LICAMM Endothelial Piezo1 channels of human placenta and their physiological roles

Summary

Piezo1 is an intriguing newly discovered membrane protein. Three Piezo1s assemble to form a trimeric Ca2+-permeable non-selective cationic channel which senses membrane tension. We showed that Piezo1 channels are critical mechanical force sensors of cardiovascular biology with special roles in vascular development and long-term implications for cardiovascular health and disease. In a seminal article we found that disruption of endothelial Piezo1 in mice caused growth retardation from embryonic day 9.5.

Moreover, endothelial cells of Piezo1-disrupted mice failed to respond to the frictional mechanical force of shear stress and reconstitution of Piezo1 channels in otherwise resistant cells conferred shear stress sensing (1, 2). We concluded that Piezo1 channels are critical sensors of shear stress driven by the newly beating heart, transducing this force into vascular maturation and organ perfusion. Furthermore we found that in adult physiology Piezo1 channels sense physical activity to advantageously reset vascular control (3). It has since been found that PIEZO1 mutations are linked to abnormalities in human lymphatic vascular development and non-immune hydrops fetalis. Therefore endothelial Piezo1 channels are important in human as well as mouse vascular development.

The aim of this project is to determine the properties of single Piezo1 channels in endothelial cells freshly-isolated from human placentas of women who delivered babies of normal or low birth weight. The studies will test the hypothesis that functional abnormalities in Piezo1 channels are a factor underlying intrauterine growth restriction.

The main techniques used in the studies will be methods for isolation of fresh endothelial cells, patch-clamp single channel and membrane potential recordings, methods for application of mechanical force, complementary biochemical and immunofluorescence approaches, and isobaric contraction recordings. Single channel recording is a specialized technique which yields highly quantitative and precise data about the properties of channels – it will be the primary focus of the main 3-year project.

The project will involve the student in an exciting collaborative project between basic scientists at the university (Jian Shi, Melanie Ludlow and David Beech) and medical doctors at the adjacent teaching hospital (Lara Morley and Nigel Simpson).

References:

Li J et al., Piezo1 integration of vascular architecture with physiological force. Nature. 2014, 515(7526):279-82.

Li J et al., Endothelial Piezo1: life depends on it. Channels (Austin). 2015;9(1):1-2

Rode B et al., Piezo1 channels sense whole body physical activity to reset cardiovascular homeostasis and enhance performance. Nat Commun. 2017: 8:350

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