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Scientific animation of blood cells inside the lumen of a blood vessel

How and why do atherosclerotic plaques develop? Scientists already know  that turbulent blood flow patterns predispose arteries to develop plaques, but it’s been unclear how turbulence in blood vessels switches healthy endothelial cell lining into a disease state. Now, in a new study published in Science Advances, Professor Ellie Tzima’s group uses a multi-disciplinary approach to identify a molecular sensor for cellular transformation.

 In areas of turbulent flow, the healthy endothelium that lines and protects blood vessels starts transforming and transitioning into a mesenchymal phenotype, a process called endothelial-to-mesenchymal transition (EndMT). During this complex process, endothelial cells lose or reduce expression of their endothelial markers, and instead, start adopting a mesenchymal phenotype, characterised by expression of mesenchymal-specific proteins. Although EndMT is critical during embryonic development, it is also an important mechanism in the pathogenesis of several human diseases, including cancer, cardiovascular disease and even COVID-19 complications.

Professor Tzima and her team were able to identify a mechano-receptor expressed in endothelial cells that senses turbulent blood flow, and signals to set off a cascade of processes that shift cells towards this endothelial-to-mesenchymal transformation. 

 Professor Ellie Tzima said: “What is most fascinating is that application of force onto a single receptor is enough to induce a complex signalling pathway that will ultimately lead to endothelial transformation and atherosclerosis.

The role of haemodynamic forces as instigators and contributors to cardiovascular disease is now widely recognised. This study identifies novel therapeutic strategies to target the mechanobiology of endothelial cells in cardiovascular disease. “

Dr Vedanta Mehta, co-first author of the study said “It is indeed very interesting that a cellular receptor, previously only known to respond to biochemical stimuli, can also respond to mechanical forces to initiate pathological signalling that ultimately culminates in atherosclerosis.

 It is now widely appreciated that fluid forces play a major contribution towards the development of cardiovascular disorders, yet there is not a single therapy to date that targets mechanotransduction pathways to ameliorate pathogenesis. We hope that this study will pave the way for the development of novel ‘mechano-medicines’ to reduce the burden of heart disease”.

 Dr Kar Lai Pang, co-first author of the paper said: “It is intriguing that our group has discovered a novel mechanoreceptor that responds to turbulent blood flow which leads to EndMT pathophysiological process and atherosclerosis. Unveiling new novel molecular targets will enhance our understanding of disease pathways and hence development of new drugs and therapeutics approaches for the vascular disease.”

This work was undertaken in collaboration with researchers from Emory University and UNC, USA. The major funders were Wellcome and the British Heart Foundation.

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