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New insights into the role of placental aquaporins and the pathogenesis of preeclampsia
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Abstracts / Placenta 36 (2015) 469e521
K11. NEW INSIGHTS INTO THE ROLE OF PLACENTAL AQUAPORINS AND THE PATHOGENESIS OF PREECLAMPSIA Szpilbarg Natalia 1, Reca Alejandra 1, Castro-Parodi Mauricio 1, Martínez n, Nora 2, Alicia E. Damiano 1. 1 Laboratorio de Biología de la Reproduccio gicas, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Biolo IFIBIO-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina; 2 Laboratorio de Fisiopatología Placentaria, CEFyBO-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina Preeclampsia is a pregnancy complication characterized by hypertension and proteinuria. Although its etiology is unknown, it is considered as a two-stage disorder. In the first stage, the reduced placental perfusion in some but not all women, could lead to the second stage where the maternal multisystem disorder is established. However, what links both stages is not determined yet. Since the placenta plays a central role in this syndrome, alterations in placental functions may contribute to the pathogenesis of preeclampsia. Accumulated evidence suggests that the expression of a variety of syncytiotrophoblast transporters is reduced or abnormal in preeclamptic placentas. In this regard, we have previously reported that the expression of aquaporins (AQPs) is altered. AQPs are involved not only in several physiological processes but also in multiple and diverse clinical dysfunctions. In other tissues, it has been proposed that AQPs may participate in cell migration/invasion processes. Therefore, we evaluated the association of AQPs with these events during placentation. Our results showed that inhibition of AQPs significantly reduced the migration and invasion of trophoblast cells. Thus, we proposed that abnormal expression of these proteins might lead to a shallow trophoblast invasion characteristic of preeclamptic placentas. Consequently, placentation takes place under fluctuations of oxygen tension, which are believed to be a potent stimulus for trophoblast apoptosis. Although apoptosis increases progressively throughout pregnancy, it is exacerbated in preeclamptic placentas. Recently, we have established that intermittent hypoxia alters placental AQPs expression and increases the apoptosis of the trophoblast. Even more, we found that the blocking of placental AQPs abrogated these processes, suggesting that AQPs may also have a role in apoptosis. In conclusion, we propose that the abnormal expression of placental AQPs, at early stages of pregnancy, may produce failures in placentation, resulting in an increase of trophoblast apotosis, which finally triggers the clinical manifestations of preeclampsia.
K12. THE FETAL HYPOXIC ENVIRONMENT OF GDM ALTERS VEGF AND FGF2 RECEPTORS IN THE VENOUS BUT NOT ARTERIAL FETO-PLACENTAL VASCULATURE 1
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U. Hiden , Y.E. Sommer , E. Wohlfahrter , I. Lang , C. Wadsack , G. Desoye 1. 1 Department of Obstetrics and Gynecology, Medical University Graz, Austria; 2 Institute of Cell Biology, Histology and Embryology, Medical University Graz, Austria Objective: Gestational diabetes (GDM) causes chronic fetal hypoxia. The VEGF and FGF2 growth factor systems are key regulators of angiogenesis and endothelial growth, and are responsive to hypoxia. Therefore, we here hypothesized that GDM alters VEGF and FGF2 system levels in the fetoplacental vasculature and thus contributes to feto-placental vascular changes associated with this metabolic disorder. Methods: Placental chorionic arteries and veins were resected from term placentas after normal (N¼12) and GDM (N¼12) pregnancies. The expression of the VEGF and FGF2 system components was quantified (RTqPCR). Expression levels were correlated to maternal clinical data. Furthermore, the effect of different oxygen concentrations (1, 5, 12 and 21%) on VEGF and FGF2 receptor expression was analyzed in vitro using isolated primary venous and arterial feto-placental endothelial cells.
