Abstract
STUDY QUESTIONDoes the shear stress sensing ion channel subunit Piezo1 have an important mechanotransduction role in human fetoplacental endothelium?SUMMARY ANSWERPiezo1 is present and functionally active in human fetoplacental endothelial cells, and disruption of Piezo1 prevents the normal response to shear stress.WHAT IS KNOWN ALREADYShear stress is an important stimulus for maturation and function of placental vasculature but the molecular mechanisms by which the force is detected and transduced are unclear. Piezo1 channels are Ca2+-permeable non-selective cationic channels which are critical for shear stress sensing and maturation of murine embryonic vasculature.STUDY DESIGN, SAMPLES/MATERIALS, METHODSWe investigated the relevance of Piezo1 to placental vasculature by studying human fetoplacental endothelial cells (FpECs) from healthy pregnancies. Endothelial cells were isolated from placental cotyledons and cultured, for the study of tube formation and cell alignment to shear stress. In addition, human placental arterial endothelial cells were isolated and studied immediately by patch-clamp electrophysiology.MAIN RESULTS AND THE ROLE OF CHANCEThe synthetic Piezo1 channel agonist Yoda1 caused strong elevation of the intracellular Ca2+ concentration with a 50% effect occurring at about 5.4 μM. Knockdown of Piezo1 by RNA interference suppressed the Yoda1 response, consistent with it being mediated by Piezo1 channels. Alignment of cells to the direction of shear stress was also suppressed by Piezo1 knockdown without loss of cell viability. Patch-clamp recordings from freshly isolated endothelium showed shear stress-activated single channels which were characteristic of Piezo1.LIMITATIONS, REASONS FOR CAUTIONThe in vitro nature of fetoplacental endothelial cell isolation and subsequent culture may affect FpEC characteristics and PIEZO1 expression. In addition to Piezo1, alternative shear stress sensing mechanisms have been suggested in other systems and might also contribute in the placenta.WIDER IMPLICATIONS OF THE FINDINGSThese data suggest that Piezo1 is an important molecular determinant of blood flow sensitivity in the placenta. Establishing and manipulating the molecular mechanisms regulating shear stress sensing could lead to novel therapeutic strategies to improve blood flow in the placenta.LARGE-SCALE DATANot applicable.STUDY FUNDING/COMPETING INTEREST(S)LCM was funded by a Clinical Research Training Fellowship from the Medical Research Council and by the Royal College of Obstetricians and Gynaecologists, and has received support from a Wellcome Trust Institutional Strategic Support Fund. JS was supported by the Wellcome Trust and a BHF Intermediate Research Fellowship. HJG, CW, AJH and PJW were supported by PhD Studentships from BHF, BBSRC and the Leeds Teaching Hospitals Charitable Foundation respectively. All authors declare no conflict of interest.
Highlights
Together with the maternal uteroplacental circulation, the fetoplacental vasculature is vital for placental perfusion and a critical determinant of foetal growth and a successful pregnancy outcome (Kingdom et al, 2000; Su, 2015)
STUDY DESIGN, SAMPLES/MATERIALS, METHODS: We investigated the relevance of Piezo1 to placental vasculature by studying human fetoplacental endothelial cells (FpECs) from healthy pregnancies
Knockdown of Piezo1 by RNA interference suppressed the Yoda1 response, consistent with it being mediated by Piezo1 channels
Summary
Together with the maternal uteroplacental circulation, the fetoplacental vasculature is vital for placental perfusion and a critical determinant of foetal growth and a successful pregnancy outcome (Kingdom et al, 2000; Su, 2015). Fetoplacental endothelial cells (FpECs) are key regulators of angiogenesis and vasomotor tone, through the production of vasoactive mediators (Su, 2015). When blood flow through the placenta is compromised, foetal growth restriction (FGR) can result (Kingdom et al, 2000; Su, 2015). Efforts to develop therapies for FGR are hampered by a lack of knowledge of the molecular mechanisms responsible for regulating blood flow through the placenta
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