Aleksandra Stangret

Fractalkine (CX3CL1) and Its Receptor CX3CR1 May Contribute to Increased Angiogenesis in Diabetic Placenta

Chemokine CX3CL1 is unique, possessing the ability to act as a dual agent: chemoattractant and adhesive compound. Acting via its sole receptor CX3CR1, CX3CL1 participates in many processes in human placental tissue, including inflammation and angiogenesis. Strongly upregulated by hypoxia and/or inflammation-induced inflammatory cytokines secretion, CX3CL1 may act locally as a key angiogenic factor. Both clinical observations and histopathological studies of the diabetic placenta have confirmed an increased incidence of hypoxia and inflammatory reactions with defective angiogenesis. In this study we examined comparatively (diabetes class C complicated versus normal pregnancy) the correlation between CX3CL1 content in placental tissue, the mean CX3CR1 expression, and density of the network of placental microvessels. A sandwich enzyme immunoassay was applied for CX3CL1 measurement in placental tissue homogenates, whereas quantitative immunohistochemical techniques were used for the assessment of CX3CR1 expression and the microvascular density. Significant differences have been observed for all analyzed parameters between the groups. The mean concentration of CX3CL1 in diabetes was increased and accompanied by augmented placental microvessel density as well as a higher expression of CX3CR1. In conclusion, we suggest involvement of CX3CL1/CX3CR1 signaling pathway in the pathomechanism of placental microvasculature remodeling in diabetes class C.

Sirtuins, epigenetics and longevity

Aging of organisms begins from a single cell at the molecular level. It includes changes related to telomere shortening, cell senescence and epigenetic modifications. These processes accumulate over the lifespan. Research studies show that epigenetic signaling contributes to human disease, tumorigenesis and aging. Epigenetic DNA modifications involve changes in the gene activity but not in the DNA sequence. An epigenome consists of chemical modifications to the DNA and histone proteins without the changes in the DNA sequence. These modifications strongly depend on the environment, could be reversible and are potentially transmittable to daughter cells. Epigenetics includes DNA methylation, noncoding RNA interference, and modifications of histone proteins. Sirtuins, a family of nicotine adenine dinucleotide (NAD+)-dependent enzymes, are involved in the cell metabolism and can regulate many cellular functions including DNA repair, inflammatory response, cell cycle or apoptosis. Literature shows the strong interconnection between sirtuin expression and aging processes. However, the direct relationship is still unknown. Here, we would like to summarize the existing knowledge about epigenetic processes in aging, especially those related to sirtuin expression. Another objective is to explain why some negative correlations between sirtuin activity and the rate of aging can be assumed.

Maternal hemoglobin concentration and hematocrit values may affect fetus development by influencing placental angiogenesis

Abstract Objective: Vasculogenesis and angiogenesis are crucial for maintaining proper placental perfusion and optimal fetal development. Among other physical and chemical factors, hypoxia is known to stimulate angiogenic processes. Preplacental type of hypoxia is often associated with maternal anemia and is thought to enhance vascularization within the fetoplacental unit. The goal of this study was to establish the correlation between the local expression of vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) receptors (flt-1, flk-1) with maternal hemoglobin (Hb) concentration, hematocrit (Ht) values and the infant birthweight. Methods: In total, 43 specimens of term placentas obtained from normal course pregnancies delivered at term were included in the study. The expression of flt-1 and flk-1 receptors was analyzed by immunohistochemical staining. Vascular/extravascular tissular index (V/EVTI) was measured by assessing a total vascular area. Nonparametric Mann–Whitney U-test and Spearman’s rank correlation were used to compare the various parameters and their differences between the groups. Results: Among the patients with low Hb concentration, nearly 2-fold greater expression of the flt-1 receptor was positively correlated with infants birthweight (p = 0.028). Conclusions: Increased placental vascular density (increased flt-1 expression), during a physiological course of gestation, may be an adaptive response to lowered maternal Hb concentration and Ht values encountered during pregnancy.

