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Forces are important in the cardiovascular system, both for the regulation of vascular homeostasis but also as instigators of pathology. Endothelial cells covering the inner lining of blood vessels are constantly exposed to mechanical (haemodynamic) forces due to the flowing blood. One of these forces is the frictional force of shear stress that can differ depending on the type and shape of the vessel. Blood flow patterns can range from uniform, laminar flow to non-uniform, disturbed flow. Laminar (or atheroprotective) flow is found in straight regions of the vasculature and is protective. Endothelial cells in these regions are aligned in the direction of flow and upregulate anti-inflammatory genes. In contrast, regions of the vasculature, such as bifurcations or branch points, that are exposed to disturbed (or atheroprone) flow patterns are more prone to development of disease because disturbed flow initiates cellular signalling pathways that promote inflammation, a reduction in the vascular lumen, atherogenesis, and eventually atherosclerosis. How do endothelial cells 'sense' the type of flow they are exposed to? How do they decode the mechanical force into biochemical signals that will ultimately determine their phenotype? Endothelial cells are equipped with the exquisite ability to sense and distinguish between these different types of blood flow and respond in completely different ways. Although considerable effort has gone into understanding endothelial responses to blood flow, the mechanisms that underlie endothelial mechanosensing remain largely a mystery.
Our laboratory has pioneered the studies of endothelial mechanosensing and has championed the use of a multi-disciplinary approach to this scientific problem. We use a variety of approaches ranging from bioengineering and elegant magnetic tweezers studies, molecular and cell biology, to in vivo models of haemodynamics using knockout and transgenic animals.
Leveraging our expertise in mechanotransduction, we have investigated the role of genetic variants identified through Coronary Artery Disease (CAD) GWAS (in a collaborative study with the Channon and Watkins labs). One of these is the junctional protein encoded by the gene JCAD, which we showed is crucial for the endothelial flow response. Ongoing work investigates the role of JCAD in mechanotransduction and mechanosensing using our force and shear stress systems.
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Nature Cardiovascular Researchno. 6 (2023): 517-529
Current Opinion in Physiology (2023): 100673
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