Atherosclerosis is a systemic disease;however, its manifestations tend to be focal and eccentric. Hemodynamics, specifically, fluid shear stress, is intimately involved in vascular oxidative stress. Oxidative stress induces molecular signaling regulates the development of intimal calcification that has been identified as a distinct, but relevant process to atherosclerosis. The vascular cells that calcify, previously termed calcifying vascular cells (CVC), are multipotent, with the capacity for chondrogenic, leiomyogenic (smooth muscle), and stromogenic (marrow stromal) lineages. Whether vascular calcification stabilizes atherosclerotic plaques or promotes plaque rupture remains undefined. We propose to assess vascular oxidative stress in non-obstructive, albeit inflammatory, lesions in explants of human coronary arteries and New Zealand White (NZW) rabbits. The development of Micro Electro Mechanical Systems (MEMS) shear stress and oxidative stress sensors in our lab has provided a means to undertake study of atherogenic hemodynamics and vascular oxidative stress. We hypothesize that flow disturbance as assessed by the micro-scale sensors in non-obstructive plaques is associated with oxidative stress relevant for initiation of the arterial plaque. This hypothesis will be tested by three Aims:
Aim 1 : Assess vascular oxidative stress in arterial regions exposed to atherogenic hemodynamics. The level of vascular oxidative stress will be determined from explants of arterial bifurcations of human coronary arteries using the MEMS oxidative stress sensors. Immunohistochemistry will validate oxidative content, including oxidized low density lipoprotein (oxLDL), foam cells and intimal calcification, in the regions exposed to atherogenic hemodynamics.
Aim 2 : Determine shear stress and oxidative stress in non-obstructive plaque. Intravascular sensors will be deployed into the aortas of NZW rabbits. Athero-prone regions will be localized by shear stress sensors and vascular oxidative stress will be assessed prior to and after hypercholesterolemic diet. The rabbit aorta will be dissected for immuno-staining for regions that harbor oxidative stress.
Aim 3 : Study whether vascular calcification stabilizes a mechanically unstable plaque. Vascular mesenchymal stem cell (MSC)-derived plaque that harbors oxLDL, foam cells, and calcification will be used in an in vitro model. Atherogenic hemodynamics;namely, low and oscillatory shear stress, will be delivered and plaque rupture will be captured in the context of vascular oxidative stress and calcification. Our proposal represents a concerted effort between two labs (Tzung Hsiai and Linda Demer) to test hypothesis, to establish causality, and to assess mechanically unstable plaque in the presence of calcification. Our research is relevant to public health because a better understanding of the biomechanics of rupture-prone plaques has the potential to reduce the morbidity and mortality associated with atherothrombotic disease.
This research is relevant to public health because a better understanding of the biomechanics of rupture-prone plaques has the potential to reduce the morbidity and mortality associated with atherothrombotic disease.
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