Aggregated transthyretin is specifically packaged into placental nano-vesicles in preeclampsia

Abstract

In preeclampsia, the serum levels of transthyretin, a carrier protein for thyroxine, are elevated. Transthyretin isolated from preeclamptic serum is also aggregated and can induce preeclampsia-like symptoms in pregnant IL10−/− mice. Using western blotting, immunofluorescence, ELISA and qRT-PCR, we investigated the production of transthyretin by preeclamptic placentae and whether transthyretin is carried into the maternal circulation via placental extracellular vesicles. Both total and aggregated transthyretin were present in higher levels in preeclamptic placentae compared to normotensive placentae (p < 0.05, n = 7), however the levels of transythretin mRNA were not significantly different (n = 8). Preeclamptic placentae secreted similar levels of total transthyretin compared to normotensive placentae (2352 ± 2949 ng/mL vs. 3250 ± 1864 ng/mL, mean ± SD, p > 0.05, n = 8), however in preeclampsia, a significant proportion is vesicle-associated (~48% vs 0%). Increased levels of aggregated transthyretin were specifically associated to preeclamptic nano-vesicles (p < 0.02, n = 8). This study showed that the placenta actively produces transthyretin and in preeclampsia, a significant amount is extruded into the maternal circulation via placental exracellular vesicles. The increased aggregation of transthyretin in preeclampsia occurs at the post-transcriptional level and while preeclamptic nano-vesicles may be removing a toxic aggregated protein from the placenta, they may also be delivering aggregated transthyretin to specific maternal organs, contributing to the pathogenesis of preeclampsia.

Undiscovered Roles for Transthyretin: From a Transporter Protein to a New Therapeutic Target for Alzheimer’s Disease

“…Although higher levels of TTR are usually an indicator of a better protein nutritional status [38], increased TTR has also been associated with disease, as in preeclampsia, where aggregated TTR, extruded into the maternal circulation via placental extracellular vesicles, was also reported [39]. Higher levels of TTR are also detected in diabetes type II [40,41] and gestational diabetes [38], suggesting that TTR levels must be kept in balance within healthy intervals.…”

Disruption in the Regulation of Immune Responses in the Placental Subtype of Preeclampsia

“…Protein toxic aggregates such as aggregated transthyretin which, is a placental toxin elevated in preeclampsia, have been suggested to contribute to the pathogenesis of this disorder. Elevated levels of aggregated transthyretin are formed in preeclampsia and transported through the secretion of placental extracellular vesicles by syncytiotrophoblasts ( 42 ). Aggregated transthyretin in these vesicles may also allow targeted delivery of these toxic proteins to other maternal organs, conducting a signal of cellular stress from the diseased placenta and contributing to the pathogenesis of preeclampsia ( 42 ).…”

“…Elevated levels of aggregated transthyretin are formed in preeclampsia and transported through the secretion of placental extracellular vesicles by syncytiotrophoblasts ( 42 ). Aggregated transthyretin in these vesicles may also allow targeted delivery of these toxic proteins to other maternal organs, conducting a signal of cellular stress from the diseased placenta and contributing to the pathogenesis of preeclampsia ( 42 ). Protein toxic aggregates is a novel approach, they have been considered to be pathogenic in other diseases, thus the possibility of contributing to excessive inflammation in preeclampsia through creating cellular stress should also be considered ( 42 – 44 ).…”

Protein Misfolding during Pregnancy: New Approaches to Preeclampsia Diagnostics

“…Recent studies have shown that misfolded proteins accumulate in the urine, serum, and the placenta of women with PE [99][100][101][102][103][104]. Indeed, proteins are vulnerable to misfolding because of changes in genetic and environmental factors [105] (Figure 1).…”