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Vascular Mechanotransduction in health and disease.

Forces are important in the cardiovascular system, acting as regulators of vascular physiology and pathology. Endothelial cells residing at the blood-vessel interface 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. These 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 generally protected from disease; 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 signalling cascades that promote chronic inflammation and eventually atherosclerosis. Endothelial cells are therefore endowed 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 vascular mechanotransduction, 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. One of the most common characteristic of heart patients is the inability of the heart muscle cells (cardiomyocytes) to contract properly. Mutations in the mechanotransduction apparatus that regulates cardiomyocyte contractility have long been assumed to be the principal driver of heart disease. However, our laboratory has obtained new evidence for a paradigm shift, requiring us to rethink mechanisms that govern heart disease. We have recent evidence that points at the importance of cellular communication between endothelial cells and cardiomyocytes in the heart both during normal embryonic development and in heart disease. We 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. The rate of protein synthesis is primarily determined by the rate of protein translation. The powerhouse of protein synthesis in the cell is the ribosome; aminoacyl tRNAs, which are formed by aminoacyl-tRNA synthetases (aaRSs) are delivered to the ribosome by elongation factors. The role of aaRSs is to pair the right amino acid with the correct tRNA, and thus, aaRSs are essential components for protein translation in every living species. In the last decade, 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 current 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.

Our team

Selected publications


Prof Hugh Watkins, University of Oxford

Prof Keith Channon, University of Oxford

Prof Armando Del Rio Hernandez, Imperial College London

Prof Craig Lygate, University of Oxford

Lab Alumni

Postdoctoral fellows

Dr Katrin Nather (2016-2017)

Dr Sally Chopra (2012-2016)

Dr Jianhua Huang (2015-2016)          

Dr Zhongming Chen (2006-2015)

Dr Yunhao Liu (2006-2011)

Postdoctoral fellows

Dr Sally Chopra (2012-2016)

Dr Jianhua Huang (2015-2016)          

Dr Zhongming Chen (2006-2015)

Dr Yunhao Liu (2006-2011)

Undergraduate Students

Ameen Bassam (2016)

Lindsey Buckingham (2006-2008)

Meghan Childs (2009-2011)

Sruthi Cherkur (2011-2013)

Tyler Moser-Katz (2012-present)

Eliezer Perez (2012)

Research Technicians

Michelle King (2006-2007)

Young Greenberg (2006-2009)