Acute atherosis of decidua basalis; characterization of spiral arteries, endothelial status and activation

Introduction Acute atherosis (AA) is a lesion affecting uteroplacental spiral arteries during pregnancy, most frequently in preeclampsia but occasionally in normal pregnancy. It is commonly observed in untransformed spiral arteries (intact smooth muscle cell layer, lacking intramural trophoblasts). The mechanism causing lesion development is unknown. AA shares some morphological similarities with atherosclerosis, in which endothelial activation occurs early. Here we histologically characterize decidua basalis spiral arteries with and without AA, focusing on endothelial status and activation. Methods Formalin-fixed and paraffin-embedded decidua basalis tissue sections from 32 patients (16 normotensive, 5 with AA, 16 preeclampsia, 7 with AA) were stained with H + E, PAS, MSB (Martius Scarlet Blue), desmin, CK7, CD68, CD31, vWF and ICAM-1. We logged remodeling status, presence of AA, endothelial morphology, endothelial CD31 intensity and activation (ICAM-1-positive cells). Results We observed fully or partially transformed spiral arteries in most decidua basalis samples, and no untransformed arteries. AA arteries were also observed, characterized by intramural CD68-positive vacuolated cells and fibrinoid necrosis. They lacked a smooth muscle cell layer and intramural trophoblasts. The fibrinoid necrosis in AA lesions stained red with MSB. AA arteries were associated with lower CD31 staining intensity of endothelial cells. More arteries had an abnormal or destroyed endothelium relative to arteries without AA. Endothelial activation was not observed in the majority of AA arteries. Discussion Our results indicate an altered endothelial phenotype as important in the development of AA, supporting previous observations. The histology of AA differs from that of atherosclerosis

Lymphocyte characterization of decidua basalis spiral arteries with acute atherosis in preeclamptic and normotensive pregnancies

Uteroplacental acute atherosis (AA) is a common spiral arterial lesion in preeclampsia, characterized by intramural foam cells, fibrinoid necrosis, and a perivascular immune cell infiltrate. A clear definition of this infiltrate is lacking. Therefore, our aim was to characterize lymphocytes in pre-defined zones regarding spiral arteries with or without AA, from preeclamptic and normotensive pregnancies. Lymphocytes were characterized in decidua basalis samples (n = 91), previously evaluated for AA, around spiral arteries in three pre-defined zones; 1) intramural, 2) perivascular and 3) interstitial. Adjacent serial sections were immunostained to identify different T-cell populations (CD3+, CD8+, FOXP3+), and NK-cells (CD56+). CD3+CD8- T-cells were also identified. These were presumed to be largely CD4+ T-cells. AA was associated with significantly higher intramural CD3+ cell concentrations in Zone 1, in both normotensives and preeclamptics. In preeclamptics only, this difference extended into Zone 2. Similar results were observed for CD3+CD8- cells. AA was also associated with increased intramural CD8+ concentration; however, the number of cells was low. Regulatory T-cells (FOXP3+) were generally scarce or absent in all pre-defined zones. Although intramural NK-cells (CD56+) were scarce, the intramural concentration was significantly lower in spiral arteries with AA compared to without AA in preeclamptics. Our main finding was that CD3+CD8-FoxP3- T-cells were associated with AA. We therefore suggest that T-cells, of a non-regulatory CD4+ subtype, could be involved in the formation of spiral artery AA in the decidua basalis. Whether AA gives rise to, or is partly mediated by increased T-cell concentration around the lesions, remains to be determined

Classical cardiovascular risk markers in pregnancy and associations to uteroplacental acute atherosis

Uteroplacental acute atherosis (AA) is a pregnancy-specific arterial lesion resembling early stages of atherosclerosis. AA is frequent in preeclamptic pregnancies, which associate with increased long-term maternal risk of atherosclerotic cardiovascular disease. We hypothesized that AA in pregnant women associates with classical risk factors for cardiovascular disease, including hypertension, hyperlipidemia, glucose intolerance, elevated C-reactive protein, age, and body mass index. We included 237 women delivered by cesarean section (healthy pregnancies, n=94; preeclampsia, n=87; pregestational and gestational diabetes mellitus, n=39; diabetes mellitus with preeclampsia, n=17). They provided blood before delivery for biomarker analyses. AA was diagnosed by immunohistochemistry in uteroplacental (decidual) tissue collected after placental removal. Statistical analyses were performed with Mann-Whitney test. Levels of traditional cardiovascular markers were not associated with decidual AA within the groups of women with normotensive pregnancies, preeclampsia, diabetes mellitus, or diabetes mellitus superimposed with preeclampsia. However, the oldest patient age quartile (36–43 years old) with AA had significantly higher levels of LDL (low-density lipoprotein) and apolipoprotein B (both P<0.01) than women of the same age without AA. AA was associated with elevated median prepregnancy/early pregnancy systolic blood pressure (P=0.01) in the total cohort, but as preeclampsia was strongly associated with this finding (P<0.01), this was likely caused by a large proportion of preeclamptic pregnancies in the AA group (62.7%). Our findings demonstrate that dyslipidemia associated with cardiovascular risk is a feature of uteroplacental AA in older women, not of AA in pregnancy in general

