Our long-term goal is the prevention and reversal in the microcirulation of the structural remodeling causing pulmonary hypertension (PH). An intrinsic feature of this remodeling is change in pericyte phenotype. In the rat model of hypoxic PH, three events are critical to this change: proliferation, production of pericellular elastin and differentiation. The first two produce lumen narrowing, while the last may increase wall rigidity. We will establish the timing of these events as a pointer to their cause and control. The contribution of hypoxia and of pericyte interaction with matrix will be analyzed. We will use antibodies of known purity and specificity to determine, by immunocytochemistry, the distribution of new elastin, basement membrane laminin and type I collagen. Ultrastructural studies of microdissected arteries will quantify adhesion plaques, through which the pericyte interacts with matrix, and junctions that connect the pericyte with the endothelium or with other pericytes. In cell culture, we will characterize the pericyte from normal rats, """"""""new"""""""" pericyte from hypoxic-exposed rats and compare them with the corresponding arterial smooth muscle cells. We will determine their (a) proliferation, (b) elastin production and (c) adhesion-as a marker of differentiation, and analyze whether hypoxia changes these functions directly or through new matrix. Because increased adhesion is a likely factor contributing to PH, we will determine if adhesion molecules, on the cell and in the matrix, are altered or increased, with particular reference to three that are markers of the smooth muscle cell - elastonectin, thrombospondin and a 38kD glycoprotein. Cell culture studies will thus provide markers of phenotype for each cell type. Overall, the results will identify the events in remodeling critical to hypertension and susceptible to the goals of prevention or reversal; in addition they will indicate ways that these goals can be achieved.
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