Roddie, H. | bioRxiv Science

bioRxiv2020

JAG1-NOTCH4 MECHANOSENSING DRIVES ATHEROSCLEROSIS

Endothelial cell (EC) sensing of fluid shear stress regulates atherosclerosis, a disease of arteries that causes heart attack and stroke. Atherosclerosis preferentially develops at regions of arteries exposed to low oscillatory shear stress (LOSS), whereas high shear regions are protected. We show using inducible EC-specific genetic deletion in hyperlipidaemic mice that the Notch ligands JAG1 and DLL4 have opposing roles in atherosclerosis. While endothelial Jag1 promoted atherosclerosis at sites of LOSS, endothelial Dll4 was atheroprotective. Analysis of porcine and murine arteries and cultured human coronary artery EC exposed to experimental flow revealed that JAG1 and its receptor NOTCH4 are strongly upregulated by LOSS. Functional studies in cultured cells and in mice with EC-specific deletion of Jag1 show that JAG1-NOTCH4 signalling drives vascular dysfunction by repressing endothelial repair. These data demonstrate a fundamental role for JAG1-NOTCH4 in sensing LOSS during disease, and suggest therapeutic targeting of this pathway to treat atherosclerosis.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pathology↗

bioRxiv2019

β1 integrin is a sensor of blood flow direction

The ability of endothelial cells (EC) to sense blood flow direction is a critical determinant of vascular health and disease. Unidirectional flow induces EC alignment and vascular homeostasis, whereas bidirectional flow has pathophysiological effects. EC express several mechanoreceptors that can respond to fluid flow (shear stress) but the mechanism for sensing the direction of shearing force is poorly understood. We observed using in vitro flow systems and magnetic tweezers that {beta}1 integrin is a key sensor of force direction because it is activated by unidirectional but not bidirectional shearing forces. Consistently, {beta}1 integrin was essential for Ca2+ signalling and cell alignment in response to unidirectional but not bidirectional shear stress. {beta}1 integrin activation by unidirectional force was amplified in EC that were pre-sheared in the same direction, indicating that alignment and {beta}1 integrin activity has a feedforward interaction which is a hallmark of system stability. En face staining and EC-specific genetic deletion studies of the murine aorta revealed that {beta}1 integrin is activated and is essential for EC alignment at sites of unidirectional flow but is not activated at sites of bidirectional flow. In summary, {beta}1 integrin sensing of unidirectional force is a key mechanism for decoding blood flow mechanics to promote vascular homeostasis.\n\nSUMMARY STATEMENTWe demonstrate using flow systems, magnetic tweezers and knockout mice that {beta}1 integrin is a sensor of shear stress direction in endothelial cells. {beta}1 integrin is activated by unidirectional hemodynamic shear force leading to calcium signalling and cell alignment, but it is not activated by bidirectional force.

cell biology↗