Biology subjects

Ridger, V.

Publications and source records attributed to Ridger, V..

4 recordsLinked to original sources

bioRxiv2025

Neutrophil derived microvesicles induce endothelial cell dysfunction associated with atherosclerotic plaque erosion.

Atherosclerosis is a major cause of death globally. It is characterised by the development of fibro-fatty lesions in the artery wall that can impede blood flow and lead to myocardial infarction. Historically, research has focused primarily on plaque rupture. However, the importance of erosion of the endothelium leading to thrombosis in plaques with lower lipid content, fewer inflammatory cells and a thick fibrous cap has emerged. Neutrophils have recently been implicated in plaque erosion through the induction of endothelial cell dysfunction. Neutrophils produce 0.1-1m extracellular vesicles (microvesicles) from their cell membrane that are linked with atherosclerotic plaque progression. The hypothesis that neutrophil microvesicles affect plaque erosion through driving endothelial cell dysfunction and platelet adhesion was investigated. Peripheral blood neutrophils and platelets were isolated from healthy subjects and neutrophils stimulated with native LDL to induce microvesicle release. These microvesicles were found to contain proteases capable of degrading extracellular matrix proteins. Incubation of human coronary artery endothelial cells with neutrophil microvesicles lead to an increase in apoptosis and detachment, and a decrease in migration and proliferation in the endothelial cells. Moreover, microvesicles induced an increase in both platelet P-selectin expression and platelet-endothelial cell interaction. This study demonstrates the propensity of neutrophil microvesicles to promote functions within human coronary artery endothelial cells that may predispose the endothelium to erosion and thrombosis and identifies a potential link between a known risk factor for atherosclerosis, elevated LDL cholesterol, and the production of neutrophil microvesicles. These findings highlight the need for further research to better understand the effects of neutrophil microvesicles in atherosclerosis.

cell biology↗

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↗

bioRxiv2018

Neutrophil microvesicles drive atherosclerosis by delivering miR-155 to atheroprone endothelium.

Neutrophils have been implicated in the pathogenesis of atherosclerosis, a lipid-driven disease of arteries, but they are seldom found in atherosclerotic plaques. To resolve this longstanding paradox, we investigated whether neutrophil-derived microvesicles may influence arterial pathophysiology. Clinical and pre-clinical studies revealed that levels of circulating neutrophil microvesicles were enhanced by exposure to a high fat diet, a known risk factor for atherosclerosis. Neutrophil microvesicles accumulated at disease-prone regions of arteries that are exposed to complex flow patterns, and they promoted vascular inflammation and atherosclerosis in a murine model. Using cultured endothelial cells exposed to disturbed flow, it was demonstrated that neutrophil microvesicles promoted inflammatory gene expression by delivering a microRNA (miR-155) that enhanced NF-{kappa}B activation. Similary, neutrophil microvesicles increased miR-155 and enhanced NF-{kappa}B at disease-prone sites of disturbed flow in arteries of mice. We conclude that delivery of microvesicles carrying miR-155 to disease-prone regions of arteries provides a novel mechanism by which neutrophils contribute to vascular inflammation and atherogenesis.

cell biology↗