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Long-Term Consequences of Placental Vascular Pathology on the Maternal and Offspring Cardiovascular Systems.

ABSTRACT: Over the last thirty years, evidence has been accumulating that Hypertensive Disorders of Pregnancy (HDP) and, specifically, Preeclampsia (PE) produce not only long-term effects on the pregnant woman, but have also lasting consequences for the fetus. At the core of these consequences is the phenomenon known as defective deep placentation, being present in virtually every major obstetrical syndrome. The profound placental vascular lesions characteristic of this pathology can induce long-term adverse consequences for the pregnant woman's entire arterial system. In addition, placental growth restriction and function can, in turn, cause a decreased blood supply to the fetus, with long-lasting effects. Women with a history of HDP have an increased risk of Cardiovascular Diseases (CVD) compared with women with normal pregnancies. Specifically, these subjects are at a future higher risk of: Hypertension; Coronary artery disease; Heart failure; Peripheral vascular disease; Cerebrovascular accidents (Stroke); CVD-related mortality. Vascular pathology in pregnancy and CVD may share a common etiology and may have common risk factors, which are unmasked by the "stress" of pregnancy. It is also possible that the future occurrence of a CVD may be the consequence of endothelial dysfunction generated by pregnancy-induced hypertension that persists after delivery. Although biochemical and biophysical markers of PE abound, information on markers for a comparative evaluation in the various groups is still lacking. Long-term consequences for the fetus are an integral part of the theory of a fetal origin of a number of adult diseases, known as the Barker hypothesis. Indeed, intrauterine malnutrition and fetal growth restriction represent significant risk factors for the development of chronic hypertension, diabetes, stroke and death from coronary artery disease in adults. Other factors will also influence the development later in life of hypertension, coronary and myocardial disease; they include parental genetic disposition, epigenetic modifications, endothelial dysfunction, concurrent intrauterine exposures, and the lifestyle of the affected individual.

SUBMITTER: Benagiano M

PROVIDER: S-EPMC8615676 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionAlkaline phosphatase is implicated in intestinal lipid transport and in the development of obesity. Placental alkaline phosphatase is localised to the microvillous plasma membrane of the placental syncytiotrophoblast at the maternal-fetal interface, but its role is unclear. We investigated the relations of placental alkaline phosphatase activity and mRNA expression with maternal body composition and offspring fat mass in humans.MethodsTerm human placentas from the UK Birthright cohort (n = 52) and the Southampton Women's Survey (SWS) (n = 95) were studied. In the Birthright cohort, alkaline phosphatase activity was measured in placental microvillous plasma membrane vesicles. In the SWS, alkaline phosphatase mRNA was measured using Nanostring. Alkaline phosphatase gene expression was compared to other lipid-related genes.ResultsIn Birthright samples placental microvillous plasma membrane alkaline phosphatase activity was positively associated with maternal triceps skinfold thickness and BMI (β = 0.04 (95% CI: 0.01-0.06) and β = 0.02 (0.00-0.03) µmol/mg protein/min per SD, P = 0.002 and P = 0.05, respectively) after adjusting for potential confounders. In SWS samples placental alkaline phosphatase mRNA expression in term placenta was positively associated with maternal triceps skinfold (β = 0.24 (0.04, 0.44) SD/SD, P = 0.02), had no association with neonatal %fat mass (β = 0.01 (-0.20 to 0.21) SD/SD, P = 0.93) and was negatively correlated with %fat mass at ages 4 (β = -0.28 (-0.52 to -0.04) SD/SD, P = 0.02), 6-7 (β = -0.25 (-0.49 to -0.02) SD/SD, P = 0.03) years. When compared with placental expression of other genes, alkaline phosphatase expression was positively related to genes including the lysophosphatidylcholine transporter MFSD2A (major facilitator superfamily domain containing 2A, P < 0.001) and negatively related to genes including the fatty acid transport proteins 2 and 3 (P = 0.001, P < 0.001).ConclusionsOur findings suggest relationships between placental alkaline phosphatase and both maternal and childhood adiposity. The inverse relationship between placental alkaline phosphatase gene expression and childhood %fat mass suggests that placental alkaline phosphatase may help to protect the foetus from the adverse effects of maternal obesity.

Project description:Bacterial infections and the concurrent inflammation have been associated with increased long-term cardiovascular (CV) risk. In patients receiving peritoneal dialysis (PD), bacterial peritonitis is a common occurrence, and each episode further increases late CV mortality risk. However, the underlying mechanism(s) remains to be elucidated before safe and efficient anti-inflammatory interventions can be developed. Damage-Associated Molecular Patterns (DAMPs) have been shown to contribute to the acute inflammatory response to infections, but a potential role for DAMPs in mediating long-term vascular inflammation and CV risk following infection resolution in PD, has not been investigated. We found that bacterial peritonitis in mice that resolved within 24h led to CV disease-promoting systemic and vascular immune-mediated inflammatory responses that were maintained up to 28 days. These included higher blood proportions of inflammatory leukocytes displaying increased adhesion molecule expression, higher plasma cytokines levels, and increased aortic inflammatory and atherosclerosis-associated gene expression. These effects were also observed in infected nephropathic mice and amplified in mice routinely exposed to PD fluids. A peritonitis episode resulted in elevated plasma levels of the DAMP Calprotectin, both in PD patients and mice, here the increase was maintained up to 28 days. In vitro, the ability of culture supernatants from infected cells to promote key inflammatory and atherosclerosis-associated cellular responses, such as monocyte chemotaxis, and foam cell formation, was Calprotectin-dependent. In vivo, Calprotectin blockade robustly inhibited the short and long-term peripheral and vascular consequences of peritonitis, thereby demonstrating that targeting of the DAMP Calprotectin is a promising therapeutic strategy to reduce the long-lasting vascular inflammatory aftermath of an infection, notably PD-associated peritonitis, ultimately lowering CV risk.

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Long-Term Consequences of Placental Vascular Pathology on the Maternal and Offspring Cardiovascular Systems.

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