Revised Two-Stage Model of Preeclampsia Based on Autophagic Dysfunction: A Comprehensive Review

Area of Science:

• Obstetrics and Gynecology
• Cellular Biology
• Pathophysiology

Background:

• Preeclampsia pathogenesis remains incompletely understood.
• Early placentation involves extravillous trophoblast invasion into the myometrium under challenging conditions.
• The 'One-Third Myometrium Enigma' highlights the necessity of trophoblast traversal to this region.

Purpose of the Study:

• To propose a revised two-stage model of preeclampsia.
• To investigate the role of autophagy in extravillous trophoblast invasion.
• To link autophagic dysfunction to preeclampsia development and maternal syndrome.

Main Methods:

• Proposed a two-stage model centered on autophagy.
• Hypothesized timed rise in basal autophagy and TFEB-driven lysosomal programs.
• Identified potential failure modes including impaired autophagic flux and persistent hypoxia signaling.

Main Results:

• Autophagic dysfunction may lead to shallow trophoblast invasion, placental hypoxia, and fetal growth restriction.
• Impaired autophagy is suggested as a contributor to preeclampsia.
• Dysfunction can arise from inhibited autophagosome-lysosome fusion or prolonged HIF-1α activity.

Conclusions:

• Preeclampsia can be reframed as a disorder of placental quality control.
• Impaired autophagy is a testable contributor to preeclampsia pathogenesis.
• Future directions include risk stratification using autophagy markers and therapeutic modulation of autophagy.