الفهرس 
AcknowledgementOnly 14 pages are availabe for public view
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Abstract
Hypertensive disorders of pregnancy are prevalent, affecting 10% of pregnancies. They are considered leading causes of maternal and perinatal morbidity and mortality, especially when the condition is of early onset. Preeclampsia (PE) is defined as a new onset of high blood pressure ≥ 140/90 in two occasions 6 hours apart after 20 weeks of gestation, with proteinuria > 300 mg / 24 hours.
PE is associated with several short- and long-term perinatal and neonatal complications. PE increases risk of prematurity, bronchopulmonary dysplasia, NEC, sepsis, neutropenia, thrombocytopenia. Infants born to preeclampsia mothers are at high risk of hypertension, metabolic syndromes, and decrease in neurocognitive function later in life.
The control and expression of genes are impacted by histone modification, particularly H3K27ac and H4K16ac, which are components of epigenetic regulation in various cells. Additionally, they play a significant role in the pathophysiology of some illnesses, such as preeclampsia.
In this study we recruited patients at the Royal London Hospital, Barts Health trust from the period of May 2021 to March 2022 as a part of PreeclampsiaEpigenetics study with ethical committee approval (REC 21/SS/0010). Sixty parents accepted and gave written consent. Twenty infants were born to normotensive mothers, twenty to PIH mothers, and twenty to PE mothers. For each patient, we assessed cardiovascular flow measurements (cardiac output and cerebral blood flow) and immune systems in cord blood (Treg cells, CD4+CD25+Foxp3). We performed experiments and analyses on placental samples of six control, five mild PE, and four severe PE patients to identify the epigenetic changes (H3k27 ac and H4K16 ac).
Reproducibility of the cardiovascular measurement were performed before starting the study either on phantom model or on the first 10 babies and it showed excellent reproducibility either intraobserver (ASA) or interobserver (ASA, SP).
Right common carotid artery (RCCA) flow was 54.8 (34.3 – 67.8) ml/minute and RCCA flow indexed to weight was 19.6 (17.0 – 24.2) ml/kg/minute, with no significant differences between study groups. RCCA flow accounted for 13% of total LVO and was similar across three groups. Assuming that RCCA and LCCA flow are equivalent, carotid blood flow accounted for 26% of LVO (roughly one quarter of the whole cardiac output). Left ventricular outflow (LVO) was 441.3 ml/minute (305.3 – 514.2) for all participants and there was no statistical difference between study groups. Antihypertensive medications did not show any effect on left ventricular outflow and cerebral blood flow in infants born to mothers who received these medications. RCCA flow increased with gestational age (r=0.59, p=<0.001) and birth weight (r=0.65, p=<0.001). The same pattern was observed for LVO, which likewise increased with gestational age and weight (r=0.58, p=<0.001 and r=0.75, p=<0.001 respectively).
In cord blood samples, CD4+CD25+ and CD4+CD25+Foxp3 cells were statistically significantly lower in PE and PIH groups than the control one. The CD4+CD25+Foxp3 marker percentage was lower in the PE group compared to the PIH group while there was no statistically significant difference in either group’s CD4+CD25+ marker.
In placental samples, several genes, including the CRH gene, FTL1 gene, DLX5 gene, FOS gene, GATA3 gene, Lep gene, and PSG cluster genes, exhibited differential acetylation levels (H3K27 ac and H4K16 ac) among the different study groups. The present study demonstrates the presence of enriched levels of H3K27ac and H4K16ac at specific subfamilies of repeat elements across the whole genome which act as promoter and enhancer for different genes. Our data showed the gene expression in different genes related to PE have different expressions across study groups such as FLT1, FSTL3, LEP and ENG, especially in the severe PE group (preterm and IUGR). These changes in RNA are correlated with some histone acetylation marks differential enrichment of the H3K27 and H4K16. These genes control important physiological processes like angiogenesis, vasoconstriction, vascular development, and inflammatory processes.