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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL041811-01
Application #
3359559
Study Section
Pathology A Study Section (PTHA)
Project Start
1988-04-01
Project End
1991-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Boota, A; Zar, H; Kim, Y M et al. (1996) IL-1 beta stimulates superoxide and delayed peroxynitrite production by pulmonary vascular smooth muscle cells. Am J Physiol 271:L932-8
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Davies, P; Patton, W (1994) Peripheral and central vascular smooth muscle cells from rat lung exhibit different cytoskeletal protein profiles but similar growth factor requirements. J Cell Physiol 159:399-406
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Weng, W; Reynolds, I J; Jani, J P et al. (1994) Desensitization of 5HT2 receptors by protein kinase C activation in distal pulmonary vascular smooth muscle cells in culture. Microcirculation 1:129-35
Kubiak, J; Mitra, M M; Steve, A R et al. (1992) Transforming growth factor-alpha gene expression in late-gestation fetal rat lung. Pediatr Res 31:286-90
Pitt, B R; Brookens, M A; Steve, A R et al. (1992) Expression of pulmonary metallothionein genes in late gestational lambs. Pediatr Res 32:424-30
Davies, P; Reid, L (1991) Hypoxic remodeling of the rat pulmonary arterial microcirculation assessed by microdissection. J Appl Physiol 71:1886-91

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