The vasculature, which is the first organ system to form in the developing embryo, delivers nutrients and oxygen to, and removes wastes from, all tissues of the body. A functional vascular system is essential for growth and development. Abnormal vascular cell growth is central to the progression of pathologies such as atherosclerosis, tumor angiogenesis and retinopathy. Therefore, it is important to understand how blood vessels are assembled, and to examine the regulation of cellular recruitment, proliferation, and differentiation necessary for vessel formation and maintenance. These are the long-term goals of this research. This proposal focuses on the hypothesis that retinoids, distributed via blood circulation, contribute to formation and maturation of blood vessels. Supportive evidence is provided by our preliminary in vitro studies as well as the fact that vessel structure in vivo is not fully established until blood flow begins. Moreover, a retinoid deficiency in utero yields lethal abnormalities in vascular structure and function; mice lacking retinoid receptors die in utero from severe cardiovascular malformations. In our proposed studies, we will investigate mechanisms by which retinoids directly and indirectly affect vascular cell growth and mural cell differentiation. Specifically, we will utilize novel endothelial-mesenchymal co culture systems previously established by the principal investigator to examine direct retinoid regulation of endothelial and mesenchymal cell growth, as well as differentiation of mesenchymal cells into mural cells (smooth muscle and pericytes). We will further define the role of extracellular matrix, found in preliminary studies to influence these processes, and further elucidate its regulation by retinoids. These studies will employ a transgenic mouse model to define the contribution of retinoids to blood vessel formation and growth control in vivo. Information gained from these studies will further the understanding and treatment of vascular pathologies, which appear to recapitulate developmental processes. This work will also further the understanding of the role of retinoids during normal development, consequences of a retinoid deficiency and retinoid use in the treatment of vascular pathologies.
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