In several major diseases of infancy, including neonatal hypertensive disorders and several congenital cardiovascular anomalies, disordered development, differentiation and remodeling of the vasculature may play an important role. During perinatal development the vasculature undergoes substantial alterations in both structure and function. Differentiation, development and remodeling of the vasculature involve interactions of both endothelial and vascular smooth muscle cells. A recently identified cell surface receptor, LRP (low density lipoprotein receptor related protein) regulates the receptor mediated endocytosis of a wide variety of ligands including plasminogen activators, antiproteases, lipoproteins) which modulate these interactions. In addition, a 39kDa protein has been identified which serves as a Iigand for LRP as well as an inhibitor of LRP function. We have recently identified abundant and functional LRP and 39kDa protein in pulmonary microvascular endothelial cells and aortic smooth muscle cells.
Our aims are (i) to elucidate the cellular biology of LRP and the 39kDa protein in these cells, (2) define the structure/function of the LRP-receptor-associated 39kDa protein, and (3) elucidate the role of LRP and the 39kDa protein in the normal developing vasculature and in a model of neonatal pulmonary hypertension. These studies will utilize cellular biological, biochemical, immunological, morphological and molecular biological approaches including immunogold electron microscopy and in situ hybridization. These studies have broad implications for understanding the normal and pathophysiological alterations which occur within the developing vasculature in the neonate.
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