Serum amyloid A1 and pregnancy zone protein in pregnancy complications and correlation with markers of placental dysfunction

BACKGROUND: Hypertensive disorders of pregnancy (preeclampsia, gestational hypertension, and chronic hypertension), diabetes mellitus, and placental dysfunction confer an increased risk of long-term maternal cardiovascular disease. Preeclampsia is also associated with acute atherosis that involves lesions of uteroplacental spiral arteries, resembling early stages of atherosclerosis. Serum amyloid A1 is involved in hypercoagulability and atherosclerosis and may aggregate into amyloid—aggregations of misfolded proteins. Pregnancy zone protein may inhibit amyloid aggregation. Amyloid is involved in Alzheimer's disease and cardiovascular disease; it has been identified in preeclampsia, but its role in preeclampsia pathophysiology is unclear. OBJECTIVE: We hypothesized that serum amyloid A1 would be increased and pregnancy zone protein decreased in hypertensive disorders of pregnancy and diabetic pregnancies and that serum amyloid A1 and pregnancy zone protein would correlate with placental dysfunction markers (fetal growth restriction and dysregulated angiogenic biomarkers) and acute atherosis. STUDY DESIGN: Serum amyloid A1 is measurable in both the serum and plasma. In our study, plasma from 549 pregnancies (normotensive, euglycemic controls: 258; early-onset preeclampsia: 71; late-onset preeclampsia: 98; gestational hypertension: 30; chronic hypertension: 9; diabetes mellitus: 83) was assayed for serum amyloid A1 and pregnancy zone protein. The serum levels of angiogenic biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor were available for 547 pregnancies, and the results of acute atherosis evaluation were available for 313 pregnancies. The clinical characteristics and circulating biomarkers were compared between the pregnancy groups using the MannWhitney U, chi-squared, or Fisher exact test as appropriate. Spearman’s rho was calculated for assessing correlations. RESULTS: In early-onset preeclampsia, serum amyloid A1 was increased compared with controls (17.1 vs 5.1 mg/mL, P<.001), whereas pregnancy zone protein was decreased (590 vs 892 mg/mL, P=.002). Pregnancy zone protein was also decreased in diabetes compared with controls (683 vs 892 mg/mL, P=.01). Serum amyloid A1 was associated with placental dysfunction (fetal growth restriction, elevated soluble fmslike tyrosine kinase-1 to placental growth factor ratio). Pregnancy zone protein correlated negatively with soluble fms-like tyrosine kinase-1 to placental growth factor ratio in all study groups. Acute atherosis was not associated with serum amyloid A1 or pregnancy zone protein. CONCLUSION: Proteins involved in atherosclerosis, hypercoagulability, and protein misfolding are dysregulated in early-onset preeclampsia and placental dysfunction, which links them and potentially contributes to future maternal cardiovascular disease

Decidua basalis and acute atherosis: Expression of atherosclerotic foam cell associated proteins

Introduction Uteroplacental acute atherosis is frequently observed in preeclampsia, and shares features with early atherosclerotic lesions, including artery wall foam cells. The lipid-associated proteins FABP4 (fatty acid binding protein 4), perilipin-2, and LOX-1 (lectin-like oxidized LDL-receptor 1) are involved in atherosclerotic foam cell formation. Increased levels of these proteins have been associated with preeclampsia systemically and in placental tissue. Their role in acute atherosis is yet unidentified. Our aim was to describe the presence of these proteins in acute atherosis, and compare our findings to what is known in early atherosclerotic lesions. Methods Serial sections of decidua basalis tissue from 12 normotensive (4 with acute atherosis) and 23 preeclamptic pregnancies (16 with acute atherosis) were stained with HE and immunostained for CK7, CD68, FABP4, perilipin-2, and LOX-1. Artery wall and perivascular protein expression was assessed in 190 spiral artery sections; 55 with acute atherosis. Results Acute atherosis foam cells were commonly positive for perilipin-2 (55%), less often for FABP4 (13%), and never for LOX-1. LOX-1 was frequently observed in intramural trophoblasts of normal spiral arteries. Perivascularly, LOX-1 positivity of decidual stromal cells surrounding arteries with acute atherosis was significantly increased as compared to arteries lacking acute atherosis (38% vs. 15%, p < 0.001). Discussion We found that perilipin-2 and FABP4 are expressed by acute atherosis foam cells, similar to atherosclerosis, supporting possible shared pathways for foam cell generation. Unlike atherosclerosis, LOX-1 is not present in acute atherosis, possibly explained by pregnancy-specific routes to decidua basalis foam cell generation

Acute Atherosis Lesions at the Fetal-Maternal Border: Current Knowledge and Implications for Maternal Cardiovascular Health

Decidua basalis, the endometrium of pregnancy, is an important interface between maternal and fetal tissues, made up of both maternal and fetal cells. Acute atherosis is a uteroplacental spiral artery lesion. These patchy arterial wall lesions containing foam cells are predominantly found in the decidua basalis, at the tips of the maternal arteries, where they feed into the placental intervillous space. Acute atherosis is prevalent in preeclampsia and other obstetric syndromes such as fetal growth restriction. Causal factors and effects of acute atherosis remain uncertain. This is in part because decidua basalis is challenging to sample systematically and in large amounts following delivery. We summarize our decidua basalis vacuum suction method, which facilitates tissue-based studies of acute atherosis. We also describe our evidence-based research definition of acute atherosis. Here, we comprehensively review the existing literature on acute atherosis, its underlying mechanisms and possible short- and long-term effects. We propose that multiple pathways leading to decidual vascular inflammation may promote acute atherosis formation, with or without poor spiral artery remodeling and/or preeclampsia. These include maternal alloreactivity, ischemia-reperfusion injury, preexisting systemic inflammation, and microbial infection. The concept of acute atherosis as an inflammatory lesion is not novel. The lesions themselves have an inflammatory phenotype and resemble other arterial lesions of more extensively studied etiology. We discuss findings of concurrently dysregulated proteins involved in immune regulation and cardiovascular function in women with acute atherosis. We also propose a novel hypothesis linking cellular fetal microchimerism, which is prevalent in women with preeclampsia, with acute atherosis in pregnancy and future cardiovascular and neurovascular disease. Finally, women with a history of preeclampsia have an increased risk of premature cardiovascular disease. We review whether presence of acute atherosis may identify women at especially high risk for premature cardiovascular disease