DPHIL OPPORTUNITIES AVAILABLE
Professor of Cardiovascular Biology
- Wellcome Trust Senior Fellow
Force sensing in the cardiovascular system
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.
Cellular Communication in the Heart
A common characteristic of heart patients is the inability of the heart muscle cells (cardiomyocytes) to contract properly. Although contractility defects are normally associated with mutations in the mechanotransduction apparatus of cardiomyocytes, our laboratory has obtained new evidence for a paradigm shift, requiring us to rethink the causative mechanisms that govern heart disease. We have recent evidence that point at the importance of cellular communication between endothelial cells and cardiomyocytes in the heart both during normal embryonic development and in heart disease.
The focus of this project is to identify novel pathways that regulate intercellular communication in the heart and, ultimately, cardiac function. We plan to use a multidisciplinary approach which integrates genetic mouse models, state-of-the-art imaging, RNA seq and metabolomics, co-culture models and in vitro studies of haemodynamics.
Eukaryotic initiation factor 6 regulates mechanical responses in endothelial cells.
Keen AN. et al, (2022), J Cell Biol, 221
Mechanical forces regulate endothelial-to-mesenchymal transition and atherosclerosis via an Alk5-Shc mechanotransduction pathway.
Mehta V. et al, (2021), Sci Adv, 7
The guidance receptor plexin D1 is a mechanosensor in endothelial cells.
Mehta V. et al, (2020), Nature, 578, 290 - 295
A mechanosensory complex that mediates the endothelial cell response to fluid shear stress.
Tzima E. et al, (2005), Nature, 437, 426 - 431
Haemodynamic and extracellular matrix cues regulate the mechanical phenotype and stiffness of aortic endothelial cells.
Collins C. et al, (2014), Nat Commun, 5
Endothelial Shc regulates arteriogenesis through dual control of arterial specification and inflammation via the notch and nuclear factor-κ-light-chain-enhancer of activated B-cell pathways.
Sweet DT. et al, (2013), Circ Res, 113, 32 - 39