Mechanotransduction in the placental endothelium: molecular mechanisms and implications for pregnancy complications

The placental endothelium is exposed to a distinctive and continuously changing mechanical microenvironment shaped by fluid shear stress, cyclic stretch, and hydrostatic pressure. Mechanotransduction maintains endothelial homeostasis through coordinated signaling involving the endothelial glycocalyx, integrin-based adhesions, mechanosensitive ion channels, including Piezo1 and TRPV4, Rho-family GTPases, and the Hippo–YAP/TAZ pathway, which serves as key regulators to convert mechanical stimuli into biochemical signals. Conversely, defective spiral-artery remodeling generates pathological placental perfusion, hypoxia-reoxygenation injury and altered paracrine signaling; these secondary disturbances may impair fetoplacental endothelial mitochondrial quality control by promoting DRP1 dependent mitochondrial fission and impairing mitochondrial fusion (MFN2/OPA1), resulting in mitochondrial fragmentation, reactive oxygen species accumulation, and endothelial dysfunction. In severe preeclampsia (PE), reduced YAP/TAZ activity has been linked to both Hippo-dependent signaling through MST1/2 and LATS1/2 and Hippo-independent regulation involving the S1PR2–RhoA/ROCK–actin axis, with consequences for extravillous trophoblast invasion. Emerging approaches targeting placental mechanotransduction, including gestational stage-specific mitochondria-targeted antioxidants, pharmacological modulation of mechanosensitive ion channels, and placenta-on-a-chip platforms for mechanistic investigation and compound screening, offer new translational opportunities. This review integrates current understanding of placental endothelial mechanotransduction, examines its dysregulation in pregnancy-related complications including PE, fetal growth restriction (FGR), and gestational hypertension (GH). While partial mechanistic overlap exists between these conditions, GH represents a distinct and generally milder clinical phenotype; fetoplacental endothelial-specific molecular features of GH remain largely uncharacterized and constitute an important knowledge gap. We further identify priorities for the development of mechanism-based precision interventions for PE, FGR and GH.