Professor of Cardiovascular Biology
- Wellcome Trust Senior Fellow
Forces are important in the cardiovascular system, both in regulating vascular homeostasis but also as instigators of pathology. Endothelial cells lining blood vessels are constantly exposed to mechanical forces due to the flowing blood. One of these forces is the frictional force of shear stress that can differ depending on vessel geometry and type. 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 considered protective. Endothelial cells in these regions are aligned in the direction of flow and exhibit an anti-inflammatory phenotype. 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. Disturbed flow initiates cellular signalling pathways that ultimately promote inflammation, a reduction in the vascular lumen, atherogenesis, and eventually atherosclerosis. Endothelial cells are therefore 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. Some questions that we are currently investigating:
- How do endothelial cells sense and respond to shear stress (blood flow)?
- What are the mechanosensitive pathways that are responsible for development of atherosclerosis and cardiovascular disease?
Cellular Communication in the Heart
Heart disease is a major cause of morbidity and mortality in developed countries. A common characteristic of heart patients is the inability of the heart muscle cells (cardiomyocytes) to contract properly. Although mutations in the mechanotransduction apparatus that regulates cardiomyocyte contractility are known to be drivers of cardiac defects, our laboratory has obtained new evidence for a paradigm shift, requiring us to rethink 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.
Protein Translation and Cardiovascular Function
Regulation of protein synthesis is critical both for maintaining cardiovascular homeostasis and during development of disease. Aminoacyl-tRNA synthetases (aaRSs) are critical enzymes in protein synthesis whose role is to pair the right amino acid with the correct tRNA. In the last 20 years, non-translational functions of vertebrate aaRSs have been discovered, including roles in the cardiovascular system. Our own work has identified a natural proteolytic fragment of tyrosine aminoacyl tRNA synthetase (mini-TyrRS) that stimulates blood vessel growth and is cardioprotective in a model of heart attack. The currect project uses expertise in biochemistry, cell biology and physiology and state-of-the-art approaches for profiling to test the functions of mini-TyrRS in the setting of cardiovascular disease.