Atherosclerosis is an inflammatory disease of arteries that leads to heart attack and stroke, which are among the most significant causes of death and disability in our society. Although the arterial endothelium is uniformly exposed to inflammatory mediators induced by systemic risk factors (e.g. obesity, dyslipidemia, diabetes), the focal nature of atherosclerotic lesions implicates spatial heterogeneity in the endothelial inflammatory response. Lacking is a thorough understanding of how signaling via hemodynamic cues converges with a multitude of other factors driven by diet, metabolism and genetics to affect atherogenesis. Our studies have contributed to the emerging paradigm that disturbed flow is permissive to atherosclerosis in that it contributes to a state of chronic stress or dysregulation which might be exacerbated by factors that affect systemic inflammation.
Vascular mimetics to study inflammation and susceptibility to atherosclerosis:
- Our laboratory uses a variety of techniques to expose cultured endothelial cells to defined flows/ shear stresses that mimic physiological conditions. We apply these in mechanistic studies to test hypotheses related to the superposition of metabolic stress with hydrodynamic factors in the regulation of endothelial function and pathology.
- We have a long-standing collaboration with Prof Simon’s group through which we apply microfluidic-based devices for the on-chip assessment of endothelial inflammatory phenotype through the real-time imaging of cell adhesion molecule expression and monocyte adhesion.
- A major advantage of this approach lies in the ability to quantify outcomes associated with endothelial dysfunction in cells exposed to inflammatory mediators such as dietary lipids and cytokines under defined hydrodynamic conditions that mirror those in atherogenic vessels.
- Ultimately, in addition to providing insight into the early inflammatory events underlying atherosclerosis, we envision that these technologies will lead to faithful ex vivo approaches for assessing an individual’s risk of inflammation-mediated cardiovascular disease.
Atherogenicity of dietary lipids:
- Atherosclerosis is exacerbated by factors such as dyslipidemia and obesity that are associated with metabolically-induced chronic low grade inflammation, an array of stress responses, and endothelial dysfunction. We apply our microfluidic platform to the analysis of the inflammatory potential of circulating lipoproteins isolated from human subjects after a high fat meal. The overall goal of the project is to identify the mechanisms by which these lipoproteins act as pro-inflammatory mediators in shifting the balance from healthy to atherogenic endothelium in subjects ranging from healthy, to those with risk factors for cardiovascular disease (i.e. metabolic syndrome), to those undergoing treatment for acute myocardial infarction. Our studies are investigating the mechanisms by which lipids impact inflammation in endothelium and monocytes, the regulation of those mechanisms by biomechanical cues, and the effects of diet and supplementation (e.g. with omega-3 fatty acids).
Shear stress modulation of RAGE-mediated inflammation:
- Diabetes is an important risk factor associated with the metabolic syndrome that affects a large proportion of our population. We recently reported a novel role for arterial hemodynamics in the regulation of RAGE (receptor for advanced glycation end products)-mediated inflammation in arterial endothelium. This receptor is found in atherosclerotic plaques and to a greater extent in diabetes. It recognizes ligands produced as a consequence of chronic hyperglycemia and the pro-inflammatory state of diabetes. We found RAGE expression and activity to be modulated by shear stress, consistent with a greater proclivity to inflammation under conditions associated with susceptibility to lesion formation in arteries. We continue to investigate the signaling mechanisms underlying the RAGE inflammatory axis and its regulation by hemodynamics.
Influence of endothelial cell aging on the inflammatory mechanisms of atherogenesis:
- This project examines aging as a risk factor for cardiovascular disease. Our objectives are to identify molecular signatures of aging that may lead to functional impairment of endothelium and measure age-associated differences in response to inflammatory activation that might contribute to atherosusceptibility.