Excessive endometrial PlGF- Rac1 signalling underlies endometrial cell stiffness linked to pre-eclampsia

Area of Science:

• Reproductive biology
• Cellular mechanics
• Biochemistry

Background:

• Cell stiffness is crucial for tissue function and is regulated by complex molecular interactions.
• The endometrium's mechanical properties are vital for successful pregnancy establishment.
• Placental Growth Factor (PlGF) is implicated in pregnancy but its role in endometrial mechanics is not fully understood.

Purpose of the Study:

• To investigate how Placental Growth Factor (PlGF) influences endometrial stromal cell (EnSC) mechanics.
• To elucidate the molecular mechanisms by which PlGF modifies the actin cytoskeleton and cell stiffness.
• To explore the potential implications of these changes in pregnancy complications like pre-eclampsia.

Main Methods:

• Proteomics to identify PlGF-affected proteins in EnSCs.
• Atomic Force Microscopy (AFM) to measure cell stiffness.
• Electrical Impedance Spectroscopy (EIS) for global cell property assessment.
• siRNA-mediated gene silencing and pharmacological inhibition to probe molecular pathways.

Main Results:

• PlGF upregulated proteins involved in RhoGTPase signaling and extracellular matrix organization.
• PlGF treatment significantly increased Rac1 and PAK1 activity, actin polymerization, and EnSC stiffness.
• Inhibition of Rac1, PAK1, or WAVE2 counteracted PlGF-induced actin polymerization.
• Pravastatin treatment reversed PlGF-induced cell stiffening and enhanced trophoblast cell invasion.

Conclusions:

• PlGF significantly alters endometrial stromal cell mechanics by promoting actin cytoskeleton remodeling via the Rac1/PAK1 pathway.
• Aberrant PlGF levels in the endometrium can lead to an altered maternal microenvironment.
• These findings provide a potential mechanistic link between PlGF, endometrial dysfunction, and conditions such as pre-eclampsia (PE).