Elastin in Vessel Development and Vascular Disease

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DESCRIPTION (provided by applicant): In studying vessel wall development, the assumption has been that structural matrix proteins such as elastin are passive players in the process and do not influence cellular differentiation. This idea has recently been called into question by the characterization of supravalvular aortic stenosis (SVAS), an elastin associated disease in humans that indicates an intricate interplay between vessel wall mechanics and cellular maturation. SVAS was recently modeled in mice where it was found that elastin haplo insufficiency results in remarkable and unexpected changes in arterial wall structure, including thinner elastic lamellae, an increased number of smooth muscle cell layers, and, in the mouse, stable hypertension. Studies show that the vascular effects of elastin insufficiency occur early in development and result in a cardiovascular system that has adapted to the altered mechanical properties of the vessel wall. The objective of this proposal is to investigate how mutations in the elastin gene influence elastic fiber formation and blood vessel development. The hypothesis being investigated is that the developing cardiovascular system is highly adaptable and responsive to changes in hemodynamics brought about by altered vessel wall mechanics, as long as these changes occur within an as yet undefined developmental window. Elastin haplo insufficiency in mice provides an excellent model to investigate this hypothesis and to begin to understand how elastin mutations alter tissue function and development in humans with SVAS and other elastinopathies. The proposal has two objectives: To investigate how changes in elastin deposition and assembly influence vessel wall mechanics, the developmental recruitment of smooth muscle cells, and cardiovascular function; and to understand how elastin mutations alter elastic fiber assembly and tissue function that, in turn, lead to vascular disease.