol
Apoptosis and its role in the trophoblast
Am J Obstet Gynecol
Placental apoptosis in preeclampsia
Obstet Gynecol
Live and let die – regulation of villous trophoblast apoptosis in normal and abnormal pregnancies
Placenta
Syncytial knots, sprouts, apoptosis, and trophoblast deportation from the human placenta
Taiwan J Obstet Gynecol
Trophoblastic oxidative stress and the release of cell-free feto-placental DNA
Am J Pathol
Ganglionar nervous cells and telocytes in the pancreas of Octodon degus
Auton Neurosci
Alcohol and xenobiotics in placenta damage
Inducible (type II) nitric oxide synthase in human placental villous tissue of normotensive, pre eclamptic and intrauterine growth-restricted pregnancies
Placenta
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
Expression of BCL-2, BAX and BAK trophoblast layer of the term human placenta: a unique model of apoptosis within a syncytium
Placenta
The preterm prediction study: risk factor for indicated preterm births
Am J Obstet Gynecol
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
Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblast
J Clin Invest
Vascular mechanisms of increased arterial pressure in preeclampsia: lessons from animal models
Am J Physiol Regul Integr Comp Physiol
Immunohistochemical expression of von Willebrand factor in the preeclamptic placenta
J Mol Histol
Increased immunohistochemical expression of thrombomodulin at placental perivascular myofibroblast in severe preeclampsia (PE)
Histol Histopathol
Maternal serum soluble vascular endothelial growth factor receptor-1 in early pregnancy ending in preeclampsia or intrauterine growth retardation
J Clin Endocrinol Metab
Oxidative stress in pre-eclampsia
Acta Obstet Gynecol Scand
Oxidative stress in the placenta
Histochem Cell Biol
Oxidative stress and altered endothelial cell function in preeclampsia
Semin Reprod Endocrinol
Placental isoprostane is significantly increased in preeclampsia
FASEB J
Antioxidant activities and mRNA expression of superoxide dismutase, catalase, and glutathione peroxidase in normal and preeclamptic placentas
J Soc Gynecol Investig
BRCA1 induces antioxidant gene expression and resistance to oxidative stress
Cancer Res
Ontogenic profile of some antioxidants and lipid peroxidation in human placental and fetal tissues
Mol Cell Biochem
Antioxidant defenses in the rat placenta in late gestation: increased labyrinthine expression of superoxide dismutases, glutathione peroxidase 3, and uncoupling protein 2
Biol Reprod
Assessment of placental oxidative stress in pre-eclampsia
J Obstet Gynaecol India
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Roles and distribution of telocytes in tissue organization in health and disease
2021, Tissue Barriers in Disease, Injury and RegenerationComprehensive analysis of oxidative stress markers and antioxidants status in preeclampsia
2018, Taiwanese Journal of Obstetrics and GynecologyCitation 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 HypothesesCitation 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 AnatomyCitation 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 BiologyCitation 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].