Comprehensive delineation of the process of ventricular remodeling after myocardial infarction requires an integrated systems approach to elucidate relationships among molecular and cellular mechanisms, complex three dimensional ventricular kinematics and mechanical signals (e.g., shear strains), and altered tissue structures and material properties. Under the aegis of this grant, the applicants reported having demonstrated the utility of high resolution ultrasound tissue characterization methods for quantifying structural alterations and material properties involved in cardiac wound healing at the microscopic level. The applicants now seek to establish specific relationships between the physical properties of tissue, and the molecular and cellular mechanisms responsible for remodeling, and in particular to examine the potential salutary but relatively unappreciated role of angiogenesis as a critically component of remodeling. Accordingly, the applicants proposed to determine: 1. the role of angiogenesis during post-infarction cardiac remodeling and the effects of ACE inhibitors on angiogenesis in would healing; 2. molecular signaling mechanisms responsible for angiogenesis and scar tissue would healing that may depend on mechanical cues such as fiber strain, by comparing spatially and temporally matched parametric images of regional contractile function, tissue material properties, cell composition (e.g., myofibroblasts), and immunocytochemistry for selected signaling events such as expression of mitogen activated protein (MAP) kinase, integrins, tissue factor, vascular endothelial growth factor (VEGF) and its receptors (KDR/flk-1); and 3.the effects of selected therapies such as coronary reperfusion to evaluate the """"""""open artery hypothesis,"""""""" which potentially evokes enhanced angiogenesis, treatment with growth factors such as bFGF to enhance angiogenesis, and the role of integrins in cardiac remodeling, with the using beta3-deficient mice that exhibit impaired would healing.
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