Fetal and maternal blood circulation in mature placenta and diabetes

Villous development is dependent on the processes of vasculogenesis and angiogenesis. During vasculogenesis, mesenchymal stem cells differentiate and form endothelial cell cords, which develop into fetal capillaries. Once the capillary network has formed, the sprouting and elongation of existing vessels occurs via angiogenesis.

Close modal Several pro- and anti-angiogenic factors are responsible for regulating angiogenesis and vascular development in the placenta. Similarly, fibroblast growth factors FGFs are highly abundant in the placenta and are known to be important in trophoblast migration, self-renewal, and invasion.

Particularly, FGF2 is known to play a significant role in placental angiogenesis and placental vascular growth throughout gestation. In several complications of pregnancy, including gestational diabetes GDM , there is villous immaturity and changes to placental vascularization and endothelial dysfunction are observed. This placental vascular dysfunction can compromise nutrient and waste exchange between the mother and the fetus, leading to placental insufficiency, where the placenta cannot fully support the developing fetus.

Gestational diabetes GDM is one of the most common complications of otherwise healthy pregnancies, in which women without pre-existing diabetes develop a state of chronic hyperglycaemia during pregnancy. There are a plethora of peri-natal complications that arise in poorly controlled GDM; most notably, infants can be born large for gestational age LGA , predisposing to multiple difficulties during birth including shoulder dystocia, newborn asphyxia, and requirement for an emergency Caesarean section.

Furthermore, infants born to GDM mothers also have a higher prevalence of respiratory distress syndrome due to hyperglycaemia-induced delay in fetal lung maturation. There is also the risk of neonatal hypoglycaemia, which can be easily rectified, but failure to diagnose promptly can produce seizures and rarely fatality.

In addition to the short-term consequences, exposure to a GDM environment in utero is associated with several biochemical alterations in the fetus that elevates long-term cardiometabolic risks for baby, indicating the public health burden of this condition may extend beyond our initial expectations. Aside from this, these women are also at a twofold high risk of cardiovascular events post-partum than mothers without GDM, regardless of their diabetes status.

Comparative to the available information on peri-natal complications, the mechanisms by which these long-term maternal and fetal cardiometabolic complications arise are not fully understood. However, it is thought to link to biochemical alterations in the placenta. The distinct association between GDM pregnancies and transgenerational metabolic disease proposes that the epigenetic alterations observed in type 2 diabetes mellitus may occur in mothers with GDM.

In turn, alterations may cross the placenta and induce fetal epigenetic changes. Placental vascular dysfunction in GDM Due to the constituently active placental growth and the mediation of angiogenesis by multiple complex biological processes, the placenta is very vulnerable to alteration in maternal and fetal metabolic function.

Principally, in women with poorly controlled GDM the placenta has several changes, particularly in the vasculature. Microscopic analysis revealed vascular morphological changes of fibrinoid necrosis and villous oedema. Furthermore, several studies have reported hypervascularization in GDM placentas, whereas others have reported hypovascularization.

These contradicting findings on placental vascularization in GDM are likely a result of other underlying factors, such as maternal obesity or levels of glycaemic control achieved or, of particular note, the degree of endothelial dysfunction. Molecular and biochemical pathways responsible for endothelial dysfunction in GDM Whilst the exact underlying molecular pathways of hyperglycaemia-induced complications in GDM are unclear, patients with diabetes outside of pregnancy display endothelial dysfunction which is partially responsible for elevating their cardiometabolic disease risk.

Endothelial dysfunction is characterized by an imbalance in the endothelium-derived vasodilating and vasoconstricting factors, thus predisposing to hypertension and atherosclerosis. To determine the presence of this association in GDM, human umbilical vein endothelial cells HUVECs were exposed to the chronic hyperglycaemia of GDM and have been seen to consequently display insulin insensitivity.

Autoantibody-mediated complement C3a receptor activation contributes to the pathogenesis of preeclampsia. Hypertension, 60 3 , Kalkanli et al. Using histopathology they found an increase in hyperplasia and hyalinization in syncytial nodules and stromal cells of the placenta. They also detected a positive reaction of CD34 in immunohistochemical studies of the chorionic villi, placenta, and hematopoietic stem cells.

At ultrastructural level they detected dilation of the endoplasmic reticulum, mitochondrial degeneration in the endothelial cells, and edema of the capillary vessels. CD34 expression of chorionic villous in pre-eclamptic placenta: an immunohistochemical and ultrastructural study. Yamaleyeva et al. Although it was established that its action is not as yet well known, due to the expression of multiple forms of the peptide, the study authors managed to establish by radioimmunoassay its expression in the chorionic villi of pregnant women with preeclampsia and normal pregnant women at 36 to 38 weeks of gestation.

