Evidence From Human Placenta, Endoplasmic Reticulum–Stressed Trophoblasts, and Transgenic Mice Links Transthyretin Proteinopathy to Preeclampsia

Abstract

Background: We have demonstrated that protein aggregation plays a pivotal role in the pathophysiology of preeclampsia and identified several aggregated proteins in the circulation of preeclampsia patients, the most prominent of which is the serum protein TTR (transthyretin). However, the mechanisms that underlie protein aggregation remain poorly addressed. Methods: We examined TTR aggregates in hypoxia/reoxygenation-exposed primary human trophoblasts (PHTs) and the preeclampsia placenta using complementary approaches, including a novel protein aggregate detection assay. Mechanistic analysis was performed in hypoxia/reoxygenation-exposed PHTs and Ttr transgenic mice overexpressing transgene-encoded wild-type human TTR or Ttr −/− mice. High-resolution ultrasound analysis was used to measure placental blood flow in pregnant mice. Results: TTR aggregation was inducible in PHTs and the TCL-1 trophoblast cell line by endoplasmic reticulum stress inducers or autophagy-lysosomal disruptors. PHTs exposed to hypoxia/reoxygenation showed increased intracellular BiP (binding immunoglobulin protein), phosphorylated IRE1α (inositol-requiring enzyme-1α), PDI (protein disulfide isomerase), and Ero-1, all markers of the unfolded protein response, and the apoptosis mediator caspase-3. Blockade of IRE1α inhibited hypoxia/reoxygenation-induced upregulation of Ero-1 in PHTs. Excessive unfolded protein response activation was observed in the early-onset preeclampsia placenta. Importantly, pregnant human TTR mice displayed aggregated TTR in the junctional zone of the placenta and severe preeclampsia-like features. High-resolution ultrasound analysis revealed low blood flow in uterine and umbilical arteries in human TTR mice compared with control mice. However, Ttr −/− mice did not show any pregnancy-associated abnormalities. Conclusions: These observations in the preeclampsia placenta, cultured trophoblasts, and Ttr transgenic mice indicate that TTR aggregation is an important causal contributor to preeclampsia pathophysiology.

HMGB1: a double-edged sword and therapeutic target in the female reproductive system

“…In patients with PE, the placenta is defective and trophoblast cells are hypoxic ( 166 ), which leads to increased secretion of HMGB1 by hypoxic trophoblastic tissues. The secretion of HMGB1 induces endothelial cell hyperpermeability via the TLR4/caveolin-1 pathway.…”

Thyroid hormones: Metabolism and transportation in the fetoplacental unit

“…TTR, as one of the most prominent aggregated proteins in preeclamptic mothers’ circulation, serves as a marker of preeclampsia. In vitro, TTR aggregations on human trophoblast are shown to be induced by endoplasmic reticulum stress inducers and autophagy disruptors, indicating that TTR could be a contributor to preeclampsia pathophysiology (Cheng et al, 2022). In line with this data, several human mutations in the TTR gene have been associated with amyloid TTR disease, resulting in systemic deposition of conglomerates of TTR in the extracellular space with variable degrees of disability (Conceição et al, 2019).…”

Gestational Age-Dependent Regulation of Transthyretin in Mice during Pregnancy

“…Our prior studies have demonstrated that TTR misfolding and aggregation contribute to the pathogenesis of preeclampsia (PE), a pregnancy-specific, multifactorial syndrome characterized by hypertension after 20 weeks of gestation [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. PE is a leading cause of maternal and fetal morbidity and mortality, affecting 3–8% of all pregnancies worldwide [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. Despite extensive investigations, the etiology of PE remains poorly understood.…”

“…Our recent studies have revealed a robust deposition of TTR aggregates in trophoblasts in the PE placenta. This is thought to be caused by excessive endoplasmic reticulum (ER) stress, exhausted unfolded protein response, and impaired autophagy-lysosomal machinery [ 17 , 18 ]. Furthermore, transgenic mice over-expressing human TTR experienced TTR aggregate accumulation in the placenta, PE-like features, and increased production of sFlt-1 and soluble endoglin [ 17 ].…”

“…This is thought to be caused by excessive endoplasmic reticulum (ER) stress, exhausted unfolded protein response, and impaired autophagy-lysosomal machinery [ 17 , 18 ]. Furthermore, transgenic mice over-expressing human TTR experienced TTR aggregate accumulation in the placenta, PE-like features, and increased production of sFlt-1 and soluble endoglin [ 17 ]. Taken together, our prior findings indicate TTR aggregation as a causative contributor to the PE etiology.…”