Results: GDM upregulated the VEGF receptors FLT1 and KDR, and the FGF2 receptors FGFR1 and FGFR2 in feto-placental veins, but not in arteries. VEGF and FGF2 were unchanged in both parts of the vasculature. In veins from normal pregnancy, FLT1 expression positively correlated with maternal pre-pregnancy body mass index, while FGFR1 and FGFR2 negatively correlated with cord blood pH, a parameter reflecting blood oxygenation. These correlations disappeared in the GDM group. In parallel to the in vivo results, hypoxia increased expression of VEGF- and FGF2receptors in primary venous, but not arterial feto-placental endothelial cells in vitro. Conclusion: GDM alters the venous feto-placental VEGF and FGF2 system in a similar manner as hypoxia. Upregulation of VEGF and FGF2 receptors may contribute to feto-placental vascular changes observed in GDM. SYMPOSIUM PRESENTATIONS. S1. EXPLORING THE PATHOPHYSIOLOGY OF GESTATIONAL DIABETES: MANY QUESTIONS STILL UNANSWERED ~o Paulo, Silvia Daher. Department of Obstetrics, Universidade Federal de Sa ~o Paulo, Brazil Sa Gestational Diabetes Mellitus (GDM),the most common endocrine disorder that occurs in pregnancy, has a strong association with maternal obesity. Low-grade inflammation and insulin resistance are part of the physiological adaptative phenomena of normal pregnancies but in GDM and in obese patients these two processes seem to be exacerbated. Adiponectin, leptin, resistin, TNF-A, IL-6 and IL-10, substances produced by the placenta and adipose tissue, are the main mediators involved in insulin resistance in pregnancy. Therefore, it has been proposed that an imbalanced production of these factors might be involved in the pathophysiology of GDM and maternal obesity. Although some reports confirm these associations, controversies remain and the role of these adipokines in the pathophysiology of GDM is still unclear. Another relevant issue yet to be explored is the role of genetic factors in this interaction, which could be fundamental in helping to understand why most obese women have normal, uneventful pregnancies, while only a small percentage of them develop GDM and also why some lean women, without any significant risk factors, go on to develop GDM. Studies that analyzed inflammatory gene polymorphisms in GDM patients with different BMIs have reported controversial results. In order to clarify these aspects, we have searched for phenotype and genotype markers associated with a successful pregnancy outcome or with GDM in obese women. In this context, we are looking at various molecules and snps related to the most important inflammatory and anti-inflammatory cytokines, and also to adipokines. Despite some important correlations, it is still unclear which are the markers related to good pregnancy outcomes in obese women. It is very likely that obese women develop GDM as a consequence of the interaction between genetic and epigenetic factors.
S2. EXTRACELLULAR MATRIX REMODELING PLACENTA OF TYPE 1 DIABETIC MICE
IN
THE
DECIDUA
AND
Rodolfo R. Favaro 1, Juliane T. Sanches 1, Fernanda A. Barrence 1, Estela Bevilacqua 1, Zuleica B. Fortes 2, Telma M.T. Zorn 1. 1 Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of ~o Paulo, Sa ~o Paulo, Brazil; 2 Department of Pharmacology, Institute of Sa ~o Paulo, Sa ~o Paulo, Brazil Biomedical Sciences, University of Sa Diabetic pregnancies are characterized by increased rates of miscarriage/ stillbirth, malformations and intrauterine growth restriction, whose causes remain, to a great extent, unknown. To expand the knowledge on this field, our group has established a mouse model of pregnancy complicated by long-term type 1 diabetes. Through the analysis of females bred at different periods after diabetes induction (D) by alloxan, we addressed the influence of diabetes progression on the development of pregnancy complications. At early pregnancy, long-term diabetes (90-110D) decreased the number of implantation sites and decidual dimensions, whereas no changes in these
Abstracts / Placenta 36 (2015) 469e521
K11. NEW INSIGHTS INTO THE ROLE OF PLACENTAL AQUAPORINS AND THE PATHOGENESIS OF PREECLAMPSIA Szpilbarg Natalia 1, Reca Alejandra 1, Castro-Parodi Mauricio 1, Martínez n, Nora 2, Alicia E. Damiano 1. 1 Laboratorio de Biología de la Reproduccio gicas, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Biolo IFIBIO-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina; 2 Laboratorio de Fisiopatología Placentaria, CEFyBO-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina Preeclampsia is a pregnancy complication characterized by hypertension and proteinuria. Although its etiology is unknown, it is considered as a two-stage disorder. In the first stage, the reduced placental perfusion in some but not all women, could lead to the second stage where the maternal multisystem disorder is established. However, what links both stages is not determined yet. Since the placenta plays a central role in this syndrome, alterations in placental functions may contribute to the pathogenesis of preeclampsia. Accumulated evidence suggests that the expression of a variety of syncytiotrophoblast transporters is reduced or abnormal in preeclamptic placentas. In this regard, we have previously reported that the expression of aquaporins (AQPs) is altered. AQPs are involved not only in several physiological processes but also in multiple and diverse clinical dysfunctions. In other tissues, it has been proposed that AQPs may participate in cell migration/invasion processes. Therefore, we evaluated the association of AQPs with these events during placentation. Our results showed that inhibition of AQPs significantly reduced the migration and invasion of trophoblast cells. Thus, we proposed that abnormal expression of these proteins might lead to a shallow trophoblast invasion characteristic of preeclamptic placentas. Consequently, placentation takes place under fluctuations of oxygen tension, which are believed to be a potent stimulus for trophoblast apoptosis. Although apoptosis increases progressively throughout pregnancy, it is exacerbated in preeclamptic placentas. Recently, we have established that intermittent hypoxia alters placental AQPs expression and increases the apoptosis of the trophoblast. Even more, we found that the blocking of placental AQPs abrogated these processes, suggesting that AQPs may also have a role in apoptosis. In conclusion, we propose that the abnormal expression of placental AQPs, at early stages of pregnancy, may produce failures in placentation, resulting in an increase of trophoblast apotosis, which finally triggers the clinical manifestations of preeclampsia.
