The role of endoplasmic reticulum stress in shedding of syncytiotrophoblast microparticles in pregnant black South African women.

Abstract

Background and aim: Preeclampsia, accounts for the majority of maternal deaths emanating from hypertension in pregnancy. Although its exact aetiology is unclear, endoplasmic reticulum (ER) stress and trophoblast apoptosis are implicated. The placental microenvironment in preeclampsia is hypoxic and induces the expression of Hypoxia inducible factor-1 alpha (HIF-1 α) and CHOP (C/EBP homologous protein) which are activated due to ER stress. Hypoxia-induced oxidative and endoplasmic reticulum stress initiate a cascade of apoptotic events with the consequential shedding of microparticles which mediate the peripheral maternal syndrome of preeclampsia. The main aim of the study was to immuno-localise the expression of HIF-1 α and CHOP in placental tissues and concomitantly characterise and quantify the syncytiotrophoblast microparticles in the maternal circulation. Materials and Methods: Plasma and placental tissue were obtained from normotensive and pre-eclamptic pregnant women. The expression of HIF-1α and CHOP was analysed using immunohistochemistry. Microvesicles in maternal circulation were isolated and their size distribution was determined using nanoparticle tracking analysis. The relative concentration of syncytiotrophoblast microvesicles (STBMs) from isolated microvesicles was determined using Placental Alkaline Phosphatase ELISA. Results: This study demonstrated an increased immuno-expression of HIF-1 α and CHOPS in preeclampsia compared to the controls (p < 0.05). Additionally, a significant increase in the mean syncytiotrophoblast microparticles concentration was observed in PE, compared to the controls (p < 0.05). Further analysis showed a positive correlation between the immunohistochemical expression of HIF-1 α and CHOP and the STBMs concentration. Conclusion: This study demonstrates increased placental-expression of HIF-1α and CHOP in preeclampsia compared to normotensive pregnancies which directly relate to the increase syncytiotrophoblast microvesicles concentration in maternal circulation. These findings indicate that placental hypoxia and ER stress are contributory factors to the pathogenesis of PE and may be a key contributory factor in placental cell apoptosis and the consequent release of placental derived debris into the maternal circulation. Key words: HIF-1α; CHOP; Syncytiotrophoblast Microvesicles; Pre- eclampsia; Endoplasmic Reticulum Stress; Hypoxia