Remodeling, defined as an enduring change in the size and/or composition of blood vessels, is a common feature of many vascular diseases, including atherosclerosis, aneurysm and graft arteriosclerosis (GA). Vascular smooth muscle cell (VSMC) proliferation and migration and matrix scaffold reorganization lead to neointimal hyperplasia and geometrical remodeling. Inflammation plays an important role in the pathogenesis. Here, we seek to establish the functional significance of a??3 integrin and materix metalloproteinase (MMP) activation in relation to neointimal hyperplasia and geometrical remodeling. We hypothesize this functional significance is valid and analogous in different forms of vascular remodeling, namely murine carotid wire injury, GA and aneurysm.
Our specific aims are to: 1) investigate the extent of a??3 integrin and MMP activation and their interdependence in VSMC and monocyte-macrophage phenotypic modulation, 2) establish the functional significance of a??3 and MMP activation as common mediators of mechanical injury-induced vascular remodeling, GA and aneurysm, and 3) assess a??3 and MMP imaging for predicting the extent of remodeling in different forms of vascular remodeling. a??3 integrin and MMP activation will be assessed by immunostaining and radioimmunoassay in differentiated and proliferative human VSMC, as well as resting monocytes and types 1 and 2 polarized macrophages. Reciprocal activation and physical association of a??3 integrin and MMP in VSMC and monocytemacrophages will be addressed. MMP and a??3 expression and activation and their correlation with geometrical remodeling and intimal hyperplasia will be established by immunostaining, Western blotting, zymography, and morphometry. Cellular sources of activated MMP and a??3 will be identified, and their functional significance confirmed using specific inhibitors. NC100692, activated a??3 - and RP782, activated MMP-targeted vascular imaging will be validated and utilized as experimental tools to study the molecular mechanisms of vascular remodeling. a??3 and MMP activation will be assessed by dual tracer a??3 and MMP-targeted imaging in longitudinal studies. This will establish the functional significance of a??3 and MMP activation as common mediators of vascular remodeling, and validate them as targets for in vivo imaging. Ultimately, this can improve the care of vascular patients through early monitoring and intervention.
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