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

• Published in: Communications biology Vol. 7; no. 1; p. 530
• Main Authors: Raja Xavier, Janet P, Rianna, Carmela, Hellwich, Emily, Nikolou, Iliana, Lankapalli, Aditya Kumar, Brucker, Sara Y, Singh, Yogesh, Lang, Florian, Schäffer, Tilman E, Salker, Madhuri S
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 04.05.2024; Nature Publishing Group UK; Nature Portfolio
• Subjects: Actin; Atomic force microscopy; Botulinum toxin; Cytoskeleton; Electrical impedance; Endometrium; Endometrium - metabolism; Endometrium - pathology; Extracellular matrix; Female; Growth factors; GTP-binding protein; Humans; Kinases; Microenvironments; Microscopy, Atomic Force; p21-Activated Kinases - genetics; p21-Activated Kinases - metabolism; Placenta; Placenta growth factor; Placenta Growth Factor - genetics; Placenta Growth Factor - metabolism; Polymerization; Pravastatin; Pre-eclampsia; Pre-Eclampsia - metabolism; Preeclampsia; Pregnancy; Pregnancy complications; Proteins; Proteomics; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Signal Transduction; siRNA; Spectroscopy; Stromal cells; Stromal Cells - metabolism
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-06220-7

Cell stiffness is regulated by dynamic interaction between ras-related C3 botulinum toxin substrate 1 (Rac1) and p21 protein-activated kinase 1 (PAK1) proteins, besides other biochemical and molecular regulators. In this study, we investigated how the Placental Growth Factor (PlGF) changes endometrial mechanics by modifying the actin cytoskeleton at the maternal interface. We explored the global effects of PlGF in endometrial stromal cells (EnSCs) using the concerted approach of proteomics, atomic force microscopy (AFM), and electrical impedance spectroscopy (EIS). Proteomic analysis shows PlGF upregulated RhoGTPases activating proteins and extracellular matrix organization-associated proteins in EnSCs. Rac1 and PAK1 transcript levels, activity, and actin polymerization were significantly increased with PlGF treatment. AFM further revealed an increase in cell stiffness with PlGF treatment. The additive effect of PlGF on actin polymerization was suppressed with siRNA-mediated inhibition of Rac1, PAK1, and WAVE2. Interestingly, the increase in cell stiffness by PlGF treatment was pharmacologically reversed with pravastatin, resulting in improved trophoblast cell invasion. Taken together, aberrant PlGF levels in the endometrium can contribute to an altered pre-pregnancy maternal microenvironment and offer a unifying explanation for the pathological changes observed in conditions such as pre-eclampsia (PE).