Mechanosensation in vascular endothelium: the role of purinergic signalling

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The lumen of arteries is lined by a monolayer of endothelium which is in direct contact with the shearing mechanical force of blood flow. The endothelium needs to sense and respond to changes in such forces (blood flow) and release signalling molecules that alter vascular tone, modulating local tissue perfusion and systemic blood pressure. The molecular basis for shear force detection in endothelium is poorly defined yet may represent an important drug target for the modulation of blood pressure and vascular remodeling following ischemia. ATP can be physiologically released by mammalian cells following mild mechanical stimulation, though the cellular release routes remain controversial. The biological effects of extracellular ATP are mediated by activation purinergic receptors (P2Y, metabotropic; P2X ionotropic). This project will investigate the molecular mechanisms underlying flow-dependent ATP release in vascular endothelium and the subsequent pathways through which purinergic receptors signal to produce vasodilatory molecules and influence vascular tone. The project will involve training in cutting-edge techniques in vascular biology and pharmacology including pressure myography, calcium imaging, lentivirus production and delivery, cellular bioimaging conditions of flow and work with human tissue.