Chronic hypoxia causes remodeling of the pulmonary arterial but not the venous tree. Specific restructuring involves thickening of the arterial walls by hypertrophy and hyperplasia of pulmonary arterial smooth muscle (PASM) and deposition of excess connective tissue. The overall objective of the proposed interdisciplinary project (biochemistry, biophysics, and cell physiology) is to quantitate cellular and functional changes in PASM that occur in response to hypoxia-induced hypertension. This investigation will test the following hypothesis: hypoxia-induced pulmonary hypertension alters pulmonary arterial smooth muscle function by causing hypertrophy and hyperplasia, accompanied by a shift from predominantly contractile towards a more synthetic smooth muscle cell population.
Specific aims of the four year proposed project will determine whether hypoxia-induced pulmonary hypertension: 1): alters maximum shortening ability, 2) alters maximum velocity of shortening, 3) results in changes in maximum isometric tension development, 4) changes relaxation rates, 5) changes reactivity and responsiveness, nad 6) causes shifts in myosin isoform pattern in PASM. Young adult rats (250-275 g) will be made hypoxic by experimentally lowering the percent inspired oxygen to 10%. A combination of biochemical and biophysical techniques will be used in this investigation. the importance of this research is threefold. First, this investigation will provide new basic information of the biophysical properties of PASM that correlates cellular changes with altered function occurring in response to hypoxia-induced pulmonary hypertension. Second, new information elucidating the contribution that PASM plays in the maintenance of hypoxia- induced pulmonary hypertension will be provided. Third, this investigation will generate fundamental knowledge concerning smooth function of the pulmonary artery. Results of this investigation will permit exploration of new therapeutic approaches in the treatment of hypoxia-induced pulmonary hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL040894-01A2
Application #
3358209
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1990-07-01
Project End
1994-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Packer, C S; Roepke, J E; Oberlies, N H et al. (1998) Myosin isoform shifts and decreased reactivity in hypoxia-induced hypertensive pulmonary arterial muscle. Am J Physiol 274:L775-85
Jin, N; Rhoades, R A (1997) Activation of tyrosine kinases in H2O2-induced contraction in pulmonary artery. Am J Physiol 272:H2686-92
Zhao, Y; Rhoades, R A; Packer, C S (1996) Hypoxia-induced pulmonary arterial contraction appears to be dependent on myosin light chain phosphorylation. Am J Physiol 271:L768-74
Zhao, Y; Packer, C S; Rhoades, R A (1996) The vein utilizes different sources of energy than the artery during pulmonary hypoxic vasoconstriction. Exp Lung Res 22:51-63
Jin, N; Siddiqui, R A; English, D et al. (1996) Communication between tyrosine kinase pathway and myosin light chain kinase pathway in smooth muscle. Am J Physiol 271:H1348-55
Zhao, Y; Packer, C S; Rhoades, R A (1995) Chronic hypoxia impairs pulmonary venous smooth muscle contraction. Respir Physiol 100:75-82
Griffith, S L; Rhoades, R A; Packer, C S (1994) Pulmonary arterial smooth muscle contractility in hypoxia-induced pulmonary hypertension. J Appl Physiol 77:406-14
Jin, N; Packer, C S; English, D et al. (1993) Inositol trisphosphate is involved in norepinephrine- but not in hypoxia-induced pulmonary arterial contraction. Am J Physiol 264:L160-4
Zhao, Y; Packer, C S; Rhoades, R A (1993) Pulmonary vein contracts in response to hypoxia. Am J Physiol 265:L87-92
Jin, N; Packer, C S; Rhoades, R A (1992) Pulmonary arterial hypoxic contraction: signal transduction. Am J Physiol 263:L73-8

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