Mild anemia during pregnancy upregulates placental vascularity development

The connection between maternal hematological status and pregnancy outcome has been shown by many independent researchers. Attention was initially focused on the adverse effects of moderate and severe anemia. Interestingly, some studies revealed that mild anemia was associated with optimal fetal development and was not affecting pregnancy outcome. The explanation for this phenomenon became a target for scientists. Hemodilution, physiologic anemia and relative decrease in hemoglobin concentration are the changes observed during pregnancy but they do not explain the reasons for the positive influence of mild anemia on a fetomaternal unit. It is hypothesized that hemodilution facilitates placental perfusion because blood viscosity is reduced. Subsequently, it may lead to a decline in hemoglobin concentration. Anemia from its definition implies decreased oxygen carrying capacity of the blood and can result in hypoxemia and even hypoxia, which is a common factor inducing new blood vessels formation. Therefore, we raised the hypothesis that the lowered hemoglobin concentration during pregnancy may upregulate vascular growth factor receptors expression such as VEGFR-1 (Flt-1) and VEGFR-2 (FLK-1/KDR). Consecutively, increased fetoplacental vasculogenesis and angiogenesis provide further expansion of vascular network development, better placental perfusion and hence neither fetus nor the mother are affected.

High Glucose Level Disturbs the Resveratrol-Evoked Curtailment of CX3CL1/CX3CR1 Signaling in Human Placental Circulation

Hyperglycemia-induced hyperactivity of chemokine CX3CL1 (fractalkine) occurs in the human placenta. Anti-inflammatory/antioxidant activities of resveratrol (3,5,4′-trihydroxy-trans-stilbene) are related to the modulation of chemokine CX3CL1 and its receptor, CX3CR1, signaling pathways. We examined the influence of high glucose (25 mmol/L glucose; HG group; N = 36) on resveratrol-mediated effects on CX3CL1 and TNF-α production by the placental lobule, CX3CR1 expression and contents of CX3CR1, TNF-α receptor 1 (TNFR1), and NF-κB proteins in placental tissue. The placental lobules perfused under normoglycemic conditions formed the control NG group (N = 36). Resveratrol (50 and 100 μM; subgroups B and C) administered into the perfusion fluid lowered the production of both CX3CL1 and TNF-α. The reductions in CX3CL1 levels were more evident in the NG group. CX3CR1 expression was significantly higher in the NG subgroups B and C compared to the HG subgroups B and C (385.2 and 426.5% versus 199.3 and 282.4%, resp.). An increase in CX3CR1 protein content in placental lysates was observed in the NG subgroups B and C. Also, resveratrol significantly decreased NF-κBp65 protein content only in the NG group, not affecting hyperglycemia-elicited TNFR1 upregulation. In conclusion, euglycemia assures optimal effects of resveratrol pertaining to CX3CL1/CX3CR1 signaling in the placenta. Future studies on resveratrol are needed, especially those including maternal-fetal risk assessments.

Fractalkine and placental growth factor: A duet of inflammation and angiogenesis in cardiovascular disorders

Inflammation and angiogenesis are two interdependent processes underlying pathogenesis of cardiovascular disorders. The initiation and progression of atherosclerosis strongly depends on specific patterns of cytokine expression. In this review, we analyze correlation between expression of two members of the cytokine family and the processes of inflammation and angiogenesis related to atherosclerosis. Placental growth factor and chemokine CX3XL1 (fractalkine) promote inflammatory cell infiltration, angiogenesis and plaque rupture. Because these cytokines share similar roles during atherosclerotic development, their combined value as a predictor or indicator of inflammation and vascular healing may be extremely useful.

Overexpression of histamine H1-receptor by human amniotic epithelial cells in chorioamnionitis correlates with augmented production of secretory leukocyte protease inhibitor

1 Department of General & Experimental Pathology, Medical University of Warsaw, ul.Krakowskie Przedmiescie 26/28, 00-928 Warsaw, Poland, Tel. (+4822) 8268141, Fax: ++4822 8264585, E-mail: Dszukiewicz@hotmail.com 2 First Department of Obstetrics & Gynecology, Second Faculty of Medicine, Medical University of Warsaw, Warsaw, Poland 3 Institute of Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland