Placental Inflammation Leads to Abnormal Embryonic Heart Development

Abstract

BACKGROUND: Placental heart development and embryonic heart development occur in parallel, and these organs have been proposed to exert reciprocal regulation during gestation. Poor placentation has been associated with congenital heart disease, an important cause of infant mortality. However, the mechanisms by which altered placental development can lead to congenital heart disease remain unresolved. METHODS: In this study, we use an in vivo neutrophil-driven placental inflammation model through antibody depletion of maternal circulating neutrophils at key stages during time-mated murine pregnancy: embryonic days 4.5 and 7.5. Pregnant mice were culled at embryonic day 14.5 to assess placental and embryonic heart development. A combination of flow cytometry, histology, and bulk RNA sequencing was used to assess placental immune cell composition and tissue architecture. We also used flow cytometry and single-cell sequencing to assess embryonic cardiac immune cells at embryonic day 14.5 and histology and gene analyses to investigate embryonic heart structure and development. In some cases, offspring were culled at postnatal days 5 and 28 to assess any postnatal cardiac changes in immune cells, structure, and cardiac function, as measured by echocardiography. RESULTS: In the present study, we show that neutrophil-driven placental inflammation leads to inadequate placental development and loss of barrier function. Consequently, placental inflammatory monocytes of maternal origin become capable of migration to the embryonic heart and alter the normal composition of resident cardiac macrophages and cardiac tissue structure. This cardiac impairment continues into postnatal life, hindering normal tissue architecture and function. Last, we show that tempering placental inflammation can prevent this fetal cardiac defect and is sufficient to promote normal cardiac function in postnatal life. CONCLUSIONS: Taken together, these observations provide a mechanistic paradigm whereby neutrophil-driven inflammation in pregnancy can preclude normal embryonic heart development as a direct consequence of poor placental development, which has major implications on cardiac function into adult life.

Early infection response of the first trimester human placenta at single-cell scale

“…These responses to infection reflect a host innate immune defence strategy to minimise impending tissue injury and spread of infection 70 . Despite serving as a protective strategy, this inflammation response disrupts the core functions of the trophoblast, particularly hormone and lipid metabolism, which could have profound impact on the transport of nutrients to the embryo and on fetal growth and organ development [71][72][73] . Inflammatory and stress conditions can induce a switch in metabolic demands 74 .…”

Don’t Break the Axis: Placental Inflammation Leads to Congenital Heart Disease

“…The study by Ward et al 10 provides an experimental preeclampsia-like model in which NDPI leads to abnormal heart development and impaired adult cardiac function in the offspring. Further research is needed to demonstrate the relevance of the NDPI model for the study of preeclampsia, most crucially, whether it reproduces the key preeclampsia features of maternal hypertension and proteinuria.…”

“…In this issue of Circulation , Ward et al 10 show that experimental neutrophil-driven placental inflammation (NDPI) in mice leads to abnormal placental development and loss of barrier function. This allows maternal placental inflammatory monocytes to migrate to the embryonic heart, skewing the composition of the resident cardiac macrophage population and altering ventricular structure.…”

Assessment of fetal cardiac functions in pregnant women with asthma

“…In one study, neutrophil‐triggered inflammation of the placenta was found to lead to inadequate placental development and a lack of barrier function. As a result, maternally derived inflammatory monocytes from the placenta may migrate into the embryonic heart and alter the structure of cardiac tissue and the normal composition of resident cardiac macrophages 6 …”

“…As a result, maternally derived inflammatory monocytes from the placenta may migrate into the embryonic heart and alter the structure of cardiac tissue and the normal composition of resident cardiac macrophages. 6 The circulatory physiology of the fetus is different from that of the newborn. The right ventricle provides greater cardiac output from the second half of pregnancy until delivery.…”