The tunica media of the aorta is comprised of alternating layers of smooth muscle cells and elastic fibers (elastic laminae). The molecules and precise mechanisms involved in the formation, organization and maintenance of these layers has yet to be defined. Recently, we have generated a null mutation in the mouse fibulin-5 gene and observed a striking phenotype of systemic elastinopathy due to a disorganization of elastic fibers. Fibulin-5 belongs to a family of similar extracellular matrix proteins and possesses 6 Ca2+ - binding EGF repeats and a single RGD motif. Fibulin-5 is significantly up-regulated in vascular injury suggesting a role in cardiovascular development and remodeling. Solid-phase binding and immunolocalization studies have indicated that fibulin-5 is a Ca2+ -dependent tropoelastin binding protein. We hypothesize that (i) fibulin-5 provides a scaffold that is essential for organizing elastic fibers by connecting elastin to cell surface integrins, (ii) fibulin-5 functions as a negative regulator of neointima formation via an RGD-dependent and/or independent mechanism. To test this hypothesis, we propose the following specific aims: (1) to characterize the vascular defects in the fibulin-5 null mice; (2) to define the molecular and genetic interaction of fibulin-5 and elastin; (3) to explore the role of fibulin-5 in cardiovascular remodeling using a model of vascular injury in fibulin-5 null mice. Results from these studies will not only provide fundamental information concerning the role of fibulin-5 in elastic fiber formation, but will ultimately establish an important basis for future studies on fibulin-5 in vascular diseases, such as supravalvular aortic stenosis, atherosclerosis and aortic aneurysms.
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