Auto-antibodies against the angiotensin II type I receptor in women with uteroplacental acute atherosis and preeclampsia at delivery and several years postpartum

Background Uteroplacental acute atherosis is a pregnancy-specific lesion resembling early stages of atherosclerosis found frequently in preeclampsia. Preeclampsia is associated with an increased risk for future maternal atherosclerotic cardiovascular disease. The renin-angiotensin-system plays a role both in atherosclerosis and in preeclampsia. Circulating agonistic autoantibodies at the angiotensin-II type 1 receptor (AT1-AA) are increased in preeclampsia. We hypothesized an association between AT1-AA at delivery and postpartum with acute atherosis in pregnancy. Material and Methods Maternal serum and decidua basalis tissue was collected at elective cesarean section (n = 41; 24 preeclampsia, 17 normotensive controls). Circulating AT1-AA were detected by a bioassay using spontaneously beating rat cardiomyocytes at delivery (n = 41) and 5–8 years postpartum in a subgroup (n = 10). Decidual acute atherosis was assessed by immunohistochemistry. Results Significantly less normotensive controls (18%; 3/17) than women with preeclampsia (58%; 14/24) were AT1-AA positive at delivery, p<0.01. Uteroplacental acute atherosis and circulating AT1-AA at delivery were not significantly correlated. Postpartum, 2 prior preeclamptic women had circulating AT1-AA, both without acute atherosis in pregnancy. Conclusions Our results confirm that circulating AT1-AA are present significantly more often in preeclampsia than in normotensive pregnancy, however without association to acute atherosis. Whether circulating maternal AT1-AA or acute atherosis target young women at increased long-term cardiovascular risk warrants further investigations

Endoglin pathway genetic variation in preeclampsia: A validation study in Norwegian and Latina cohorts

Objective: The purpose of this study was to validate our previous genetic association findings related to the endoglin (ENG) pathway from an American Caucasian preeclampsia cohort in independent preeclampsia cohorts. We also sought to explore the ENG pathway for new genetic associations in these independent cohorts. Study design: We used a tagging single nucleotide (tSNP) approach to assess genetic variability across five ENG pathway genes (ENG, TGFβ1, TGFβR1, ALK1, and TGFβR2) in a Caucasian cohort from Norway (n = 77 preeclampsia cases & n = 63 normotensive controls) and a White Hispanic cohort from Southern California (n = 69 preeclampsia cases & n = 106 normotensive controls). Main outcome measures: Univariate analyses (Chi Square, Fisher’s Exact) and multivariate logistic regression were conducted to evaluate the association between tSNP genotype distributions and pregnancy outcome in each cohort. Logistic regression models were adjusted for maternal age at delivery, infant sex, parity, smoking during pregnancy, and pre-pregnancy BMI. Results: Although we were unable to replicate our previous SNP-specific findings (ENG rs11792480, rs10121110; TGFβR2 rs6550005; p’s > 0.05), we found that genetic variation in TGFβR1[ALK5] (rs6478974) and TGFβR2 (rs11129420, rs6802220, rs1155708, rs3773640, rs3773663) was significantly associated with preeclampsia in the Norwegian cohort and genetic variation in ALK1 (rs706819) and TGFβR2 (rs9843942) was significantly associated with preeclampsia in the Latina cohort. Conclusion: Overall, our results provide further support for the involvement and investigation of the endoglin pathway in preeclampsia

DHA induces ER stress and growth arrest in human colon cancer cells: associations with cholesterol and calcium homeostasis *s⃞

Polyunsaturated fatty acids (PUFAs) are normal constituents of the diet, but have properties different from other fatty acids (e.g., through generation of signaling molecules). N-3 PUFAs reduce cancer cell growth, but no unified mechanism has been identified. We show that docosahexaenoic acid (DHA; 22:6 n-3) causes extensive changes in gene expression patterns at mRNA level in the colon cancer cell line SW620. Early changes include unfolded protein response (UPR) and increased levels of phosphorylated eIF2α as verified at protein level. The latter is considered a hallmark of endoplasmic reticulum (ER) stress and is abundantly present already after 3 h. It may coordinate many of the downstream changes observed, including signaling pathways for cell cycle arrest/apoptosis, calcium homeostasis, cholesterol metabolism, ubiquitination, and proteasomal degradation. Also, eicosapentaenoic acid (EPA), but not oleic acid (OA), induced key mediators of ER stress and UPR at protein level. Accumulation of esterified cholesterol was not compensated for by increased total levels of cholesterol, and mRNAs for cholesterol biosynthesis as well as de novo synthesis of cholesterol were reduced. These results suggest that cytotoxic effects of DHA are associated with signaling pathways involving lipid metabolism and ER stress