They established the expression of a smaller amount of apelin in human placental chorionic villi in patients with preeclampsia, with Pyr1 -apelin being the predominant form of endogenous apelin in the chorionic villi of normal pregnancies and with preeclampsia. The potential mechanism of lower apelin expression in the chorionic villi of pregnancies with preeclampsia may imply a negative regulation of apelin by angiotensin II.

Downregulation of apelin in the human placental chorionic villi from preeclamptic pregnancies. According to the review, these alterations are related to an oxygenation deficiency in the fetus, changes in the transplacental transport of nutrients and other alterations that cause fetal overgrowth by increasing their availability, and other consequences to the developing fetus. High blood pressure during pregnancy produces accelerated maturation and rapid aging of the chorionic villi with the risk of inducing a placental abruption.

In addition, placental circulation is reduced by a third, decreasing oxygen saturation in the umbilical vessels and placing the health of the fetus at risk. The two pathologies are frequently associated in the same pregnancy. Links Ashfaq, M. Effect of gestational diabetes and maternal hypertension on gross morphology of placenta. Abbottabad, 17 1 , Links Asmussen, I. Ultrastructure of the villi and fetal capillaries of the placentas delivered by non-smoking diabetic women White group D.

Acta Pathol. A, 90 2 , Links Bastos Aires, M. Effects of maternal diabetes on trophoblast cells. World J. Diabetes, 6 2 , The impact of insulin treatment on the expression of vascular endothelial cadherin and Beta-catenin in human fetoplacental vessels. Links Beauharnais, C. High rate of placental infarcts in type2 compared with type 1 diabetes. Links Bernirschke, K. Pathology of the Human Placenta. Nueva York, Springer-Verlag, Links Blackburn, S.

Prenatal Period and Placental Physiology. Maryland Heights, Saunders, Links Carlson, B. Ann Arbour, Elsevier, Salud Univ. Carabobo, 8 3 , Links Correa, R. Links Daskalakis, G. Placental pathology in women with gestational diabetes. Acta Obstet. Links Evers, I. Placental pathology in women with type 1 diabetes and in a control group with normal and large for gestational age infants. Placenta, 24 , Links George, E.

Placental ischemia induces changes in gene expression in chorionic tissue. Genome, 25 56 , Links Grigoriadis, C. Hofbauer cells morphology and density in placentas from normal and pathological gestations. Links Higgins, M. Clinical associations with a placental diagnosis of delayed villous maturation: a retrospective study. Links Huppertz, B. The anatomy of the normal placenta. Links Huynh, J.

A systematic review of placental pathology in maternal diabetes mellitus. Placenta, 36 2 , Links Janthanaphan, M. Placental weight and its ratio to birth weight in normal pregnancy at Songkhlanagarind Hospital.

Links Jawerbaum, A. Diabetic pregnancies: the challenge of developing in a pro-inflammatory environment. Links Jirkovska, M. Comparison of the thickness of the capillary basement membrane of the human placenta under normal conditions and in type 1 diabetes. Three-dimensional arrangement of the capillary bed and its relationship to microrheology in the terminal villi of normal term placenta. Placenta, 29 10 , Topological properties and spatial organization of villous capillaries in normal and diabetic placentas.

Links Kalkanli, S. Links Karlsson, K. Blood flow of reproductive system in renal hypertensive rats during pregnancy.

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The placenta is the critical organ mediating all communications between mother and fetus, and thus must be involved in the effects of maternal diabetes on offspring [ 15 ]. Functional changes occurring in response to maternal diabetes include reduced fatty acid oxidation, impaired mitochondrial function, and increased production of reactive oxygen species [ 16 , 17 ]. Abnormal placental function could in turn affect nutrient transfer and alter the constituency of bio-active molecules released into the fetal circulation, ultimately affecting fetal growth and predisposing offspring to metabolic disease in later life [ 18 — 20 ].

Furthermore, sexual dimorphism in structure, function [ 21 ] and gene expression [ 22 ] in human placenta has been shown, suggesting that sex-specific placental responses and adaptation may mediate certain fetal sex-associated differences. Research Design and Methods Subjects for Placenta Samples Placental samples were obtained from self-identified Native American and Hispanic women with gestational diabetes GDM , pregestational type 2 diabetes, or with normoglycemic pregnancies.

Mothers and offspring were enrolled into a prospective longitudinal study on the impact of in utero exposure to diabetes, as previously described [ 27 ]. Gestational and type 2 diabetes in the mothers was diagnosed according to ADA guidelines [ 28 ].

