Mechanotransduction in vascular physiology and pathology

Endothelial cells that line blood vessels are constantly exposed to forces, such as shear stress, due
to the flowing blood. These forces are not only critical for vascular development, but also regulate
vessel physiology and disease postnatally. Shear stress is sensed by mechanoreceptors expressed
on endothelial surfaces which decode mechanical signals into biochemical signalling cascades that
will ultimately define vessel phenotype and function. We have recently discovered a novel
mechanoreceptor that dictates formation of atherosclerotic plaques in areas of disturbed flow. We
now propose to use a cross-disciplinary approach to address the relevance of this mechanoreceptor
in human disease; its relevance in physiological responses and its molecular mechanism of action.
Completion of this work will not only define fundamental principles in basic science and
mechanotransduction, but will opens up new avenues for translational research and therapeutic
development against atherosclerosis and cardiovascular disease.

The frictional force per unit area of shear stress is an essential regulator of vascular homeostasis and pathology. Endothelial cells that line blood vessels sense and decode shear stress patterns using mechanoreceptors expressed on their surface. Areas of disturbed shear stress are prone to development of atherosclerotic plaques due to chronic activation of pro-inflammatory pathways in endothelial cells. In contrast, straight regions of arteries that are exposed to laminar shear stress are largely protected from disease. We have recently identified the cell guidance receptor, Plexin D1 (PLXND1), as a novel mechanoreceptor in endothelial cells. We have shown that endothelial PLXND1 is required for sensing shear stress and activation of inflammatory pathways that will ultimately lead to development of atherosclerosis. We therefore hypothesise that PLXND1 is a central regulator of endothelial mechanotransduction and therefore represents a novel target for atherosclerosis. To test this hypothesis, we propose three work packages (WPs) that will determine the molecular mechanisms by which PLXND1 regulates mechanotransduction; the role of PLXND1 in physiological flow-mediated remodelling; and its role in human atherosclerosis and association of PLXND1 variants with coronary artery disease.