Several disorders cause pathological changes in the pulmonary vascular bed. This """"""""pulmonary vascular disease"""""""" may lead to right ventricular failure and premature death. The cellular events underlying these pathologic changes are poorly understood, but it is clear that abnormal growth and synthetic function of vascular smooth muscle are important. Although it is not known what modulates this abnormal smooth muscle function, clinical and experimental observations suggest that mechanical stimuli may play an important role. It is proposed to examine the hypothesis that stretch acts as a growth stimulus for pulmonary vascular smooth muscle. Previously characterized, cultured smooth muscle cells from rat pulmonary artery will be grown on a collagen-coated silicone membrane and subjected to step or repetitive stretch to determine: 1) Whether stretch affects the rate of mitosis (by 3H-thymidine), cell size, and protein content. Expression of the growth-associated proto- oncogenes c-myc and c-fos (by Northern blot analysis) will also be determined. 2. If stretch modulates overall protein production (by 3H-leucine and 35S-methionine), and whether this is effected by an altered rate of protein synthesis (measurement of total and ribosomal RNA, amino acid uptake, and S6 kinase activation) and/or degradation (using 3H-phenylalanine). 3) If stretch modulates contractile protein (myosin heavy and regulatory light chains, smooth muscle specific alpha actin, and smooth muscle specific alpha-tropomyosin) message or protein production, and/or collagen and elastin (gel electrophoresis and immunoprecipitation) synthesis. 4) If, as anticipated, stretch does have a physiological effect(s), its mechanism will be studied, with intracellular """"""""signals"""""""" linked with growth (Na+ influx, intracellular pH and (Ca++), and activation of Na+/K+ ATP-ase) being the initial focus of investigation. The initial goal of the proposed studies is to determine which smooth muscle functions may be influenced by stretch, and to explore the mechanism(s) by which stretch affects cell physiology. Over the longer run, it is hoped that probes may be developed to make possible in vivo explorations of the role of mechanical deformation in vascular pathology.
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