Abstract:
The decidual transformation during the menstrual cycle is pivotal in preparing the endometrium to support a healthy pregnancy1,2. This physiological adaptation of the endometrium involves changes in cell proliferation, morphology, mechanotransduction responses, immune cell modulation, and vascular remodelling3,4. Disruptions in these processes can result in pregnancy complications such as implantation failure, recurrent miscarriage, or preeclampsia, as well as contribute to cancer progression4,5. This underscores the importance of endometrial preconditioning occurring during each menstrual cycle in women's health. Preeclampsia is an obstetric complication characterized by inadequate extravillous trophoblast invasion and abnormal placentation6. Identifying molecular targets for early detection and treatment of preeclampsia is crucial, considering its severe clinical outcomes and lack of preventative measures7. Emerging evidence indicate that endometrial factors (altered decidual mechanics and angiogenesis) play a role in the onset of preeclampsia5,8-10. Therefore, investigating the maternal decidual health before pregnancy becomes imperative to uncover novel molecular pathways associated with defective decidua formation, which could potentially contribute to the pathogenesis of preeclampsia. PlGF, a pleiotropic cytokine, plays expanding roles in diverse biological processes, notably in disease advancement11. Anomalies in PlGF production within the endometrial stroma correlate with early pregnancy loss12. Elevated PlGF levels are associated with disruptions in cytoskeletal organization and aberrant angiogenesis across various tumor and disease pathologies13,14. This thesis aims to investigate the potential contribution of abnormal PlGF levels to the formation of defective decidua by influencing endometrial cellular mechanics and angiogenesis, with implications for preeclampsia pathogenesis. Additionally, it aims to explore if aberrant endometrial milieu influences the progression of cancer. Earlier studies indicate a possible involvement of abnormal endometrial PlGF and altered decidual biomechanics in the development of preeclampsia8,15,16. This thesis (Manuscript 1) shows aberrant PlGF stimulation leads to increased Rac1 activity, actin polymerization, and cell stiffness in endometrial stromal cells in vitro. Furthermore, dysregulation of Rac1 and actin induced by abnormal PlGF can be mitigated by treatment with the pharmacological drug pravastatin. Intriguingly, improved actin dynamics in the endometrium with pravastatin also enhances trophoblast cell invasion through endometrial cell monolayers. Aberrant PlGF also activates anti-angiogenic pathways in endometrial stromal cells through the NFAT5-SGK1-VEGF-A signaling cascade (Manuscript 2), hindering normal angiogenic cues in endothelial cells by promoting hypersprouting and impairment of endothelial barrier function. Inhibition of SGK1 improves angiogenic effects and promotes placental cell invasion, implicating SGK1 as a key modulator of PlGF-NFAT5 mediated pathological angiogenic signaling. Pathological angiogenesis is a key factor in fueling tumor growth and facilitating metastasis17. Increased NFAT5 expression was found to be correlated with more aggressive forms of endometrial cancer (Manuscript 3). In vitro NFAT5 overexpression influenced endometrial cancer cell activity with enhanced cell proliferation and migration. Intriguingly, increased NFAT5 expression triggered the activation of HIF-1α and COX2, fostering an inflammatory milieu within endometrial cancer cells. This environment is characterized by increased levels of PGE2, likely exacerbating tumour aggressiveness. Taken together, this thesis sheds light on how abnormal endometrial PlGF levels before pregnancy can disrupt mechanotransduction and uterine vessel development, contributing to impaired decidua formation. These novel maternal mechanistic pathways, which support defective decidua formation prior to conception, may potentially play a role in the manifestation of preeclampsia. Pravastatin emerges as a promising pharmacological candidate to reverse aberrant decidua, offering new therapeutic possibilities for managing preeclampsia. Furthermore, the shared involvement of NFAT5 in abnormal angiogenesis and carcinogenesis underscores the significance of pathological endometrial preconditioning in various endometrial pathologies.
Decidua