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Introduction A successful pregnancy outcome depends on optimal physiological remodelling of the uteroplacental vasculature, a process driven by and regulated by blood flow, and characterised by vasodilatation and structural remodelling. This remodelling is key to ensuring that the developing placenta and fetus receive an adequate supply of nutrients and oxygen. When these processes go awry, pregnancies are afflicted by pre-eclampsia and fetal growth restriction (FGR), which can result in maternal and fetal complications, and an increased pre-disposition to heart and circulatory disorders in both the mother and the offspring. Despite extensive research over several years, our understanding of the molecular and cellular events that underpin pathophysiological uteroplacental remodelling is still very limited.Previous work from our lab has shown that the adaptor protein Shc plays a key role in flow-mediated collateral expansion and atherosclerosis. We now examine the importance of Shc in flow-mediated remodelling of the utero-placental vessels during pregnancy.Methods Conditional endothelial specific Shc knockout mice (Shc ECKO mice) and littermate controls were time-mated, and fetuses harvested at embryonic day (E)18.5. Uterine artery and fetal morphometrics were measured along with placental weights. Structural remodelling of the uterine spiral arteries, as assayed by trophoblast invasion (Fig 1), was assessed by staining for cytokeratin-8. In vitro experiments involving application of shear stress and tensional force were performed on control and SHC-depleted human uterine endothelial cells (ECs) to elucidate the mechanistic role of SHC in flow-mediated remodelling.Results Uterine arteries from Shc ECKO mice had significantly smaller lumen area and lumen circumference than controls. The extent of trophoblast invasion was attenuated in the uterine spiral arteries from Shc ECKO mice, suggestive of diminished remodelling. Placentae and fetuses harvested from Shc ECKO mice were also significantly lighter. Fetuses from Shc ECKO mice demonstrated the adaptive response of preferential growth of the brain over the rest of the body (brain sparing), a hallmark of asymmetric FGR. Exposure of SHC-depleted uterine ECs to shear stress and tensional force resulted in reduced mechano-activation of key signalling mediators.Conclusion Shc is a key mechanotransducer that governs the flow-mediated remodelling of the uteroplacental vasculature in pregnancy.