Key result
ER stress inhibits trophoblast invasion and increases sFLT1/PlGF ratio via HTRA1.
Why the study?
The pathogenesis of hypertensive disorder of pregnancy is incompletely understood, and the involvement of endoplasmic reticulum stress in regulating HTRA subtype expression and pathophysiology had not been characterized in extravillous trophoblasts.
ER stress may contribute to the pathogenesis of hypertensive disorders of pregnancy by inhibiting extravillous trophoblast invasion via downregulation of HTRA1.
May implicate ER stress in preeclampsia pathogenesis via HTRA1; hypothesis-generating in animal models, human validation needed.
The pathogenesis of hypertensive disorder of pregnancy (HDP), which affects about 10% of pregnant women, is still incompletely understood. Our previous study showed that endoplasmic reticulum (ER) stress influences high-temperature requirement A serine peptidase 1 (HTRA1) expression and trophoblast invasion. However, the involvement of ER stress in the regulation of HTRA subtype expression and pathophysiology of HDP has not been characterized in extravillous trophoblasts (EVTs). To investigate this, HTR8/SVneo EVTs cell line was treated with the ER stress inducers Thapsigargin (Thap) or Tunicamycin (Tuni). Treatment with either Thap or Tuni inhibited trophoblast invasion, reduced HTRA1 and HTRA3 expression, but did not alter HTRA2 or HTRA4 expression. Knockdown of HTRA1 or HTRA3 also inhibited trophoblast invasion. Furthermore, treatment with either ER stress inducer or HTRA1 silencing increased the ratio of soluble fms-like tyrosine kinase-1/placental growth factor (sFLT1/PlGF), which is a marker of HDP. Immunohistochemical analysis revealed that HTRA1 is localized to EVTs and the endometrial decidua in the placenta of patients with HDP. These results suggest that factors that cause ER stress could result in the inhibition of EVTs invasion via HTRA1.
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Yoshida et al. (2022) studied Hypertensive disorder of pregnancy. ER stress inducers (Thapsigargin or Tunicamycin) and HTRA1 silencing was evaluated on Trophoblast invasion, HTRA expression, and sFLT1/PlGF ratio. Treatment of extravillous trophoblasts with ER stress inducers or HTRA1 silencing inhibited invasion and increased the sFLT1/PlGF ratio, suggesting ER stress inhibits invasion via HTRA1.
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