Women were excluded if the infants were small for gestational age, had a major malformation, or chromosome abnormality. They also were excluded if they delivered prior to 37 weeks gestation, had type 1 diabetes, pre-eclampsia, chronic hypertension, renal disorders or a smoking history of more than 5 cigarettes per day during pregnancy. Maternal fasting blood glucose concentrations before the fasting oral glucose tolerance tests were obtained retrospectively from medical records.

Placentae Dissection Term placentae were dissected as soon as possible after delivery, generally within one hour, and processed as previously described [ 23 ]. An approximately three cm diameter core was obtained by cutting from the fetal surface down through the maternal surface. The core was cut into thirds such that one-third was fetal-side tissue, one-third was maternal-side tissue and the other the middle third.

Previous findings suggested that increased oxidative stress 19 , endothelial dysfunction 20 , 21 and angiogenic imbalance 20 , 22 were altered in both GDM and PE. GDM and PE share several risk factors, including advanced maternal age, nulliparity, twin pregnancy, ethnicity and pre-pregnancy obesity 23 , GDM itself is a risk factor for PE and viceversa 25 , 26 , 27 , 28 , Results Study population Clinical features of the study population are reported in Table 1. A slight increase of fibrinogen levels is reported in GDM Table 1 Clinical features of the study population.

Gestational ages at maternal blood collection are comparable between CTRL Discussion GDM and PE pregnancies share some pathognomonic anomalies, including endothelial dysfunction and angiogenic imbalance. There are increased evidences for the role of placental angiogenic biomarkers in predicting obstetrical complications associated with placental dysfunction 37 , 38 , However, there are limited data on angiogenic factors in GDM patients.

Since it has been described that sFlt1 and PlGF alterations appear before clinical signs 18 , 35 , they may serve as important PE predictive markers to alert clinicians to increase GDM patients monitoring. Since the placenta is the main source of circulating pro- and anti-angiogenic molecules during pregnancy 36 , we suggested that in CKD pregnancies the endothelial damage was limited to the kidney and, thus, of maternal origin Therefore, GDM vascular damage could not affect the fetal-placental unit.

As mentioned above, the placenta plays a key role in sFlt1 and PlGF production and a defective placentation, typical of PE, significantly contributes to increased circulating anti-angiogenic sFlt1 levels Decreased maternal PlGF serum levels in preeclampsia have been attributed to reduced placental production and to the inhibition of free PlGF by over-expressed circulating sFlt1 We observed a positive correlation between placental weight and sFlt1 but not PlGF serum concentrations in GDM patients, thus excluding that PlGF placental over-production was due to higher placental cells number.

In accordance with an environment that promotes vascularization, in GDM placentae we described no differences in placental sFlt1 expression while we reported a significant increase of pro-angiogenic PlGF relative to CTRL. Accordingly, Pietro L and colleagues described that the hyperglycemic placenta over-expressed the pro-angiogenic mediator VEGF Abbade et al.

They reported in GDM pregnancies that a reduced placental ceramide facilitate anabolism in the fetal-placental unit by upregulating the acid ceramidase ASAH1, an enzyme involved in the degradation of ceramide into sphingosine and fatty acids, thus avoiding the enhanced mitochondrial fission and cell death typical of PE 7. Our data are consistent with Shainker et al. Differently by PE, where high sFlt1 expression is associated with shallow placentation and placental hypoperfusion 55 , 56 , placental sFlt1 downregulation in GDM-PE could result in invasive placentation and deeper implantation along with hyperperfusion as previously suggested by McMahnon et al.

In addition, decreased sFlt1 expression might be an adaptation to increased blood flow 58 and it may allow vascular growth factors to increase placental angiogenesis in accordance with the developing fetus needs It is widely accepted that proteinuria, typical hallmark of PE, is a consequence of glomerular damage caused by vascular endothelium destruction. The same mechanism was suggested to be involved in glomerular damage in patients with GDM Overall, our results suggest a less severe endothelial dysfunction in gestational diabetes relative to preeclampsia.

Given the small number of patients enrolled, further analyses are required to confirm our data. Conclusions This is the first time to our knowledge that the association among GDM, PE and placental biomarkers was investigated. Several studies supported the imbalance of placental pro- and anti-angiogenic factors as a plausible mechanism for PE endothelial dysfunction The study was performed in adherence to the Declaration of Helsinki.

Physiological controls were obtained from normal term healthy singleton pregnancies that did not show any which are signs of of PE, GDM or other placental disease. In case of normal OGTT results, the test was repeated at 24—28 weeks of gestation. Furthermore, 30 min daily moderate exercise was recommended i. Insulin treatment was prescribed in presence of hyperglycemia in accordance with guidelines During the third trimester of pregnancy 31—34 weeks , maternal venous blood samples 5 mL were collected into Vacutainer tubes without anticoagulant.