Stephanie Lehoux, PhD

Cardiovascular diseases, the most prevalent cause of death in Canada, usually result from atherosclerosis. During atherogenesis, elevated plasma lipids and inflammation lead to the accumulation of monocytes/macrophages, other leukocytes, and smooth muscle cell in the arterial wall, which in turn contribute to plaque growth and encroachment in the vascular lumen. Clinical events arise when the atherosclerotic plaque impedes blood low, either through gradual lesion growth of because of sudden rupture or erosion of the plaque.

Over the years, we have established a diverse research program spanning biomechanical factors to molecular biology to immunology, as we strive to understand why plaques form and how lesion formation can be reduced or reversed. Our projects include:

• Deciphering how high blood flow induces atherosclerotic plaque regression. Atherosclerotic plaques form in regions of low blood flow, whereas vessels exposed to protective high shear stress remain lesion-free. We developed a model of arteriovenous fistula in mice, where the right carotid artery is anastomosed into the jugular vein. This procedure increases the blood flow in the brachiocephalic artery and leads to a drastic plaque regression. We are investigating how changes in signaling within the plaque alters plaque composition and facilitates the exit of cell from the lesion. Our findings show that not only is shear stress protective against plaque development, but it can effectively reverse the atherosclerotic process.
• Evaluating how changes in gene transcription and translation impact atherosclerotic plaque formation. We are using mouse models where cell specific pathways are targeted to understand key processes that mediate the response to inflammation. On the one hand, we are examining how gene or protein methylation influence the behavior of myeloid cells in the liver and atheroma of mice fed a high fat diet. On the other, we have discovered that cap-binding dependent translation plays a key role in the phenotypic transition of smooth muscle cells from the arterial wall to the atherosclerotic plaque.
• Investigating the protective role of mannose in atherosclerotic plaque formation. This work hinged on the unique properties of D-mannose, a C−2 epimer of glucose. It is an important monosaccharide for protein glycosylation that also has potent anti-inflammatory properties that distinguishes it from other sugars. D-mannose supplementation has been shown to alter gut microbiota and to prevent obesity in young mice fed a high fat diet, and we have uncovered that this protective effect extends to animals with atherosclerosis. In our models, mannose supplementation appears to work though modification of the gut microbiota and circulating immune cells.