Simvastatin Restores Uteroplacental Hemodynamics and Trophoblast Function in Obstetric Antiphospholipid Syndrome in a Placenta-on-a-Chip Model.

Abstract

Obstetric antiphospholipid syndrome (OAPS) presents substantial clinical challenges owing to limited therapeutic options. The hemodynamic mechanisms underlying statin protection in OAPS remain unclear. In this study, the therapeutic potential of simvastatin in OAPS was investigated. Herein, an OAPS mouse model was used to evaluate the effects of simvastatin on pregnancy outcomes and uteromaternal hemodynamics. A placenta-on-a-chip platform was engineered to assess trophoblast invasion under high shear stress. Transcriptome sequencing and molecular assays validated the mechanisms by which simvastatin mitigates endothelial injury induced by antiphospholipid antibodies. Simvastatin attenuated maternal vascular inflammation and rectified uteromaternal hemodynamic aberrations in mice. Furthermore, treatment indirectly promoted trophoblast invasion under high shear stress, facilitating spiral artery remodeling and improving placental perfusion. Mechanistically, these effects were mediated by activation of the endothelial Kruppel-like factor 2 (KLF2)/endothelial nitric oxide synthase (eNOS) pathway. In summary, simvastatin ameliorates placental hypoperfusion and restores trophoblast function disrupted by aberrant hemodynamics via regulation of endothelial KLF2/eNOS signaling. These findings highlight simvastatin as a potential therapeutic option for refractory OAPS.