In vivo targets of human placental micro-vesicles vary with exposure time and pregnancy

Abstract

Throughout human gestation, the placenta extrudes vast quantities of extracellular vesicles (EVs) of different sizes into the maternal circulation. Although multinucleated macro-vesicles are known to become trapped in the maternal lungs and do not enter the peripheral circulation, the maternal organs and cells that smaller placental micro-vesicles interact with remain unknown. This study aimed to characterise the interaction between placental micro-vesicles and endothelial cells and to elucidate which organs placental micro-vesicles localise to Placental macro- and micro-vesicles were isolated from cultured human first trimester placental explants by sequential centrifugation and exposed to human microvascular endothelial cells for up to 72 h. , placental macro- and micro-vesicles were administered to both non-pregnant and pregnant CD1 mice, and after two or 30 min or 24 h, organs were imaged on an IVIS Kinetic Imager. Placental EVs rapidly interacted with endothelial cells via phagocytic and clathrin-mediated endocytic processes, with over 60% of maximal interaction being achieved by 30 min of exposure. , placental macro-vesicles were localised exclusively to the lungs regardless of time of exposure, whereas micro-vesicles were localised to the lungs, liver and kidneys, with different distribution patterns depending on the length of exposure and whether the mouse was pregnant or not. The fact that placental EVs can rapidly interact with endothelial cells and localise to different organs supports that different size fractions of placental EVs are likely to have different downstream effects on foeto-maternal communication.

Endoplasmic reticulum stress occurs in association with the extrusion of toxic extracellular vesicles from human placentae treated with antiphospholipid antibodies

“…The syncytiotrophoblast is bathed in maternal blood and produces vast quantities of EVs in normal pregnancy. These EVs are extruded directly into the maternal blood and target specific maternal organs [5,6]. We have previously shown that EVs produced by the syncytiotrophoblast in normal pregnancies are tolerogenic to both immune and endothelial cells, but EVs from preeclamptic placentae are dangerous/toxic and activate endothelial cells [32][33][34][35].…”

“…If, following exposure to antiphospholipid antibodies, the syncytiotrophoblast is not functioning adequately because it is responding to endoplasmic reticulum stress, this may cause reduced nutrient/gas transfer across the placenta and lead to fetal growth restriction, one of the complications that occurs in women with Antiphospholipid antibody Syndrome [48]. In addition, the export of both micro-EVs and nano-EVs containing misfolded proteins may harm the maternal cells that take up these vesicles [5,49]. We have previously shown that EVs from placentae treated with antiphospholipid antibodies contain increased amounts of various danger signals including mitochondrial DNA [50] and HMGB1 [51].…”

“…During pregnancy, large quantities of placental extracellular vesicles (EVs) are extruded from placental syncytiotrophoblast into the maternal circulation [3,4]. These EVs contain proteins and nucleic acids and can transfer their cargo to recipient cells/tissues and affect the function of those recipient cells [5][6][7][8]. We have previously shown that antiphospholipid antibodies are internalized into the syncytiotrophoblast resulting in the production of toxic EVs [9].…”

Micro- and Nano-vesicles from First Trimester Human Placentae Carry Flt-1 and Levels Are Increased in Severe Preeclampsia

“…Despite the increased levels of Flt-1 on micro- and nano-vesicles from PE placentae, vesicle-associated Flt-1 accounted for less than 7% of the total sFlt-1 secreted by PE placentae. Nevertheless, EV-associated Flt-1 may still be an important contributor to the pathogenesis of preeclampsia because: (1) we have shown that increased numbers of micro- and nano-vesicles are extruded by PE placentae and (2) we have previously reported that different size fractions of EVs are targeted to specific maternal organs such as the kidneys and liver, organs that are affected in preeclampsia (52, 54). Therefore, while increased levels of free sFlt-1 may mediate global endothelial cell dysfunction by sequestering circulating VEGF, vesicle-associated Flt-1 may be concentrated in specific organs such that even a low circulating level of vesicle-associated Flt-1 may have a large biological significance by causing organ-specific endothelial cell damage, such as glomerular endotheliosis which is commonly reported in women with preeclampsia (3, 6).…”

Extracellular vesicles in normal pregnancy and pregnancy‐related diseases

“…Intriguingly, the bioactivity of exosomes is greatest during first trimester and gradually decline with increasing gestational age . Tong et al demonstrate that different size fractions of placental EVs can rapidly interact with ECs and localize to different organs in vivo, which supports the notion that placental EVs are likely to have effects on endothelial functions. Placental nano‐vesicles interact with ECs rapidly in vitro through a combination of mechanisms including phagocytosis, endocytosis and cell surface binding.…”