The role of mechanosensing in placental vascular function

Introduction The mechanical force of blood flow is a fundamental determinant of vascular homeostasis. This frictional stimulation of cells, fluid shear stress (FSS), is increasingly recognised as being essential to placental development and function. FSS generates vasodilatation through the release of endothelial nitric oxide, a process vital for normal pregnancy vascular adaption. The fetus is reliant on placental perfusion to meet its circulatory and metabolic demands. Failure of the mechanisms enabling responsive interaction between fetoplacental and maternal circulations results in placental insufficiency, a cause of fetal growth restriction. The mechanosensitive cation channel, Piezo1, is reported to be a direct sensor of FSS, and is required for murine embryonic vascular development. This study aimed to determine whether Piezo1 is important for mechanosensing in human fetoplacental endothelial cells (FpECs), in normal pregnancy and that affected by placental insufficiency. Methods and main results Patients were consented at Leeds Teaching Hospitals Trust. Samples were allocated as appropriately grown for gestational age (AGA), or small for gestational age (SGA), defined as birthweight <10th percentile. FpECs were highly responsive to FSS, demonstrating alignment, upregulation of PIEZO1, eNOS phosphorylation, and activation of ADAM10- a downstream Notch signalling enzyme. FSS-induced alignment was suppressed by Piezo1 depletion. The Piezo1 chemical activator, Yoda1, caused strong dose-dependent elevation of the intracellular Ca2+ concentration. Yoda1 increased eNOS phosphorylation, and upregulated ADAM10 activity. SGA FpECs showed increased total and phosphorylated eNOS. Expression of PIEZO1 and Notch receptor 3 (NOTCH3) were upregulated in SGA. Yoda1-induced Ca2+ entry was reduced in the SGA group. Furthermore, Yoda1-evoked upregulation of Notch components was strikingly blunted in SGA. Conclusion Piezo1 channels are present and functional in the fetoplacental endothelium. Piezo1 is important for the normal response of FpECs to FSS, and activation initiates downstream pathways with important roles in vascular regulation. In placental insufficiency, mechanisms of FSS-sensing are compromised, allowing vasoconstrictor and anti-angiogenic effects to dominate. Efforts to compensate restricted blood flow via peNOS may be insufficient due to a lack of flow responsiveness and saturated NO system. Enhanced Piezo1 activity in response to Yoda1 suggests the possibility for developing tools to manipulate mechanosensors. As such, Piezo1 is an entry point to a more nuanced understanding of placental FSS-sensing, presenting an opportunity for future intervention in placental insufficiency.