K12. THE FETAL HYPOXIC ENVIRONMENT OF GDM ALTERS VEGF AND FGF2 RECEPTORS IN THE VENOUS BUT NOT ARTERIAL FETO-PLACENTAL VASCULATURE 1
1
1
2
1
U. Hiden , Y.E. Sommer , E. Wohlfahrter , I. Lang , C. Wadsack , G. Desoye 1. 1 Department of Obstetrics and Gynecology, Medical University Graz, Austria; 2 Institute of Cell Biology, Histology and Embryology, Medical University Graz, Austria Objective: Gestational diabetes (GDM) causes chronic fetal hypoxia. The VEGF and FGF2 growth factor systems are key regulators of angiogenesis and endothelial growth, and are responsive to hypoxia. Therefore, we here hypothesized that GDM alters VEGF and FGF2 system levels in the fetoplacental vasculature and thus contributes to feto-placental vascular changes associated with this metabolic disorder. Methods: Placental chorionic arteries and veins were resected from term placentas after normal (N¼12) and GDM (N¼12) pregnancies. The expression of the VEGF and FGF2 system components was quantified (RTqPCR). Expression levels were correlated to maternal clinical data. Furthermore, the effect of different oxygen concentrations (1, 5, 12 and 21%) on VEGF and FGF2 receptor expression was analyzed in vitro using isolated primary venous and arterial feto-placental endothelial cells.
Results: GDM upregulated the VEGF receptors FLT1 and KDR, and the FGF2 receptors FGFR1 and FGFR2 in feto-placental veins, but not in arteries. VEGF and FGF2 were unchanged in both parts of the vasculature. In veins from normal pregnancy, FLT1 expression positively correlated with maternal pre-pregnancy body mass index, while FGFR1 and FGFR2 negatively correlated with cord blood pH, a parameter reflecting blood oxygenation. These correlations disappeared in the GDM group. In parallel to the in vivo results, hypoxia increased expression of VEGF- and FGF2receptors in primary venous, but not arterial feto-placental endothelial cells in vitro. Conclusion: GDM alters the venous feto-placental VEGF and FGF2 system in a similar manner as hypoxia. Upregulation of VEGF and FGF2 receptors may contribute to feto-placental vascular changes observed in GDM. SYMPOSIUM PRESENTATIONS. S1. EXPLORING THE PATHOPHYSIOLOGY OF GESTATIONAL DIABETES: MANY QUESTIONS STILL UNANSWERED ~o Paulo, Silvia Daher. Department of Obstetrics, Universidade Federal de Sa ~o Paulo, Brazil Sa Gestational Diabetes Mellitus (GDM),the most common endocrine disorder that occurs in pregnancy, has a strong association with maternal obesity. Low-grade inflammation and insulin resistance are part of the physiological adaptative phenomena of normal pregnancies but in GDM and in obese patients these two processes seem to be exacerbated. Adiponectin, leptin, resistin, TNF-A, IL-6 and IL-10, substances produced by the placenta and adipose tissue, are the main mediators involved in insulin resistance in pregnancy. Therefore, it has been proposed that an imbalanced production of these factors might be involved in the pathophysiology of GDM and maternal obesity. Although some reports confirm these associations, controversies remain and the role of these adipokines in the pathophysiology of GDM is still unclear. Another relevant issue yet to be explored is the role of genetic factors in this interaction, which could be fundamental in helping to understand why most obese women have normal, uneventful pregnancies, while only a small percentage of them develop GDM and also why some lean women, without any significant risk factors, go on to develop GDM. Studies that analyzed inflammatory gene polymorphisms in GDM patients with different BMIs have reported controversial results. In order to clarify these aspects, we have searched for phenotype and genotype markers associated with a successful pregnancy outcome or with GDM in obese women. In this context, we are looking at various molecules and snps related to the most important inflammatory and anti-inflammatory cytokines, and also to adipokines. Despite some important correlations, it is still unclear which are the markers related to good pregnancy outcomes in obese women. It is very likely that obese women develop GDM as a consequence of the interaction between genetic and epigenetic factors.
S2. EXTRACELLULAR MATRIX REMODELING PLACENTA OF TYPE 1 DIABETIC MICE
IN
THE
DECIDUA
AND
Rodolfo R. Favaro 1, Juliane T. Sanches 1, Fernanda A. Barrence 1, Estela Bevilacqua 1, Zuleica B. Fortes 2, Telma M.T. Zorn 1. 1 Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of ~o Paulo, Sa ~o Paulo, Brazil; 2 Department of Pharmacology, Institute of Sa ~o Paulo, Sa ~o Paulo, Brazil Biomedical Sciences, University of Sa Diabetic pregnancies are characterized by increased rates of miscarriage/ stillbirth, malformations and intrauterine growth restriction, whose causes remain, to a great extent, unknown. To expand the knowledge on this field, our group has established a mouse model of pregnancy complicated by long-term type 1 diabetes. Through the analysis of females bred at different periods after diabetes induction (D) by alloxan, we addressed the influence of diabetes progression on the development of pregnancy complications. At early pregnancy, long-term diabetes (90-110D) decreased the number of implantation sites and decidual dimensions, whereas no changes in these