Pilot & Feasibility Program Application Abstract
Noninvasive evaluation of vascular structure and function in mouse models of metabolic disease
Attila Kovacs (St. Louis, MO)
The metabolic syndrome, which affects ~25% of USA adults, is associated with premature vascular disease and increased mortality. Non-invasive imaging studies play an important role in the early detection and longitudinal follow-up of the vascular manifestations of this syndrome. Modeling of metabolic syndrome through dietary, pharmacologic and genetic manipulation in mice is a critical tool in deciphering the molecular mechanisms responsible for the altered vascular structure and function associated with this disease. The major goal of this proposal is to develop novel imaging of vascular structure-function properties in murine model of dysmetabolic vascular disease by use of high-frequency ultrasound. Specifically, we propose to perform a series of validation studies to establish the usefulness of pulse wave velocity (PWV) and aortic intima-media thickness (IMT) in mouse models of metabolic syndrome. PWV as a functional parameter of aortic compliance has been widely used in clinical studies for the early detection of vascular involvement in various disease states. We propose to use a novel way of measuring PWV longitudinally in two different mouse models of metabolic syndrome, i.e. the LDL receptor deficient mouse on high fat diet (LDLR-/-HF), and the UCP-DTA mouse. Furthermore, we seek to establish the role of various hemodynamic factors, such as heart rate, loading conditions, and cardiac contractility in influencing PWV measurement in acute hemodynamic experiments. Increased IMT is a well established structural parameter of vascular involvement in various diseases including hypertension and atherosclerosis. We propose to use highresololution ultrasound bio-microscope to non-invasively study IMT on a longitudinal basis in the LDLR-/-HF and UCP-DTA mouse models, and perform validation studies by comparing non-invasive IMT measurements with quantitative histology. The novel application of high-resolution ultrasound will critically evaluate the usefulness of this technique as an important tool in the phenotypic characterization of vascular abnormalities in mouse models of metabolic syndrome.
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